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<h3>Research Article</h3> <div class='row'> <div class='small-10 medium-7 large-5 small-centered columns'> <ul class='tabs row' data-tab> <li class='tab-title small-6 centered active'> <a href='#articles'>25,383 Articles</a> </li> <li class='tab-title small-6 centered '> <a href='#posts'>0 Posts</a> </li> </ul> </div> </div> <div class='tabs-content'> <div class='content active' id='articles'> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/51?content=articles&page=2">2</a></li> <li><a href="/tags/51?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/51?content=articles&page=2538">2538</a></li> <li><a href="/tags/51?content=articles&page=2539">2539</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/51?content=articles&page=2">Next →</a></li></ul></div> </div> </div> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/178550">TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/178550">Yu Zeng, … , Ye Song, Aidong Zhou</a> <a class='hide-for-small show-more' data-reveal-id='article45887-more' href='#'> <div class='article-authors'> Yu Zeng, … , Ye Song, Aidong Zhou </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e178550. <a href="https://doi.org/10.1172/JCI178550">https://doi.org/10.1172/JCI178550</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/178550">Text</a> | <a href="/articles/view/178550/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI178550' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/178550/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/178000/178550/small/JCI178550.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45887-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/178550">TRAF3 loss protects glioblastoma cells from lipid peroxidation and immune elimination via dysregulated lipid metabolism</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/178550">Text</a></li> <li><a class="button tiny" href="/articles/view/178550/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Glioblastoma (GBM) is a highly aggressive form of brain tumor characterized by dysregulated metabolism. Increased fatty acid oxidation (FAO) protects tumor cells from lipid peroxidation–induced cell death, although the precise mechanisms involved remain unclear. Here, we report that loss of TNF receptor–associated factor 3 (TRAF3) in GBM critically regulated lipid peroxidation and tumorigenesis by controlling the oxidation of polyunsaturated fatty acids (PUFAs). TRAF3 was frequently repressed in GBM due to promoter hypermethylation. TRAF3 interacted with enoyl-CoA hydratase 1 (ECH1), an enzyme that catalyzes the isomerization of unsaturated FAs (UFAs) and mediates K63-linked ubiquitination of ECH1 at Lys214. ECH1 ubiquitination impeded TOMM20-dependent mitochondrial translocation of ECH1, which otherwise promoted the oxidation of UFAs, preferentially the PUFAs, and limited lipid peroxidation. Overexpression of TRAF3 enhanced the sensitivity of GBM to ferroptosis and anti–programmed death–ligand 1 (anti–PD-L1) immunotherapy in mice. Thus, the TRAF3/ECH1 axis played a key role in the metabolism of PUFAs and was crucial for lipid peroxidation damage and immune elimination in GBM.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yu Zeng, Liqian Zhao, Kunlin Zeng, Ziling Zhan, Zhengming Zhan, Shangbiao Li, Hongchao Zhan, Peng Chai, Cheng Xie, Shengfeng Ding, Yuxin Xie, Li Wang, Cuiying Li, Xiaoxia Chen, Daogang Guan, Enguang Bi, Jianyou Liao, Fan Deng, Xiaochun Bai, Ye Song, Aidong Zhou</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/180802">Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/180802">Yoon Mee Yang, … , Alexander M. Xu, Ekihiro Seki</a> <a class='hide-for-small show-more' data-reveal-id='article45888-more' href='#'> <div class='article-authors'> Yoon Mee Yang, … , Alexander M. Xu, Ekihiro Seki </div> </a> <span class='article-published-at'> Published February 13, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e180802. <a href="https://doi.org/10.1172/JCI180802">https://doi.org/10.1172/JCI180802</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/180802">Text</a> | <a href="/articles/view/180802/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI180802' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/180802/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/180000/180802/small/JCI180802.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45888-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/180802">Metastatic tumor growth in steatotic liver is promoted by HAS2-mediated fibrotic tumor microenvironment</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/180802">Text</a></li> <li><a class="button tiny" href="/articles/view/180802/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Steatotic liver enhances liver metastasis of colorectal cancer (CRC), but this process is not fully understood. Steatotic liver induced by a high-fat diet increases cancer-associated fibroblast (CAF) infiltration and collagen and hyaluronic acid (HA) production. We investigated the role of HA synthase 2 (HAS2) in the fibrotic tumor microenvironment in steatotic liver using Has2ΔHSC mice, in which Has2 is deleted from hepatic stellate cells. Has2ΔHSC mice had reduced steatotic liver–associated metastatic tumor growth of MC38 CRC cells, collagen and HA deposition, and CAF and M2 macrophage infiltration. We found that low–molecular weight HA activates Yes-associated protein (YAP) in cancer cells, which then releases connective tissue growth factor to further activate CAFs for HAS2 expression. Single-cell analyses revealed a link between CAF-derived HAS2 and M2 macrophages and CRC cells through CD44; these cells were associated with exhausted CD8+ T cells via programmed death–ligand 1 and programmed cell death protein 1 (PD-1). HA synthesis inhibitors reduced steatotic liver–associated metastasis of CRC, YAP expression, and CAF and M2 macrophage infiltration, and improved response to anti–PD-1 antibody. In conclusion, steatotic liver modulates a fibrotic tumor microenvironment to enhance metastatic cancer activity through a bidirectional regulation between CAFs and metastatic tumors, enhancing the metastatic potential of CRC in the liver.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yoon Mee Yang, Jieun Kim, Zhijun Wang, Jina Kim, So Yeon Kim, Gyu Jeong Cho, Jee Hyung Lee, Sun Myoung Kim, Takashi Tsuchiya, Michitaka Matsuda, Vijay Pandyarajan, Stephen J. Pandol, Michael S. Lewis, Alexandra Gangi, Paul W. Noble, Dianhua Jiang, Akil Merchant, Edwin M. Posadas, Neil A. Bhowmick, Shelly C. Lu, Sungyong You, Alexander M. Xu, Ekihiro Seki</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/182931">Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/182931">Geoffrey Canet, … , Esther M. Blessing, Emmanuel Planel</a> <a class='hide-for-small show-more' data-reveal-id='article45890-more' href='#'> <div class='article-authors'> Geoffrey Canet, … , Esther M. Blessing, Emmanuel Planel </div> </a> <span class='article-published-at'> Published February 4, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e182931. <a href="https://doi.org/10.1172/JCI182931">https://doi.org/10.1172/JCI182931</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/182931">Text</a> | <a href="/articles/view/182931/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI182931' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/182931/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/182000/182931/small/JCI182931.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45890-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/182931">Sleep-wake variation in body temperature regulates tau secretion and correlates with CSF and plasma tau</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/182931">Text</a></li> <li><a class="button tiny" href="/articles/view/182931/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Sleep disturbance is bidirectionally associated with an increased risk of Alzheimer’s disease and other tauopathies. While the sleep-wake cycle regulates interstitial and cerebrospinal fluid (CSF) tau levels, the underlying mechanisms remain unknown. Understanding these mechanisms is crucial, given the evidence that tau pathology spreads through neuron-to-neuron transfer, involving the secretion and internalization of pathological tau forms. Here, we combined in vitro, in vivo, and clinical methods to reveal a pathway by which changes in body temperature (BT) over the sleep-wake cycle modulate extracellular tau levels. In mice, a higher BT during wakefulness and sleep deprivation increased CSF and plasma tau levels, while also upregulating unconventional protein secretion pathway I (UPS-I) events including (a) intracellular tau dephosphorylation, (b) caspase 3–mediated cleavage of tau (TauC3), and (c) membrane translocation of tau through binding to phosphatidylinositol 4,5-bisphosphate (PIP2) and syndecan 3. In humans, the increase in CSF and plasma tau levels observed after wakefulness correlated with BT increases during wakefulness. By demonstrating that sleep-wake variation in BT regulates extracellular tau levels, our findings highlight the importance of thermoregulation in linking sleep disturbances to tau-mediated neurodegeneration and the preventative potential of thermal interventions.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Geoffrey Canet, Felipe Da Gama Monteiro, Emma Rocaboy, Sofia Diego-Diaz, Boutheyna Khelaifia, Kelly Godbout, Aymane Lachhab, Jessica Kim, Daphne I. Valencia, Audrey Yin, Hau-Tieng Wu, Jordan Howell, Emily Blank, Francis Laliberté, Nadia Fortin, Emmanuelle Boscher, Parissa Fereydouni-Forouzandeh, Stéphanie Champagne, Isabelle Guisle, Sébastien S. Hébert, Vincent Pernet, Haiyan Liu, William Lu, Ludovic Debure, David M. Rapoport, Indu Ayappa, Andrew W. Varga, Ankit Parekh, Ricardo S. Osorio, Steve Lacroix, Mark P. Burns, Brendan P. Lucey, Esther M. Blessing, Emmanuel Planel</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/163730">Phosphorylation of CRYAB induces a condensatopathy to worsen post–myocardial infarction left ventricular remodeling</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/163730">Moydul Islam, … , Kartik Mani, Abhinav Diwan</a> <a class='hide-for-small show-more' data-reveal-id='article45892-more' href='#'> <div class='article-authors'> Moydul Islam, … , Kartik Mani, Abhinav Diwan </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e163730. <a href="https://doi.org/10.1172/JCI163730">https://doi.org/10.1172/JCI163730</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/163730">Text</a> | <a href="/articles/view/163730/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI163730' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/163730/figure/1' ref='group' title='Desmin, α-actinin, and actin and the serine 59 phosphorylated form of their chaperone protein, CRYAB, localize to protein aggregates in human ICM. (A) Representative immunohistochemical images from left ventricular myocardium of individuals evaluated as controls (donor) or patients with end-stage ICM stained for desmin, α-actinin, and actin. Arrows point to mislocalization of these proteins from their physiologic location on Z-discs and intercalated discs (desmin), Z-disc (α-actinin), and sarcomere (actin) in donor myocardium to protein aggregates in ICM myocardium. (B) Quantitation of striation score and aggregate score for desmin, α-actinin, and actin in ICM and donor hearts. n = 3-4 hearts/group. For striation scoring, normal localization of proteins got scored as 0, and abnormal striation or mislocalization of proteins was scored as 1. For scoring aggregates, absence of aggregates was scored as 0 and presence of aggregates was scored as 2. (C–G) Immunoblot (C) and quantitation (fold change as compared with donor mean) depicting total p62 (D), polyUb proteins (E), CRYAB (F), and pS59-CRYAB and pS45-CRYAB (G) in NP40-detergent-insoluble fractions from human hearts from patients with ICM and donors. Ponceau S staining is shown as loading control. (H–K) Immunoblot (H) and quantitation for p62 (I), CRYAB (J), and pS59-CRYAB and pS45-CRYAB (K) abundance in NP-40 detergent soluble biochemical fractions from human hearts as in C–G. GAPDH was used as loading control. n = 6 samples/group for C–K. *P < 0.05; **P < 0.01; ***P < 0.001 versus donor as control by t test.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/163000/163730/small/JCI163730.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45892-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/163730">Phosphorylation of CRYAB induces a condensatopathy to worsen post–myocardial infarction left ventricular remodeling</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/163730">Text</a></li> <li><a class="button tiny" href="/articles/view/163730/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart-failure syndromes remains mechanistically unexamined. We observed mislocalization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post–myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by the R120G mutation in the cognate chaperone protein CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine 59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phosphomimetic mutation of serine 59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates, and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knockin was sufficient to induce desmin mislocalization and myocardial protein aggregates, while S59A CRYAB knockin rescued left ventricular systolic dysfunction after myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine 59 phosphorylation and rescued post–myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Moydul Islam, David R. Rawnsley, Xiucui Ma, Walter Navid, Chen Zhao, Xumin Guan, Layla Foroughi, John T. Murphy, Honora Navid, Carla J. Weinheimer, Attila Kovacs, Jessica Nigro, Aaradhya Diwan, Ryan P. Chang, Minu Kumari, Martin E. Young, Babak Razani, Kenneth B. Margulies, Mahmoud Abdellatif, Simon Sedej, Ali Javaheri, Douglas F. Covey, Kartik Mani, Abhinav Diwan</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/186416">MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/186416">Rong-Chi Hu, … , Zheng Xia, Thomas A. Cooper</a> <a class='hide-for-small show-more' data-reveal-id='article45897-more' href='#'> <div class='article-authors'> Rong-Chi Hu, … , Zheng Xia, Thomas A. Cooper </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e186416. <a href="https://doi.org/10.1172/JCI186416">https://doi.org/10.1172/JCI186416</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/186416">Text</a> | <a href="/articles/view/186416/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI186416' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/186416/figure/1' ref='group' title='Exogenous MBNL1 and MBNL2 are overexpressed in ventricles and atria of CUG960 +dox mice by AAV9 delivery. (A) Diagram of the pAAV vectors used to express control tdTomato protein (pAAV-tdTomato), 3xFLAG-MBNL1, and 3xMYC-MBNL2. (B) Diagram of the experimental design including time points and assays. (C) Cardiac ventricular and atrial protein expression was evaluated by Western blotting. n = 3 animals per cohort.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/186000/186416/small/JCI186416.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45897-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/186416">MBNL overexpression rescues cardiac phenotypes in a myotonic dystrophy type 1 heart mouse model</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/186416">Text</a></li> <li><a class="button tiny" href="/articles/view/186416/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Myotonic dystrophy type 1 (DM1) is an autosomal dominant disease caused by a CTG repeat expansion in the dystrophia myotonica protein kinase (DMPK) gene. The expanded CUG repeat RNA (CUGexp RNA) transcribed from the mutant allele sequesters the muscleblind-like (MBNL) family of RNA-binding proteins, causing their loss of function and disrupting regulated pre-mRNA processing. We used a DM1 heart mouse model that inducibly expresses CUGexp RNA to test the contribution of MBNL loss to DM1 cardiac abnormalities and explored MBNL restoration as a potential therapy. AAV9-mediated overexpression of MBNL1 and/or MBNL2 significantly rescued DM1 cardiac phenotypes including conduction delays, contractile dysfunction, hypertrophy, and misregulated alternative splicing and gene expression. While robust, the rescue was partial compared with reduced CUGexp RNA and plateaued with increased exogenous MBNL expression. These findings demonstrate that MBNL loss is a major contributor to DM1 cardiac manifestations and suggest that additional mechanisms play a role, highlighting the complex nature of DM1 pathogenesis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Rong-Chi Hu, Yi Zhang, Larissa Nitschke, Sara J. Johnson, Ayrea E. Hurley, William R. Lagor, Zheng Xia, Thomas A. Cooper</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/183440">Endothelial cell–specific postnatal deletion of <i>Nos3</i> preserves intraocular pressure homeostasis via macrophage recruitment and NOS2 upregulation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/183440">Ruth A. Kelly, … , Darryl R. Overby, W. Daniel Stamer</a> <a class='hide-for-small show-more' data-reveal-id='article45899-more' href='#'> <div class='article-authors'> Ruth A. Kelly, … , Darryl R. Overby, W. Daniel Stamer </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e183440. <a href="https://doi.org/10.1172/JCI183440">https://doi.org/10.1172/JCI183440</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/183440">Text</a> | <a href="/articles/view/183440/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI183440' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/183440/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/183000/183440/small/JCI183440.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45899-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/183440">Endothelial cell–specific postnatal deletion of <i>Nos3</i> preserves intraocular pressure homeostasis via macrophage recruitment and NOS2 upregulation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/183440">Text</a></li> <li><a class="button tiny" href="/articles/view/183440/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Polymorphisms in Nos3 increase risk for glaucoma, the leading cause of irreversible blindness worldwide. A key modifiable risk factor for glaucoma is intraocular pressure (IOP), which is regulated by NO — a product of nitric oxide synthase 3 (encoded by Nos3) — in Schlemm’s canal of the conventional outflow pathway. We studied the effects of a conditional, endothelial cell–specific postnatal deletion of Nos3 (Endo-SclCre-ERT;Nos3fl/fl) on tissues of the outflow pathway. We observed that Cre-ERT expression spontaneously and gradually increased with time in vascular endothelia including in Schlemm’s canal, beginning at P10, with complete Nos3 deletion occurring around P90. Whereas outflow resistance was reduced in global Nos3-KO mice, outflow resistance and IOP in Endo-SclCre-ERT;Nos3fl/fl mice were normal. We observed — coincident with Nos3 deletion — recruitment of macrophages to and induction of both ELAM1 and NOS2 expression by endothelia in the distal portion of the outflow pathway, which increased vessel diameter. These adjustments reduced outflow resistance to maintain IOP in these Endo-SclCre-ERT;Nos3fl/fl mice. Selective inhibition of iNOS by 1400W resulted in narrowing of distal vessels and IOP elevation. Together, the results emphasize the pliability of the outflow system and the importance of NO signaling in IOP control, and imply an substantial role for macrophages in IOP homeostasis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ruth A. Kelly, Megan S. Kuhn, Ester Reina-Torres, Revathi Balasubramanian, Kristin M. Perkumas, Guorong Li, Takamune Takahashi, Simon W.M. John, Michael H. Elliott, Darryl R. Overby, W. Daniel Stamer</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185796">Ablating VHL in rod photoreceptors modulates RPE glycolysis and improves preclinical model of retinitis pigmentosa</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185796">Salvatore Marco Caruso, … , James B. Hurley, Stephen H. Tsang</a> <a class='hide-for-small show-more' data-reveal-id='article45900-more' href='#'> <div class='article-authors'> Salvatore Marco Caruso, … , James B. Hurley, Stephen H. Tsang </div> </a> <span class='article-published-at'> Published February 12, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e185796. <a href="https://doi.org/10.1172/JCI185796">https://doi.org/10.1172/JCI185796</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185796">Text</a> | <a href="/articles/view/185796/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185796' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185796/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185796/small/JCI185796.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45900-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185796">Ablating VHL in rod photoreceptors modulates RPE glycolysis and improves preclinical model of retinitis pigmentosa</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185796">Text</a></li> <li><a class="button tiny" href="/articles/view/185796/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Neuroretinal degenerations including retinitis pigmentosa (RP) comprise a heterogeneous collection of pathogenic mutations that ultimately result in blindness. Despite recent advances in precision medicine, therapies for rarer mutations are hindered by burdensome developmental costs. To this end, Von Hippel-Lindau (VHL) is an attractive therapeutic target to treat RP. By ablating VHL in rod photoreceptors and elevating hypoxia-inducible factor (HIF) levels, we demonstrate a path to therapeutically enhancing glycolysis independent of the underlying genetic variant that slows degeneration of both rod and cone photoreceptors in a preclinical model of retinitis pigmentosa. This rod-specific intervention also resulted in reciprocal, decreased glycolytic activity within the retinal pigment epithelium (RPE) cells despite no direct genetic modifications to the RPE. Suppressing glycolysis in the RPE provided notable, noncell-autonomous therapeutic benefits to the photoreceptors, indicative of metabolically sensitive crosstalk between different cellular compartments of the retina. Surprisingly, targeting HIF2A in RPE cells did not impact RPE glycolysis, potentially implicating HIF1A as a major regulator in mouse RPE and providing a rationale for future therapeutic efforts aimed at modulating RPE metabolism.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Salvatore Marco Caruso, Xuan Cui, Brian M. Robbings, Noah Heapes, Aykut Demikrol, Bruna Lopes Da Costa, Daniel T. Hass, Peter M.J. Quinn, Jianhai Du, James B. Hurley, Stephen H. Tsang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/187024">Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/187024">Kang Sun, … , Xueli Bai, Tingbo Liang</a> <a class='hide-for-small show-more' data-reveal-id='article45901-more' href='#'> <div class='article-authors'> Kang Sun, … , Xueli Bai, Tingbo Liang </div> </a> <span class='article-published-at'> Published January 30, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e187024. <a href="https://doi.org/10.1172/JCI187024">https://doi.org/10.1172/JCI187024</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/187024">Text</a> | <a href="/articles/view/187024/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI187024' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/187024/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/187000/187024/small/JCI187024.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45901-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/187024">Elevated protein lactylation promotes immunosuppressive microenvironment and therapeutic resistance in pancreatic ductal adenocarcinoma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/187024">Text</a></li> <li><a class="button tiny" href="/articles/view/187024/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Metabolic reprogramming shapes the tumor microenvironment (TME) and may lead to immunotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Elucidating the impact of pancreatic cancer cell metabolism in the TME is essential to therapeutic interventions. “Immune cold” PDAC is characterized by elevated lactate levels resulting from tumor cell metabolism, abundance of protumor macrophages, and reduced cytotoxic T cells in the TME. Analysis of fluorine-18 fluorodeoxyglucose (18F-FDG) uptake in patients showed that increased global protein lactylation in PDAC correlates with worse clinical outcomes in immunotherapy. Inhibition of lactate production in pancreatic tumors via glycolysis or mutant-KRAS inhibition reshaped the TME, thereby increasing their sensitivity to immune checkpoint blockade (ICB) therapy. In pancreatic tumor cells, lactate induces K63 lactylation of endosulfine α (ENSA-K63la), a crucial step that triggers STAT3/CCL2 signaling. Consequently, elevated CCL2 secreted by tumor cells facilitates tumor-associated macrophage (TAM) recruitment to the TME. High levels of lactate also drive transcriptional reprogramming in TAMs via ENSA-STAT3 signaling, promoting an immunosuppressive environment. Targeting ENSA-K63la or CCL2 enhances the efficacy of ICB therapy in murine and humanized pancreatic tumor models. In conclusion, elevated lactylation reshapes the TME and promotes immunotherapy resistance in PDAC. A therapeutic approach targeting ENSA-K63la or CCL2 has shown promise in sensitizing pancreatic cancer immunotherapy.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Kang Sun, Xiaozhen Zhang, Jiatao Shi, Jinyan Huang, Sicheng Wang, Xiang Li, Haixiang Lin, Danyang Zhao, Mao Ye, Sirui Zhang, Li Qiu, Minqi Yang, Chuyang Liao, Lihong He, Mengyi Lao, Jinyuan Song, Na Lu, Yongtao Ji, Hanshen Yang, Lingyue Liu, Xinyuan Liu, Yan Chen, Shicheng Yao, Qianhe Xu, Jieru Lin, Yan Mao, Jingxing Zhou, Xiao Zhi, Ke Sun, Xiongbin Lu, Xueli Bai, Tingbo Liang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/177724">Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/177724">Jiawen Yang, … , James A. DeCaprio, Megha Padi</a> <a class='hide-for-small show-more' data-reveal-id='article45909-more' href='#'> <div class='article-authors'> Jiawen Yang, … , James A. DeCaprio, Megha Padi </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e177724. <a href="https://doi.org/10.1172/JCI177724">https://doi.org/10.1172/JCI177724</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/177724">Text</a> | <a href="/articles/view/177724/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI177724' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/177724/figure/1' ref='group' title='MCPyV-perturbed cell model reveals signaling pathways altered during MCC development. IMR90 normal human fibroblasts expressing inducible MCPyV early region (ER) were subjected to bulk RNA-seq. (A) Principal component analysis (PCA) performed on all 13,870 expressed genes in the time series RNA-seq data. (B) The eigengenes of the 14 WGCNA modules were projected onto each time point and the modules were grouped by their dynamic patterns using hierarchical clustering. (C) Force-directed network of hub genes in the 14 WGCNA modules. The attraction forces between nodes were defined by the topological overlap matrix and were inversely proportional to the length of edges in the graph. (D) GO term enrichment analysis of each WGCNA gene module. The terms are ranked by adjusted P value, and the top-ranked terms are shown. Neuroendocrine related terms are highlighted in red, Wnt signaling related terms are highlighted in blue.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/177000/177724/small/JCI177724.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45909-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/177724">Integrative analysis reveals therapeutic potential of pyrvinium pamoate in Merkel cell carcinoma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/177724">Text</a></li> <li><a class="button tiny" href="/articles/view/177724/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Merkel Cell Carcinoma (MCC) is an aggressive neuroendocrine cutaneous malignancy arising from either ultraviolet-induced mutagenesis or Merkel cell polyomavirus (MCPyV) integration. Despite extensive research, our understanding of the molecular mechanisms driving the transition from normal cells to MCC remains limited. To address this knowledge gap, we assessed the impact of inducible MCPyV T antigens on normal human fibroblasts by performing RNA-seq. Our data uncovered changes in expression and regulation of Wnt signaling pathway members. Building on this observation, we bioinformatically evaluated various Wnt pathway perturbagens for their ability to reverse the MCC gene expression signature and identified pyrvinium pamoate, an FDA-approved anthelminthic drug known for its antitumor activity in other cancers. Leveraging transcriptomic, network, and molecular analyses, we found that pyrvinium targets multiple MCC vulnerabilities. Pyrvinium not only reverses the neuroendocrine features of MCC by modulating canonical and noncanonical Wnt signaling but also inhibits cancer cell growth by activating p53-mediated apoptosis, disrupting mitochondrial function, and inducing endoplasmic reticulum stress. Finally, we demonstrated that pyrvinium reduces tumor growth in an MCC mouse xenograft model. These findings offer a deeper understanding of the role of Wnt signaling in MCC and highlight the utility of pyrvinium as a potential treatment for MCC.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jiawen Yang, James T. Lim, Paul Victor Santiago Raj, Marcelo G. Corona, Chen Chen, Hunain Khawaja, Qiong Pan, Gillian D. Paine-Murrieta, Rick G. Schnellmann, Denise J. Roe, Prafulla C. Gokhale, James A. DeCaprio, Megha Padi</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/185489">Rapamycin enhances CAR-T control of HIV replication and reservoir elimination in vivo</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/185489">Wenli Mu, … , Scott G. Kitchen, Anjie Zhen</a> <a class='hide-for-small show-more' data-reveal-id='article45910-more' href='#'> <div class='article-authors'> Wenli Mu, … , Scott G. Kitchen, Anjie Zhen </div> </a> <span class='article-published-at'> Published February 11, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e185489. <a href="https://doi.org/10.1172/JCI185489">https://doi.org/10.1172/JCI185489</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/185489">Text</a> | <a href="/articles/view/185489/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI185489' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/185489/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/185000/185489/small/JCI185489.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45910-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/185489">Rapamycin enhances CAR-T control of HIV replication and reservoir elimination in vivo</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/185489">Text</a></li> <li><a class="button tiny" href="/articles/view/185489/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Chimeric antigen receptor (CAR) T cell therapy shows promise for various diseases. Our studies in humanized mice and nonhuman primates demonstrate that hematopoietic stem cells (HSCs) modified with anti-HIV CAR achieve lifelong engraftment, providing functional antiviral CAR-T cells that reduce viral rebound after antiretroviral therapy (ART) withdrawal. However, T cell exhaustion due to chronic immune activation remains a key obstacle to sustained CAR-T efficacy, necessitating additional measures to achieve functional cure. We recently showed that low-dose rapamycin treatment reduced inflammation and improved anti-HIV T cell function in HIV-infected humanized mice. Here, we report that rapamycin improved CAR-T cell function both in vitro and in vivo. In vitro treatment with rapamycin enhanced CAR-T cell mitochondrial respiration and cytotoxicity. In vivo treatment with low-dose rapamycin in HIV-infected, CAR-HSC mice decreased chronic inflammation, prevented exhaustion of CAR-T cells, and improved CAR-T control of viral replication. RNA-sequencing analysis of CAR-T cells from humanized mice showed that rapamycin downregulated multiple checkpoint inhibitors and upregulated key survival genes. Mice treated with CAR-HSCs and rapamycin had delayed viral rebound after ART and reduced HIV reservoir compared with those treated with CAR-HSCs alone. These findings suggest that HSC-based anti-HIV CAR-T cells combined with rapamycin treatment are a promising approach for treating persistent inflammation and improving immune control of HIV replication.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Wenli Mu, Shallu Tomer, Jeffrey Harding, Nandita Kedia, Valerie Rezek, Ethan Cook, Vaibahavi Patankar, Mayra A. Carrillo, Heather Martin, Hwee Ng, Li Wang, Matthew D. Marsden, Scott G. Kitchen, Anjie Zhen</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/51?content=articles&page=2">2</a></li> <li><a href="/tags/51?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/51?content=articles&page=2538">2538</a></li> <li><a href="/tags/51?content=articles&page=2539">2539</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/51?content=articles&page=2">Next →</a></li></ul></div> </div> </div> </div> <div class='content ' id='posts'> <p>No posts were found with this tag.</p> </div> </div> </div> <div class='large-2 medium-3 hide-for-small columns' style='padding: 12px 9px 12px 9px;'> <div style='width:100%; text-align: center;'> <div id='jci-interior-skyscraper-right-col'> <span class='secondary label'>Advertisement</span> <script> try { googletag.cmd.push(function () { googletag.display('jci-interior-skyscraper-right-col'); }); } catch(e){} </script> </div> </div> </div> </div> </div> </div> </div> </div> <div id='footer'> <div class='row panel-padding'> <div class='small-6 columns'> <div id='social-links'> <a onclick="trackOutboundLink('/twitter?ref=footer');" href="/twitter"><img title="Twitter" src="/assets/social/twitter-round-blue-78025a92064e3594e44e4ccf5446aefeafba696cd3c8e4a7be1850c7c9f62aba.png" /></a> <a onclick="trackOutboundLink('/facebook?ref=footer');" href="/facebook"><img title="Facebook" src="/assets/social/facebook-round-blue-2787910d46dcbdbee4bd34030fee044e5a77cfda2221af9191d437b2f5fadeb1.png" /></a> <a href="/rss"><img title="RSS" src="/assets/social/rss-round-color-6f5fa8e93dc066ee4923a36ba6a7cb97d53c5b77de78a2c7b2a721adc603f342.png" /></a> </div> <br> Copyright © 2025 <a href="http://www.the-asci.org">American Society for Clinical Investigation</a> <br> ISSN: 0021-9738 (print), 1558-8238 (online) </div> <div class='small-6 columns'> <div class='row'> <div class='small-12 columns'> <h4 class='notices-signup'>Sign up for email alerts</h4> <form action='https://notices.jci.org/subscribers/new' method='get'> <input name='utm_source' type='hidden' value='jci'> <input name='utm_medium' type='hidden' value='web'> <input name='utm_campaign' type='hidden' value='email_signup'> <input name='utm_content' type='hidden' value='footer'> <div class='row'> <div class='small-12 medium-9 columns'> <input name='email_address' placeholder='Your email address' required type='text'> </div> <div class='small-12 medium-3 columns'> <input class='button tiny orange' type='submit' value='Sign up'> </div> </div> </form> </div> </div> </div> </div> </div> </div> <script src="/assets/application-27f18b5fe3b7302e5b3e3c6d7cf9bb3f54759fad32679209f5aef429b89f3aef.js"></script>  <script src="//s7.addthis.com/js/300/addthis_widget.js#pubid=ra-4d8389db4b0bb592" async="async"></script> <script src="//d1bxh8uas1mnw7.cloudfront.net/assets/embed.js" async="async"></script>  </body> </html>