EBioMedicine最新文献

{"title":"Near-infrared II fluorescence-guided glioblastoma surgery targeting monocarboxylate transporter 4 combined with photothermal therapy.","authors":"Hongyang Zhao, Chunzhao Li, Xiaojing Shi, Jinnan Zhang, Xiaohua Jia, Zhenhua Hu, Yufei Gao, Jie Tian","doi":"10.1016/j.ebiom.2024.105243","DOIUrl":"10.1016/j.ebiom.2024.105243","url":null,"abstract":"<p><strong>Background: </strong>Surgery is crucial for glioma treatment, but achieving complete tumour removal remains challenging. We evaluated the effectiveness of a probe targeting monocarboxylate transporter 4 (MCT4) in recognising gliomas, and of near-infrared window II (NIR-II) fluorescent molecular imaging and photothermal therapy as treatment strategies.</p><p><strong>Methods: </strong>We combined an MCT4-specific monoclonal antibody with indocyanine green to create the probe. An orthotopic mouse model and a transwell model were used to evaluate its ability to guide tumour resection using NIR-II fluorescence and to penetrate the blood-brain barrier (BBB), respectively. A subcutaneous tumour model was established to confirm photothermal therapy efficacy. Probe specificity was assessed in brain tissue from mice and humans. Finally, probe effectiveness in photothermal therapy was investigated.</p><p><strong>Findings: </strong>MCT4 was differentially expressed in tumour and normal brain tissue. The designed probe exhibited precise tumour targeting. Tumour imaging was precise, with a signal-to-background (SBR) ratio of 2.8. Residual tumour cells were absent from brain tissue postoperatively (SBR: 6.3). The probe exhibited robust penetration of the BBB. Moreover, the probe increased the tumour temperature to 50 °C within 5 min of laser excitation. Photothermal therapy significantly reduced tumour volume and extended survival time in mice without damage to vital organs.</p><p><strong>Interpretation: </strong>These findings highlight the potential efficacy of our probe for fluorescence-guided surgery and therapeutic interventions.</p><p><strong>Funding: </strong>Jilin Province Department of Science and Technology (20200403079SF), Department of Finance (2021SCZ06) and Development and Reform Commission (20200601002JC); National Natural Science Foundation of China (92059207, 92359301, 62027901, 81930053, 81227901, U21A20386); and CAS Youth Interdisciplinary Team (JCTD-2021-08).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11284385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616153","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":"Blood pressure response index and clinical outcomes in patients with septic shock: a multicenter cohort study.","authors":"Yujie Chen, Huizhen Jiang, Yuna Wei, Yehan Qiu, Longxiang Su, Jieqing Chen, Xin Ding, Lu Wang, Dandan Ma, Feng Zhang, Wen Zhu, Xiaoyang Meng, Guoqiang Sun, Lian Ma, Yao Wang, Linfeng Li, Guiren Ruan, Fuping Guo, Ting Shu, Xiang Zhou, Bin Du","doi":"10.1016/j.ebiom.2024.105257","DOIUrl":"10.1016/j.ebiom.2024.105257","url":null,"abstract":"<p><strong>Background: </strong>Sepsis is a leading cause of mortality in intensive care units and vasoactive drugs are widely used in septic patients. The cardiovascular response of septic shock patients during resuscitation therapies and the relationship of the cardiovascular response and clinical outcome has not been clearly described.</p><p><strong>Methods: </strong>We included adult patients admitted to the ICU with sepsis from Peking Union Medical College Hospital (internal), Medical Information Mart for Intensive Care IV (MIMIC-IV) and eICU Collaborative Research Database (eICU-CRD). The Blood Pressure Response Index (BPRI) was defined as the ratio between the mean arterial pressure and the vasoactive-inotropic score. BRRI was compared with existing risk scores on predicting in-hospital death. The relationship between BPRI and in-hospital mortality was calculated. A XGBoost's machine learning model identified the features that influence short-term changes in BPRI.</p><p><strong>Findings: </strong>There were 2139, 9455, and 4202 patients in the internal, MIMIC-IV and eICU-CRD cohorts, respectively. BPRI had a better AUROC for predicting in-hospital mortality than SOFA (0.78 vs. 0.73, p = 0.01) and APS (0.78 vs. 0.74, p = 0.03) in the internal cohort. The estimated odds ratio for death per unit decrease in BPRI was 1.32 (95% CI 1.20-1.45) when BPRI was below 7.1 vs. 0.99 (95% CI 0.97-1.01) when BPRI was above 7.1 in the internal cohort; similar relationships were found in MIMIC-IV and eICU-CRD. Respiratory support and latest cumulative 12-h fluid balance were intervention-related features influencing BPRI.</p><p><strong>Interpretation: </strong>BPRI is an easy, rapid, precise indicator of the response of patients with septic shock to vasoactive drugs. It is a comparable and even better predictor of prognosis than SOFA and APS in sepsis and it is simpler and more convenient in use. The application of BPRI could help clinicians identify potentially at-risk patients and provide clues for treatment.</p><p><strong>Funding: </strong>Fundings for the Beijing Municipal Natural Science Foundation; the National High Level Hospital Clinical Research Funding; the CAMS Innovation Fund for Medical Sciences (CIFMS) from Chinese Academy of Medical Sciences and the National Key R&D Program of China, Ministry of Science and Technology of the People's Republic of China.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338059/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141765781","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":"KIT in oocytes: a key factor for oocyte survival and reproductive lifespan.","authors":"Yi Luan, Wonmi So, Rosemary Dong, Amirhossein Abazarikia, So-Youn Kim","doi":"10.1016/j.ebiom.2024.105263","DOIUrl":"10.1016/j.ebiom.2024.105263","url":null,"abstract":"<p><strong>Background: </strong>The KITL-KIT interaction is known as an important initiator in oocyte activation through the downstream pathway of PI3K-AKT-FOXO3 signalling. Previous studies utilising germ cell-specific Kit mutant knockin and kinase domain knockout models with Vasa-Cre suggested the crucial role of KIT in oocyte activation at the primordial follicle stage.</p><p><strong>Methods: </strong>We utilised mice with complete postnatal deletion of KIT expression in oocytes via Gdf9-iCre and conducted analyses on ovarian follicle development, specific markers, hormone assays, and fertility outcomes.</p><p><strong>Findings: </strong>Our findings reveal contrasting phenotypes compared to previous mouse models with prenatal deletion of Kit. Specifically, postnatal deletion of Kit exhibit no defects in germ cell nest breakdown, follicle activation, and folliculogenesis during development. Remarkably, upon reaching full maturity, mice with postnatal deletion of Kit experience a complete loss of ovarian reserve, growing follicles, and ovarian function. Furthermore, mice display smaller ovarian size and weight, delayed folliculogenesis, and phenotypes indicative of primary ovarian insufficiency (POI), including elevated serum levels of FSH, reduced AMH, and absence of ovarian follicles, ultimately resulting in infertility. Additionally, the ovaries exhibit randomly distributed expression of granulosa and theca cell markers such as Inhibin α, ACVR2B, and LHR. Notably, there is the uncontrolled expression of p-SMAD3 and Ki67 throughout the ovarian sections, along with the widespread presence of luteinised stroma cells and cleaved Caspase-3-positive dying cells.</p><p><strong>Interpretation: </strong>These genetic studies underscore the indispensable role of KIT in oocytes for maintaining the survival of ovarian follicles and ensuring the reproductive lifespan.</p><p><strong>Funding: </strong>This work was supported by National Institutes of Health grant R01HD096042 and startup funds from UNMC (S.Y.K.).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338130/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787592","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":"A susceptibility gene signature for ERBB2-driven mammary tumour development and metastasis in collaborative cross mice.","authors":"Hui Yang, Xinzhi Wang, Adrián Blanco-Gómez, Li He, Natalia García-Sancha, Roberto Corchado-Cobos, Manuel Jesús Pérez-Baena, Alejandro Jiménez-Navas, Pin Wang, Jamie L Inman, Antoine M Snijders, David W Threadgill, Allan Balmain, Hang Chang, Jesus Perez-Losada, Jian-Hua Mao","doi":"10.1016/j.ebiom.2024.105260","DOIUrl":"10.1016/j.ebiom.2024.105260","url":null,"abstract":"<p><strong>Background: </strong>Deeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis.</p><p><strong>Methods: </strong>732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice.</p><p><strong>Findings: </strong>Distinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a, Oxr1, Plxna2, and Tbc1d31) independently tied to various tumour characteristics, designated as a mTSGS. hTSGS scores (hTSGSS) based on their transcriptional level showed prognostic values, superseding clinical factors and PAM50 subtype across multiple human BC cohorts, and predicted pathological complete response independent of and superior to MammaPrint score in I-SPY2 study. The power of mTSGS score for predicting chemotherapy response was further validated in an in vivo mouse MMTV-Erbb2 model, showing that, like findings in human patients, mouse tumours with low mTSGS scores were most likely to respond to treatment.</p><p><strong>Interpretation: </strong>Our investigation has unveiled many new genes predisposing individuals to ERBB2-driven cancer. Translational findings indicate that hTSGS holds promise as a biomarker for refining treatment strategies for patients with BC.</p><p><strong>Funding: </strong>The U.S. Department of Defense (DoD) Breast Cancer Research Program (BCRP) (BC190820), United States; MCIN/AEI/10.13039/501100011039 (PID2020-118527RB-I00, PDC2021-121735-I00), the \"European Union Next Generation EU/PRTR,\" the Regional Government of Castile and León (CSI144P20), European Union.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11338061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787590","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":"Alterations in bile acid kinetics after bariatric surgery in patients with obesity with or without type 2 diabetes.","authors":"Annika Wahlström, Ömrüm Aydin, Lisa M Olsson, Wilhelm Sjöland, Marcus Henricsson, Annika Lundqvist, Hanns-Ulrich Marschall, Rutger Franken, Arnold van de Laar, Victor Gerdes, Abraham S Meijnikman, Dag Hofsø, Albert K Groen, Jøran Hjelmesæth, Max Nieuwdorp, Fredrik Bäckhed","doi":"10.1016/j.ebiom.2024.105265","DOIUrl":"10.1016/j.ebiom.2024.105265","url":null,"abstract":"<p><strong>Background: </strong>Bariatric surgery is an effective treatment option for obesity and provides long-term weight loss and positive effects on metabolism, but the underlying mechanisms are poorly understood. Alterations in bile acid metabolism have been suggested as a potential contributing factor, but comprehensive studies in humans are lacking.</p><p><strong>Methods: </strong>In this study, we analysed the postprandial responses of bile acids, C4 and FGF19 in plasma, and excretion of bile acids in faeces, before and after bariatric surgery in patients (n = 38; 74% females) with obesity with or without type 2 diabetes from the BARIA cohort.</p><p><strong>Findings: </strong>We observed that total fasting plasma bile acid levels increased, and faecal excretion of bile acids decreased after surgery suggesting increased reabsorption of bile acids. Consistent with increased bile acid levels after surgery we observed increased postprandial levels of FGF19 and suppression of the bile acid synthesis marker C4, suggesting increased FXR activation in the gut. We also noted that a subset of bile acids had altered postprandial responses before and after surgery. Finally, fasting plasma levels of 6α-hydroxylated bile acids, which are TGR5 agonists and associated with improved glucose metabolism, were increased after surgery and one of them, HDCA, covaried with diabetes remission in an independent cohort.</p><p><strong>Interpretation: </strong>Our findings provide new insights regarding bile acid kinetics and suggest that bariatric surgery in humans alters bile acid profiles leading to activation of FXR and TGR5, which may contribute to weight loss, improvements in glucose metabolism, and diabetes remission.</p><p><strong>Funding: </strong>Novo Nordisk Fonden, Leducq Foundation, Swedish Heart-Lung Foundation, Knut and Alice Wallenberg Foundation, the ALF-agreement, ZonMw.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11345581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888789","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":"Dysglycaemia in Ebola virus disease: a retrospective analysis from the 2018 to 2020 outbreak.","authors":"Kasereka Masumbuko Claude, Daniel Mukadi-Bamuleka, Kitenge-Omasumbu Richard, Katsuva Mbahweka Francois, Paluku Mwalitsa Jean Paul, Kavugho Muliwavyo, François Edidi-Atani, Meris Matondo Kuamfumu, Sabue Mulangu, Olivier Tshiani-Mbaya, Placide Mbala-Kingebeni, Steve Ahuka-Mundeke, Jean-Jacques Muyembe-Tamfum, Bonita E Lee, Stan Houston, Zubia Mumtaz, Michael T Hawkes","doi":"10.1016/j.ebiom.2024.105241","DOIUrl":"10.1016/j.ebiom.2024.105241","url":null,"abstract":"<p><strong>Background: </strong>Ebola virus disease (EVD) is associated with multisystem organ failure and high mortality. Severe hypoglycaemia is common, life-threatening, and correctable in critically ill patients, but glucose monitoring may be limited in EVD treatment units.</p><p><strong>Methods: </strong>We conducted a retrospective review of patients admitted to EVD treatment units in Butembo and Katwa, Eastern DRC. Glucose measurements were done using a handheld glucometer at the bedside or using the Piccolo xpress Chemistry Analyzer on venous samples.</p><p><strong>Findings: </strong>384 patients (median age 30 years (interquartile range, IQR, 20-45), 57% female) and 6422 glucose measurements (median 11 per patient, IQR 4-22) were included in the analysis. Severe hypoglycaemia (≤2.2 mmol/L) and hyperglycaemia (>10 mmol/L) were recorded at least once during the ETU admission in 97 (25%) and 225 (59%) patients, respectively. A total of 2004 infusions of glucose-containing intravenous solutions were administered to 302 patients (79%) with a median cumulative dose of 175g (IQR 100-411). The overall case fatality rate was 157/384 (41%) and was 2.2-fold higher (95% CI 1.3-3.8) in patients with severe hypoglycaemia than those without hypoglycaemia (p = 0.0042). In a multivariable Cox proportional hazards model, periods of severe hypoglycaemia (adjusted hazard ratio (aHR) 6.2, 95% CI 3.2-12, p < 0.0001) and moderate hypoglycaemia (aHR 3.0, 95% CI 1.9-4.8, p < 0.0001) were associated with elevated mortality.</p><p><strong>Interpretation: </strong>Hypoglycaemia is common in EVD, requires repeated correction with intravenous dextrose solutions, and is associated with mortality.</p><p><strong>Funding: </strong>This study was not supported by any specific funding.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11292428/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563008","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":"Single nucleus RNA-sequencing integrated into risk variant colocalization discovers 17 cell-type-specific abdominal obesity genes for metabolic dysfunction-associated steatotic liver disease.","authors":"Seung Hyuk T Lee, Kristina M Garske, Uma Thanigai Arasu, Asha Kar, Zong Miao, Marcus Alvarez, Amogha Koka, Nicholas Darci-Maher, Jihane N Benhammou, David Z Pan, Tiit Örd, Dorota Kaminska, Ville Männistö, Sini Heinonen, Martin Wabitsch, Markku Laakso, Vatche G Agopian, Joseph R Pisegna, Kirsi H Pietiläinen, Jussi Pihlajamäki, Minna U Kaikkonen, Päivi Pajukanta","doi":"10.1016/j.ebiom.2024.105232","DOIUrl":"10.1016/j.ebiom.2024.105232","url":null,"abstract":"<p><strong>Background: </strong>Abdominal obesity increases the risk for non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD).</p><p><strong>Methods: </strong>To elucidate the directional cell-type level biological mechanisms underlying the association between abdominal obesity and MASLD, we integrated adipose and liver single nucleus RNA-sequencing and bulk cis-expression quantitative trait locus (eQTL) data with the UK Biobank genome-wide association study (GWAS) data using colocalization. Then we used colocalized cis-eQTL variants as instrumental variables in Mendelian randomization (MR) analyses, followed by functional validation experiments on the target genes of the cis-eQTL variants.</p><p><strong>Findings: </strong>We identified 17 colocalized abdominal obesity GWAS variants, regulating 17 adipose cell-type marker genes. Incorporating these 17 variants into MR discovers a putative tissue-of-origin, cell-type-aware causal effect of abdominal obesity on MASLD consistently with multiple MR methods without significant evidence for pleiotropy or heterogeneity. Single cell data confirm the adipocyte-enriched mean expression of the 17 genes. Our cellular experiments across human adipogenesis identify risk variant -specific epigenetic and transcriptional mechanisms. Knocking down two of the 17 genes, PPP2R5A and SH3PXD2B, shows a marked decrease in adipocyte lipidation and significantly alters adipocyte function and adipogenesis regulator genes, including DGAT2, LPL, ADIPOQ, PPARG, and SREBF1. Furthermore, the 17 genes capture a characteristic MASLD expression signature in subcutaneous adipose tissue.</p><p><strong>Interpretation: </strong>Overall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis.</p><p><strong>Funding: </strong>NIH grants R01HG010505, R01DK132775, and R01HL170604; the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (Grant No. 802825), Academy of Finland (Grants Nos. 333021), the Finnish Foundation for Cardiovascular Research the Sigrid Jusélius Foundation and the Jane and Aatos Erkko Foundation; American Association for the Study of Liver Diseases (AASLD) Advanced Transplant Hepatology award and NIH/NIDDK (P30DK41301) Pilot and Feasibility award; NIH/NIEHS F32 award (F32ES034668); Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2021), the Academy of Finland grant (Contract no. 138006); Academy of Finland (Grant Nos 335443, 314383, 272376 and 266286), Sigrid Jusélius Foundation, Finnish Medical Foundation, Finnish Diabetes Research Foundation, Novo Nordisk Foundation (#NNF20OC0060547, NNF17OC0027232, NNF10OC1013354) and Government Research Funds to Helsinki University Hospital; Orion Research Foundation, Maud Kuistila Foundation, Finish Medical Foundation, and University of Helsin","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141589933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diversity and selection analyses identify transmission-blocking antigens as the optimal vaccine candidates in Plasmodium falciparum.","authors":"Ilinca I Ciubotariu, Bradley K Broyles, Shaojun Xie, Jyothi Thimmapuram, Mulenga C Mwenda, Brenda Mambwe, Conceptor Mulube, Japhet Matoba, Jessica L Schue, William J Moss, Daniel J Bridges, Qixin He, Giovanna Carpi","doi":"10.1016/j.ebiom.2024.105227","DOIUrl":"10.1016/j.ebiom.2024.105227","url":null,"abstract":"<p><strong>Background: </strong>A highly effective vaccine for malaria remains an elusive target, at least in part due to the under-appreciated natural parasite variation. This study aimed to investigate genetic and structural variation, and immune selection of leading malaria vaccine candidates across the Plasmodium falciparum's life cycle.</p><p><strong>Methods: </strong>We analysed 325 P. falciparum whole genome sequences from Zambia, in addition to 791 genomes from five other African countries available in the MalariaGEN Pf3k Database. Ten vaccine antigens spanning three life-history stages were examined for genetic and structural variations, using population genetics measures, haplotype network analysis, and 3D structure selection analysis.</p><p><strong>Findings: </strong>Among the ten antigens analysed, only three in the transmission-blocking vaccine category display P. falciparum 3D7 as the dominant haplotype. The antigens AMA1, CSP, MSP1₁₉ and CelTOS, are much more diverse than the other antigens, and their epitope regions are under moderate to strong balancing selection. In contrast, Rh5, a blood stage antigen, displays low diversity yet slightly stronger immune selection in the merozoite-blocking epitope region. Except for CelTOS, the transmission-blocking antigens Pfs25, Pfs48/45, Pfs230, Pfs47, and Pfs28 exhibit minimal diversity and no immune selection in epitopes that induce strain-transcending antibodies, suggesting potential effectiveness of 3D7-based vaccines in blocking transmission.</p><p><strong>Interpretation: </strong>These findings offer valuable insights into the selection of optimal vaccine candidates against P. falciparum. Based on our results, we recommend prioritising conserved merozoite antigens and transmission-blocking antigens. Combining these antigens in multi-stage approaches may be particularly promising for malaria vaccine development initiatives.</p><p><strong>Funding: </strong>Purdue Department of Biological Sciences; Puskas Memorial Fellowship; National Institute of Allergy and Infectious Diseases (U19AI089680).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141633031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A broad-spectrum multiepitope vaccine against seasonal influenza A and B viruses in mice.","authors":"Lifang Yuan, Shengze Zhang, Rongjun Bi, Xuejie Liu, Zirong Han, Minchao Li, Xinzhong Liao, Ting Xie, Shaohui Bai, Qian Xie, Chuming Luo, Ying Jiang, Jianhui Yuan, Huanle Luo, Huacheng Yan, Caijun Sun, Yuelong Shu","doi":"10.1016/j.ebiom.2024.105269","DOIUrl":"10.1016/j.ebiom.2024.105269","url":null,"abstract":"<p><strong>Background: </strong>Influenza viruses pose a persistent threat to global public health, necessitating the development of innovative and broadly effective vaccines.</p><p><strong>Methods: </strong>This study focuses on a multiepitope vaccine (MEV) designed to provide broad-spectrum protection against different influenza viruses. The MEV, containing 19 B-cell linear epitopes, 7 CD4⁺ T cells, and 11 CD8⁺ T cells epitopes identified through enzyme-linked immunospot assay (ELISPOT) in influenza viruses infected mice, was administered through a regimen of two doses of DNA vaccine followed by one dose of a protein vaccine in C57BL/6 female mice.</p><p><strong>Findings: </strong>Upon lethal challenge with both seasonal circulating strains (H1N1, H3N2, BV, and BY) and historical strains (H1N1-PR8 and H3N2-X31), MEV demonstrated substantial protection against different influenza seasonal strains, with partial efficacy against historical strains. Notably, the increased germinal centre B cells and antibody-secreting cells, along with robust T cell immune responses, highlighted the comprehensive immune defence elicited by MEV. Elevated hemagglutinin inhibition antibody was also observed against seasonal circulating and historical strains. Additionally, mice vaccinated with MEV exhibited significantly lower counts of inflammatory cells in the lungs compared to negative control groups.</p><p><strong>Interpretation: </strong>Our results demonstrated the efficacy of a broad-spectrum MEV against influenza viruses in mice. Conducting long-term studies to evaluate the durability of MEV-induced immune responses and explore its potential application in diverse populations will offer valuable insights for the continued advancement of this promising vaccine.</p><p><strong>Funding: </strong>Funding bodies are described in the Acknowledgments section.</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11350506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141901268","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":"NR4A3 prevents diabetes induced atrial cardiomyopathy by maintaining mitochondrial energy metabolism and reducing oxidative stress.","authors":"Hong Peng, Jiali Yuan, Zhengshuai Wang, Binfeng Mo, Yihui Wang, Yuepeng Wang, Qunshan Wang","doi":"10.1016/j.ebiom.2024.105268","DOIUrl":"10.1016/j.ebiom.2024.105268","url":null,"abstract":"<p><strong>Background: </strong>Atrial cardiomyopathy (ACM) is responsible for atrial fibrillation (AF) and thromboembolic events. Diabetes mellitus (DM) is an important risk factor for ACM. However, the potential mechanism between ACM and DM remains elusive.</p><p><strong>Methods: </strong>Atrial tissue samples were obtained from patients diagnosed with AF or sinus rhythm (SR) to assess alterations in NR4A3 expression, and then two distinct animal models were generated by subjecting Nr4a3-/- mice and WT mice to a high-fat diet (HFD) and Streptozotocin (STZ), while db/db mice were administered AAV9-Nr4a3 or AAV9-ctrl. Subsequently, in vivo and in vitro experiments were conducted to assess the impact of NR4A3 on diabetes-induced atrial remodeling through electrophysiological, biological, and histological analyses. RNA sequencing (RNA-seq) and metabolomics analysis were employed to unravel the downstream mechanisms.</p><p><strong>Findings: </strong>The expression of NR4A3 was significantly decreased in atrial tissues of both AF patients and diabetic mice compared to their respective control groups. NR4A3 deficiency exacerbated atrial hypertrophy and atrial fibrosis, and increased susceptibility to pacing-induced AF. Conversely, overexpression of NR4A3 alleviated atrial structural remodeling and reduced AF induction rate. Mechanistically, we confirmed that NR4A3 improves mitochondrial energy metabolism and reduces oxidative stress injury by preserving the transcriptional expression of Sdha, thereby exerting a protective influence on atrial remodeling induced by diabetes.</p><p><strong>Interpretation: </strong>Our data confirm that NR4A3 plays a protective role in atrial remodeling caused by diabetes, so it may be a new target for treating ACM.</p><p><strong>Funding: </strong>This study was supported by the major research program of National Natural Science Foundation of China (NSFC) No: 82370316 (to Q-S. W.), No. 81974041 (to Y-P. W.), and No. 82270447 (to Y-P. W.) and Fundation of Shanghai Hospital Development Center (No. SHDC2022CRD044 to Q-S. W.).</p>","PeriodicalId":11494,"journal":{"name":"EBioMedicine","volume":null,"pages":null},"PeriodicalIF":9.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11334830/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888790","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}