eLife最新文献

{"title":"Untargeted pixel-by-pixel metabolite ratio imaging as a novel tool for biomedical discovery in mass spectrometry imaging.","authors":"Huiyong Cheng, Dawson Miller, Nneka Southwell, Paola Porcari, Joshua L Fischer, Isobel Taylor, J Michael Salbaum, Claudia Kappen, Fenghua Hu, Cha Yang, Kayvan R Keshari, Steven S Gross, Marilena D'Aurelio, Qiuying Chen","doi":"10.7554/eLife.96892","DOIUrl":"10.7554/eLife.96892","url":null,"abstract":"<p><p>Mass spectrometry imaging (MSI) is a powerful technology used to define the spatial distribution and relative abundance of metabolites across tissue cryosections. While software packages exist for pixel-by-pixel individual metabolite and limited target pairs of ratio imaging, the research community lacks an easy computing and application tool that images any metabolite abundance ratio pairs. Importantly, recognition of correlated metabolite pairs may contribute to the discovery of unanticipated molecules in shared metabolic pathways. Here, we describe the development and implementation of an untargeted R package workflow for pixel-by-pixel ratio imaging of all metabolites detected in an MSI experiment. Considering untargeted MSI studies of murine brain and embryogenesis, we demonstrate that ratio imaging minimizes systematic data variation introduced by sample handling, markedly enhances spatial image contrast, and reveals previously unrecognized metabotype-distinct tissue regions. Furthermore, ratio imaging facilitates identification of novel regional biomarkers and provides anatomical information regarding spatial distribution of metabolite-linked biochemical pathways. The algorithm described herein is applicable to any MSI dataset containing spatial information for metabolites, peptides or proteins, offering a potent hypothesis generation tool to enhance knowledge obtained from current spatial metabolite profiling technologies.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656439","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":"Spatial transcriptomics in the adult <i>Drosophila</i> brain and body.","authors":"Jasper Janssens, Pierre Mangeol, Nikolai Hecker, Gabriele Partel, Katina I Spanier, Joy N Ismail, Gert J Hulselmans, Stein Aerts, Frank Schnorrer","doi":"10.7554/eLife.92618","DOIUrl":"10.7554/eLife.92618","url":null,"abstract":"<p><p>Recently, we have achieved a significant milestone with the creation of the Fly Cell Atlas. This single-nuclei atlas encompasses the entire fly, covering the entire head and body, in addition to all major organs. This atlas catalogs many hundreds of cell types, of which we annotated 250. Thus, a large number of clusters remain to be fully characterized, in particular in the brain. Furthermore, by applying single-nuclei sequencing, all information about the spatial location of the cells in the body and of about possible subcellular localization of the mRNAs within these cells is lost. Spatial transcriptomics promises to tackle these issues. In a proof-of-concept study, we have here applied spatial transcriptomics using a selected gene panel to pinpoint the locations of 150 mRNA species in the adult fly. This enabled us to map unknown clusters identified in the Fly Cell Atlas to their spatial locations in the fly brain. Additionally, spatial transcriptomics discovered interesting principles of mRNA localization and transcriptional diversity within the large and crowded muscle cells that may spark future mechanistic investigations. Furthermore, we present a set of computational tools that will allow for easier integration of spatial transcriptomics and single-cell datasets.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919255/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656473","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":"Enhanced neural speech tracking through noise indicates stochastic resonance in humans.","authors":"Björn Herrmann","doi":"10.7554/eLife.100830","DOIUrl":"10.7554/eLife.100830","url":null,"abstract":"<p><p>Neural activity in auditory cortex tracks the amplitude-onset envelope of continuous speech, but recent work counterintuitively suggests that neural tracking increases when speech is masked by background noise, despite reduced speech intelligibility. Noise-related amplification could indicate that stochastic resonance - the response facilitation through noise - supports neural speech tracking, but a comprehensive account is lacking. In five human electroencephalography experiments, the current study demonstrates a generalized enhancement of neural speech tracking due to minimal background noise. Results show that (1) neural speech tracking is enhanced for speech masked by background noise at very high signal-to-noise ratios (~30 dB SNR) where speech is highly intelligible; (2) this enhancement is independent of attention; (3) it generalizes across different stationary background maskers, but is strongest for 12-talker babble; and (4) it is present for headphone and free-field listening, suggesting that the neural-tracking enhancement generalizes to real-life listening. The work paints a clear picture that minimal background noise enhances the neural representation of the speech onset-envelope, suggesting that stochastic resonance contributes to neural speech tracking. The work further highlights non-linearities of neural tracking induced by background noise that make its use as a biological marker for speech processing challenging.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656460","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":"The autophagy protein ATG14 safeguards against unscheduled pyroptosis activation to enable embryo transport during early pregnancy.","authors":"Pooja Popli, Arin K Oestreich, Vineet K Maurya, Marina N Rowen, Yong Zhang, Michael J Holtzman, Ramya Masand, John P Lydon, Shizuo Akira, Kelle Moley, Ramakrishna Kommagani","doi":"10.7554/eLife.97325","DOIUrl":"10.7554/eLife.97325","url":null,"abstract":"<p><p>Recurrent pregnancy loss, characterized by two or more failed clinical pregnancies, poses a significant challenge to reproductive health. In addition to embryo quality and endometrial function, proper oviduct function is also essential for successful pregnancy establishment. Therefore, structural abnormalities or inflammation resulting from infection in the oviduct may impede the transport of embryos to the endometrium, thereby increasing the risk of miscarriage. However, our understanding of the biological processes that preserve the oviductal cellular structure and functional integrity is limited. Here, we report that autophagy-related protein ATG14 plays a crucial role in maintaining the cellular integrity of the oviduct by controlling inflammatory responses, thereby supporting efficient embryo transport. Specifically, the conditional depletion of the autophagy-related gene <i>Atg14</i> in the oviduct causes severe structural abnormalities compromising its cellular integrity, leading to the abnormal retention of embryos. Interestingly, the selective loss of <i>Atg14</i> in oviduct ciliary epithelial cells did not impact female fertility, highlighting the specificity of ATG14 function in distinct cell types within the oviduct. Mechanistically, loss of <i>Atg14</i> triggered unscheduled pyroptosis via altering the mitochondrial integrity, leading to inappropriate embryo retention and impeded embryo transport in the oviduct. Finally, pharmacological activation of pyroptosis in pregnant mice phenocopied the genetically induced defect and caused impairment in embryo transport. Together, we found that ATG14 safeguards against unscheduled pyroptosis activation to enable embryo transport from the oviduct to uterus for the successful implantation. Of clinical significance, these findings provide possible insights into the underlying mechanism(s) of early pregnancy loss and might aid in developing novel prevention strategies using autophagy modulators.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919251/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656435","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":"Pain persists in mice lacking both Substance P and CGRPα signaling.","authors":"Donald Iain MacDonald, Monessha Jayabalan, Jonathan T Seaman, Rakshita Balaji, Alec R Nickolls, Alexander Theodore Chesler","doi":"10.7554/eLife.93754","DOIUrl":"10.7554/eLife.93754","url":null,"abstract":"<p><p>The neuropeptides Substance P and CGRPα have long been thought important for pain sensation. Both peptides and their receptors are expressed at high levels in pain-responsive neurons from the periphery to the brain making them attractive therapeutic targets. However, drugs targeting these pathways individually did not relieve pain in clinical trials. Since Substance P and CGRPα are extensively co-expressed, we hypothesized that their simultaneous inhibition would be required for effective analgesia. We therefore generated <i>Tac1</i> and <i>Calca</i> double knockout (DKO) mice and assessed their behavior using a wide range of pain-relevant assays. As expected, Substance P and CGRPα peptides were undetectable throughout the nervous system of DKO mice. To our surprise, these animals displayed largely intact responses to mechanical, thermal, chemical, and visceral pain stimuli, as well as itch. Moreover, chronic inflammatory pain and neurogenic inflammation were unaffected by loss of the two peptides. Finally, neuropathic pain evoked by nerve injury or chemotherapy treatment was also preserved in peptide-deficient mice. Thus, our results demonstrate that even in combination, Substance P and CGRPα are not required for the transmission of acute and chronic pain.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11919252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143656467","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":"A differentiable Gillespie algorithm for simulating chemical kinetics, parameter estimation, and designing synthetic biological circuits.","authors":"Krishna Rijal, Pankaj Mehta","doi":"10.7554/eLife.103877","DOIUrl":"10.7554/eLife.103877","url":null,"abstract":"<p><p>The Gillespie algorithm is commonly used to simulate and analyze complex chemical reaction networks. Here, we leverage recent breakthroughs in deep learning to develop a fully differentiable variant of the Gillespie algorithm. The differentiable Gillespie algorithm (DGA) approximates discontinuous operations in the exact Gillespie algorithm using smooth functions, allowing for the calculation of gradients using backpropagation. The DGA can be used to quickly and accurately learn kinetic parameters using gradient descent and design biochemical networks with desired properties. As an illustration, we apply the DGA to study stochastic models of gene promoters. We show that the DGA can be used to: (1) successfully learn kinetic parameters from experimental measurements of mRNA expression levels from two distinct <i>Escherichia coli</i> promoters and (2) design nonequilibrium promoter architectures with desired input-output relationships. These examples illustrate the utility of the DGA for analyzing stochastic chemical kinetics, including a wide variety of problems of interest to synthetic and systems biology.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647758","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":"How herpes is assembled.","authors":"Dawid S Zyla","doi":"10.7554/eLife.106419","DOIUrl":"10.7554/eLife.106419","url":null,"abstract":"<p><p>A combination of imaging techniques reveals how herpes simplex virus type 1 assembles within infected cells, highlighting the roles of essential viral proteins in viral assembly and exit.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647760","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":"Proactive distractor suppression in early visual cortex.","authors":"David Richter, Dirk van Moorselaar, Jan Theeuwes","doi":"10.7554/eLife.101733","DOIUrl":"10.7554/eLife.101733","url":null,"abstract":"<p><p>Avoiding distraction by salient yet irrelevant stimuli is critical when accomplishing daily tasks. One possible mechanism to accomplish this is by suppressing stimuli that may be distracting such that they no longer compete for attention. While the behavioral benefits of distractor suppression are well established, its neural underpinnings are not yet fully understood. In a functional MRI (fMRI) study, we examined whether and how sensory responses in early visual areas show signs of distractor suppression after incidental learning of spatial statistical regularities. Participants were exposed to an additional singleton task where, unbeknownst to them, one location more frequently contained a salient distractor. We analyzed whether visual responses in terms of fMRI BOLD were modulated by this distractor predictability. Our findings indicate that implicit spatial priors shape sensory processing even at the earliest stages of cortical visual processing, evident in early visual cortex as a suppression of stimuli at locations which frequently contained distracting information. Notably, while this suppression was spatially (receptive field) specific, it did extend to nearby neutral locations and occurred regardless of whether distractors, nontarget items, or targets were presented at this location, suggesting that suppression arises before stimulus identification. Crucially, we observed similar spatially specific neural suppression even if search was only anticipated, but no search display was presented. Our results highlight proactive modulations in early visual cortex, where potential distractions are suppressed preemptively, before stimulus onset, based on learned expectations. Combined, our study underscores how the brain leverages implicitly learned prior knowledge to optimize sensory processing and attention allocation.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647756","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":"Endosomal-lysosomal organellar assembly (ELYSA) structures coordinate lysosomal degradation systems through mammalian oocyte-to-embryo transition.","authors":"Yuhkoh Satouh, Takaki Tatebe, Isei Tanida, Junji Yamaguchi, Yasuo Uchiyama, Ken Sato","doi":"10.7554/eLife.99358","DOIUrl":"10.7554/eLife.99358","url":null,"abstract":"<p><p>Mouse oocytes undergo drastic changes in organellar composition and their activities during maturation from the germinal vesicle (GV) to metaphase II (MII) stage. After fertilization, the embryo degrades parts of the maternal components via lysosomal degradation systems, including autophagy and endocytosis, as zygotic gene expression begins during embryogenesis. Here, we demonstrate that endosomal-lysosomal organelles form large spherical assembly structures, termed endosomal-lysosomal organellar assemblies (ELYSAs), in mouse oocytes. ELYSAs are observed in GV oocytes, attaining sizes up to 7-8 μm in diameter in MII oocytes. ELYSAs comprise tubular-vesicular structures containing endosomes and lysosomes along with cytosolic components. Most ELYSAs are also positive for an autophagy regulator, LC3. These characteristics of ELYSA resemble those of ELVA (endolysosomal vesicular assemblies) identified independently. The signals of V1-subunit of vacuolar ATPase tends to be detected on the periphery of ELYSAs in MII oocytes. After fertilization, the localization of the V1-subunit on endosomes and lysosomes increase as ELYSAs gradually disassemble at the 2-cell stage, leading to further acidification of endosomal-lysosomal organelles. These findings suggest that the ELYSA/ELVA maintain endosomal-lysosomal activity in a static state in oocytes for timely activation during early development.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647753","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":"Becker muscular dystrophy mice showed site-specific decay of type IIa fibers with capillary change in skeletal muscle.","authors":"Daigo Miyazaki, Mitsuto Sato, Naoko Shiba, Takahiro Yoshizawa, Akinori Nakamura","doi":"10.7554/eLife.100665","DOIUrl":"10.7554/eLife.100665","url":null,"abstract":"<p><p>Becker muscular dystrophy (BMD), an X-linked muscular dystrophy, is mostly caused by an in-frame deletion of Duchenne muscular dystrophy (DMD). BMD severity varies from asymptomatic to severe, associated with the genotype of DMD. However, the underlying mechanisms remain unclear. We established BMD mice carrying three representative exon deletions: ex45-48 del., ex45-47 del., and ex45-49 del. (d45-48, d45-47, and d45-49), with high frequencies and different severities in the human BMD hotspot. All three BMD mice showed muscle weakness, muscle degeneration, and fibrosis, but these changes appeared at different times for each exon deletion, consistent with the severities obtained by the natural history study of BMD. BMD mice showed site-specific muscle changes, unlike <i>mdx</i> mice, which showed diffuse muscle changes, and we demonstrated selective type IIa fiber reduction in BMD mice. Furthermore, BMD mice showed sarcolemmal neuronal nitric oxide synthase (nNOS) reduction and morphological capillary changes around type IIa fibers. These results suggest that capillary changes caused by nNOS reduction may be associated with the mechanism of skeletal muscle degeneration and type IIa fiber reduction in BMD mice. BMD mice may be useful in elucidating the pathomechanisms and developing vascular targeted therapies for human BMD.</p>","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11913446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647751","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}