IF 6.4 1区生物学

eLife Pub Date : 2025-05-28 DOI: 10.7554/eLife.95857

Shinichi Nakagawa, William K Cornwell, Corey T Callaghan

引用次数: 0

Oxydifficidin, a potent Neisseria gonorrhoeae antibiotic due to DedA-assisted uptake and ribosomal protein RplL sensitivity. Oxydifficidin，一种有效的淋病奈瑟菌抗生素，由于deda辅助摄取和核糖体蛋白RplL敏感性。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-28 DOI: 10.7554/eLife.99281

Jingbo Kan, Adrian Morales-Amador, Yozen Hernandez, Melinda A Ternei, Christophe Lemetre, Logan W Maclntyre, Nicolas Biais, Sean F Brady

{"title":"Oxydifficidin, a potent Neisseria gonorrhoeae antibiotic due to DedA-assisted uptake and ribosomal protein RplL sensitivity.","authors":"Jingbo Kan, Adrian Morales-Amador, Yozen Hernandez, Melinda A Ternei, Christophe Lemetre, Logan W Maclntyre, Nicolas Biais, Sean F Brady","doi":"10.7554/eLife.99281","DOIUrl":"https://doi.org/10.7554/eLife.99281","url":null,"abstract":"Gonorrhea, which is caused by Neisseria gonorrhoeae, is the second most reported sexually transmitted infection worldwide. The increasing appearance of isolates that are resistant to approved therapeutics raises the concern that gonorrhea may become untreatable. Here, we serendipitously identified oxydifficidin as a potent N. gonorrhoeae antibiotic through the observation of a Bacillus amyloliquefaciens contaminant in a lawn of N. gonorrhoeae. Oxydifficidin is active against both wild-type and multidrug-resistant N. gonorrhoeae. Its potent activity results from a combination of DedA-assisted uptake into the cytoplasm and the presence of an oxydifficidin-sensitive ribosomal protein L7/L12 (RplL). Our data indicate that oxydifficidin binds to the ribosome at a site that is distinct from other antibiotics and that L7/L12 is uniquely associated with its mode of action. This study opens a potential new avenue for addressing antibiotic resistant gonorrhea and underscores the possibility of identifying overlooked natural products from cultured bacteria, particularly those with activity against previously understudied pathogens.","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":"144157395","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}

引用次数: 0

Quantification of the effect of hemodynamic occlusion in two-photon imaging of mouse cortex. 小鼠皮质双光子成像血流动力学阻塞效应的定量分析。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-28 DOI: 10.7554/eLife.104914

Baba Yogesh, Matthias Heindorf, Rebecca Jordan, Georg B Keller

{"title":"Quantification of the effect of hemodynamic occlusion in two-photon imaging of mouse cortex.","authors":"Baba Yogesh, Matthias Heindorf, Rebecca Jordan, Georg B Keller","doi":"10.7554/eLife.104914","DOIUrl":"https://doi.org/10.7554/eLife.104914","url":null,"abstract":"The last few years have seen an explosion in the number of tools available to measure neuronal activity using fluorescence imaging (Chen et al., 2013; Feng et al., 2019; Jing et al., 2019; Sun et al., 2018; Wan et al., 2021). When performed in vivo, these measurements are invariably contaminated by hemodynamic occlusion artifacts. In widefield calcium imaging, this problem is well recognized. For two-photon imaging, however, the effects of hemodynamic occlusion have only been sparsely characterized. Here, we perform a quantification of hemodynamic occlusion effects using measurements of fluorescence changes observed with GFP expression using both widefield and two-photon imaging in mouse cortex. We find that in many instances the magnitude of signal changes attributable to hemodynamic occlusion is comparable to that observed with activity sensors. Moreover, we find that hemodynamic occlusion effects were spatially heterogeneous, both over cortical regions and across cortical depth, and exhibited a complex relationship with behavior. Thus, hemodynamic occlusion is an important caveat to consider when analyzing and interpreting not just widefield but also two-photon imaging data.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157402","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}

引用次数: 0

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IF 6.4 1区生物学

eLife Pub Date : 2025-05-28 DOI: 10.7554/eLife.107246

Ling Liu

引用次数: 0

Structural mechanisms of PIP₂ activation and SEA0400 inhibition in human cardiac sodium-calcium exchanger NCX1. 人心脏钠钙交换器NCX1中PIP2激活和SEA0400抑制的结构机制

IF 6.4 1区生物学

eLife Pub Date : 2025-05-28 DOI: 10.7554/eLife.105396

Jing Xue, Weizhong Zeng, Scott John, Nicole Attiq, Michela Ottolia, Youxing Jiang

{"title":"Structural mechanisms of PIP2 activation and SEA0400 inhibition in human cardiac sodium-calcium exchanger NCX1.","authors":"Jing Xue, Weizhong Zeng, Scott John, Nicole Attiq, Michela Ottolia, Youxing Jiang","doi":"10.7554/eLife.105396","DOIUrl":"https://doi.org/10.7554/eLife.105396","url":null,"abstract":"Na+/Ca2+ exchangers (NCXs) transport Ca2+ across the plasma membrane in exchange for Na+ and play a vital role in maintaining cellular Ca2+ homeostasis. Our previous structural study of human cardiac NCX1 (HsNCX1) reveals the overall architecture of the eukaryotic exchanger and the formation of the inactivation assembly by the intracellular regulatory domain that underlies the cytosolic Na+-dependent inactivation and Ca2+ activation of NCX1. Here, we present the cryo-EM structures of HsNCX1 in complex with a physiological activator phosphatidylinositol 4,5-bisphosphate (PIP2), or pharmacological inhibitor SEA0400, that enhances the inactivation of the exchanger. We demonstrate that PIP2 binding stimulates NCX1 activity by inducing a conformational change at the interface between the transmembrane (TM) and cytosolic domains that destabilizes the inactivation assembly. In contrast, SEA0400 binding in the TM domain of NCX1 stabilizes the exchanger in an inward-facing conformation that facilitates the formation of the inactivation assembly, thereby promoting the Na+-dependent inactivation of NCX1. Thus, this study reveals the structural basis of PIP2 activation and SEA0400 inhibition of NCX1 and provides some mechanistic understandings of cellular regulation and pharmacology of NCX family proteins.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157427","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}

引用次数: 0

Criterion placement threatens the construct validity of neural measures of consciousness. 标准的设置威胁到意识神经测量的构念效度。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-28 DOI: 10.7554/eLife.102335

Johannes Jacobus Fahrenfort, Philippa A Johnson, Niels A Kloosterman, Timo Stein, Simon van Gaal

{"title":"Criterion placement threatens the construct validity of neural measures of consciousness.","authors":"Johannes Jacobus Fahrenfort, Philippa A Johnson, Niels A Kloosterman, Timo Stein, Simon van Gaal","doi":"10.7554/eLife.102335","DOIUrl":"10.7554/eLife.102335","url":null,"abstract":"How consciousness arises from brain activity has been a topic of intense scientific research for decades. But how does one identify the neural basis of something that is intrinsically personal and subjective? A hallmark approach has been to ask human observers to judge stimuli as 'seen' (conscious) and 'unseen' (unconscious) and use post hoc sorting of neural measurements based these judgments. Unfortunately, cognitive and response biases are known to strongly affect how observers place their criterion for judging stimuli as 'seen' versus 'unseen', thereby confounding neural measures of consciousness. Surprisingly however, the effect of conservative and liberal criterion placement on neural measures of unconscious and conscious processing has never been explicitly investigated. Here, we use simulations and electrophysiological brain measurements to show that conservative criterion placement has an unintuitive consequence: rather than selectively providing a cautious estimate of conscious processing, it inflates effect sizes in neural measures of both conscious and unconscious processing, while liberal criterion placement does the reverse. After showing this in simulation, we performed decoding analyses on two electroencephalography studies that employ common subjective indicators of conscious awareness, in which we experimentally manipulated the response criterion. The results confirm that the predicted confounding effects of criterion placement on neural measures of unconscious and conscious processing occur in empirical data, while further showing that the most widely used subjective scale, the Perceptual Awareness Scale (PAS), does not guard against criterion confounds. Follow-up simulations explicate how the experimental context determines whether the relative confounding effect of criterion placement is larger in neural measures of either conscious or unconscious processing. We conclude that criterion placement threatens the construct validity of neural measures of conscious and unconscious processing.","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":"144157387","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}

引用次数: 0

Evolutionary and functional analyses reveal a role for the RHIM in tuning RIPK3 activity across vertebrates. 进化和功能分析揭示了RHIM在调节脊椎动物RIPK3活性中的作用。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-28 DOI: 10.7554/eLife.102301

Elizabeth J Fay, Kolya Isterabadi, Charles M Rezanka, Jessica Le, Matthew D Daugherty

引用次数: 0

An antisense oligonucleotide-based strategy to ameliorate cognitive dysfunction in the 22q11.2 Deletion Syndrome. 基于反义寡核苷酸的策略改善22q11.2缺失综合征的认知功能障碍。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.103328

Pratibha Thakur, Martin Lackinger, Anastasia Diamantopoulou, Sneha Rao, Yijing Chen, Khakima Khalizova, Annie Ferng, Curt Mazur, Holly Kordasiewicz, Robert J Shprintzen, Sander Markx, Bin Xu, Joseph A Gogos

{"title":"An antisense oligonucleotide-based strategy to ameliorate cognitive dysfunction in the 22q11.2 Deletion Syndrome.","authors":"Pratibha Thakur, Martin Lackinger, Anastasia Diamantopoulou, Sneha Rao, Yijing Chen, Khakima Khalizova, Annie Ferng, Curt Mazur, Holly Kordasiewicz, Robert J Shprintzen, Sander Markx, Bin Xu, Joseph A Gogos","doi":"10.7554/eLife.103328","DOIUrl":"https://doi.org/10.7554/eLife.103328","url":null,"abstract":"Adults and children with the 22q11.2 Deletion Syndrome demonstrate cognitive, social, and emotional impairments and high risk for schizophrenia. Work in mouse model of the 22q11.2 deletion provided compelling evidence for abnormal expression and processing of microRNAs. A major transcriptional effect of the microRNA dysregulation is upregulation of Emc10, a component of the ER membrane complex, which promotes membrane insertion of a subset of polytopic and tail-anchored membrane proteins. We previously uncovered a key contribution of EMC10 in mediating the behavioral phenotypes observed in 22q11.2 deletion mouse models. Here, we show that expression and processing of miRNAs is abnormal and EMC10 expression is elevated in neurons derived from 22q11.2 deletion carriers. Reduction of EMC10 levels restores defects in neurite outgrowth and calcium signaling in patient neurons. Furthermore, antisense oligonucleotide administration and normalization of Emc10 in the adult mouse brain not only alleviates cognitive deficits in social and spatial memory but remarkably sustains these improvements for over 2 months post-injection, indicating its therapeutic potential. Broadly, our study integrates findings from both animal models and human neurons to elucidate the translational potential of modulating EMC10 levels and downstream targets as a specific venue to ameliorate disease progression in 22q11.2 Deletion Syndrome.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149869","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}

引用次数: 0

Evolutionary unique N-glycan-dependent protein quality control system plays pivotal roles in cellular fitness and extracellular vesicle transport in Cryptococcus neoformans. 进化独特的n-聚糖依赖蛋白质量控制系统在新型隐球菌的细胞适应性和细胞外囊泡运输中起关键作用。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.103729

Catia Mota, Kiseung Kim, Ye Ji Son, Eun Jung Thak, Su-Bin Lee, Ju-El Kim, Jeong-Kee Yoon, Min-Ho Kang, Heeyoun Hwang, Yong-Sun Bahn, J Andrew Alspaugh, Hyun Ah Kang

{"title":"Evolutionary unique N-glycan-dependent protein quality control system plays pivotal roles in cellular fitness and extracellular vesicle transport in Cryptococcus neoformans.","authors":"Catia Mota, Kiseung Kim, Ye Ji Son, Eun Jung Thak, Su-Bin Lee, Ju-El Kim, Jeong-Kee Yoon, Min-Ho Kang, Heeyoun Hwang, Yong-Sun Bahn, J Andrew Alspaugh, Hyun Ah Kang","doi":"10.7554/eLife.103729","DOIUrl":"https://doi.org/10.7554/eLife.103729","url":null,"abstract":"A conserved N-glycan-dependent endoplasmic reticulum protein quality control (ERQC) system has evolved in eukaryotes to ensure accuracy during glycoprotein folding. The human pathogen Cryptococcus neoformans possesses a unique N-glycosylation pathway that affects microbial physiology and interactions with the infected host. To investigate the molecular features and functions of the ERQC system in C. neoformans, we characterized a set of mutants with deletion of genes coding for the ERQC sensor UDP-glucose:glycoprotein glucosyltransferase (UGG1) and putative α1,2-mannose-trimming enzymes (MNS1, MNS101, MNL1, and MNL2). The ugg1Δ, mns1Δ, mns101Δ, and mns1Δ101Δ mutants showed alterations in N-glycan profiles, defective cell surface organization, decreased survival in host cells, and varying degrees of reduced in vivo virulence. The ugg1Δ strain exhibited severely impaired extracellular secretion of capsular polysaccharides and virulence-related enzymes. Comparative transcriptome analysis showed the upregulation of protein folding, proteolysis, and cell wall remodeling genes, indicative of induced endoplasmic reticulum stress. However, no apparent changes were observed in the expression of genes involved in protein secretion or capsule biosynthesis. Additionally, extracellular vesicle (EV) analysis combined with proteomic analysis showed significant alterations in the number, size distribution, and cargo composition of EVs in ugg1Δ. These findings highlight the essential role of the functional ERQC system for cellular fitness under adverse conditions and proper EV-mediated transport of virulence factors, which are crucial for the full fungal pathogenicity of C. neoformans.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157391","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}

引用次数: 0

Scrutinized lipid utilization disrupts Amphotericin-B responsiveness in clinical isolates of Leishmania donovani. 仔细检查脂质利用破坏两性霉素b在临床分离利什曼多诺瓦原虫的反应。

IF 6.4 1区生物学

eLife Pub Date : 2025-05-27 DOI: 10.7554/eLife.102857

Supratim Pradhan, Dhruba Dhar, Debolina Manna, Shubhangi Chakraborty, Arkapriya Bhattacharyya, Khushi Chauhan, Rimi Mukherjee, Abhik Sen, Krishna Pandey, Soumen Das, Budhaditya Mukherjee

{"title":"Scrutinized lipid utilization disrupts Amphotericin-B responsiveness in clinical isolates of Leishmania donovani.","authors":"Supratim Pradhan, Dhruba Dhar, Debolina Manna, Shubhangi Chakraborty, Arkapriya Bhattacharyya, Khushi Chauhan, Rimi Mukherjee, Abhik Sen, Krishna Pandey, Soumen Das, Budhaditya Mukherjee","doi":"10.7554/eLife.102857","DOIUrl":"https://doi.org/10.7554/eLife.102857","url":null,"abstract":"The management of Leishmania donovani (LD), responsible for fatal visceral leishmaniasis (VL), faces increasing challenges due to rising drug unresponsiveness, leading to increasing treatment failures. While hypolipidemia characterizes VL, LD, a cholesterol auxotroph, relies on host lipid scavenging for its intracellular survival. The aggressive pathology, in terms of increased organ parasite load, observed in hosts infected with antimony-unresponsive-LD (LD-R) as compared to their sensitive counterparts (LD-S), highlights LD-R's heightened reliance on host lipids. Here, we report that LD-R-infection in mice promotes fluid-phase endocytosis in the host macrophages, selectively accumulating neutral lipids while excluding oxidized-low-density lipoprotein (LDL). LD-R enhances the fusion of endocytosed LDL-vesicles with its phagolysosomal membrane and inhibits cholesterol mobilization from these vesicles by suppressing NPC-1. This provides LD-R amastigotes with excess lipids, supporting their rapid proliferation and membrane synthesis. This excess LDL-influx leads to an eventual accumulation of neutral lipid droplets around LD-R amastigotes, thereby increasing their unresponsiveness toward Amphotericin-B, a second-line amphiphilic antileishmanial. Notably, VL patients showing relapse with Amphotericin-B treatment exhibited significantly lower serum LDL and cholesterol than cured cases. Treatment with Aspirin, a lipid droplet blocker, reduced lipid droplets around LD-R amastigotes, restoring Amphotericin-B responsiveness.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144157404","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}

引用次数: 0

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