EMBO Molecular Medicine最新文献

{"title":"Liver protects neuron viability and electrocortical activity in post-cardiac arrest brain injury.","authors":"Zhiyong Guo, Meixian Yin, Chengjun Sun, Guixing Xu, Tielong Wang, Zehua Jia, Zhiheng Zhang, Caihui Zhu, Donghua Zheng, Linhe Wang, Shanzhou Huang, Di Liu, Yixi Zhang, Rongxing Xie, Ningxin Gao, Liqiang Zhan, Shujiao He, Yifan Zhu, Yuexin Li, Björn Nashan, Schlegel Andrea, Jin Xu, Qiang Zhao, Xiaoshun He","doi":"10.1038/s44321-024-00140-z","DOIUrl":"10.1038/s44321-024-00140-z","url":null,"abstract":"<p><p>Brain injury is the leading cause of mortality among patients who survive cardiac arrest (CA). Clinical studies have shown that the presence of post-CA hypoxic hepatitis or pre-CA liver disease is associated with increased mortality and inferior neurological recovery. In our in vivo global cerebral ischemia model, we observed a larger infarct area, elevated tissue injury scores, and increased intravascular CD45+ cell adhesion in reperfused brains with simultaneous hepatic ischemia than in those without it. In the ex vivo brain normothermic machine perfusion (NMP) model, we demonstrated that addition of a functioning liver to the brain NMP circuit significantly reduced post-CA brain injury, increased neuronal viability, and improved electrocortical activity. Furthermore, significant alterations were observed in both the transcriptome and metabolome in the presence or absence of hepatic ischemia. Our study highlights the crucial role of the liver in the pathogenesis of post-CA brain injury.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2322-2348"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479250/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fertility protection during chemotherapy treatment by boosting the NAD(P)⁺ metabolome.","authors":"Wing-Hong Jonathan Ho, Maria B Marinova, Dave R Listijono, Michael J Bertoldo, Dulama Richani, Lynn-Jee Kim, Amelia Brown, Angelique H Riepsamen, Safaa Cabot, Emily R Frost, Sonia Bustamante, Ling Zhong, Kaisa Selesniemi, Derek Wong, Romanthi Madawala, Maria Marchante, Dale M Goss, Catherine Li, Toshiyuki Araki, David J Livingston, Nigel Turner, David A Sinclair, Kirsty A Walters, Hayden A Homer, Robert B Gilchrist, Lindsay E Wu","doi":"10.1038/s44321-024-00119-w","DOIUrl":"10.1038/s44321-024-00119-w","url":null,"abstract":"<p><p>Chemotherapy induced ovarian failure and infertility is an important concern in female cancer patients of reproductive age or younger, and non-invasive, pharmacological approaches to maintain ovarian function are urgently needed. Given the role of reduced nicotinamide adenine dinucleotide phosphate (NADPH) as an essential cofactor for drug detoxification, we sought to test whether boosting the NAD(P)⁺ metabolome could protect ovarian function. We show that pharmacological or transgenic strategies to replenish the NAD⁺ metabolome ameliorates chemotherapy induced female infertility in mice, as measured by oocyte yield, follicle health, and functional breeding trials. Importantly, treatment of a triple-negative breast cancer mouse model with the NAD⁺ precursor nicotinamide mononucleotide (NMN) reduced tumour growth and did not impair the efficacy of chemotherapy drugs in vivo or in diverse cancer cell lines. Overall, these findings raise the possibility that NAD⁺ precursors could be a non-invasive strategy for maintaining ovarian function in cancer patients, with potential benefits in cancer therapy.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2583-2618"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473878/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016724","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The gray boundaries of aberrant shortening of the cellular timekeepers' edges.","authors":"Guillermo Guenechea, Nestor W Meza","doi":"10.1038/s44321-024-00122-1","DOIUrl":"10.1038/s44321-024-00122-1","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2276-2278"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142092506","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An enhanced intracellular delivery platform based on a distant diphtheria toxin homolog that evades pre-existing antitoxin antibodies.","authors":"Shivneet K Gill, Seiji N Sugiman-Marangos, Greg L Beilhartz, Elizabeth Mei, Mikko Taipale, Roman A Melnyk","doi":"10.1038/s44321-024-00116-z","DOIUrl":"10.1038/s44321-024-00116-z","url":null,"abstract":"<p><p>Targeted intracellular delivery of therapeutic proteins remains a significant unmet challenge in biotechnology. A promising approach is to leverage the intrinsic capabilities of bacterial toxins like diphtheria toxin (DT) to deliver a potent cytotoxic enzyme into cells with an associated membrane translocation moiety. Despite showing promising clinical efficacy, widespread deployment of DT-based therapeutics is complicated by the prevalence of pre-existing antibodies in the general population arising from childhood DT toxoid vaccinations, which impact the exposure, efficacy, and safety of these potent molecules. Here, we describe the discovery and characterization of a distant DT homolog from the ancient reptile pathogen Austwickia chelonae that we have dubbed chelona toxin (ACT). We show that ACT is comparable to DT structure and function in all respects except that it is not recognized by pre-existing anti-DT antibodies circulating in human sera. Furthermore, we demonstrate that ACT delivers heterologous therapeutic cargos into target cells more efficiently than DT. Our findings highlight ACT as a promising new chassis for building next-generation immunotoxins and targeted delivery platforms with improved pharmacokinetic and pharmacodynamic properties.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2638-2651"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473700/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-sporozoite malaria vaccines: where we are, where we are going.","authors":"Diana Moita, Miguel Prudêncio","doi":"10.1038/s44321-024-00131-0","DOIUrl":"10.1038/s44321-024-00131-0","url":null,"abstract":"<p><p>The malaria vaccination landscape has seen significant advancements with the recent endorsement of RTS,S/AS01 and R21/Matrix-M vaccines, which target the pre-erythrocytic stages of Plasmodium falciparum (Pf) infection. However, several challenges remain to be addressed, including the incomplete protection afforded by these vaccines, their dependence on a single Pf antigen, and the fact that they were not designed to protect against P. vivax (Pv) malaria. Injectable formulations of whole-sporozoite (WSpz) malaria vaccines offer a promising alternative to existing subunit vaccines, with recent developments including genetically engineered parasites and optimized administration regimens. Clinical evaluations demonstrate varying efficacy, influenced by factors, such as immune status, prior exposure to malaria, and age. Despite significant progress, a few hurdles persist in vaccine production, deployment, and efficacy in malaria-endemic regions, particularly in children. Concurrently, transgenic parasites expressing Pv antigens emerge as potential solutions for PvWSpz vaccine development. Ongoing clinical studies and advancements in vaccine technology, including the recently described PfSPZ-LARC2 candidate, signify a hopeful future for WSpz malaria vaccines, which hold great promise in the global fight against malaria.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2279-2289"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473726/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Can we manipulate the ovary's own metabolism to protect it from chemotherapy-induced damage?","authors":"Adomas Liugaila, Agnes Stefansdottir, Norah Spears","doi":"10.1038/s44321-024-00124-z","DOIUrl":"10.1038/s44321-024-00124-z","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2274-2275"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473692/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125157","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human breast tissue engineering in health and disease.","authors":"Maj-Britt Buchholz, Demi I Scheerman, Riccardo Levato, Ellen J Wehrens, Anne C Rios","doi":"10.1038/s44321-024-00112-3","DOIUrl":"10.1038/s44321-024-00112-3","url":null,"abstract":"<p><p>The human mammary gland represents a highly organized and dynamic tissue, uniquely characterized by postnatal developmental cycles. During pregnancy and lactation, it undergoes extensive hormone-stimulated architectural remodeling, culminating in the formation of specialized structures for milk production to nourish offspring. Moreover, it carries significant health implications, due to the high prevalence of breast cancer. Therefore, gaining insight into the unique biology of the mammary gland can have implications for managing breast cancer and promoting the well-being of both women and infants. Tissue engineering techniques hold promise to narrow the translational gap between existing breast models and clinical outcomes. Here, we provide an overview of the current landscape of breast tissue engineering, outline key requirements, and the challenges to overcome for achieving more predictive human breast models. We propose methods to validate breast function and highlight preclinical applications for improved understanding and targeting of breast cancer. Beyond mammary gland physiology, representative human breast models can offer new insight into stem cell biology and developmental processes that could extend to other organs and clinical contexts.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2299-2321"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next generation of \"magic bullets\", solutions from the microbial pangenome.","authors":"Vega Masignani, Rino Rappuoli, Mariagrazia Pizza","doi":"10.1038/s44321-024-00133-y","DOIUrl":"10.1038/s44321-024-00133-y","url":null,"abstract":"","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2271-2273"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infection length and host environment influence on Plasmodium falciparum dry season reservoir.","authors":"Carolina M Andrade, Manuela Carrasquilla, Usama Dabbas, Jessica Briggs, Hannah van Dijk, Nikolay Sergeev, Awa Sissoko, Moussa Niangaly, Christina Ntalla, Emily LaVerriere, Jeff Skinner, Klara Golob, Jeremy Richter, Hamidou Cisse, Shanping Li, Jason A Hendry, Muhammad Asghar, Didier Doumtabe, Anna Farnert, Thomas Ruppert, Daniel E Neafsey, Kassoum Kayentao, Safiatou Doumbo, Aissata Ongoiba, Peter D Crompton, Boubacar Traore, Bryan Greenhouse, Silvia Portugal","doi":"10.1038/s44321-024-00127-w","DOIUrl":"10.1038/s44321-024-00127-w","url":null,"abstract":"<p><p>Persistence of malaria parasites in asymptomatic hosts is crucial in areas of seasonally-interrupted transmission, where P. falciparum bridges wet seasons months apart. During the dry season, infected erythrocytes exhibit extended circulation with reduced cytoadherence, increasing the risk of splenic clearance of infected cells and hindering parasitaemia increase. However, what determines parasite persistence for long periods of time remains unknown. Here, we investigated whether seasonality affects plasma composition so that P. falciparum can detect and adjust to changing serological cues; or if alternatively, parasite infection length dictates clinical presentation and persistency. Data from Malian children exposed to alternating ~6-month wet and dry seasons show that plasma composition is unrelated to time of year in non-infected children, and that carrying P. falciparum only minimally affects plasma constitution in asymptomatic hosts. Parasites persisting in the blood of asymptomatic children from the dry into the ensuing wet season rarely if ever appeared to cause malaria in their hosts as seasons changed. In vitro culture in the presence of plasma collected in the dry or the wet seasons did not affect parasite development, replication or host-cell remodelling. The absence of a parasite-encoded sensing mechanism was further supported by the observation of similar features in P. falciparum persisting asymptomatically in the dry season and parasites in age- and sex-matched asymptomatic children in the wet season. Conversely, we show that P. falciparum clones transmitted early in the wet season had lower chance of surviving until the end of the following dry season, contrasting with a higher likelihood of survival of clones transmitted towards the end of the wet season, allowing for the re-initiation of transmission. We propose that the decreased virulence observed in persisting parasites during the dry season is not due to the parasites sensing ability, nor is it linked to a decreased capacity for parasite replication but rather a consequence decreased cytoadhesion associated with infection length.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2349-2375"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473648/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142282189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rational structure-guided design of a blood stage malaria vaccine immunogen presenting a single epitope from PfRH5.","authors":"Thomas E Harrison, Nawsad Alam, Brendan Farrell, Doris Quinkert, Amelia M Lias, Lloyd D W King, Lea K Barfod, Simon J Draper, Ivan Campeotto, Matthew K Higgins","doi":"10.1038/s44321-024-00123-0","DOIUrl":"10.1038/s44321-024-00123-0","url":null,"abstract":"<p><p>There is an urgent need for improved malaria vaccine immunogens. Invasion of erythrocytes by Plasmodium falciparum is essential for its life cycle, preceding symptoms of disease and parasite transmission. Antibodies which target PfRH5 are highly effective at preventing erythrocyte invasion and the most potent growth-inhibitory antibodies bind a single epitope. Here we use structure-guided approaches to design a small synthetic immunogen, RH5-34EM which recapitulates this epitope. Structural biology and biophysics demonstrate that RH5-34EM is correctly folded and binds neutralising monoclonal antibodies with nanomolar affinity. In immunised rats, RH5-34EM induces PfRH5-targeting antibodies that inhibit parasite growth. While PfRH5-specific antibodies were induced at a lower concentration by RH5-34EM than by PfRH5, RH5-34EM induced antibodies that were a thousand-fold more growth-inhibitory as a factor of PfRH5-specific antibody concentration. Finally, we show that priming with RH5-34EM and boosting with PfRH5 achieves the best balance between antibody quality and quantity and induces the most effective growth-inhibitory response. This rationally designed vaccine immunogen is now available for use as part of future malaria vaccines, alone or in combination with other immunogens.</p>","PeriodicalId":11597,"journal":{"name":"EMBO Molecular Medicine","volume":" ","pages":"2539-2559"},"PeriodicalIF":9.0,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11473951/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}