IF 6.4 1区生物学

eLife Pub Date : 2025-03-17 DOI: 10.7554/eLife.103877

Krishna Rijal, Pankaj Mehta

{"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":"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 Escherichia coli 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.","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}

引用次数: 0

How herpes is assembled.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-17 DOI: 10.7554/eLife.106419

Dawid S Zyla

引用次数: 0

Proactive distractor suppression in early visual cortex.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-17 DOI: 10.7554/eLife.101733

David Richter, Dirk van Moorselaar, Jan Theeuwes

{"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":"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.","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}

引用次数: 0

Endosomal-lysosomal organellar assembly (ELYSA) structures coordinate lysosomal degradation systems through mammalian oocyte-to-embryo transition.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-17 DOI: 10.7554/eLife.99358

Yuhkoh Satouh, Takaki Tatebe, Isei Tanida, Junji Yamaguchi, Yasuo Uchiyama, Ken Sato

{"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":"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.","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}

引用次数: 0

Becker muscular dystrophy mice showed site-specific decay of type IIa fibers with capillary change in skeletal muscle.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-17 DOI: 10.7554/eLife.100665

Daigo Miyazaki, Mitsuto Sato, Naoko Shiba, Takahiro Yoshizawa, Akinori Nakamura

{"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":"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 mdx 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.","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}

引用次数: 0

A microglia clonal inflammatory disorder in Alzheimer's disease.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.96519

Rocio Vicario, Stamatina Fragkogianni, Leslie Weber, Tomi Lazarov, Yang Hu, Samantha Y Hayashi, Barbara Craddock, Nicholas D Socci, Araitz Alberdi, Ann Baako, Oyku Ay, Masato Ogishi, Estibaliz Lopez-Rodrigo, Rajya Kappagantula, Agnes Viale, Christine A Iacobuzio-Donahue, Ting Zhou, Richard M Ransohoff, Richard Chesworth, Omar Abdel-Wahab, Bertrand Boisson, Olivier Elemento, Jean-Laurent Casanova, W Todd Miller, Frédéric Geissmann

{"title":"A microglia clonal inflammatory disorder in Alzheimer's disease.","authors":"Rocio Vicario, Stamatina Fragkogianni, Leslie Weber, Tomi Lazarov, Yang Hu, Samantha Y Hayashi, Barbara Craddock, Nicholas D Socci, Araitz Alberdi, Ann Baako, Oyku Ay, Masato Ogishi, Estibaliz Lopez-Rodrigo, Rajya Kappagantula, Agnes Viale, Christine A Iacobuzio-Donahue, Ting Zhou, Richard M Ransohoff, Richard Chesworth, Omar Abdel-Wahab, Bertrand Boisson, Olivier Elemento, Jean-Laurent Casanova, W Todd Miller, Frédéric Geissmann","doi":"10.7554/eLife.96519","DOIUrl":"10.7554/eLife.96519","url":null,"abstract":"Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer's disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630310","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}

引用次数: 0

Receptor tyrosine kinases CAD96CA and FGFR1 function as the cell membrane receptors of insect juvenile hormone.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.97189

Yan-Xue Li, Xin-Le Kang, Yan-Li Li, Xiao-Pei Wang, Qiao Yan, Jin-Xing Wang, Xiao-Fan Zhao

引用次数: 0

Microprism-based two-photon imaging of the mouse inferior colliculus reveals novel organizational principles of the auditory midbrain.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.93063

Baher A Ibrahim, Yoshitaka Shinagawa, Austin Douglas, Gang Xiao, Alexander R Asilador, Daniel A Llano

{"title":"Microprism-based two-photon imaging of the mouse inferior colliculus reveals novel organizational principles of the auditory midbrain.","authors":"Baher A Ibrahim, Yoshitaka Shinagawa, Austin Douglas, Gang Xiao, Alexander R Asilador, Daniel A Llano","doi":"10.7554/eLife.93063","DOIUrl":"10.7554/eLife.93063","url":null,"abstract":"To navigate real-world listening conditions, the auditory system relies on the integration of multiple sources of information. However, to avoid inappropriate cross-talk between inputs, highly connected neural systems need to strike a balance between integration and segregation. Here, we develop a novel approach to examine how repeated neurochemical modules in the mouse inferior colliculus lateral cortex (LC) allow controlled integration of its multimodal inputs. The LC had been impossible to study via imaging because it is buried in a sulcus. Therefore, we coupled two-photon microscopy with the use of a microprism to reveal the first-ever sagittal views of the LC to examine neuronal responses with respect to its neurochemical motifs under anesthetized and awake conditions. This approach revealed marked differences in the acoustic response properties of LC and neighboring non-lemniscal portions of the inferior colliculus. In addition, we observed that the module and matrix cellular motifs of the LC displayed distinct somatosensory and auditory responses. Specifically, neurons in modules demonstrated primarily offset responses to acoustic stimuli with enhancement in responses to bimodal stimuli, whereas matrix neurons showed onset response to acoustic stimuli and suppressed responses to bimodal stimulation. Thus, this new approach revealed that the repeated structural motifs of the LC permit functional integration of multimodal inputs while retaining distinct response properties.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908782/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630323","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}

引用次数: 0

Gaskell, Langley, and the "para-sympathetic" idea.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.104826

Jean-François Brunet

引用次数: 0

Dual role of FOXG1 in regulating gliogenesis in the developing neocortex via the FGF signalling pathway.

IF 6.4 1区生物学

eLife Pub Date : 2025-03-14 DOI: 10.7554/eLife.101851

Mahima Bose, Ishita Talwar, Varun Suresh, Urvi Mishra, Shiona Biswas, Anuradha Yadav, Shital T Suryavanshi, Simon Hippenmeyer, Shubha Tole

{"title":"Dual role of FOXG1 in regulating gliogenesis in the developing neocortex via the FGF signalling pathway.","authors":"Mahima Bose, Ishita Talwar, Varun Suresh, Urvi Mishra, Shiona Biswas, Anuradha Yadav, Shital T Suryavanshi, Simon Hippenmeyer, Shubha Tole","doi":"10.7554/eLife.101851","DOIUrl":"10.7554/eLife.101851","url":null,"abstract":"In the developing vertebrate central nervous system, neurons and glia typically arise sequentially from common progenitors. Here, we report that the transcription factor Forkhead Box G1 (Foxg1) regulates gliogenesis in the mouse neocortex via distinct cell-autonomous roles in progenitors and postmitotic neurons that regulate different aspects of the gliogenic FGF signalling pathway. We demonstrate that loss of Foxg1 in cortical progenitors at neurogenic stages causes premature astrogliogenesis. We identify a novel FOXG1 target, the pro-gliogenic FGF pathway component Fgfr3, which is suppressed by FOXG1 cell-autonomously to maintain neurogenesis. Furthermore, FOXG1 can also suppress premature astrogliogenesis triggered by the augmentation of FGF signalling. We identify a second novel function of FOXG1 in regulating the expression of gliogenic cues in newborn neocortical upper-layer neurons. Loss of FOXG1 in postmitotic neurons non-autonomously enhances gliogenesis in the progenitors via FGF signalling. These results fit well with the model that newborn neurons secrete cues that trigger progenitors to produce the next wave of cell types, astrocytes. If FGF signalling is attenuated in Foxg1 null progenitors, they progress to oligodendrocyte production. Therefore, loss of FOXG1 transitions the progenitor to a gliogenic state, producing either astrocytes or oligodendrocytes depending on FGF signalling levels. Our results uncover how FOXG1 integrates extrinsic signalling via the FGF pathway to regulate the sequential generation of neurons, astrocytes, and oligodendrocytes in the cerebral cortex.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143630312","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}

引用次数: 0

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