eLifePub Date : 2026-09-07DOI: 10.7554/eLife.109440
Anda de Witte, Anouck Matthijs, Benjamin Parrell, Dante Mantini, Jolien Gooijers, Jean-Jacques Orban de Xivry
{"title":"Preserved cerebellar functions despite structural degeneration in older adults.","authors":"Anda de Witte, Anouck Matthijs, Benjamin Parrell, Dante Mantini, Jolien Gooijers, Jean-Jacques Orban de Xivry","doi":"10.7554/eLife.109440","DOIUrl":"https://doi.org/10.7554/eLife.109440","url":null,"abstract":"<p><p>Aging is frequently perceived negatively due to its association with declines in brain and motor function yet not all aspects of brain function are equally affected. The cerebellum, a brain region closely linked to motor control, undergoes clear structural changes with age, but the impact of this degeneration on cerebellar function remains debated. The present study thoroughly investigates the impact of age on cerebellar function by measuring cerebellar motor and cognitive performance across the lifespan in 50 young adults (20-35 years), 80 older adults (55-70 years), and 30 older-old adults (over 80 years). Participants completed a test battery comprising seven motor control tasks and one cognitive task each designed to probe both cerebellar-specific and general sensorimotor function. Our results revealed that, despite age-related changes in cerebellar structure, cerebellar-specific functions remained intact in older adults compared to young adults, even among those above 80 years old. In contrast, general sensorimotor measures showed a clear pattern of decline with age. Together, these findings indicate that cerebellar function is largely preserved despite pronounced structural degeneration, providing compelling evidence for the cerebellum's remarkable functional resilience.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"15 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900318","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}
eLifePub Date : 2026-09-04DOI: 10.7554/eLife.110251
Ting Li, Song Zhang, Zelin Wang, Wei Huang, Zejin Zhang, Fang Wang, Dong Liu, Xiaoyong Cui, Rongxiao Che
{"title":"Soil extracellular DNA fragments show variable degradation rates among sequences and environmental conditions.","authors":"Ting Li, Song Zhang, Zelin Wang, Wei Huang, Zejin Zhang, Fang Wang, Dong Liu, Xiaoyong Cui, Rongxiao Che","doi":"10.7554/eLife.110251","DOIUrl":"10.7554/eLife.110251","url":null,"abstract":"<p><p>While extracellular DNA (eDNA) persistence substantially influences soil microbiome investigations, its degradation kinetics remain poorly quantified. Here, we developed a primer-labeled DNA approach coupled with microcosm incubation to determine the overall and sequence-specific degradation rates of eDNA amplicon fragments across China. We observed substantial variations in the overall degradation rates of extracellular 16S rRNA gene amplicon fragments among the study sites, with degradation rate constants ranging from 0.05 to 0.16 day<sup>-1</sup>. The overall degradation rate constants showed significant correlations with soil moisture content, prokaryotic abundance, prokaryotic community profiles, and mean annual precipitation. The significant influences of moisture content on the overall degradation rates were further verified by a moisture gradient microcosm experiment. The sequence-specific degradation rate constant profiles were additionally correlated with pH, nitrogen content, and mean annual temperature. Furthermore, propidium monoazide-based exclusion of eDNA signals significantly altered soil prokaryotic abundance, richness, and prokaryotic community profiles, and the pool sizes of sequence-specific extracellular 16S rRNA gene amplicon fragments were significantly correlated with their respective degradation rates. This study developed a methodology for determining the overall and sequence-specific degradation rates of eDNA amplicon fragments, highlighting the profound influences of eDNA on soil microbial research and informing the optimization of environmental DNA technologies.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"15 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2026-09-04DOI: 10.7554/eLife.107791
Jenny A Hurcombe, Lusyan Dayalan, Fern Barrington, Frederic Burdet, Lan Ni, Joseph Talih Coward, Mark Ibberson, Paul T Brinkkoetter, Martin Holzenberger, Aaron R Jeffries, Sebastian Oltean, Gavin I Welsh, Richard J M Coward
{"title":"The insulin/IGF axis is critically important for controlling gene transcription in the podocyte.","authors":"Jenny A Hurcombe, Lusyan Dayalan, Fern Barrington, Frederic Burdet, Lan Ni, Joseph Talih Coward, Mark Ibberson, Paul T Brinkkoetter, Martin Holzenberger, Aaron R Jeffries, Sebastian Oltean, Gavin I Welsh, Richard J M Coward","doi":"10.7554/eLife.107791","DOIUrl":"10.7554/eLife.107791","url":null,"abstract":"<p><p>Podocyte integrity depends critically on signalling through the insulin receptor and IGF1 receptor<b>,</b> and this study defines their combined importance using dual-receptor knockdown in mice and cultured podocytes. Podocyte-specific reduction of both receptors in transgenic mice caused kidney disease characterised by albuminuria and glomerulosclerosis, with premature death occurring in some animals between 4 and 24 weeks. Receptor-deficient cultured podocytes exhibited >50% cell loss within 7 days. Integrated proteomic and transcriptomic analyses revealed marked depletion of spliceosome-associated proteins and widespread intron retention with premature termination codons, indicating profound disruption of RNA processing. Phospho-proteomic profiling further showed that insulin/IGF1 stimulation induces dynamic post-translational modifications across spliceosomal components and regulatory kinases. Together, these findings uncover a previously unrecognised role for podocyte insulin/IGF1 signalling in maintaining spliceosomal integrity and transcriptional fidelity, establishing this hormonal axis as a key extrinsic regulator of podocyte gene expression.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890819","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2026-09-04DOI: 10.7554/eLife.102752
Zhuo Bi, Yu-Xiang Chen, Iris D Young, Mohamad T Dandan, Hemant Joshi, Hong-Wei Su, Yuemeng Chen, Jiayao Hong, James S Fraser, Babak Javid
{"title":"Ribosomal RNA methylation by GidB modulates discrimination of mischarged tRNA.","authors":"Zhuo Bi, Yu-Xiang Chen, Iris D Young, Mohamad T Dandan, Hemant Joshi, Hong-Wei Su, Yuemeng Chen, Jiayao Hong, James S Fraser, Babak Javid","doi":"10.7554/eLife.102752","DOIUrl":"10.7554/eLife.102752","url":null,"abstract":"<p><p>Despite redundant cellular pathways to minimize translational errors, errors in protein synthesis are common. Pathways and mechanisms to minimize errors are classified as pre-ribosomal or ribosomal. Pre-ribosomal pathways are primarily concerned with the appropriate charging of tRNAs with their cognate amino acids. By contrast, the ribosomal decoding center is considered 'blind' to mischarged tRNAs since these have cognate codon•anti-codon pairing. Here, we identified that in mycobacteria, deletion of the 16S ribosomal RNA methyltransferase <i>gidB</i> led to increased ribosomal discrimination of mischarged tRNAs. Discrimination only occurred in mycobacteria enriched from environments or genetic backgrounds with high rates of mistranslation. GidB deletion was necessary, but not sufficient for reducing mistranslation due to misacylation. Analysis of new cryo-EM structures of the <i>M. smegmatis</i> ribosomes derived from wild-type and <i>gidB</i>-deleted strains point to the interaction between the base methylated by GidB on the 16S RNA and an asparagine on the ribosomal S12 protein that, when mistranslated to aspartate, may be involved in altering translational fidelity. Our data suggest a mechanism by which mycobacterial ribosomes can discriminate mischarged tRNAs and that 16S rRNA differential methylation by GidB may act to prevent catastrophic translational error.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544909/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Low-frequency tibial neuromodulation excites bladder activity in humans.","authors":"Aidan McConnell-Trevillion, Milad Jabbari, Wei Ju, Elliot Lister, Abbas Erfanian, Srinjoy Mitra, Kianoush Nazarpour","doi":"10.7554/eLife.106174","DOIUrl":"10.7554/eLife.106174","url":null,"abstract":"<p><p>Despite widespread clinical adoption for disorders of incontinence such as overactive bladder, there remain unknowns surrounding the mechanism that underpins tibial nerve stimulation (TNS). Current understanding suggests that TNS counteracts incontinence by the inhibition of brainstem and spinal cord activity. How this inhibition alters bladder function is not fully understood. We hypothesize that the supraspinal components of the system act as a high-pass filter, allowing voiding signals to proceed only when bladder filling reaches a critical level. Testing this hypothesis may explain how TNS is able to induce both an inhibitory and a little-explored excitatory effect on bladder activity in response to high-frequency (20 Hz) and low-frequency (1 Hz) stimulation, respectively. We performed a single-blinded trial in healthy human participants administered high- and low-frequency transcutaneous TNS. We also developed a computational model of the lower-urinary tract and control circuit to study the frequency-dependent effects of TNS. For the first time, we report a frequency-dependent effect of TNS via the ability to alter urge perception and upregulate and downregulate bladder activity, corroborating model predictions. These results provide a foundation for the development of targeted and effective TNS therapies, benefiting from in silico models. We hope that future clinical research will determine the efficacy of low-frequency TNS as a non-invasive treatment option for urinary retention.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2026-09-04DOI: 10.7554/eLife.108208
Guanhua Sun, James Hazelden, Ruby Kim, Daniel B Forger
{"title":"Realistic coupling enables flexible macroscopic traveling waves in the mouse cortex.","authors":"Guanhua Sun, James Hazelden, Ruby Kim, Daniel B Forger","doi":"10.7554/eLife.108208","DOIUrl":"10.7554/eLife.108208","url":null,"abstract":"<p><p>Traveling waves are ubiquitous in neuronal systems across different spatial scales. While microscopic and mesoscopic waves are relatively well studied, the emergence of macroscopic traveling waves remains less understood. Here, by modeling the mouse cortex using spatial transcriptomic and connectivity data, we show that realistic cortical connectivity can generate a significantly higher level of macroscopic traveling waves than artificial local and uniform connectivity across multiple oscillation frequency bands, with the strongest advantage appearing in the theta, alpha, and beta frequency bands. By probing the model in different dynamic regimes, we find that macroscopic wave activity depends on both network connectivity and excitatory coupling strength, with a non-monotonic dependence on coupling. Together, our work shows how flexible macroscopic traveling waves can emerge in the mouse cortex and offers a computational framework to further study traveling waves in the mouse brain at the single-cell level.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544912/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2026-09-04DOI: 10.7554/eLife.108186
William J F Rieger, Mikael Bodén, Frances Arnold, Ariane Mora
{"title":"Squidly harnesses enzyme functional hierarchy and contrastive learning to efficiently predict catalytic residues from sequence.","authors":"William J F Rieger, Mikael Bodén, Frances Arnold, Ariane Mora","doi":"10.7554/eLife.108186","DOIUrl":"10.7554/eLife.108186","url":null,"abstract":"<p><p>Enzymes present a sustainable alternative to traditional chemical industries, drug synthesis, and bioremediation applications. Because catalytic residues are the key amino acids that drive enzyme function, their accurate prediction facilitates enzyme function prediction. Sequence similarity-based approaches such as BLAST are fast but require previously annotated homologues. Machine-learning (ML) approaches aim to overcome this limitation; however, current gold-standard ML-based methods require high-quality 3D structures limiting their application to large datasets. To address these challenges, we developed Squidly, a sequence-only tool that leverages contrastive representation learning with a biology-informed, rationally designed pairing scheme to distinguish catalytic from non-catalytic residues using per-token Protein Language Model embeddings. Squidly surpasses state-of-the-art ML annotation methods in catalytic residue prediction while remaining sufficiently fast to enable wide-scale screening of databases. We ensemble Squidly with BLAST to provide an efficient tool that annotates catalytic residues with high precision and recall for both in- and out-of-distribution sequences.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Polo-like kinase phosphorylation of the orphan kinesin KIN-G negatively regulates centrin arm biogenesis in <i>Trypanosoma brucei</i>.","authors":"Yasuhiro Kurasawa, Qing Zhou, Kyu Joon Lee, Huiqing Hu, Ziyin Li","doi":"10.7554/eLife.110793","DOIUrl":"10.7554/eLife.110793","url":null,"abstract":"<p><p>The unicellular parasite <i>Trypanosoma brucei</i> assembles a motile flagellum that is required for locomotion, cell division plane placement, and cell-cell communication. Inheritance of the flagellum during the cell cycle relies on the faithful duplication/segregation of multiple flagellum-associated cytoskeletal structures, including a centrin-marked, bar-shaped structure termed centrin arm, which also determines the site for Golgi assembly. Biogenesis of the centrin arm requires the Polo-like kinase homolog TbPLK and the orphan kinesin KIN-G, but the mechanistic role of TbPLK in centrin arm biogenesis remains elusive. Here, we report that TbPLK phosphorylates KIN-G, disrupts its microtubule-binding activity, and negatively regulates its function. TbPLK phosphorylates KIN-G in vitro at multiple residues, two of which are in vivo TbPLK phosphosites, including the Thr301 residue within one of the microtubule-binding motifs of the kinesin motor domain. Phosphorylation of Thr301 by TbPLK inhibits the microtubule-binding activity of KIN-G in vitro, and expression of a Thr301 phospho-mimic mutant in <i>T. brucei</i> disrupts centrin arm integrity, Golgi duplication, flagellum attachment zone elongation, flagellum positioning, and cell division plane placement. In wild-type <i>T. brucei</i> cells, Thr301 phosphorylation occurs on a small portion of the KIN-G population, suggesting that KIN-G undergoes phosphorylation/dephosphorylation cycles to regulate its activity. Together, these findings uncover a negative role of TbPLK-mediated phosphorylation of KIN-G in regulating centrin arm biogenesis in trypanosomes.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"15 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890794","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2026-09-04DOI: 10.7554/eLife.109159
Mingyu Yang, Oxana Eschenko
{"title":"Differential locus coeruleus-hippocampus interactions during offline states.","authors":"Mingyu Yang, Oxana Eschenko","doi":"10.7554/eLife.109159","DOIUrl":"10.7554/eLife.109159","url":null,"abstract":"<p><p>Patterns of locus coeruleus (LC) activity and norepinephrine (NE) release during non-rapid-eye-movement sleep suggest a critical role for the LC-NE system in offline modulation of forebrain circuits. NE transmission promotes synaptic plasticity and is required for memory consolidation, but the field has only begun to uncover how LC activity contributes to coordinated forebrain network dynamics. Hippocampal ripples, a hallmark of memory replay, are temporally coupled with thalamocortical oscillations; however, the circuit mechanisms underlying system-level consolidation across larger brain networks remain incompletely understood. Here, using multi-site electrophysiology, we examined LC firing in relation to hippocampal ripples in freely behaving rats. LC activity and ripple occurrence were state-dependent and inversely related: heightened arousal was associated with increased LC firing and reduced ripple rates. At finer timescales, LC spiking decreased ∼1-2 s before ripple onset, with the strongest modulation during awake ripples but minimal change during ripple-spindle coupling. These findings reveal state-dependent dynamics of LC-hippocampal interactions, positioning the LC as a key component of a cortical-subcortical network supporting system-level memory consolidation.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13544908/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148891533","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
eLifePub Date : 2026-09-03DOI: 10.7554/eLife.107818
Binnu Gangadharan, Daniel L Kober, Luke M Rice
{"title":"A biochemical mechanism for Stu2/XMAP215-family microtubule polymerases.","authors":"Binnu Gangadharan, Daniel L Kober, Luke M Rice","doi":"10.7554/eLife.107818","DOIUrl":"10.7554/eLife.107818","url":null,"abstract":"<p><p>Defining quantitative biochemical mechanisms of microtubule dynamics and regulation is a current challenge. Stu2/XMAP215-family polymerases use tubulin-binding TOG domains to catalyze microtubule growth, but how polymerase activity results from the number and tubulin-binding properties of TOGs is not understood. We tested whether an enzyme-like biochemical model for the unrelated actin polymerase Ena/VASP could be applied to quantitatively relate Stu2 microtubule polymerase activity to the number of its TOGs, and the rate constants governing their interactions with tubulin. Stu2 activity displayed enzyme-like characteristics consistent with the biochemical model: Stu2 stimulated microtubule growth rates with hyperbolic dependence on tubulin concentration, and the amount of Stu2 on the microtubule end did not vary with tubulin concentration (microtubule growth rate). Complementary measurements of TOG:tubulin binding revealed high affinity (10 nM) and slow dissociation (0.03 s<sup>-1</sup>). The polymerase and binding measurements can be unified within the biochemical model: Stu2 operates with high efficiency, acting as a tubulin-shuttling antenna on the microtubule end that is primarily limited by the rate of tubulin:TOG association. Our work thus provides a quantitative biochemical mechanism for TOG-based polymerases. That unrelated microtubule and actin polymerases use the same enzyme-like mechanism provides an example of convergent evolution in the cytoskeleton.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13541299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148886697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}