IF 6.4 1区生物学

eLife Pub Date : 2025-04-01 DOI: 10.7554/eLife.103718

Yi Li, Long Gong, Jing Wu, Wesley Hung, Mei Zhen, Shangbang Gao

{"title":"UBR-1 deficiency leads to ivermectin resistance in Caenorhabditis elegans.","authors":"Yi Li, Long Gong, Jing Wu, Wesley Hung, Mei Zhen, Shangbang Gao","doi":"10.7554/eLife.103718","DOIUrl":"10.7554/eLife.103718","url":null,"abstract":"Resistance to anthelmintics, particularly the macrocyclic lactone ivermectin (IVM), presents a substantial global challenge for parasite control. We found that the functional loss of an evolutionarily conserved E3 ubiquitin ligase, UBR-1, leads to IVM resistance in Caenorhabditis elegans. Multiple IVM-inhibiting activities, including viability, body size, pharyngeal pumping, and locomotion, were significantly ameliorated in various ubr-1 mutants. Interestingly, exogenous application of glutamate induces IVM resistance in wild-type animals. The sensitivity of all IVM-affected phenotypes of ubr-1 is restored by eliminating proteins associated with glutamate metabolism or signaling: GOT-1, a transaminase that converts aspartate to glutamate, and EAT-4, a vesicular glutamate transporter. We demonstrated that IVM-targeted GluCls (glutamate-gated chloride channels) are downregulated and that the IVM-mediated inhibition of serotonin-activated pharynx Ca2+ activity is diminished in ubr-1. Additionally, enhancing glutamate uptake in ubr-1 mutants through ceftriaxone completely restored their IVM sensitivity. Therefore, UBR-1 deficiency-mediated aberrant glutamate signaling leads to ivermectin resistance in C. elegans.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961118/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751446","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

Modularity of the segmentation clock and morphogenesis. 分割时钟和形态发生的模块化。

IF 6.4 1区生物学

eLife Pub Date : 2025-04-01 DOI: 10.7554/eLife.106316

James E Hammond, Ruth E Baker, Berta Verd

引用次数: 0

Infralimbic parvalbumin neural activity facilitates cued threat avoidance. 边缘下小白蛋白神经活动促进威胁回避。

IF 6.4 1区生物学

eLife Pub Date : 2025-04-01 DOI: 10.7554/eLife.91221

Yi-Yun Ho, Qiuwei Yang, Priyanka Boddu, David A Bulkin, Melissa R Warden

{"title":"Infralimbic parvalbumin neural activity facilitates cued threat avoidance.","authors":"Yi-Yun Ho, Qiuwei Yang, Priyanka Boddu, David A Bulkin, Melissa R Warden","doi":"10.7554/eLife.91221","DOIUrl":"10.7554/eLife.91221","url":null,"abstract":"The infralimbic cortex (IL) is essential for flexible behavioral responses to threatening environmental events. Reactive behaviors such as freezing or flight are adaptive in some contexts, but in others a strategic avoidance behavior may be more advantageous. IL has been implicated in avoidance, but the contribution of distinct IL neural subtypes with differing molecular identities and wiring patterns is poorly understood. Here, we study IL parvalbumin (PV) interneurons in mice as they engage in active avoidance behavior, a behavior in which mice must suppress freezing in order to move to safety. We find that activity in inhibitory PV neurons increases during movement to avoid the shock in this behavioral paradigm, and that PV activity during movement emerges after mice have experienced a single shock, prior to learning avoidance. PV neural activity does not change during movement toward cued rewards or during general locomotion in the open field, behavioral paradigms where freezing does not need to be suppressed to enable movement. Optogenetic suppression of PV neurons increases the duration of freezing and delays the onset of avoidance behavior, but does not affect movement toward rewards or general locomotion. These data provide evidence that IL PV neurons support strategic avoidance behavior by suppressing freezing.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"12 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751454","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

Bringing signaling complexity into focus. 关注信号的复杂性。

IF 6.4 1区生物学

eLife Pub Date : 2025-04-01 DOI: 10.7554/eLife.106519

Sarah Y Coomson, Salil A Lachke

引用次数: 0

Enzymatic protein fusions with 100% product yield. 酶蛋白融合物，产品收率100%。

IF 6.4 1区生物学

eLife Pub Date : 2025-04-01 DOI: 10.7554/eLife.102765

Adrian C D Fuchs

引用次数: 0

Peripheral opioid receptor antagonism alleviates fentanyl-induced cardiorespiratory depression and is devoid of aversive behavior. 外周阿片受体拮抗剂可减轻芬太尼诱导的心肺抑制，且无不良行为。

IF 6.4 1区生物学

eLife Pub Date : 2025-04-01 DOI: 10.7554/eLife.104469

Brian C Ruyle, Sarah Masud, Rohith Kesaraju, Mubariz Tahirkheli, Juhi Modh, Caroline G Roth, Sofia Angulo-Lopera, Tania Lintz, Jessica A Higginbotham, Nicolas Massaly, Jose A Morón

{"title":"Peripheral opioid receptor antagonism alleviates fentanyl-induced cardiorespiratory depression and is devoid of aversive behavior.","authors":"Brian C Ruyle, Sarah Masud, Rohith Kesaraju, Mubariz Tahirkheli, Juhi Modh, Caroline G Roth, Sofia Angulo-Lopera, Tania Lintz, Jessica A Higginbotham, Nicolas Massaly, Jose A Morón","doi":"10.7554/eLife.104469","DOIUrl":"10.7554/eLife.104469","url":null,"abstract":"Millions of Americans suffering from Opioid Use Disorders face a high risk of fatal overdose due to opioid-induced respiratory depression (OIRD). Fentanyl, a powerful synthetic opioid, is a major contributor to the rising rates of overdose deaths. Reversing fentanyl overdoses has proved challenging due to its high potency and the rapid onset of OIRD. We assessed the contributions of central and peripheral mu opioid receptors (MORs) in mediating fentanyl-induced physiological responses. The peripherally restricted MOR antagonist naloxone methiodide (NLXM) both prevented and reversed OIRD to a degree comparable to that of naloxone (NLX), indicating substantial involvement of peripheral MORs to OIRD. Interestingly, NLXM-mediated OIRD reversal did not produce aversive behaviors observed after NLX. We show that neurons in the nucleus of the solitary tract (nTS), the first central synapse of peripheral afferents, exhibit a biphasic activity profile following fentanyl exposure. NLXM pretreatment attenuates this activity, suggesting that these responses are mediated by peripheral MORs. Together, these findings establish a critical role for peripheral MORs, including ascending inputs to the nTS, as sites of dysfunction during OIRD. Furthermore, selective peripheral MOR antagonism could be a promising therapeutic strategy for managing OIRD by sparing CNS-driven acute opioid-associated withdrawal and aversion observed after NLX.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11961120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751439","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

Decoding m⁶Am by simultaneous transcription-start mapping and methylation quantification. 通过同步转录启动图谱和甲基化量化解码m6Am。

IF 6.4 1区生物学

eLife Pub Date : 2025-03-31 DOI: 10.7554/eLife.104139

Jianheng Fox Liu, Ben R Hawley, Luke S Nicholson, Samie R Jaffrey

{"title":"Decoding m6Am by simultaneous transcription-start mapping and methylation quantification.","authors":"Jianheng Fox Liu, Ben R Hawley, Luke S Nicholson, Samie R Jaffrey","doi":"10.7554/eLife.104139","DOIUrl":"10.7554/eLife.104139","url":null,"abstract":"N 6,2'-O-dimethyladenosine (m6Am) is a modified nucleotide located at the first transcribed position in mRNA and snRNA that is essential for diverse physiological processes. m6Am mapping methods assume each gene uses a single start nucleotide. However, gene transcription usually involves multiple start sites, generating numerous 5' isoforms. Thus, gene-level annotations cannot capture the diversity of m6Am modification in the transcriptome. Here, we describe CROWN-seq, which simultaneously identifies transcription-start nucleotides and quantifies m6Am stoichiometry for each 5' isoform that initiates with adenosine. Using CROWN-seq, we map the m6Am landscape in nine human cell lines. Our findings reveal that m6Am is nearly always a high stoichiometry modification, with only a small subset of cellular mRNAs showing lower m6Am stoichiometry. We find that m6Am is associated with increased transcript expression and provide evidence that m6Am may be linked to transcription initiation associated with specific promoter sequences and initiation mechanisms. These data suggest a potential new function for m6Am in influencing transcription.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751664","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

Interdependence between SEB-3 receptor and NLP-49 peptides shifts across predator-induced defensive behavioral modes in Caenorhabditis elegans. 秀丽隐杆线虫SEB-3受体和NLP-49肽之间的相互依赖关系在捕食者诱导的防御行为模式中发生变化。

IF 6.4 1区生物学

eLife Pub Date : 2025-03-31 DOI: 10.7554/eLife.98262

Kathleen T Quach, Gillian A Hughes, Sreekanth H Chalasani

{"title":"Interdependence between SEB-3 receptor and NLP-49 peptides shifts across predator-induced defensive behavioral modes in Caenorhabditis elegans.","authors":"Kathleen T Quach, Gillian A Hughes, Sreekanth H Chalasani","doi":"10.7554/eLife.98262","DOIUrl":"10.7554/eLife.98262","url":null,"abstract":"Prey must balance predator avoidance with feeding, a central dilemma in prey refuge theory. Additionally, prey must assess predatory imminence-how close threats are in space and time. Predatory imminence theory classifies defensive behaviors into three defense modes: pre-encounter, post-encounter, and circa-strike, corresponding to increasing levels of threat--suspecting, detecting, and contacting a predator. Although predatory risk often varies in spatial distribution and imminence, how these factors intersect to influence defensive behaviors is poorly understood. Integrating these factors into a naturalistic environment enables comprehensive analysis of multiple defense modes in consistent conditions. Here, we combine prey refuge and predatory imminence theories to develop a model system of nematode defensive behaviors, with Caenorhabditis elegans as prey and Pristionchus pacificus as predator. In a foraging environment comprised of a food-rich, high-risk patch and a food-poor, low-risk refuge, C. elegans innately exhibits circa-strike behaviors. With experience, it learns post- and pre-encounter behaviors that proactively anticipate threats. These defense modes intensify with predator lethality, with only life-threatening predators capable of eliciting all three modes. SEB-3 receptors and NLP-49 peptides, key stress regulators, vary in their impact and interdependence across defense modes. Overall, our model system reveals fine-grained insights into how stress-related signaling regulates defensive behaviors.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957542/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751165","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

2-oxoglutarate triggers assembly of active dodecameric Methanosarcina mazei glutamine synthetase. 2-氧戊二酸触发十二聚甲基甲烷谷氨酰胺合成酶的组装。

IF 6.4 1区生物学

eLife Pub Date : 2025-03-31 DOI: 10.7554/eLife.97484

Eva Herdering, Tristan Reif-Trauttmansdorff, Anuj Kumar, Tim Habenicht, Georg Hochberg, Stefan Bohn, Jan Schuller, Ruth Anne Schmitz

{"title":"2-oxoglutarate triggers assembly of active dodecameric Methanosarcina mazei glutamine synthetase.","authors":"Eva Herdering, Tristan Reif-Trauttmansdorff, Anuj Kumar, Tim Habenicht, Georg Hochberg, Stefan Bohn, Jan Schuller, Ruth Anne Schmitz","doi":"10.7554/eLife.97484","DOIUrl":"10.7554/eLife.97484","url":null,"abstract":"Glutamine synthetases (GS) are central enzymes essential for the nitrogen metabolism across all domains of life. Consequently, they have been extensively studied for more than half a century. Based on the ATP-dependent ammonium assimilation generating glutamine, GS expression and activity are strictly regulated in all organisms. In the methanogenic archaeon Methanosarcina mazei, it has been shown that the metabolite 2-oxoglutarate (2-OG) directly induces the GS activity. Besides, modulation of the activity by interaction with small proteins (GlnK1 and sP26) has been reported. Here, we show that the strong activation of M. mazei GS (GlnA1) by 2-OG is based on the 2-OG dependent dodecamer assembly of GlnA1 by using mass photometry (MP) and single particle cryo-electron microscopy (cryo-EM) analysis of purified strep-tagged GlnA1. The dodecamer assembly from dimers occurred without any detectable intermediate oligomeric state and was not affected in the presence of GlnK1. The 2.39 Å cryo-EM structure of the dodecameric complex in the presence of 12.5 mM 2-OG demonstrated that 2-OG is binding between two monomers. Thereby, 2-OG appears to induce the dodecameric assembly in a cooperative way. Furthermore, the active site is primed by an allosteric interaction cascade caused by 2-OG-binding towards an adaption of an open active state conformation. In the presence of additional glutamine, strong feedback inhibition of GS activity was observed. Since glutamine dependent disassembly of the dodecamer was excluded by MP, feedback inhibition most likely relies on the binding of glutamine to the catalytic site. Based on our findings, we propose that under nitrogen limitation the induction of M. mazei GS into a catalytically active dodecamer is not affected by GlnK1 and crucially depends on the presence of 2-OG.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751660","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

Allosteric inhibition of trypanosomatid pyruvate kinases by a camelid single-domain antibody. 骆驼单域抗体对丙酮酸锥虫激酶的变构抑制作用。

IF 6.4 1区生物学

eLife Pub Date : 2025-03-31 DOI: 10.7554/eLife.100066

Joar Esteban Pinto Torres, Mathieu Claes, Rik Hendrickx, Meng Yuan, Natalia Smiejkowska, Pieter Van Wielendaele, Aysima Hacisuleyman, Hans De Winter, Serge Muyldermans, Paul A M Michels, Malcolm D Walkinshaw, Wim Versées, Guy Caljon, Stefan Magez, Yann G-J Sterckx

{"title":"Allosteric inhibition of trypanosomatid pyruvate kinases by a camelid single-domain antibody.","authors":"Joar Esteban Pinto Torres, Mathieu Claes, Rik Hendrickx, Meng Yuan, Natalia Smiejkowska, Pieter Van Wielendaele, Aysima Hacisuleyman, Hans De Winter, Serge Muyldermans, Paul A M Michels, Malcolm D Walkinshaw, Wim Versées, Guy Caljon, Stefan Magez, Yann G-J Sterckx","doi":"10.7554/eLife.100066","DOIUrl":"10.7554/eLife.100066","url":null,"abstract":"African trypanosomes are the causative agents of neglected tropical diseases affecting both humans and livestock. Disease control is highly challenging due to an increasing number of drug treatment failures. African trypanosomes are extracellular, blood-borne parasites that mainly rely on glycolysis for their energy metabolism within the mammalian host. Trypanosomal glycolytic enzymes are therefore of interest for the development of trypanocidal drugs. Here, we report the serendipitous discovery of a camelid single-domain antibody (sdAb aka Nanobody) that selectively inhibits the enzymatic activity of trypanosomatid (but not host) pyruvate kinases through an allosteric mechanism. By combining enzyme kinetics, biophysics, structural biology, and transgenic parasite survival assays, we provide a proof-of-principle that the sdAb-mediated enzyme inhibition negatively impacts parasite fitness and growth.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-03-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11957543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751661","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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