Science Translational Medicine最新文献

{"title":"NFIA regulates articular chondrocyte fatty acid metabolism and joint homeostasis","authors":"Cuicui Wang,&nbsp;Liang Fang,&nbsp;Meng Shi,&nbsp;Xiangfeng Niu,&nbsp;Tiandao Li,&nbsp;Xiaofei Li,&nbsp;Kevin Cho,&nbsp;Yonghua He,&nbsp;Shuang Liu,&nbsp;Aiwu Lu,&nbsp;Xiaoyun Xing,&nbsp;Jessica Lukowski,&nbsp;Young Ah Goo,&nbsp;John R. Speakman,&nbsp;Di Chen,&nbsp;Regis J. O’Keefe,&nbsp;Gary J. Patti,&nbsp;Michael J. Zuscik,&nbsp;Bo Zhang,&nbsp;Jie Shen","doi":"10.1126/scitranslmed.adm9488","DOIUrl":"10.1126/scitranslmed.adm9488","url":null,"abstract":"<div >Osteoarthritis (OA) is a joint disease with an etiology partially rooted in metabolic dysfunction, yet the underlying mechanisms in this context are not determined, limiting opportunities to develop therapeutic treatments. In this study, we used a multiomic approach combining RNA sequencing, ATAC-seq, MRE-seq, and metabolomics to reveal that OA articular chondrocytes induced by imbalanced transforming growth factor–β (TGF-β) and bone morphogenetic protein (BMP) signaling have increased fatty acid synthesis and oxidation processes regulated by nuclear factor I A (NFIA) up-regulation. Inhibition of <i>NFIA</i> suppressed the elevated gene expression of essential metabolic enzymes, including acetyl-CoA carboxylase A (<i>ACACA</i>) and carnitine palmitoyltransferase 2 (<i>CPT2</i>), leading to the restoration of fatty acid metabolism and cellular homeostasis in both murine and human OA articular chondrocytes. Obese mice displayed metabolic stress with elevated expression of NFIA, ACACA, and CPT2 in joint tissues, and they simultaneously developed profound synovitis, cartilage degeneration, subchondral bone sclerosis, and pain after joint injury. Both <i>Nfia</i> inhibition and pharmacological suppression of fatty acid metabolism in obese mice preserved joint integrity and mitigated synovitis and pain in the context of injury-induced OA settings. Overall, this work identifies a role for NFIA in the regulation of fatty acid metabolism and articular chondrocyte homeostasis and highlights fatty acid metabolism as a potential therapeutic target for OA treatment, particularly under obesity conditions.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737637","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":"Impairment of stromal-epithelial regenerative cross-talk in Hirschsprung disease primes for the progression to enterocolitis","authors":"Zhen Zhang,&nbsp;Dorothy Lee,&nbsp;Lingya Liu,&nbsp;Yi Xiong,&nbsp;Carol Lee,&nbsp;Ji-Eun Kim,&nbsp;Sinobol Chusilp,&nbsp;Ethan Lau,&nbsp;Yina Tian,&nbsp;Mehrsa Feizi,&nbsp;Mashriq Alganabi,&nbsp;Anthea Lafreniere,&nbsp;Tianran Cheng,&nbsp;Ruijie Zhou,&nbsp;Lu Han,&nbsp;Lihua Wu,&nbsp;Ping Xiao,&nbsp;Ya Gao,&nbsp;Giada Benedetti,&nbsp;Lucy Holland,&nbsp;Lucinda Tullie,&nbsp;Giovanni Giuseppe Giobbe,&nbsp;Long Li,&nbsp;Qi Li,&nbsp;Atsuyuki Yamataka,&nbsp;Vivian S. W. Li,&nbsp;Paolo De Coppi,&nbsp;Qian Jiang,&nbsp;Agostino Pierro,&nbsp;Bo Li","doi":"10.1126/scitranslmed.adp4679","DOIUrl":"10.1126/scitranslmed.adp4679","url":null,"abstract":"<div >Hirschsprung disease (HSCR) is a congenital condition characterized by the improper migration of enteric neural crest cells, leading to aganglionosis most commonly in the rectosigmoid colon. This severe and life-threatening disorder often results in the development of Hirschsprung-associated enterocolitis (HAEC), which can occur either before or after surgical resection of the affected bowel segment. Using colonic tissue from patients with HSCR alongside the well-established endothelin receptor B knockout mouse model, we investigated epithelial regeneration dynamics and stromal-epithelial cross-talk in the distal ganglionic colon, a critical site for HAEC development. In individuals with HSCR but without epithelial damage, the distal ganglionic colon displayed impaired epithelial regeneration and alteration of intestinal stem cell dynamics, characterized by the reduction of leucine-rich repeat-containing G protein–coupled receptor 5 (LGR5⁺) epithelial stem cells. This phenomenon was consistent in the mouse model, where impaired regenerative ability preceded HAEC when epithelial damage occurred on site. Patients with HSCR also exhibited remodeling in stromal cells in this distal ganglionic colon region, with fewer primary sources of Wingless-related integration site (Wnt) signal-releasing stromal cells and the exclusive presence of proinflammatory (matrix metalloproteinase 1⁺) stromal cells. Stromal cells from the HSCR distal ganglionic colon failed to sustain the growth of colonic organoids. However, ibuprofen suppressed the proinflammatory stromal cells, leading to effective restoration of epithelial organoid growth. These observations underscore the crucial role of impaired stromal-epithelial cross-talk in HSCR and the pathogenesis of HAEC and suggest potential therapeutic targets for the prevention or treatment of the condition.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737507","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":"Vaccination with an mRNA-encoded membrane-bound HIV envelope trimer induces neutralizing antibodies in animal models","authors":"Parham Ramezani-Rad,&nbsp;Christopher A. Cottrell,&nbsp;Ester Marina-Zárate,&nbsp;Alessia Liguori,&nbsp;Elise Landais,&nbsp;Jonathan L. Torres,&nbsp;Amber Myers,&nbsp;Jeong Hyun Lee,&nbsp;Sabyasachi Baboo,&nbsp;Claudia Flynn,&nbsp;Katherine McKenney,&nbsp;Eugenia Salcedo,&nbsp;Xiaoya Zhou,&nbsp;Oleksandr Kalyuzhniy,&nbsp;Erik Georgeson,&nbsp;Nicole Phelps,&nbsp;Danny Lu,&nbsp;Saman Eskandarzadeh,&nbsp;Sergey Menis,&nbsp;Michael Kubitz,&nbsp;Bettina Groschel,&nbsp;Nushin Alavi,&nbsp;Abigail M. Jackson,&nbsp;Wen-Hsin Lee,&nbsp;Andy S. Tran,&nbsp;Elana Ben-Akiva,&nbsp;Katarzyna Kaczmarek Michaels,&nbsp;Jolene K. Diedrich,&nbsp;Chiamaka A. Enemuo,&nbsp;Vanessa Lewis,&nbsp;Arpan Pradhan,&nbsp;Sudhir Pai Kasturi,&nbsp;Torben Schiffner,&nbsp;Jon M. Steichen,&nbsp;Diane G. Carnathan,&nbsp;Sunny Himansu,&nbsp;John R. Yates III,&nbsp;James C. Paulson,&nbsp;Gabriel Ozorowski,&nbsp;Darrell J. Irvine,&nbsp;Guido Silvestri,&nbsp;Devin Sok,&nbsp;Andrew B. Ward,&nbsp;Shane Crotty,&nbsp;William R. Schief","doi":"10.1126/scitranslmed.adw0721","DOIUrl":"10.1126/scitranslmed.adw0721","url":null,"abstract":"<div >A protective vaccine against human immunodeficiency virus (HIV) will likely need to induce broadly neutralizing antibodies (bnAbs) that engage relatively conserved epitopes on the HIV envelope glycoprotein (Env) trimer. Nearly all vaccine strategies to induce bnAbs require the use of complex immunization regimens involving a series of different immunogens, most of which are Env trimers. Producing protein-based clinical material to evaluate such relatively complex regimens in humans presents major challenges in cost and time. Furthermore, immunization with HIV trimers as soluble proteins induces strong nonneutralizing responses to the trimer base, which is normally occluded on the virion. These base responses could potentially detract from the elicitation of nAbs and the eventual induction of bnAbs. mRNA vaccine platforms offer potential advantages over protein delivery for HIV vaccine development, including increased production speed, reduced cost, and the ability to deliver membrane-bound trimers that might facilitate improved immuno-focusing to nonbase epitopes. We report the design of mRNA-delivered soluble and membrane-bound forms of a stabilized native-like Env trimer (BG505 MD39.3); initial immunogenicity evaluation in rabbits that triggered clinical evaluation; and more comprehensive evaluation of B cell, T cell, and antibody responses in nonhuman primates. mRNA-encoded membrane-bound Env immunization elicited reduced off-target base-directed Env responses and stronger nAb responses compared with mRNA-encoded soluble Env. Overall, mRNA delivery of membrane-bound Env appears promising for enhancing B cell responses to subdominant epitopes and facilitating rapid translation to clinical testing, which should assist HIV vaccine development.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adw0721","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737511","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":"Systematic analysis of cellular cross-talk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease","authors":"Ricardo D’Oliveira Albanus,&nbsp;Gina M. Finan,&nbsp;Logan Brase,&nbsp;Nicholas Sweeney,&nbsp;Tae Yeon Kim,&nbsp;Shuo Chen,&nbsp;Yeonsu Ryoo,&nbsp;Joseph Park,&nbsp;Qi Guo,&nbsp;Abhirami Kannan,&nbsp;Mariana Acquarone,&nbsp;Shih-Feng You,&nbsp;Brenna C. Novotny,&nbsp;Emily M. Mace,&nbsp;Patricia M. Ribeiro Pereira,&nbsp;John C. Morris,&nbsp;David M. Holtzman,&nbsp;Eric McDade,&nbsp;Martin Farlow,&nbsp;Jasmeer P. Chhatwal,&nbsp;Bruno A. Benitez,&nbsp;Laura Piccio,&nbsp;Richard J. Perrin,&nbsp;Greg T. Sutherland,&nbsp;Qin Ma,&nbsp;Celeste M. Karch,&nbsp;Doo Yeon Kim,&nbsp;Rudolph E. Tanzi,&nbsp;Hongjun Fu,&nbsp;Oscar Harari,&nbsp;Tae-Wan Kim","doi":"10.1126/scitranslmed.adx0027","DOIUrl":"10.1126/scitranslmed.adx0027","url":null,"abstract":"<div >Cellular cross-talk, mediated by membrane receptors and their ligands, is crucial for brain homeostasis and can contribute to neurodegenerative diseases such as Alzheimer’s disease (AD). To find cross-talk dysregulations involved in AD, we reconstructed cross-talk networks from single-nucleus transcriptional profiles of 67 clinically and neuropathologically well-characterized controls and AD brain donors from the Knight Alzheimer Disease Research Center and the Dominantly Inherited Alzheimer Network cohorts. We predicted a role for TREM2 and additional AD risk genes mediating neuron-microglia cross-talk in AD. We identified a gene network mediating neuron-microglia cross-talk through TREM2 and neuronal SEMA6D, which we predicted is disrupted in late AD stages. Using spatial transcriptomics on the human brain, we observed that the SEMA6D-TREM2 cross-talk gene network is activated near Aβ plaques and SEMA6D-expressing cells. Using tissue immunostaining of human brains, we found that SEMA6D colocalizes with Aβ plaques and TREM2-activated microglia. In addition, we found that plaque-proximal SEMA6D abundance decreased with the disease stage, which correlated with a reduction in microglial activation near plaques. These findings suggest that the loss of SEMA6D signaling impairs microglial activation and Αβ clearance. To validate this hypothesis, we leveraged <i>TREM2</i> knockout human induced pluripotent stem cell–derived microglia and observed that SEMA6D induces microglial activation and Aβ plaque phagocytosis in a TREM2-dependent manner. In summary, we demonstrate that characterizing cellular cross-talk networks can yield insights into AD biology, provide additional context to understand AD genetic risk, and find previously unknown therapeutic targets and pathways.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737636","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":"Erratum for the Research Article “Engineering a highly elastic human protein–based sealant for surgical applications” by N. Annabi et al.","authors":"","doi":"10.1126/scitranslmed.aea4285","DOIUrl":"10.1126/scitranslmed.aea4285","url":null,"abstract":"","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144740575","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":"AGPAT4 targeted covalent inhibitor potentiates targeted therapy to overcome cancer cell plasticity in hepatocellular carcinoma mouse models","authors":"Kai-Yu Ng,&nbsp;Tin-Yan Koo,&nbsp;Ianto Bosheng Huang,&nbsp;Terence Kin-Wah Lee,&nbsp;Tsz-Lok Fong,&nbsp;Ya Gao,&nbsp;Tin-Lok Wong,&nbsp;Yuan Gao,&nbsp;Jing-Ping Yun,&nbsp;Xin-Yuan Guan,&nbsp;Ming Liu,&nbsp;Clive Yik-Sham Chung,&nbsp;Stephanie Ma","doi":"10.1126/scitranslmed.adn9472","DOIUrl":"10.1126/scitranslmed.adn9472","url":null,"abstract":"<div >The development of cancerous cells leads to considerable changes in metabolic processes to meet the demands of tumor growth. Tumor lineage plasticity has been identified as a key factor in therapy resistance and tumor recurrence. Herein, we showed one aspect of this plasticity to be abnormal glycerophospholipid metabolism, specifically the presence of a metabolic protein called 1-acylglycerol-3-phosphate <i>o</i>-acyltransferase 4 (AGPAT4). We identified AGPAT4 as an oncofetal protein that is abundant in embryonic stem cells and hepatocellular carcinoma (HCC) tumor cells but is low or absent in most normal tissues. We demonstrated that AGPAT4 is a functional regulator of tumor lineage plasticity, which correlates with enhanced metastasis and resistance to sorafenib. Heightened plasticity was induced as a result of increased AGPAT4-mediated conversion of LPA (lysophosphatidic acid) to phosphatidic acid (PA), which then acts on its downstream mTOR/S6K/S6 signaling pathway. Inhibition of Agpat4 by the AAV8-mediated liver-directed strategy in an immunocompetent HCC mouse model reduced tumorigenicity and stemness and sensitized tumors to sorafenib. Through a chemical biology approach, a cysteine-reacting compound that specifically targets AGPAT4 at the Cys²²⁸ residue and therefore hinders its acyltransferase activity was identified and found to work synergistically with sorafenib in suppressing HCC in tumor xenograft models derived from patients with preclinical HCC and sorafenib-resistant HCC. Toxicological analysis revealed minimal side effects associated with the covalent inhibitor. In conclusion, the plasticity of tumor lineages induced by AGPAT4 represents a potential target for HCC treatment and could expand the effectiveness of sorafenib treatment, offering new possibilities for HCC therapy.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737506","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":"Viral spike antigen clearance and augmented recovery in children with post-COVID multisystem inflammatory syndrome treated with larazotide","authors":"Lael M. Yonker,&nbsp;Abigail S. Kane,&nbsp;Zoe Swank,&nbsp;Lena Papadakis,&nbsp;Victoria Kenyon,&nbsp;Samuel Han,&nbsp;Rosiane Lima,&nbsp;Lauren B. Guthrie,&nbsp;Bryan Alvarez-Carcamo,&nbsp;Manuella Lahoud-Rahme,&nbsp;Duraisamy Balaguru,&nbsp;Ryan W. Carroll,&nbsp;Josephine Lok,&nbsp;Chadi El Saleeby,&nbsp;David R. Walt,&nbsp;Alessio Fasano","doi":"10.1126/scitranslmed.adu4284","DOIUrl":"10.1126/scitranslmed.adu4284","url":null,"abstract":"<div >Multisystem inflammatory syndrome (MIS) is a severe disease that occurs weeks to months after acute infection with SARS-CoV-2, often occurring in children (MISC). Symptoms include high fever, rash, nausea, diarrhea, and abdominal pain. Children with MISC can develop cardiovascular injury including ventricular failure, coronary artery aneurysms, or shock. Current treatment strategies for these postacute sequelae of COVID-19 primarily target the hyperinflammatory response. However, a potential role for viral spike protein translocated via zonulin-mediated trafficking from gastrointestinal reservoirs of SARS-CoV-2 into the circulation has been suggested. Here, we report results from a phase 2a randomized, double-blind, placebo-controlled clinical trial testing the zonulin antagonist larazotide in 12 children with MISC with a median age of 5.7 years. Children were enrolled during hospitalization for acute MISC and were treated with adjuvant larazotide therapy four times daily for 3 weeks. Patients were monitored for 24 weeks for safety follow-up. No larazotide-related adverse events were reported. The concentration of SARS-CoV-2 spike protein antigen in blood samples correlated with inflammatory markers, including interferon-γ (IFN-γ) (<i>P</i> = 0.004) and interleukin-6 (IL-6) (<i>P</i> &lt; 0.0001), and with gastrointestinal symptoms as assessed by the PedsQL GI symptom score (<i>P</i> = 0.003). Children treated with larazotide displayed faster resolution of gastrointestinal symptoms, faster clearance of spike antigen, and a faster return to usual activities. Our findings suggest that larazotide treatment may be safe in children and may improve resolution of symptoms when used as an adjuvant therapy for MISC.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 809","pages":""},"PeriodicalIF":14.6,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144737509","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":"Hindbrain octadecaneuropeptide gliotransmission as a therapeutic target for energy balance control without nausea or emesis","authors":"Caroline E. Geisler,&nbsp;Kylie S. Chichura,&nbsp;Oleksandr Orativskyi,&nbsp;Jiayin Hu,&nbsp;Drew L. Belser,&nbsp;Caitlyn M. Pelletier,&nbsp;Tito Borner,&nbsp;Caitlin Baumer-Harrison,&nbsp;Bart C. De Jonghe,&nbsp;Richard C. Crist,&nbsp;Benjamin C. Reiner,&nbsp;Robert P. Doyle,&nbsp;Matthew R. Hayes","doi":"10.1126/scitranslmed.adu6764","DOIUrl":"10.1126/scitranslmed.adu6764","url":null,"abstract":"<div >Glia play a dynamic role in central nutrient sensing and appetite regulation yet represent underexplored targets in treating dysregulated energy balance. Glia within the dorsal vagal complex of the hindbrain synthesize the anorexigenic peptide octadecaneuropeptide (ODN), the influence and therapeutic potential of which remain to be explored. We demonstrate that hindbrain-targeted ODN induced weight loss, counteracted glucoprivation, and improved glucose clearance in rats. Furthermore, blocking central ODN signaling attenuated the anorectic response to GLP-1R agonists in rats. Peripheral administration of an ODN derivative, TDN, improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp in obese mice and induced weight loss without pica behavior, a proxy for nausea in rats, or emesis in the musk shrew, a vomiting mammalian model. Central ODN and TDN treatment in rats was not accompanied by changes in core body temperature, physical activity, or heart rate. This work highlights hindbrain ODN signaling as an important modulator of energy balance and demonstrates the potential for targeting this gliopeptide system to treat dysregulated feeding and metabolic activity without side effects.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684777","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 inner ear fluid imbalance detected by optical coherence tomography correlates with hearing loss","authors":"Wihan Kim,&nbsp;Dorothy W. Pan,&nbsp;Bong Jik Kim,&nbsp;Zihan Yang,&nbsp;Marcela Moran Mojica,&nbsp;Joni K. Doherty,&nbsp;Seiji B. Shibata,&nbsp;Brian E. Applegate,&nbsp;John S. Oghalai","doi":"10.1126/scitranslmed.adv3783","DOIUrl":"10.1126/scitranslmed.adv3783","url":null,"abstract":"<div >Hearing loss and vertigo occur when there is an imbalance between the two inner ear fluids, endolymph and perilymph. The inner ear is a small delicate structure encased in dense bone deep in the base of the skull, making it challenging to image with high resolution. Because the fluid chambers are so small, there is no reliable way to measure their balance in a living patient to guide therapy. Here, we translated the technology of optical coherence tomography (OCT) for use in the human inner ear. Peering through the otic capsule bone during mastoid surgery, we imaged the lateral and posterior semicircular canals of patients with Ménière’s disease or vestibular schwannoma and measured the endolymph-to-perilymph ratio. Compared with normal controls, both patient groups demonstrated increased endolymph and reduced perilymph, a disorder termed endolymphatic hydrops. OCT imaging demonstrated good repeatability for measuring the endolymph-to-perilymph ratio. Our data indicate that increased endolymph-to-perilymph ratios correlated with the degree of hearing loss. Thus, small yet meaningful changes in inner ear fluid balance are detectable with this approach with better resolution than gadolinium-enhanced 3 Tesla magnetic resonance imaging, the current gold standard clinical imaging modality. Our findings support the feasibility of imaging the human inner ear during surgical procedures with OCT and demonstrate the ability to detect endolymphatic hydrops. Moreover, this technique permits the measurement of the fluid chambers within the inner ear in real time during surgical procedures with adequate sensitivity to guide the management of complex but common ear diseases.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684765","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":"Preexisting immunity to the 2009 pandemic H1N1 virus reduces susceptibility to H5N1 infection and disease in ferrets","authors":"Katherine H. Restori,&nbsp;Veronika Weaver,&nbsp;Devanshi R. Patel,&nbsp;Grace A. Merrbach,&nbsp;Kayla M. Septer,&nbsp;Cassandra J. Field,&nbsp;Michael J. Bernabe,&nbsp;Ethan M. Kronthal,&nbsp;Allen Minns,&nbsp;Scott E. Lindner,&nbsp;Seema S. Lakdawala,&nbsp;Valerie Le Sage,&nbsp;Troy C. Sutton","doi":"10.1126/scitranslmed.adw4856","DOIUrl":"10.1126/scitranslmed.adw4856","url":null,"abstract":"<div >Zoonotic infections with emerging influenza viruses occur in the context of population-wide immunity to seasonal strains. Because of the worldwide spread of highly pathogenic clade 2.3.4.4b H5N1 influenza viruses in wild birds, there have been numerous spillover events into mammals. This includes a recent spillover into dairy cows that started an ongoing outbreak across the United States. Human infections with avian and bovine origin H5N1 influenza viruses have been documented, raising concern that these viruses may cause a pandemic. Therefore, using a ferret model, we evaluated the impact of preexisting, infection-elicited immunity on susceptibility to H5N1 infection and on severity of disease. Preexisting immunity to the 2009 pandemic H1N1 influenza virus prevented severe H5N1 disease and reduced susceptibility to infection through direct contact with an infected donor ferret. These studies demonstrate that preexisting immunity to influenza viruses, especially the 2009 pandemic H1N1 virus, is a barrier to infection and disease caused by clade 2.3.4.4b H5N1 viruses.</div>","PeriodicalId":21580,"journal":{"name":"Science Translational Medicine","volume":"17 808","pages":""},"PeriodicalIF":15.8,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/scitranslmed.adw4856","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684766","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}