Science Translational Medicine最新文献

{"title":"A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis","authors":"Rong Li,&nbsp;Michela Colombo,&nbsp;Guanlin Wang,&nbsp;Antonio Rodriguez-Romera,&nbsp;Camelia Benlabiod,&nbsp;Natalie J. Jooss,&nbsp;Jennifer O’Sullivan,&nbsp;Charlotte K. Brierley,&nbsp;Sally-Ann Clark,&nbsp;Juan M. Pérez Sáez,&nbsp;Pedro Aragón Fernández,&nbsp;Erwin M. Schoof,&nbsp;Bo Porse,&nbsp;Yiran Meng,&nbsp;Abdullah O. Khan,&nbsp;Sean Wen,&nbsp;Pengwei Dong,&nbsp;Wenjiang Zhou,&nbsp;Nikolaos Sousos,&nbsp;Lauren Murphy,&nbsp;Matthew Clarke,&nbsp;Aude-Anais Olijnik,&nbsp;Zoë C. Wong,&nbsp;Christina Simoglou Karali,&nbsp;Korsuk Sirinukunwattana,&nbsp;Hosuk Ryou,&nbsp;Ruggiero Norfo,&nbsp;Qian Cheng,&nbsp;Joana Carrelha,&nbsp;Zemin Ren,&nbsp;Supat Thongjuea,&nbsp;Vijay A. Rathinam,&nbsp;Anandi Krishnan,&nbsp;Daniel Royston,&nbsp;Gabriel A. Rabinovich,&nbsp;Adam J. Mead,&nbsp;Bethan Psaila","doi":"10.1126/scitranslmed.adj7552","DOIUrl":"10.1126/scitranslmed.adj7552","url":null,"abstract":"<div >Myeloproliferative neoplasms are stem cell–driven cancers associated with a large burden of morbidity and mortality. Most patients present with early-stage disease, but a substantial proportion progress to myelofibrosis or secondary leukemia, advanced cancers with a poor prognosis and high symptom burden. Currently, it remains difficult to predict progression, and therapies that reliably prevent or reverse fibrosis are lacking. A major bottleneck to the discovery of disease-modifying therapies has been an incomplete understanding of the interplay between perturbed cellular and molecular states. Several cell types have individually been implicated, but a comprehensive analysis of myelofibrotic bone marrow is lacking. We therefore mapped the cross-talk between bone marrow cell types in myelofibrotic bone marrow. We found that inflammation and fibrosis are orchestrated by a “quartet” of immune and stromal cell lineages, with basophils and mast cells creating a TNF signaling hub, communicating with megakaryocytes, mesenchymal stromal cells, and proinflammatory fibroblasts. We identified the β-galactoside–binding protein galectin-1 as a biomarker of progression to myelofibrosis and poor survival in multiple patient cohorts and as a promising therapeutic target, with reduced myeloproliferation and fibrosis in vitro and in vivo and improved survival after galectin-1 inhibition. In human bone marrow organoids, TNF increased galectin-1 expression, suggesting a feedback loop wherein the proinflammatory myeloproliferative neoplasm clone creates a self-reinforcing niche, fueling progression to advanced disease. This study provides a resource for studying hematopoietic cell–niche interactions, with relevance for cancer-associated inflammation and disorders of tissue fibrosis.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 768","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392999","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":"Sleep-sensitive dopamine receptor expression in male mice underlies attention deficits after a critical period of early adversity","authors":"Yuichi Makino,&nbsp;Nathaniel W. Hodgson,&nbsp;Emma Doenier,&nbsp;Anna Victoria Serbin,&nbsp;Koya Osada,&nbsp;Pietro Artoni,&nbsp;Matthew Dickey,&nbsp;Breanna Sullivan,&nbsp;Amelia Potter-Dickey,&nbsp;Jelena Komanchuk,&nbsp;Bikram Sekhon,&nbsp;Nicole Letourneau,&nbsp;Neal D. Ryan,&nbsp;Jeanette Trauth,&nbsp;Judy L. Cameron,&nbsp;Takao K. Hensch","doi":"10.1126/scitranslmed.adh9763","DOIUrl":"10.1126/scitranslmed.adh9763","url":null,"abstract":"<div >Early life stress (ELS) yields cognitive impairments of unknown molecular and physiological origin. We found that fragmented maternal care of mice during a neonatal critical period from postnatal days P2–9 elevated dopamine receptor D2R and suppressed D4R expression, specifically within the anterior cingulate cortex (ACC) in only the male offspring. This was associated with poor performance on a two-choice visual attention task, which was acutely rescued in adulthood by local or systemic pharmacological rebalancing of D2R/D4R activity. Furthermore, ELS male mice demonstrated heightened hypothalamic orexin and persistently disrupted sleep. Given that acute sleep deprivation in normally reared male mice mimicked the ACC dopamine receptor subtype modulation and disrupted attention of ELS mice, sleep loss likely underlies cognitive deficits in ELS mice. Likewise, sleep impairment mediated the attention deficits associated with early adversity in human children, as demonstrated by path analysis on data collected with multiple questionnaires for a large child cohort. A deeper understanding of the sex-specific cognitive consequences of ELS thus has the potential to reveal therapeutic strategies for overcoming them.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 768","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393002","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 multispecific antibody against SARS-CoV-2 prevents immune escape in vitro and confers prophylactic protection in vivo","authors":"John Misasi,&nbsp;Ronnie R. Wei,&nbsp;Lingshu Wang,&nbsp;Amarendra Pegu,&nbsp;Chih-Jen Wei,&nbsp;Olamide K. Oloniniyi,&nbsp;Tongqing Zhou,&nbsp;Juan I. Moliva,&nbsp;Bingchun Zhao,&nbsp;Misook Choe,&nbsp;Eun Sung Yang,&nbsp;Yi Zhang,&nbsp;Marika Boruszczak,&nbsp;Man Chen,&nbsp;Kwanyee Leung,&nbsp;Juan Li,&nbsp;Zhi-Yong Yang,&nbsp;Hanne Andersen,&nbsp;Kevin Carlton,&nbsp;Sucheta Godbole,&nbsp;Darcy R. Harris,&nbsp;Amy R. Henry,&nbsp;Vera B. Ivleva,&nbsp;Q. Paula Lei,&nbsp;Cuiping Liu,&nbsp;Lindsay Longobardi,&nbsp;Jonah S. Merriam,&nbsp;Danielle Nase,&nbsp;Adam S. Olia,&nbsp;Laurent Pessaint,&nbsp;Maciel Porto,&nbsp;Wei Shi,&nbsp;Shannon M. Wallace,&nbsp;Jeremy J. Wolff,&nbsp;Daniel C. Douek,&nbsp;Mehul S. Suthar,&nbsp;Jason G. Gall,&nbsp;Richard A. Koup,&nbsp;Peter D. Kwong,&nbsp;John R. Mascola,&nbsp;Gary J. Nabel,&nbsp;Nancy J. Sullivan","doi":"10.1126/scitranslmed.ado9026","DOIUrl":"10.1126/scitranslmed.ado9026","url":null,"abstract":"<div >Despite effective countermeasures, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persists worldwide because of its ability to diversify and evade human immunity. This evasion stems from amino acid substitutions, particularly in the receptor binding domain (RBD) of the spike protein that confers resistance to vaccine-induced antibodies and antibody therapeutics. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different RBD sites into multispecific antibodies. Here, we describe multispecific antibodies, including a trivalent trispecific antibody that potently neutralized diverse SARS-CoV-2 variants and prevented virus escape more effectively than single antibodies or mixtures of the parental antibodies. Despite being generated before the appearance of Omicron, this trispecific antibody neutralized all major Omicron variants through BA.4/BA.5 at nanomolar concentrations. Negative stain electron microscopy suggested that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated binding across more than one spike protein. Moreover, a tetravalent trispecific antibody containing the same variable regions as the trivalent trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2, and BA.5 challenge, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. These results demonstrated that multispecific antibodies have the potential to provide broad SARS-CoV-2 coverage, decrease the likelihood of escape, simplify treatment, and provide a strategy for antibody therapies that could help eliminate pandemic spread for this and other pathogens.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 768","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392998","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":"An altered natural killer cell immunophenotype characterizes clinically severe pediatric RSV infection","authors":"Roisin B. Reilly,&nbsp;Saïsha K. Ramdour,&nbsp;Mary E. Fuhlbrigge,&nbsp;Luciana P. Tavares,&nbsp;Steven J. Staffa,&nbsp;Jocelyn M. Booth,&nbsp;Nandini Krishnamoorthy,&nbsp;Bruce D. Levy,&nbsp;Melody G. Duvall","doi":"10.1126/scitranslmed.ado6606","DOIUrl":"10.1126/scitranslmed.ado6606","url":null,"abstract":"<div >Respiratory syncytial virus (RSV) infects nearly all children by 2 years of age and is a leading cause of pediatric hospitalizations. A subset of children with RSV infection (RSV⁺ children) develop respiratory failure requiring intensive care, but immune mechanisms distinguishing severe pediatric RSV infection are not fully elucidated. Natural killer (NK) cells are key innate immune effectors of viral host defense. In this study of 47 critically ill RSV⁺ children, we coupled NK cell immunophenotype and cytotoxic function with clinical parameters to identify an NK cell immune signature of severe pediatric RSV disease. Airway NK cells were increased in intubated RSV⁺ children with severe hypoxemia and prolonged duration of mechanical ventilation and were correlated with clinical severity scores. Peripheral blood NK cells were decreased in RSV⁺ patients and had altered activating receptor expression, with increased expression of CD69 and decreased expression of NKG2D. Ex vivo, circulating NK cells from RSV⁺ patients exhibited functional impairment characterized by decreased cytotoxicity as well as aberrant immune synapse assembly and lytic granule trafficking. NK cell frequency and phenotype correlated with clinical measures that defined disease severity. These findings implicate a role for NK cells in mediating RSV immunopathology and suggest that an altered NK cell immunophenotype is associated with severe RSV disease in young children.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 768","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393000","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":"Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury","authors":"Luping Zhou,&nbsp;Marc Torres Pereiro,&nbsp;Yanqun Li,&nbsp;Marcus Derigs,&nbsp;Carsten Kuenne,&nbsp;Thomas Hielscher,&nbsp;Wei Huang,&nbsp;Bettina Kränzlin,&nbsp;Gang Tian,&nbsp;Kazuhiro Kobayashi,&nbsp;Gia-Hue Natalie Lu,&nbsp;Kevin Roedl,&nbsp;Claudia Schmidt,&nbsp;Stefan Günther,&nbsp;Mario Looso,&nbsp;Johannes Huber,&nbsp;Yong Xu,&nbsp;Thorsten Wiech,&nbsp;Jan-Peter Sperhake,&nbsp;Dominic Wichmann,&nbsp;Hermann-Josef Gröne,&nbsp;Thomas Worzfeld","doi":"10.1126/scitranslmed.adk5005","DOIUrl":"10.1126/scitranslmed.adk5005","url":null,"abstract":"<div >Acute kidney injury (AKI) is a frequent and challenging clinical condition associated with high morbidity and mortality and represents a common complication in critically ill patients with COVID-19. In AKI, renal tubular epithelial cells (TECs) are a primary site of damage, and recovery from AKI depends on TEC plasticity. However, the molecular mechanisms underlying adaptation and maladaptation of TECs in AKI remain largely unclear. Here, our study of an autopsy cohort of patients with COVID-19 provided evidence that injury of TECs by myoglobin, released as a consequence of rhabdomyolysis, is a major pathophysiological mechanism for AKI in severe COVID-19. Analyses of human kidney biopsies, mouse models of myoglobinuric and gentamicin-induced AKI, and mouse kidney tubuloids showed that TEC injury resulted in activation of the glucocorticoid receptor by endogenous glucocorticoids, which aggravated tubular damage. The detrimental effect of endogenous glucocorticoids on injured TECs was exacerbated by the administration of a widely clinically used synthetic glucocorticoid, dexamethasone, as indicated by experiments in mouse models of myoglobinuric- and folic acid–induced AKI, human and mouse kidney tubuloids, and human kidney slice cultures. Mechanistically, studies in mouse models of AKI, mouse tubuloids, and human kidney slice cultures demonstrated that glucocorticoid receptor signaling in injured TECs orchestrated a maladaptive transcriptional program to hinder DNA repair, amplify injury-induced DNA double-strand break formation, and dampen mTOR activity and mitochondrial bioenergetics. This study identifies glucocorticoid receptor activation as a mechanism of epithelial maladaptation, which is functionally important for AKI.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 767","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363129","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 peptide encoded by upstream open reading frame of MYC binds to tropomyosin receptor kinase B and promotes glioblastoma growth in mice","authors":"Fanying Li,&nbsp;Kailin Yang,&nbsp;Xinya Gao,&nbsp;Maolei Zhang,&nbsp;Danling Gu,&nbsp;Xujia Wu,&nbsp;Chenfei Lu,&nbsp;Qiulian Wu,&nbsp;Deobrat Dixit,&nbsp;Ryan C. Gimple,&nbsp;Yongping You,&nbsp;Stephen C. Mack,&nbsp;Yu Shi,&nbsp;Tiebang Kang,&nbsp;Sameer A. Agnihotri,&nbsp;Michael D. Taylor,&nbsp;Jeremy N. Rich,&nbsp;Nu Zhang,&nbsp;Xiuxing Wang","doi":"10.1126/scitranslmed.adk9524","DOIUrl":"10.1126/scitranslmed.adk9524","url":null,"abstract":"<div >MYC promotes tumor growth through multiple mechanisms. Here, we show that, in human glioblastomas, the variant <i>MYC</i> transcript encodes a 114–amino acid peptide, MYC pre-mRNA encoded protein (MPEP), from the upstream open reading frame (uORF) <i>MPEP</i>. Secreted MPEP promotes patient-derived xenograft tumor growth in vivo, independent of MYC through direct binding, and activation of tropomyosin receptor kinase B (TRKB), which induces downstream AKT-mTOR signaling. Targeting MPEP through genetic ablation reduced growth of patient-derived 4121 and 3691 glioblastoma stem cells. Administration of an MPEP-neutralizing antibody in combination with a small-molecule TRKB inhibitor reduced glioblastoma growth in patient-derived xenograft tumor–bearing mice. The overexpression of MPEP in surgical glioblastoma specimens predicted a poor prognosis, supporting its clinical relevance. In summary, our results demonstrate that tumor-specific translation of a <i>MYC</i>-associated uORF promotes glioblastoma growth, suggesting a new therapeutic strategy for glioblastoma.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 767","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363111","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":"Dynamic structural remodeling of LINC01956 enhances temozolomide resistance in MGMT-methylated glioblastoma","authors":"Xinyi Liao,&nbsp;Shuxia Zhang,&nbsp;Xincheng Li,&nbsp;Wanying Qian,&nbsp;Man Li,&nbsp;Suwen Chen,&nbsp;Xingui Wu,&nbsp;Xuexin Yu,&nbsp;Ziwen Li,&nbsp;Miaoling Tang,&nbsp;Yingru Xu,&nbsp;Ruyuan Yu,&nbsp;Qiliang Zhang,&nbsp;Geyan Wu,&nbsp;Nu Zhang,&nbsp;Libing Song,&nbsp;Jun Li","doi":"10.1126/scitranslmed.ado1573","DOIUrl":"10.1126/scitranslmed.ado1573","url":null,"abstract":"<div >The mechanisms underlying stimuli-induced dynamic structural remodeling of RNAs for the maintenance of cellular physiological function and survival remain unclear. Here, we showed that in <i>MGMT</i> promoter–methylated glioblastoma (GBM), the RNA helicase DEAD-box helicase 46 (DDX46) is phosphorylated by temozolomide (TMZ)–activated checkpoint kinase 1 (CHK1), resulting in a dense-to-loose conformational change and an increase in DDX46 helicase activity. DDX46-mediated tertiary structural remodeling of LINC01956 exposes the binding motifs of LINC01956 to the 3′ untranslated region of O⁶-methylguanine DNA methyltransferase (<i>MGMT</i>). This accelerates recruitment of <i>MGMT</i> mRNA to the RNA export machinery and transportation of <i>MGMT</i> mRNA from the nucleus to the cytoplasm, leading to increased MGMT abundance and TMZ resistance. Using patient-derived xenograft (PDX) and tumor organoid models, we found that treatment with the CHK1 inhibitor SRA737abolishes TMZ-induced structural remodeling of LINC01956 and subsequent MGMT up-regulation, resensitizing TMZ-resistant <i>MGMT</i> promoter–methylated GBM to TMZ. In conclusion, these findings highlight a mechanism underlying temozolomide-induced RNA structural remodeling and may represent a potential therapeutic strategy for patients with TMZ-resistant <i>MGMT</i> promoter–methylated GBM.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 767","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.ado1573","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363067","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":"LRRK2 regulates production of reactive oxygen species in cell and animal models of Parkinson’s disease","authors":"Matthew T. Keeney,&nbsp;Emily M. Rocha,&nbsp;Eric K. Hoffman,&nbsp;Kyle Farmer,&nbsp;Roberto Di Maio,&nbsp;Julie Weir,&nbsp;Weston G. Wagner,&nbsp;Xiaoping Hu,&nbsp;Courtney L. Clark,&nbsp;Sandra L. Castro,&nbsp;Abigail Scheirer,&nbsp;Marco Fazzari,&nbsp;Briana R. De Miranda,&nbsp;Sean A. Pintchovski,&nbsp;William D. Shrader,&nbsp;Patrick J. Pagano,&nbsp;Teresa G. Hastings,&nbsp;J. Timothy Greenamyre","doi":"10.1126/scitranslmed.adl3438","DOIUrl":"10.1126/scitranslmed.adl3438","url":null,"abstract":"<div >Oxidative stress has long been implicated in Parkinson’s disease (PD) pathogenesis, although the sources and regulation of reactive oxygen species (ROS) production are poorly defined. Pathogenic mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are associated with increased kinase activity and a greater risk of PD. The substrates and downstream consequences of elevated LRRK2 kinase activity are still being elucidated, but overexpression of mutant LRRK2 has been associated with oxidative stress, and antioxidants reportedly mitigate LRRK2 toxicity. Here, using CRISPR-Cas9 gene-edited HEK293 cells, RAW264.7 macrophages, rat primary ventral midbrain cultures, and PD patient–derived lymphoblastoid cells, we found that elevated LRRK2 kinase activity was associated with increased ROS production and lipid peroxidation and that this was blocked by inhibitors of either LRRK2 kinase or NADPH oxidase 2 (NOX2). Oxidative stress induced by the pesticide rotenone was ameliorated by LRRK2 kinase inhibition and was absent in cells devoid of LRRK2. In a rat model of PD induced by rotenone, a LRRK2 kinase inhibitor prevented the lipid peroxidation and NOX2 activation normally seen in nigral dopaminergic neurons in this model. Mechanistically, LRRK2 kinase activity was shown to regulate phosphorylation of serine-345 in the p47^phox subunit of NOX2. This, in turn, led to translocation of p47^phox from the cytosol to the membrane-associated gp91^phox (NOX2) subunit, activation of the NOX2 enzyme complex, and production of ROS. Thus, LRRK2 kinase activity may drive cellular ROS production in PD through the regulation of NOX2 activity.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 767","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363066","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 microbiome-directed therapeutic food for children recovering from severe acute malnutrition","authors":"Steven J. Hartman,&nbsp;Matthew C. Hibberd,&nbsp;Ishita Mostafa,&nbsp;Nurun N. Naila,&nbsp;Md. Munirul Islam,&nbsp;Mahabub Uz Zaman,&nbsp;Sayeeda Huq,&nbsp;Mustafa Mahfuz,&nbsp;Md. Tazul Islam,&nbsp;Kallol Mukherji,&nbsp;Vaha Akbary Moghaddam,&nbsp;Robert Y. Chen,&nbsp;Michael A. Province,&nbsp;Daniel M. Webber,&nbsp;Suzanne Henrissat,&nbsp;Bernard Henrissat,&nbsp;Nicolas Terrapon,&nbsp;Dmitry A. Rodionov,&nbsp;Andrei L. Osterman,&nbsp;Michael J. Barratt,&nbsp;Tahmeed Ahmed,&nbsp;Jeffrey I. Gordon","doi":"10.1126/scitranslmed.adn2366","DOIUrl":"10.1126/scitranslmed.adn2366","url":null,"abstract":"<div >Globally, severe acute malnutrition (SAM), defined as a weight-for-length <i>z</i>-score more than three SDs below a reference mean (WLZ &lt; −3), affects 14 million children under 5 years of age. Complete anthropometric recovery after standard, short-term interventions is rare, with children often left with moderate acute malnutrition (MAM; WLZ −2 to −3). We conducted a randomized controlled trial (RCT) involving 12- to 18-month-old Bangladeshi children from urban and rural sites, who, after initial hospital-based treatment for SAM, received a 3-month intervention with a microbiome-directed complementary food (MDCF-2) or a calorically more dense, standard ready-to-use supplementary food (RUSF). The rate of WLZ improvement was significantly greater in MDCF-2–treated children (<i>P</i> = 8.73 × 10⁻³), similar to our previous RCT of Bangladeshi children with MAM without antecedent SAM (<i>P</i> = 0.032). A correlated meta-analysis of plasma levels of 4520 proteins in both RCTs revealed 215 positively associated with WLZ (largely representing musculoskeletal and central nervous system development) and 44 negatively associated (primarily related to immune activation). Moreover, the positively associated proteins were significantly enriched by MDCF-2 (<i>q</i> = 1.1 × 10⁻⁶). Characterizing the abundances of 754 bacterial metagenome-assembled genomes in serially collected fecal samples disclosed the effects of acute rehabilitation for SAM on the microbiome and how, during treatment for MAM, specific strains of <i>Prevotella copri</i> function at the intersection between MDCF-2 glycan metabolism and anthropometric recovery. These results provide a rationale for further testing the generalizability of MDCF efficacy and for identifying biomarkers to define treatment responses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 767","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363070","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":"Neutrophil extracellular traps protect the kidney from ascending infection and are required for a positive leukocyte dipstick test","authors":"Andrew P. Stewart,&nbsp;Kevin W. Loudon,&nbsp;Matthew Routledge,&nbsp;Colin Y. C. Lee,&nbsp;Patrick Trotter,&nbsp;Nathan Richoz,&nbsp;Eleanor Gillman,&nbsp;Robin Antrobus,&nbsp;James Mccaffrey,&nbsp;David Posner,&nbsp;Andrew Conway Morris,&nbsp;Fiona E. Karet Frankl,&nbsp;Menna R. Clatworthy","doi":"10.1126/scitranslmed.adh5090","DOIUrl":"10.1126/scitranslmed.adh5090","url":null,"abstract":"<div >Lower urinary tract infection (UTI) is common but only rarely complicated by pyelonephritis. However, the mechanisms preventing extension to the kidney are unclear. Here, we identified neutrophil extracellular traps (NETs) in healthy human urine that provide an antibacterial defense strategy within the urinary tract. In both in vivo murine models of UTI where uropathogenic <i>E. coli</i> are inoculated into the bladder and ex vivo human urine models, NETs interacted with uromodulin to form large webs that entrapped the bacteria. Peptidyl arginine deiminase 4 (PADI4) inhibition in mice blocked NETosis and resulted in progression of cystitis into pyelonephritis, suggesting that NETosis of urinary neutrophils acts to prevent bacterial ascent into the kidney. Analysis of UK Biobank data revealed that genetic variants in <i>PADI4</i> that associated with increased risk of rheumatoid arthritis in multiple genome-wide association studies were consistently associated with reduced susceptibility to UTI. Last, we showed that urine dipstick testing for leukocyte esterase was negative in the presence of intact blood neutrophils but became positive when neutrophils were stimulated to NET, and this could be prevented by selective PADI4 inhibition, demonstrating that this test does not detect absolute neutrophil count, as has long been assumed, but specifically detects neutrophils that have undergone NETosis. These findings highlight the role of NETosis in preventing ascending infections in the urinary tract and improve our understanding of one of the most common clinical tests in medicine.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 766","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142320964","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}