Science Translational Medicine最新文献

{"title":"Repeated COVID-19 mRNA-based vaccination contributes to SARS-CoV-2 neutralizing antibody responses in the mucosa","authors":"Jozefien Declercq,&nbsp;Sarah Gerlo,&nbsp;Sharon Van Nevel,&nbsp;Natalie De Ruyck,&nbsp;Gabriele Holtappels,&nbsp;Liesbeth Delesie,&nbsp;Els Tobback,&nbsp;Inés Lammens,&nbsp;Nikita Gerebtsov,&nbsp;Koen Sedeyn,&nbsp;Xavier Saelens,&nbsp;Bart N. Lambrecht,&nbsp;Philippe Gevaert,&nbsp;Linos Vandekerckhove,&nbsp;Stijn Vanhee","doi":"10.1126/scitranslmed.adn2364","DOIUrl":"10.1126/scitranslmed.adn2364","url":null,"abstract":"<div >To prevent infection by respiratory viruses and consequently limit virus circulation, vaccines need to promote mucosal immunity. The extent to which the currently used messenger RNA (mRNA)–based COVID-19 vaccines induce mucosal immunity remains poorly characterized. We evaluated mucosal neutralizing antibody responses in a cohort of 183 individuals. Participants were sampled at several time points after primary adenovirus vector–based or mRNA-based COVID-19 vaccination and after mRNA-based booster vaccinations. Our findings revealed that repeated vaccination with mRNA boosters promoted severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies in nasal secretions. Nasal and serum neutralizing antibody titers of both IgG and IgA isotypes correlated to one another. We investigated the source of these mucosal antibodies in a mouse model wherein mice received repeated mRNA vaccines for SARS-CoV-2. These experiments indicated that neutralizing antibody–producing cells reside in the spleen and bone marrow, whereas no proof of tissue homing to the respiratory mucosa was observed, despite the detection of mucosal antibodies. Serum transfer experiments confirmed that circulating antibodies were able to migrate to the respiratory mucosa. Collectively, these results demonstrate that, especially upon repeated vaccination, the currently used COVID-19 mRNA vaccines can elicit mucosal neutralizing antibodies and that vaccination might also stimulate mucosal immunity induced by previous SARS-CoV-2 infection. Moreover, migration of circulating antibodies to the respiratory mucosa might be a main mechanism. These findings advance our understanding of mRNA vaccine–induced immunity and have implications for the design of vaccine strategies to combat respiratory infections.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 770","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142487826","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":"Follistatin drives neuropathic pain in mice through IGF1R signaling in nociceptive neurons","authors":"Bao-Chun Jiang,&nbsp;Yue-Juan Ling,&nbsp;Meng-Lin Xu,&nbsp;Jun Gu,&nbsp;Xiao-Bo Wu,&nbsp;Wei-Lin Sha,&nbsp;Tian Tian,&nbsp;Xue-Hui Bai,&nbsp;Nan Li,&nbsp;Chang-Yu Jiang,&nbsp;Ouyang Chen,&nbsp;Ling-Jie Ma,&nbsp;Zhi-Jun Zhang,&nbsp;Yi-Bin Qin,&nbsp;Meixuan Zhu,&nbsp;Hong-Jie Yuan,&nbsp;Long-Jun Wu,&nbsp;Ru-Rong Ji,&nbsp;Yong-Jing Gao","doi":"10.1126/scitranslmed.adi1564","DOIUrl":"10.1126/scitranslmed.adi1564","url":null,"abstract":"<div >Neuropathic pain is a debilitating chronic condition that lacks effective treatment. The role of cytokine- and chemokine-mediated neuroinflammation in its pathogenesis has been well documented. Follistatin (FST) is a secreted protein known to antagonize the biological activity of cytokines in the transforming growth factor–β (TGF-β) superfamily. The involvement of FST in neuropathic pain and the underlying mechanism remain largely unknown. Here, we report that FST was up-regulated in A-fiber sensory neurons after spinal nerve ligation (SNL) in mice. Inhibition or deletion of FST alleviated neuropathic pain and reduced the nociceptive neuron hyperexcitability induced by SNL. Conversely, intrathecal or intraplantar injection of recombinant FST, or overexpression of FST in the dorsal root ganglion (DRG) neurons, induced pain hypersensitivity. Furthermore, exogenous FST increased neuronal excitability in nociceptive neurons. The biolayer interferometry (BLI) assay and coimmunoprecipitation (co-IP) demonstrated direct binding of FST to the insulin-like growth factor–1 receptor (IGF1R), and IGF1R inhibition reduced FST-induced activation of extracellular signal–regulated kinase (ERK) and protein kinase B (AKT), as well as neuronal hyperexcitability. Further co-IP analysis revealed that the N-terminal domain of FST exhibits the highest affinity for IGF1R, and blocking this interaction with a peptide derived from FST attenuated Nav1.7-mediated neuronal hyperexcitability and neuropathic pain after SNL. In addition, FST enhanced neuronal excitability in human DRG neurons through IGF1R. Collectively, our findings suggest that FST, released from A-fiber neurons, enhances Nav1.7-mediated hyperexcitability of nociceptive neurons by binding to IGF1R, making it a potential target for neuropathic pain treatment.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 769","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adi1564","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443654","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":"High-fidelity PAMless base editing of hematopoietic stem cells to treat chronic granulomatous disease","authors":"Vera Bzhilyanskaya,&nbsp;Linyuan Ma,&nbsp;Siyuan Liu,&nbsp;Lauren R. Fox,&nbsp;Madelynn N. Whittaker,&nbsp;Ronald J. Meis,&nbsp;Uimook Choi,&nbsp;Amanda Lawson,&nbsp;Michelle Ma,&nbsp;Narda Theobald,&nbsp;Sandra Burkett,&nbsp;Colin L. Sweeney,&nbsp;Cicera R. Lazzarotto,&nbsp;Shengdar Q. Tsai,&nbsp;Justin B. Lack,&nbsp;Xiaolin Wu,&nbsp;Gary A. Dahl,&nbsp;Harry L. Malech,&nbsp;Benjamin P. Kleinstiver,&nbsp;Suk See De Ravin","doi":"10.1126/scitranslmed.adj6779","DOIUrl":"10.1126/scitranslmed.adj6779","url":null,"abstract":"<div >X-linked chronic granulomatous disease (X-CGD) is an inborn error of immunity (IEI) resulting from genetic mutations in the cytochrome b-245 beta chain (<i>CYBB</i>) gene. The applicability of base editors (BEs) to correct mutations that cause X-CGD is constrained by the requirement of Cas enzymes to recognize specific protospacer adjacent motifs (PAMs). Our recently engineered PAMless Cas enzyme, SpRY, can overcome the PAM limitation. However, the efficiency, specificity, and applicability of SpRY-based BEs to correct mutations in human hematopoietic stem and progenitor cells (HSPCs) have not been thoroughly examined. Here, we demonstrated that the adenine BE ABE8e-SpRY can access a range of target sites in HSPCs to correct mutations causative of X-CGD. For the prototypical X-CGD mutation <i>CYBB</i> c.676C&gt;T, ABE8e-SpRY achieved up to 70% correction, reaching efficiencies greater than three-and-one-half times higher than previous CRISPR nuclease and donor template approaches. We profiled potential off-target DNA edits, transcriptome-wide RNA edits, and chromosomal perturbations in base-edited HSPCs, which together revealed minimal off-target or bystander edits. Edited alleles persisted after transplantation of the base-edited HSPCs into immunodeficient mice. Together, these investigational new drug–enabling studies demonstrated efficient and precise correction of an X-CGD mutation with PAMless BEs, supporting a first-in-human clinical trial (NCT06325709) and providing a potential blueprint for treatment of other IEI mutations.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 769","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443662","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":"Melatonin receptor 1A variants as genetic cause of idiopathic osteoporosis","authors":"Brygida Bisikirska,&nbsp;Rossella Labella,&nbsp;Alvaro Cuesta-Dominguez,&nbsp;Na Luo,&nbsp;Jessica De Angelis,&nbsp;Ioanna Mosialou,&nbsp;Chyuan-Sheng Lin,&nbsp;David Beck,&nbsp;Sneh Lata,&nbsp;Peter Timothy Shyu,&nbsp;Donald J. McMahon,&nbsp;Edward Guo,&nbsp;Jacob Hagen,&nbsp;Wendy K. Chung,&nbsp;Elizabeth Shane,&nbsp;Adi Cohen,&nbsp;Stavroula Kousteni","doi":"10.1126/scitranslmed.adj0085","DOIUrl":"10.1126/scitranslmed.adj0085","url":null,"abstract":"<div >Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A (<i>MTNR1A</i>) with a potential pathogenic outcome. A rare <i>MTNR1A</i> variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an <i>MTNR1A</i> variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [<i>MTNR1A</i>c.184+1G&gt;T (<i>MTNR1A</i>^{<i>c.</i>184+1G&gt;T})] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that <i>MTNR1A</i> mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the <i>MTNR1A</i> variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 769","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443659","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":"Intraoperative evaluation of tumor margins using a TROP2 near-infrared imaging probe to enable human breast-conserving surgery","authors":"Weiling Chen,&nbsp;Yongqu Zhang,&nbsp;Lixin Zhang,&nbsp;Xiangjie Luo,&nbsp;Xia Yang,&nbsp;Yuanyuan Zhu,&nbsp;Guimei Wang,&nbsp;Wenhe Huang,&nbsp;Deliang Zhang,&nbsp;Yunzhu Zeng,&nbsp;Ronghui Li,&nbsp;Cuiping Guo,&nbsp;Jiazheng Wang,&nbsp;Zhao Wu,&nbsp;Na Liu,&nbsp;Guojun Zhang","doi":"10.1126/scitranslmed.ado2461","DOIUrl":"10.1126/scitranslmed.ado2461","url":null,"abstract":"<div >Intraoperative surgical margin assessment remains a challenge during breast-conserving surgery. Here, we report a combined strategy of immuno–positron emission tomography (PET) for preoperative detection of breast cancer and guided assessment of margins in breast-conserving surgery through second near-infrared (NIR-II) fluorescence imaging of trophoblastic cell surface antigen 2 (TROP2). We demonstrated that the intensity of PET signals in the tumors was nearly five times higher than in normal breast tissue with a zirconium-89 tracer conjugated to sacituzumab govitecan (SG) in a mouse spontaneous breast cancer model, enabling the identification of tumors. We further generated a NIR-II probe of indocyanine green conjugated to SG (ICG-SG) and developed a rapid incubation imaging method for intraoperative margin assessment in a relevant time window for the operation workflow. The ICG-SG NIR-II fluorescence image guidance was first verified to remove tumors completely and accurately in mouse breast cancer models. Moreover, the rapid incubation imaging method was applied to distinguish benign and malignant breast lesions in samples from 26 patients with breast cancer. Therefore, we have developed both nuclide and optical probes targeting TROP2 for rapid and precise identification of tumor margins during breast-conserving surgery in humans.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 769","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443651","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":"Human OX40L–CAR-Tregs target activated antigen-presenting cells and control T cell alloreactivity","authors":"Xianliang Rui,&nbsp;Francesca Alvarez Calderon,&nbsp;Holly Wobma,&nbsp;Ulrike Gerdemann,&nbsp;Alexandre Albanese,&nbsp;Lorenzo Cagnin,&nbsp;Connor McGuckin,&nbsp;Katherine A. Michaelis,&nbsp;Kisa Naqvi,&nbsp;Bruce R. Blazar,&nbsp;Victor Tkachev,&nbsp;Leslie S. Kean","doi":"10.1126/scitranslmed.adj9331","DOIUrl":"10.1126/scitranslmed.adj9331","url":null,"abstract":"<div >Regulatory T cells (T_regs) make major contributions to immune homeostasis. Because T_reg dysfunction can lead to both allo- and autoimmunity, there is interest in correcting these disorders through T_reg adoptive transfer. Two of the central challenges in clinically deploying T_reg cellular therapies are ensuring phenotypic stability and maximizing potency. Here, we describe an approach to address both issues through the creation of OX40 ligand (OX40L)–specific chimeric antigen receptor (CAR)–T_regs under the control of a synthetic forkhead box P3 (<i>FOXP3</i>) promoter. The creation of these CAR-T_regs enabled selective T_reg stimulation by engagement of OX40L, a key activation antigen in alloimmunity, including both graft-versus-host disease and solid organ transplant rejection, and autoimmunity, including rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus. We demonstrated that OX40L–CAR-T_regs were robustly activated in the presence of OX40L-expressing cells, leading to up-regulation of T_reg suppressive proteins without induction of proinflammatory cytokine production. Compared with control T_regs, OX40L–CAR-T_regs more potently suppressed alloreactive T cell proliferation in vitro and were directly inhibitory toward activated monocyte-derived dendritic cells (DCs). We identified trogocytosis as one of the central mechanisms by which these CAR-T_regs effectively decrease extracellular display of OX40L, resulting in decreased DC stimulatory capacity. OX40L–CAR-T_regs demonstrated an enhanced ability to control xenogeneic graft-versus-host disease compared with control T_regs without abolishing the graft-versus-leukemia effect. These results suggest that OX40L–CAR-T_regs may have wide applicability as a potent cellular therapy to control both allo- and autoimmune diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"16 769","pages":""},"PeriodicalIF":15.8,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443647","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":"Decreased mitochondrial creatine kinase 2 impairs skeletal muscle mitochondrial function independently of insulin in type 2 diabetes","authors":"David Rizo-Roca,&nbsp;Dimitrius Santiago P. S. F. Guimarães,&nbsp;Logan A. Pendergrast,&nbsp;Nicolas Di Leo,&nbsp;Alexander V. Chibalin,&nbsp;Salwan Maqdasy,&nbsp;Mikael Rydén,&nbsp;Erik Näslund,&nbsp;Juleen R. Zierath,&nbsp;Anna Krook","doi":"10.1126/scitranslmed.ado3022","DOIUrl":"10.1126/scitranslmed.ado3022","url":null,"abstract":"<div >Increased plasma creatine concentrations are associated with the risk of type 2 diabetes, but whether this alteration is associated with or causal for impairments in metabolism remains unexplored. Because skeletal muscle is the main disposal site of both creatine and glucose, we investigated the role of intramuscular creatine metabolism in the pathophysiology of insulin resistance in type 2 diabetes. In men with type 2 diabetes, plasma creatine concentrations were increased, and intramuscular phosphocreatine content was reduced. These alterations were coupled to reduced expression of sarcomeric mitochondrial creatine kinase 2 (<i>CKMT2</i>). In C57BL/6 mice fed a high-fat diet, neither supplementation with creatine for 2 weeks nor treatment with the creatine analog β-GPA for 1 week induced changes in glucose tolerance, suggesting that increased circulating creatine was associated with insulin resistance rather than causing it. In C2C12 myotubes, silencing <i>Ckmt2</i> using small interfering RNA reduced mitochondrial respiration, membrane potential, and glucose oxidation. Electroporation-mediated overexpression of <i>Ckmt2</i> in skeletal muscle of high-fat diet–fed male mice increased mitochondrial respiration, independent of creatine availability. Given that overexpression of <i>Ckmt2</i> improved mitochondrial function, we explored whether exercise regulates CKMT2 expression. Analysis of public data revealed that CKMT2 content was up-regulated by exercise training in both humans and mice. We reveal a previously underappreciated role of CKMT2 in mitochondrial homeostasis beyond its function for creatine phosphorylation, independent of insulin action. Collectively, our data provide functional evidence for how CKMT2 mediates mitochondrial dysfunction associated with type 2 diabetes.</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":"https://www.science.org/doi/reader/10.1126/scitranslmed.ado3022","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142393001","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 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}