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<div class='row cover-caption'> <div class='small-12 columns'> <h3 class='issue'> Issue published February 1, 2024 <span class='browse'> <a id="issue#show_previous_issue" href="/134/2">Previous issue</a> | <a id="issue#show_next_issue" href="/134/4">Next issue</a> </span> </h3> </div> </div> <div class='row'> <div class='large-3 medium-4 columns'> <img class="issue-cover" src="//dm5migu4zj3pb.cloudfront.net/volumes/134/3/134-3-cover.jpg" /> </div> <div class='large-9 medium-8 columns'> <ul class='no-bullet'> <li> Volume 134, Issue 3 </li> </ul> <h5>Go to section:</h5> <ul class='no-bullet'> <li> <a href='#100th_anniversary_viewpoints'> 100th Anniversary Viewpoints </a> </li> <li> <a href='#viewpoint'> Viewpoint </a> </li> <li> <a href='#review'> Reviews </a> </li> <li> <a href='#commentary'> Commentaries </a> </li> <li> <a href='#research_letter'> Research Letter </a> </li> <li> <a href='#research_article'> Research Articles </a> </li> <li> <a href='#corrigendum'> Corrigendum </a> </li> </ul> </div> </div> <div class='row'> <div class='small-12 columns'> <h4 class='cover-story-headline'> On the cover: KIBRA in tauopathy-related memory loss </h4> <div><p><a href="/articles/view/169064">Kauwe and Pareja-Navarro et al.</a> identify a KIBRA-dependent mechanism involved in repair of plasticity at synapses that is dysregulated in neurons underlying the loss of memory in tauopathy. The cover art depicts the recovery of the functional plasticity at synapses on neurons despite tau-induced toxicity in the brain. Image credit: Larissa Brown.</p> </div> </div> </div> <a class='in-page' name='100th_anniversary_viewpoints'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel0' name='100th_anniversary_viewpoints'> <strong></strong> <span class='toggle-icon'></span> 100th Anniversary Viewpoints </a> <div class='content active' id='panel0'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/176253">Clinical investigation of hypoxia-inducible factors: getting there</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/176253">Gregg L. Semenza</a> <a class='hide-for-small show-more' data-reveal-id='article44750-more' href='#'> <div class='article-authors'> Gregg L. Semenza </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e176253. <a href="https://doi.org/10.1172/JCI176253">https://doi.org/10.1172/JCI176253</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/176253">Text</a> | <a href="/articles/view/176253/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/JCI176253' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44750-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/176253">Clinical investigation of hypoxia-inducible factors: getting there</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/176253">Text</a></li> <li><a class="button tiny" href="/articles/view/176253/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Gregg L. Semenza</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/176738">Pancreatic <b>β</b> cell function versus insulin resistance: application of the hyperbolic law of glucose tolerance</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/176738">Richard N. Bergman</a> <a class='hide-for-small show-more' data-reveal-id='article44740-more' href='#'> <div class='article-authors'> Richard N. Bergman </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e176738. <a href="https://doi.org/10.1172/JCI176738">https://doi.org/10.1172/JCI176738</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/176738">Text</a> | <a href="/articles/view/176738/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/JCI176738' 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/176738/figure/1' ref='group' title='The hyperbolic law of glucose tolerance. Insulin resistance (in the face of, for example, obesity, pregnancy, or puberty) is represented by moving up and to the left on the curve (from position 1 to position 2). A higher position on the curve reflects enhanced insulin release from the pancreatic β cells. Improved insulin sensitivity (e.g., exercise) is represented by moving down and to the right on the curve, eliciting a lesser insulin response.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/176000/176738/small/JCI176738.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44740-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/176738">Pancreatic <b>β</b> cell function versus insulin resistance: application of the hyperbolic law of glucose tolerance</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/176738">Text</a></li> <li><a class="button tiny" href="/articles/view/176738/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Richard N. Bergman</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='viewpoint'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel1' name='viewpoint'> <strong></strong> <span class='toggle-icon'></span> Viewpoint </a> <div class='content active' id='panel1'> <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/176736">Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/176736">Karthik Vasan, Navdeep S. Chandel</a> <a class='hide-for-small show-more' data-reveal-id='article44746-more' href='#'> <div class='article-authors'> Karthik Vasan, Navdeep S. Chandel </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e176736. <a href="https://doi.org/10.1172/JCI176736">https://doi.org/10.1172/JCI176736</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/176736">Text</a> | <a href="/articles/view/176736/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/JCI176736' 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/176736/figure/1' ref='group' title='Drugs that target the mitochondrial electron transport chain in cancer cells have antineoplastic properties. Mitochondrial electron transport chain (ETC) is necessary to sustain metabolites required for cancer cell growth. Metformin’s primary anticancer mechanism involves the inhibition of mitochondrial ETC complex I. The drug’s safety and efficacy are associated with organic cation transporters (OCTs), which have varying presence across regular tissues and cancers. Metformin relies on OCTs for cell entry, and variability in OCT expression levels along with the ability of cancer cells to metabolically adjust to the tumor microenvironment might account for inconsistent results in clinical trials. New drugs on the horizon targeting the ETC include the antimalaria drug atovaquone, an inhibitor of mitochondrial complex III, and ONC201, an activator of mitochondrial protease caseinolytic protease P (CLPP) that degrades ETC proteins. The molecular determinants that would make these drugs effective and their specific therapeutic window need to be addressed.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/176000/176736/small/JCI176736.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44746-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/176736">Molecular and cellular mechanisms underlying the failure of mitochondrial metabolism drugs in cancer clinical trials</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/176736">Text</a></li> <li><a class="button tiny" href="/articles/view/176736/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Karthik Vasan, Navdeep S. Chandel</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='review'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel2' name='review'> <strong></strong> <span class='toggle-icon'></span> Reviews </a> <div class='content active' id='panel2'> <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/175706">Circadian immunity from bench to bedside: a practical guide</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/175706">Huram Mok, … , Guy Hazan, Jeffrey A. Haspel</a> <a class='hide-for-small show-more' data-reveal-id='article44747-more' href='#'> <div class='article-authors'> Huram Mok, … , Guy Hazan, Jeffrey A. Haspel </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e175706. <a href="https://doi.org/10.1172/JCI175706">https://doi.org/10.1172/JCI175706</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/175706">Text</a> | <a href="/articles/view/175706/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/JCI175706' 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/175706/figure/1' ref='group' title='The oscillator model of circadian rhythm generation. In this model, the circadian molecular clock acts as a cell-autonomous rhythm generator (center) that produces rhythmic patterns of gene expression. At the organism level, the system has two parts: a central pacemaker housed in the central nervous system within the suprachiasmatic nucleus (SCN) of the hypothalamus and local pacemakers within peripheral tissues responsible for physiological outputs. To set the biological time of day (the circadian phase), the clock within the central pacemaker converts rhythms in external light into synchronized oscillations in hormone secretion (melatonin and hypothalamic pituitary axis), autonomic neural activity, arousal, appetite, and core body temperature. These rhythmic internal cues are converted by oscillators within peripheral cells into tissue-specific circadian rhythms. Circadian rhythms can modify the external environment around cells and, in so doing, can affect the amplitude and phase of the peripheral clock through feedback regulation.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/175000/175706/small/JCI175706.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44747-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/175706">Circadian immunity from bench to bedside: a practical guide</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/175706">Text</a></li> <li><a class="button tiny" href="/articles/view/175706/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>The immune system is built to counteract unpredictable threats, yet it relies on predictable cycles of activity to function properly. Daily rhythms in immune function are an expanding area of study, and many originate from a genetically based timekeeping mechanism known as the circadian clock. The challenge is how to harness these biological rhythms to improve medical interventions. Here, we review recent literature documenting how circadian clocks organize fundamental innate and adaptive immune activities, the immunologic consequences of circadian rhythm and sleep disruption, and persisting knowledge gaps in the field. We then consider the evidence linking circadian rhythms to vaccination, an important clinical realization of immune function. Finally, we discuss practical steps to translate circadian immunity to the patient’s bedside.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Huram Mok, Elaine Ostendorf, Alex Ganninger, Avi J. Adler, Guy Hazan, Jeffrey A. Haspel</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/176345">Alcohol-associated liver disease</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/176345">Bryan Mackowiak, … , Luca Maccioni, Bin Gao</a> <a class='hide-for-small show-more' data-reveal-id='article44745-more' href='#'> <div class='article-authors'> Bryan Mackowiak, … , Luca Maccioni, Bin Gao </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e176345. <a href="https://doi.org/10.1172/JCI176345">https://doi.org/10.1172/JCI176345</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/176345">Text</a> | <a href="/articles/view/176345/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/JCI176345' 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/176345/figure/1' ref='group' title='Spectrum of ALD, risk factors, and comorbidities. Almost all individuals who drink heavily (90%–95%) develop steatosis; some of them may develop more severe forms of ALD, including alcohol-associated steatohepatitis (ASH), cirrhosis, and hepatocellular carcinoma (HCC). Some patients with underlying ALD develop acute alcohol-associated hepatitis (AH) with the typical clinical syndrome jaundice. AH is often referred to as a severe form of AH that has a high short-term morality. ASH is diagnosed based on histology, while AH is diagnosed based on clinical symptoms. Many risk factors promote the development of the severe forms of ALD. Alcohol intake and comorbid factors synergistically promote the progression of ALD. Adapted with permission from Gastroenterology (4).'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/176000/176345/small/JCI176345.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44745-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/176345">Alcohol-associated liver disease</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/176345">Text</a></li> <li><a class="button tiny" href="/articles/view/176345/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Bryan Mackowiak, Yaojie Fu, Luca Maccioni, Bin Gao</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='commentary'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel3' name='commentary'> <strong></strong> <span class='toggle-icon'></span> Commentaries </a> <div class='content active' id='panel3'> <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/176547">Biofilm-derived oxylipin 10-HOME mediated immune response in women with breast implants</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/176547">Tyler M. Bauer, Katherine A. Gallagher</a> <a class='hide-for-small show-more' data-reveal-id='article44743-more' href='#'> <div class='article-authors'> Tyler M. Bauer, Katherine A. Gallagher </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e176547. <a href="https://doi.org/10.1172/JCI176547">https://doi.org/10.1172/JCI176547</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/176547">Text</a> | <a href="/articles/view/176547/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/JCI176547' 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/176547/figure/1' ref='group' title='10-HOME from biofilm on implants provides a model for the immune response in women with BII. Bacteria such as S. epidermidis can establish bacterial biofilms on the surface of breast implants. S. epidermidis and/or other bacterial strains oxidize oleic acid to produce 10-HOME, which perfuses into periprosthetic breast tissue and blood. CD4+ T cells exposed to 10-HOME show increased expression of TBET and polarize into Th1 cells. Secretion of inflammatory factors by Th1 cells drives inflammatory macrophage polarization to yield an M1-like proinflammatory phenotype and related symptoms.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/176000/176547/small/JCI176547.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44743-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/176547">Biofilm-derived oxylipin 10-HOME mediated immune response in women with breast implants</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/176547">Text</a></li> <li><a class="button tiny" href="/articles/view/176547/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Breast implant illness (BII) is a poorly understood disease in which patients develop symptoms typical of autoimmune conditions following breast implantation. There is no known underlying cause, and patients often resort to breast implant removal and capsulectomy to alleviate symptoms. In this issue of the JCI, Khan and colleagues examined 86 breast explants from patients that reported BII symptoms and 55 control explants. The BII group showed a disproportionally high degree of biofilm, which was associated with oxylipin (10-HOME) on the implant surfaces. Injections of 10-HOME in the mammary fat pad of a murine model recapitulated BII symptoms and increased Th1 cell populations. Notably, macrophages in the periprosthetic tissue from BII patients were more likely to exhibit a proinflammatory phenotype, and naive T cells exposed to 10-HOME caused naive macrophages to differentiate to a proinflammatory phenotype. This work provides a pathophysiologic mechanism for a currently understudied and poorly characterized disease.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Tyler M. Bauer, Katherine A. Gallagher</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/176879">Should I stay or should I go? Transsulfuration influences invasion and growth in glioblastoma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/176879">András K. Ponti, … , Christopher Hine, Justin D. Lathia</a> <a class='hide-for-small show-more' data-reveal-id='article44748-more' href='#'> <div class='article-authors'> András K. Ponti, … , Christopher Hine, Justin D. Lathia </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e176879. <a href="https://doi.org/10.1172/JCI176879">https://doi.org/10.1172/JCI176879</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/176879">Text</a> | <a href="/articles/view/176879/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/JCI176879' 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/176879/figure/1' ref='group' title='Multiomics analysis indicates the importance of CTH in GBM brain infiltration. Metabolomics, lipidomics, RNA-Seq, and a CRISPR knockout screen identify CTH-mediated cysteine production as a potent regulator of oxidative stress–induced invasive potential in GBM. Samples along the invasive tumor front show elevated levels of CTH, cystathionine, and peroxide ROS. The absence of CTH leads to a reduction in cysteine production, resulting in an increased accumulation of hydroxyl radical ROS, which yields reduced brain infiltration while driving enhanced tumor growth. CSE-γ-IN, cystathionine-γ-lyase-IN-1.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/176000/176879/small/JCI176879.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44748-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/176879">Should I stay or should I go? Transsulfuration influences invasion and growth in glioblastoma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/176879">Text</a></li> <li><a class="button tiny" href="/articles/view/176879/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>A major challenge in treating patients with glioblastoma is the inability to eliminate highly invasive cells with chemotherapy, radiation, or surgical resection. As cancer cells face the issue of replicating or invading neighboring tissue, they rewire their metabolism in a concerted effort to support necessary cellular processes and account for altered nutrient abundance. In this issue of the JCI, Garcia et al. compared an innovative 3D hydrogel–based invasion device to regional patient biopsies through a comprehensive multiomics-based approach paired with a CRISPR knockout screen. Their findings elucidate a role for cystathionine γ-lyase (CTH), an enzyme in the transsulfuration pathway, as a means of regulating the cellular response to oxidative stress. CTH-mediated conversion of cystathionine to cysteine was necessary for regulating reactive oxygen species to support invasion. Meanwhile, inhibition of CTH suppressed the invasive glioblastoma phenotype. However, inhibiting CTH resulted in a larger overall tumor mass. These findings suggest that targeting the transsulfuration pathway may serve as a means of redirecting glioblastoma to proliferate or invade.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>András K. Ponti, Daniel J. Silver, Christopher Hine, Justin D. Lathia</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/177609">AEP promotes aberrant RNA splicing through DDX3X cleavage in solid tumors</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/177609">Yadong Xie, … , Haohao Zhang, Xinyang Song</a> <a class='hide-for-small show-more' data-reveal-id='article44732-more' href='#'> <div class='article-authors'> Yadong Xie, … , Haohao Zhang, Xinyang Song </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e177609. <a href="https://doi.org/10.1172/JCI177609">https://doi.org/10.1172/JCI177609</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/177609">Text</a> | <a href="/articles/view/177609/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/JCI177609' 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/177609/figure/1' ref='group' title='AEP cleaves DDX3X to drive tumor-promoting AS events. Tumor microenvironmental stresses, such as hypoxia and nutrient deprivation, activate AEP from its inactive form (pro-AEP) into the mature form through HIF1A. AEP cleaves DDX3X at amino acid 124 to induce its nuclear translocation. Once in the nucleus, t-DDX3X-C affects downstream tumor AS events in a hnRNPA1-dependent manner. Examples of pre-mRNAs affected include transcripts that encode ARRB1, involved in the regulation of glycolysis, and PRDM2, which is important for tumor suppression.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/177000/177609/small/JCI177609.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44732-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/177609">AEP promotes aberrant RNA splicing through DDX3X cleavage in solid tumors</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/177609">Text</a></li> <li><a class="button tiny" href="/articles/view/177609/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Aberrant alternative splicing (AS) events have been identified in a variety of cancers. Although somatic mutations of splicing factors and dysregulation of RNA-binding proteins (RBPs) have been linked to AS and tumor malignancy, it remains unclear how upstream mechanisms contribute to cancer development via alternative gene splicing. In this issue of the JCI, Wenrui Zhang and colleagues identified the role of asparagine endopeptidase (AEP), an intracellular cysteine endopeptidase, in promoting solid tumor–associated RNA splicing. The authors demonstrated that tumor environmental factors such as oxygen and nutrient deprivation induce the activity of AEP in a HIF1A-dependent manner. The activated AEP, in turn, cleaves an RNA helicase DDX3X to promote its nuclear retention. The authors further showed that this DDX3X nuclear fraction engages with splicing machinery to induce AS events in several cancer cells. These findings suggest that targeting an AEP-dependent aberrant RNA splicing cascade may facilitate therapeutics for solid tumors.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Yadong Xie, Haohao Zhang, Xinyang Song</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/177610">Controlled human infection study underpins efficacy of the tetravalent live-attenuated dengue vaccine TV005</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/177610">Annelies Wilder-Smith</a> <a class='hide-for-small show-more' data-reveal-id='article44759-more' href='#'> <div class='article-authors'> Annelies Wilder-Smith </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e177610. <a href="https://doi.org/10.1172/JCI177610">https://doi.org/10.1172/JCI177610</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/177610">Text</a> | <a href="/articles/view/177610/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/JCI177610' 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/177610/figure/1' ref='group' title='TV005 protects participants in controlled human infection studies. Six months following a single dose of TV005 or placebo, participants were challenged with attenuated dengue DENV2 or DENV3 virus. The TV005 vaccine effectively protected vaccinated individuals from viremia and rash in both challenges. All participants (100%) who received placebo and the DENV2 virus developed viremia, and 85% of participants challenged with the DENV3 virus developed viremia.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/177000/177610/small/JCI177610.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44759-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/177610">Controlled human infection study underpins efficacy of the tetravalent live-attenuated dengue vaccine TV005</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/177610">Text</a></li> <li><a class="button tiny" href="/articles/view/177610/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Dengue fever, caused by four distinct serotypes of the dengue virus (DENV1–4), poses a public health concern for much of the world. The NIH’s Laboratory of Infectious Diseases at the National Institute of Allergy and Infectious Diseases (NIAID) has developed a series of single-dose, live-attenuated tetravalent DENV vaccines, including TV005. However, phase III trials require a lengthy three-to-five year follow-up. In contrast, controlled human infection models (CHIMs) offer a faster means to assess vaccine efficacy for any of the four serotypes. In this issue of the JCI, Pierce, Durbin, and colleagues conducted a CHIM study with attenuated DENV2 and DENV3 challenge viruses in individuals six months after vaccination with TV005. The TV005 vaccine was well tolerated and effectively protected all vaccinated individuals from viremia and rash during challenges with DENV2 or DENV3. Notably, vaccine recipients also showed serotype-specific efficacy. While long-term studies are still needed, these findings represent an important step in providing protection against dengue virus.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Annelies Wilder-Smith</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='research_letter'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel4' name='research_letter'> <strong></strong> <span class='toggle-icon'></span> Research Letter </a> <div class='content active' id='panel4'> <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/175626">Noncoding SNPs decrease expression of FABP5 during COPD exacerbations</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/175626">Manale El Kharbili, … , Russell P. Bowler, Fabienne Gally</a> <a class='hide-for-small show-more' data-reveal-id='article44725-more' href='#'> <div class='article-authors'> Manale El Kharbili, … , Russell P. Bowler, Fabienne Gally </div> </a> <span class='article-published-at'> Published December 19, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e175626. <a href="https://doi.org/10.1172/JCI175626">https://doi.org/10.1172/JCI175626</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/175626">Text</a> | <a href="/articles/view/175626/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/JCI175626' 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/175626/figure/1' ref='group' title='The rs202275 SNP binds regulatory regions of open chromatin and interacts with the FABP5 transcription start site, decreasing FABP5 expression and reducing oxidative metabolism in mononuclear cells from COPD patients. (A) FABP5 SNPs associated with prospective severe exacerbations in the COPDGene non-Hispanic White cohort. Data were generated using R (https://www.r-project.org/). n = 6,649. (B) SNP locations within the FABP5 locus (black lines) on chromosome 8 (chr8). (C) ATAC-seq profiles (reads per million mapped) at the FABP5 locus showing accessible chromatin at the rs202275 SNP. (D) PRO-seq data at the FABP5 locus showing bidirectionality of the RNA polymerase II loading at rs202275. (E) Micro-C interactions at the FABP5 locus, with arcs (top) and boxes connecting 1-kb interacting regions across genomic space (bottom). TSS, transcription start site. Data in B–E (bottom) were visualized in the UCSC Genome Browser (https://genome.ucsc.edu/) using airway epithelial cells. (F) Normalized gene array expression levels of FABP5 (GEO GSE42057) in 116 noncarrier and 20 SNP carrier PBMCs. (G) Mitochondrial respiration measured by oxygen consumption rate (OCR) in PBMCs by genotype and associated mitochondrial parameters. Data represent 10 COPD noncarrier and 9 COPD SNP carrier donor samples. Data in F and G represent mean ± SEM. *P < 0.05, groups compared via 2-tailed Student’s t test. Experimental details can be found in the Supplemental Methods. All raw data can be found in the supplemental Supporting Data Values file.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/175000/175626/small/JCI175626.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44725-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/175626">Noncoding SNPs decrease expression of FABP5 during COPD exacerbations</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/175626">Text</a></li> <li><a class="button tiny" href="/articles/view/175626/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Manale El Kharbili, Sarah K. Sasse, Lynn Sanford, Sean Jacobson, Katja Aviszus, Arnav Gupta, Claire Guo, Susan M. Majka, Robin D. Dowell, Anthony N. Gerber, Russell P. Bowler, Fabienne Gally</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='research_article'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel5' name='research_article'> <strong></strong> <span class='toggle-icon'></span> Research Articles </a> <div class='content active' id='panel5'> <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/162533">Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/162533">Spencer Greatorex, … , Matthew J. Watt, Tony Tiganis</a> <a class='hide-for-small show-more' data-reveal-id='article44744-more' href='#'> <div class='article-authors'> Spencer Greatorex, … , Matthew J. Watt, Tony Tiganis </div> </a> <span class='article-published-at'> Published December 7, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e162533. <a href="https://doi.org/10.1172/JCI162533">https://doi.org/10.1172/JCI162533</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/162533">Text</a> | <a href="/articles/view/162533/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/JCI162533' 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/162533/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/162000/162533/small/JCI162533.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44744-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/162533">Mitochondria- and NOX4-dependent antioxidant defense mitigates progression to nonalcoholic steatohepatitis in obesity</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/162533">Text</a></li> <li><a class="button tiny" href="/articles/view/162533/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Nonalcoholic fatty liver disease (NAFLD) is prevalent in the majority of individuals with obesity, but in a subset of these individuals, it progresses to nonalcoholic steatohepatitis (0NASH) and fibrosis. The mechanisms that prevent NASH and fibrosis in the majority of patients with NAFLD remain unclear. Here, we report that NAD(P)H oxidase 4 (NOX4) and nuclear factor erythroid 2–related factor 2 (NFE2L2) were elevated in hepatocytes early in disease progression to prevent NASH and fibrosis. Mitochondria-derived ROS activated NFE2L2 to induce the expression of NOX4, which in turn generated H2O2 to exacerbate the NFE2L2 antioxidant defense response. The deletion or inhibition of NOX4 in hepatocytes decreased ROS and attenuated antioxidant defense to promote mitochondrial oxidative stress, damage proteins and lipids, diminish insulin signaling, and promote cell death upon oxidant challenge. Hepatocyte NOX4 deletion in high-fat diet–fed obese mice, which otherwise develop steatosis, but not NASH, resulted in hepatic oxidative damage, inflammation, and T cell recruitment to drive NASH and fibrosis, whereas NOX4 overexpression tempered the development of NASH and fibrosis in mice fed a NASH-promoting diet. Thus, mitochondria- and NOX4-derived ROS function in concert to drive a NFE2L2 antioxidant defense response to attenuate oxidative liver damage and progression to NASH and fibrosis in obesity.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Spencer Greatorex, Supreet Kaur, Chrysovalantou E. Xirouchaki, Pei K. Goh, Florian Wiede, Amanda J. Genders, Melanie Tran, YaoYao Jia, Arthe Raajendiran, Wendy A. Brown, Catriona A. McLean, Junichi Sadoshima, Matthew J. Watt, Tony Tiganis</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/163145">Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via regulation of key regenerative pathways</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/163145">Xue-Wei Wang, … , Chang-Mei Liu, Feng-Quan Zhou</a> <a class='hide-for-small show-more' data-reveal-id='article44724-more' href='#'> <div class='article-authors'> Xue-Wei Wang, … , Chang-Mei Liu, Feng-Quan Zhou </div> </a> <span class='article-published-at'> Published November 28, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e163145. <a href="https://doi.org/10.1172/JCI163145">https://doi.org/10.1172/JCI163145</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/163145">Text</a> | <a href="/articles/view/163145/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/JCI163145' 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/163145/figure/1' ref='group' title='Ezh2 is developmentally downregulated in the nervous system and upregulated in DRG neurons following peripheral nerve injury. (A and B) Representative immunoblotting showing that Ezh2 is developmentally downregulated in the DRG (A) and cerebral cortex (B). (C) Immunoblotting showing that Ezh2 is significantly increased in L4/5 DRGs 3 days after sciatic nerve transection. (D) Quantification of relative protein levels of Ezh2 in A (n = 2 independent experiments). (E) Quantification of relative protein levels of Ezh2 in B (1-way ANOVA followed by Tukey’s multiple comparisons; P < 0.0001; n = 3 independent experiments). (F) Quantification of relative protein levels of Ezh2 in C (unpaired, 2-tailed t test; P = 0.0092; n = 3 for sham, n = 5 for sciatic nerve transection). (G) Representative immunofluorescence of DRG sections showing increased H3K27me3 levels in nuclei of DRG neurons 1 or 3 days after sciatic nerve transection. DRG sections were stained with anti-H3K27me3 (green) and anti-β-tubulin III (red). The rightmost column displays enlarged images of the areas outlined in white, dashed boxes. Yellow arrows indicate H3K27me3 in nuclei of DRG neurons. Scale bars: 100 μm, 30 μm for enlarged images. (H) Quantification of fluorescence intensity of H3K27me3 immunoreactivity in DRG neurons in G (1-way ANOVA followed by Tukey’s multiple comparisons; P < 0.0001; n = 3 mice for all). SNT, sciatic nerve transection. **P < 0.01, ***P < 0.001, ****P < 0.0001.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/163000/163145/small/JCI163145.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44724-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/163145">Histone methyltransferase Ezh2 coordinates mammalian axon regeneration via regulation of key regenerative pathways</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/163145">Text</a></li> <li><a class="button tiny" href="/articles/view/163145/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Current treatments for neurodegenerative diseases and neural injuries face major challenges, primarily due to the diminished regenerative capacity of neurons in the mammalian CNS as they mature. Here, we investigated the role of Ezh2, a histone methyltransferase, in regulating mammalian axon regeneration. We found that Ezh2 declined in the mouse nervous system during maturation but was upregulated in adult dorsal root ganglion neurons following peripheral nerve injury to facilitate spontaneous axon regeneration. In addition, overexpression of Ezh2 in retinal ganglion cells in the CNS promoted optic nerve regeneration via both histone methylation–dependent and –independent mechanisms. Further investigation revealed that Ezh2 fostered axon regeneration by orchestrating the transcriptional silencing of genes governing synaptic function and those inhibiting axon regeneration, while concurrently activating various factors that support axon regeneration. Notably, we demonstrated that GABA transporter 2, encoded by Slc6a13, acted downstream of Ezh2 to control axon regeneration. Overall, our study underscores the potential of modulating chromatin accessibility as a promising strategy for promoting CNS axon regeneration.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Xue-Wei Wang, Shu-Guang Yang, Ming-Wen Hu, Rui-Ying Wang, Chi Zhang, Anish R. Kosanam, Arinze J. Ochuba, Jing-Jing Jiang, Ximei Luo, Yun Guan, Jiang Qian, Chang-Mei Liu, Feng-Quan Zhou</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/164199">TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/164199">Jingshu Tang, … , Lei Wu, Ying Peng</a> <a class='hide-for-small show-more' data-reveal-id='article44739-more' href='#'> <div class='article-authors'> Jingshu Tang, … , Lei Wu, Ying Peng </div> </a> <span class='article-published-at'> Published November 28, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e164199. <a href="https://doi.org/10.1172/JCI164199">https://doi.org/10.1172/JCI164199</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/164199">Text</a> | <a href="/articles/view/164199/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/JCI164199' 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/164199/figure/1' ref='group' title='TIMP2 ameliorates neurological dysfunction and alleviates Evans blue extravasation in TBI. (A) Experimental scheme for TBI establishment, rmTIMP2 administration, neurological behavior assessment, and BBB integrity analysis in mice. WDI, weight drop injury. (B–D) TBI mice were intravenously given rmTIMP2 (10, 30, and 100 μg/kg) or PBS for 3 consecutive days, and neurological function was assessed at 24, 48, and 72 hours after TBI (n = 7 per group). (B) Fall latency of accelerated rotarod of mice from the indicated treatment groups. (C) Beam balance scores for mice from the indicated treatment groups. (D) mNSS of mice from the indicated treatment groups. (E) Representative images of brain tissues from the indicated treatment groups at 72 hours after TBI. The blue area indicates extravasation of Evans blue dye. (F) Quantification of leaked Evans blue dye in the ipsilateral cerebral hemisphere of mice from the indicated groups (n = 7 per group). ##P < 0.01 vs. sham group, *P < 0.05 and **P < 0.01 vs. model group, by 1-way ANOVA.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/164000/164199/small/JCI164199.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44739-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/164199">TIMP2 ameliorates blood-brain barrier disruption in traumatic brain injury by inhibiting Src-dependent VE-cadherin internalization</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/164199">Text</a></li> <li><a class="button tiny" href="/articles/view/164199/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Blood-brain barrier (BBB) disruption is a serious pathological consequence of traumatic brain injury (TBI), for which there are limited therapeutic strategies. Tissue inhibitor of metalloproteinase-2 (TIMP2), a molecule with dual functions of inhibiting MMP activity and displaying cytokine-like activity through receptor binding, has been reported to inhibit VEGF-induced vascular hyperpermeability. Here, we investigate the ability of TIMP2 to ameliorate BBB disruption in TBI and the underlying molecular mechanisms. Both TIMP2 and AlaTIMP2, a TIMP2 mutant without MMP-inhibiting activity, attenuated neurological deficits and BBB leakage in TBI mice; they also inhibited junctional protein degradation and translocation to reduce paracellular permeability in human brain microvascular endothelial cells (ECs) exposed to hypoxic plus inflammatory insult. Mechanistic studies revealed that TIMP2 interacted with α3β1 integrin on ECs, inhibiting Src activation–dependent VE-cadherin phosphorylation, VE-cadherin/catenin complex destabilization, and subsequent VE-cadherin internalization. Notably, localization of VE-cadherin on the membrane was critical for TIMP2-mediated EC barrier integrity. Furthermore, TIMP2-mediated increased membrane localization of VE-cadherin enhanced the level of active Rac1, thereby inhibiting stress fiber formation. All together, our studies have identified an MMP-independent mechanism by which TIMP2 regulates EC barrier integrity after TBI. TIMP2 may be a therapeutic agent for TBI and other neurological disorders involving BBB breakdown.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jingshu Tang, Yuying Kang, Yujun Zhou, Nianying Shang, Xinnan Li, Hongyue Wang, Jiaqi Lan, Shuai Wang, Lei Wu, Ying Peng</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/164325">PD-1H/VISTA mediates immune evasion in acute myeloid leukemia</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/164325">Tae Kon Kim, … , Steven D. Gore, Lieping Chen</a> <a class='hide-for-small show-more' data-reveal-id='article44741-more' href='#'> <div class='article-authors'> Tae Kon Kim, … , Steven D. Gore, Lieping Chen </div> </a> <span class='article-published-at'> Published December 7, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e164325. <a href="https://doi.org/10.1172/JCI164325">https://doi.org/10.1172/JCI164325</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/164325">Text</a> | <a href="/articles/view/164325/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/JCI164325' 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/164325/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/164000/164325/small/JCI164325.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44741-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/164325">PD-1H/VISTA mediates immune evasion in acute myeloid leukemia</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/164325">Text</a></li> <li><a class="button tiny" href="/articles/view/164325/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Acute myeloid leukemia (AML) presents a pressing medical need in that it is largely resistant to standard chemotherapy as well as modern therapeutics, such as targeted therapy and immunotherapy, including anti–programmed cell death protein (anti-PD) therapy. We demonstrate that programmed death-1 homolog (PD-1H), an immune coinhibitory molecule, is highly expressed in blasts from the bone marrow of AML patients, while normal myeloid cell subsets and T cells express PD-1H. In studies employing syngeneic and humanized AML mouse models, overexpression of PD-1H promoted the growth of AML cells, mainly by evading T cell–mediated immune responses. Importantly, ablation of AML cell-surface PD-1H by antibody blockade or genetic knockout significantly inhibited AML progression by promoting T cell activity. In addition, the genetic deletion of PD-1H from host normal myeloid cells inhibited AML progression, and the combination of PD-1H blockade with anti-PD therapy conferred a synergistic antileukemia effect. Our findings provide the basis for PD-1H as a potential therapeutic target for treating human AML.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Tae Kon Kim, Xue Han, Qianni Hu, Esten N. Vandsemb, Carly M. Fielder, Junshik Hong, Kwang Woon Kim, Emily F. Mason, R. Skipper Plowman, Jun Wang, Qi Wang, Jian-Ping Zhang, Ti Badri, Miguel F. Sanmamed, Linghua Zheng, Tianxiang Zhang, Jude Alawa, Sang Won Lee, Amer M. Zeidan, Stephanie Halene, Manoj M. Pillai, Namrata S. Chandhok, Jun Lu, Mina L. Xu, Steven D. Gore, Lieping Chen</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/165644">Biofilm-derived oxylipin 10-HOME–mediated immune response in women with breast implants</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/165644">Imran Khan, … , Marshall E. Kadin, Mithun Sinha</a> <a class='hide-for-small show-more' data-reveal-id='article44734-more' href='#'> <div class='article-authors'> Imran Khan, … , Marshall E. Kadin, Mithun Sinha </div> </a> <span class='article-published-at'> Published November 30, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e165644. <a href="https://doi.org/10.1172/JCI165644">https://doi.org/10.1172/JCI165644</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/165644">Text</a> | <a href="/articles/view/165644/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/JCI165644' 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/165644/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/165000/165644/small/JCI165644.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44734-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/165644">Biofilm-derived oxylipin 10-HOME–mediated immune response in women with breast implants</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/165644">Text</a></li> <li><a class="button tiny" href="/articles/view/165644/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>This study investigates a mechanistic link of bacterial biofilm–mediated host-pathogen interaction leading to immunological complications associated with breast implant illness (BII). Over 10 million women worldwide have breast implants. In recent years, women have described a constellation of immunological symptoms believed to be related to their breast implants. We report that periprosthetic breast tissue of participants with symptoms associated with BII had increased abundance of biofilm and biofilm-derived oxylipin 10-HOME compared with participants with implants who are without symptoms (non-BII) and participants without implants. S. epidermidis biofilm was observed to be higher in the BII group compared with the non-BII group and the normal tissue group. Oxylipin 10-HOME was found to be immunogenically capable of polarizing naive CD4+ T cells with a resulting Th1 subtype in vitro and in vivo. Consistently, an abundance of CD4+Th1 subtype was observed in the periprosthetic breast tissue and blood of people in the BII group. Mice injected with 10-HOME also had increased Th1 subtype in their blood, akin to patients with BII, and demonstrated fatigue-like symptoms. The identification of an oxylipin-mediated mechanism of immune activation induced by local bacterial biofilm provides insight into the possible pathogenesis of the implant-associated immune symptoms of BII.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Imran Khan, Robert E. Minto, Christine Kelley-Patteson, Kanhaiya Singh, Lava Timsina, Lily J. Suh, Ethan Rinne, Bruce W. Van Natta, Colby R. Neumann, Ganesh Mohan, Mary Lester, R. Jason VonDerHaar, Rana German, Natascia Marino, Aladdin H. Hassanein, Gayle M. Gordillo, Mark H. Kaplan, Chandan K. Sen, Marshall E. Kadin, Mithun Sinha</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/168558">DNA methylation–mediated <i>Rbpjk</i> suppression protects against fracture nonunion caused by systemic inflammation</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/168558">Ding Xiao, … , Yousef Abu-Amer, Jie Shen</a> <a class='hide-for-small show-more' data-reveal-id='article44761-more' href='#'> <div class='article-authors'> Ding Xiao, … , Yousef Abu-Amer, Jie Shen </div> </a> <span class='article-published-at'> Published December 5, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e168558. <a href="https://doi.org/10.1172/JCI168558">https://doi.org/10.1172/JCI168558</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/168558">Text</a> | <a href="/articles/view/168558/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/JCI168558' 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/168558/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/168000/168558/small/JCI168558.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44761-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/168558">DNA methylation–mediated <i>Rbpjk</i> suppression protects against fracture nonunion caused by systemic inflammation</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/168558">Text</a></li> <li><a class="button tiny" href="/articles/view/168558/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Challenging skeletal repairs are frequently seen in patients experiencing systemic inflammation. To tackle the complexity and heterogeneity of the skeletal repair process, we performed single-cell RNA sequencing and revealed that progenitor cells were one of the major lineages responsive to elevated inflammation and this response adversely affected progenitor differentiation by upregulation of Rbpjk in fracture nonunion. We then validated the interplay between inflammation (via constitutive activation of Ikk2, Ikk2ca) and Rbpjk specifically in progenitors by using genetic animal models. Focusing on epigenetic regulation, we identified Rbpjk as a direct target of Dnmt3b. Mechanistically, inflammation decreased Dnmt3b expression in progenitor cells, consequently leading to Rbpjk upregulation via hypomethylation within its promoter region. We also showed that Dnmt3b loss-of-function mice phenotypically recapitulated the fracture repair defects observed in Ikk2ca-transgenic mice, whereas Dnmt3b-transgenic mice alleviated fracture repair defects induced by Ikk2ca. Moreover, Rbpjk ablation restored fracture repair in both Ikk2ca mice and Dnmt3b loss-of-function mice. Altogether, this work elucidates a common mechanism involving a NF-κB/Dnmt3b/Rbpjk axis within the context of inflamed bone regeneration. Building on this mechanistic insight, we applied local treatment with epigenetically modified progenitor cells in a previously established mouse model of inflammation-mediated fracture nonunion and showed a functional restoration of bone regeneration under inflammatory conditions through an increase in progenitor differentiation potential.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Ding Xiao, Liang Fang, Zhongting Liu, Yonghua He, Jun Ying, Haocheng Qin, Aiwu Lu, Meng Shi, Tiandao Li, Bo Zhang, Jianjun Guan, Cuicui Wang, Yousef Abu-Amer, Jie Shen</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/169064">KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/169064">Grant Kauwe, … , Kaitlin B. Casaletto, Tara E. Tracy</a> <a class='hide-for-small show-more' data-reveal-id='article44722-more' href='#'> <div class='article-authors'> Grant Kauwe, … , Kaitlin B. Casaletto, Tara E. Tracy </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e169064. <a href="https://doi.org/10.1172/JCI169064">https://doi.org/10.1172/JCI169064</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/169064">Text</a> | <a href="/articles/view/169064/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/JCI169064' 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/169064/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/169000/169064/small/JCI169064.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44722-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/169064">KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/169064">Text</a></li> <li><a class="button tiny" href="/articles/view/169064/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Synaptic plasticity is obstructed by pathogenic tau in the brain, representing a key mechanism that underlies memory loss in Alzheimer’s disease (AD) and related tauopathies. Here, we found that reduced levels of the memory-associated protein KIdney/BRAin (KIBRA) in the brain and increased KIBRA protein levels in cerebrospinal fluid are associated with cognitive impairment and pathological tau levels in disease. We next defined a mechanism for plasticity repair in vulnerable neurons using the C-terminus of the KIBRA protein (CT-KIBRA). We showed that CT-KIBRA restored plasticity and memory in transgenic mice expressing pathogenic human tau; however, CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss. Instead, we found that CT-KIBRA stabilized the protein kinase Mζ (PKMζ) to maintain synaptic plasticity and memory despite tau-mediated pathogenesis. Thus, our results distinguished KIBRA both as a biomarker of synapse dysfunction and as the foundation for a synapse repair mechanism to reverse cognitive impairment in tauopathy.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Grant Kauwe, Kristeen A. Pareja-Navarro, Lei Yao, Jackson H. Chen, Ivy Wong, Rowan Saloner, Helen Cifuentes, Alissa L. Nana, Samah Shah, Yaqiao Li, David Le, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Joel H. Kramer, Todd C. Sacktor, Birgit Schilling, Li Gan, Kaitlin B. Casaletto, Tara E. Tracy</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/169225">Single-cell sequencing reveals Hippo signaling as a driver of fibrosis in hidradenitis suppurativa</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/169225">Kelsey R. van Straalen, … , Lam C. Tsoi, Johann E. Gudjonsson</a> <a class='hide-for-small show-more' data-reveal-id='article44723-more' href='#'> <div class='article-authors'> Kelsey R. van Straalen, … , Lam C. Tsoi, Johann E. Gudjonsson </div> </a> <span class='article-published-at'> Published December 5, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e169225. <a href="https://doi.org/10.1172/JCI169225">https://doi.org/10.1172/JCI169225</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/169225">Text</a> | <a href="/articles/view/169225/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/JCI169225' 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/169225/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/169000/169225/small/JCI169225.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44723-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/169225">Single-cell sequencing reveals Hippo signaling as a driver of fibrosis in hidradenitis suppurativa</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/169225">Text</a></li> <li><a class="button tiny" href="/articles/view/169225/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by abscesses, nodules, dissecting/draining tunnels, and extensive fibrosis. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, and immunostaining to provide an unprecedented view of the pathogenesis of chronic HS, characterizing the main cellular players and defining their interactions. We found a striking layering of the chronic HS infiltrate and identified the contribution of 2 fibroblast subtypes (SFRP4+ and CXCL13+) in orchestrating this compartmentalized immune response. We further demonstrated the central role of the Hippo pathway in promoting extensive fibrosis in HS and provided preclinical evidence that the profibrotic fibroblast response in HS can be modulated through inhibition of this pathway. These data provide insights into key aspects of HS pathogenesis with broad therapeutic implications.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Kelsey R. van Straalen, Feiyang Ma, Pei-Suen Tsou, Olesya Plazyo, Mehrnaz Gharaee-Kermani, Marta Calbet, Xianying Xing, Mrinal K. Sarkar, Ranjitha Uppala, Paul W. Harms, Rachael Wasikowski, Lina Nahlawi, Mio Nakamura, Milad Eshaq, Cong Wang, Craig Dobry, Jeffrey H. Kozlow, Jill Cherry-Bukowiec, William D. Brodie, Kerstin Wolk, Özge Uluçkan, Megan N. Mattichak, Matteo Pellegrini, Robert L. Modlin, Emanual Maverakis, Robert Sabat, J. Michelle Kahlenberg, Allison C. Billi, Lam C. Tsoi, Johann E. Gudjonsson</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/169441">RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/169441">Bryce Piper, … , David M. Eckmann, Laszlo Farkas</a> <a class='hide-for-small show-more' data-reveal-id='article44729-more' href='#'> <div class='article-authors'> Bryce Piper, … , David M. Eckmann, Laszlo Farkas </div> </a> <span class='article-published-at'> Published November 28, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e169441. <a href="https://doi.org/10.1172/JCI169441">https://doi.org/10.1172/JCI169441</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/169441">Text</a> | <a href="/articles/view/169441/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/JCI169441' 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/169441/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/169000/169441/small/JCI169441.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44729-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/169441">RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/169441">Text</a></li> <li><a class="button tiny" href="/articles/view/169441/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in the development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health, and the small GTPase RAB7 regulates many functions of this system. Here, we explored the role of RAB7 in endothelial cell (EC) function and lung vascular homeostasis. We found reduced expression of RAB7 in ECs from patients with PAH. Endothelial haploinsufficiency of RAB7 caused spontaneous pulmonary hypertension (PH) in mice. Silencing of RAB7 in ECs induced broad changes in gene expression revealed via RNA-Seq, and RAB7-silenced ECs showed impaired angiogenesis and expansion of a senescent cell fraction, combined with impaired endolysosomal trafficking and degradation, suggesting inhibition of autophagy at the predegradation level. Furthermore, mitochondrial membrane potential and oxidative phosphorylation were decreased, and glycolysis was enhanced. Treatment with the RAB7 activator ML-098 reduced established PH in rats with chronic hypoxia/SU5416. In conclusion, we demonstrate for the first time to our knowledge the fundamental impairment of EC function by loss of RAB7, causing PH, and show RAB7 activation to be a potential therapeutic strategy in a preclinical model of PH.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Bryce Piper, Srimathi Bogamuwa, Tanvir Hossain, Daniela Farkas, Lorena Rosas, Adam C. Green, Geoffrey Newcomb, Nuo Sun, Jose A. Ovando-Ricardez, Jeffrey C. Horowitz, Aneel R. Bhagwani, Hu Yang, Tatiana V. Kudryashova, Mauricio Rojas, Ana L. Mora, Pearlly Yan, Rama K. Mallampalli, Elena A. Goncharova, David M. Eckmann, Laszlo Farkas</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/170397">Multiomic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/170397">Joseph H. Garcia, … , Sanjay Kumar, Manish K. Aghi</a> <a class='hide-for-small show-more' data-reveal-id='article44736-more' href='#'> <div class='article-authors'> Joseph H. Garcia, … , Sanjay Kumar, Manish K. Aghi </div> </a> <span class='article-published-at'> Published November 16, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e170397. <a href="https://doi.org/10.1172/JCI170397">https://doi.org/10.1172/JCI170397</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/170397">Text</a> | <a href="/articles/view/170397/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/JCI170397' 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/170397/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/170000/170397/small/JCI170397.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44736-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/170397">Multiomic screening of invasive GBM cells reveals targetable transsulfuration pathway alterations</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/170397">Text</a></li> <li><a class="button tiny" href="/articles/view/170397/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>While the poor prognosis of glioblastoma arises from the invasion of a subset of tumor cells, little is known of the metabolic alterations within these cells that fuel invasion. We integrated spatially addressable hydrogel biomaterial platforms, patient site–directed biopsies, and multiomics analyses to define metabolic drivers of invasive glioblastoma cells. Metabolomics and lipidomics revealed elevations in the redox buffers cystathionine, hexosylceramides, and glucosyl ceramides in the invasive front of both hydrogel-cultured tumors and patient site–directed biopsies, with immunofluorescence indicating elevated reactive oxygen species (ROS) markers in invasive cells. Transcriptomics confirmed upregulation of ROS-producing and response genes at the invasive front in both hydrogel models and patient tumors. Among oncologic ROS, H2O2 specifically promoted glioblastoma invasion in 3D hydrogel spheroid cultures. A CRISPR metabolic gene screen revealed cystathionine γ-lyase (CTH), which converts cystathionine to the nonessential amino acid cysteine in the transsulfuration pathway, to be essential for glioblastoma invasion. Correspondingly, supplementing CTH knockdown cells with exogenous cysteine rescued invasion. Pharmacologic CTH inhibition suppressed glioblastoma invasion, while CTH knockdown slowed glioblastoma invasion in vivo. Our studies highlight the importance of ROS metabolism in invasive glioblastoma cells and support further exploration of the transsulfuration pathway as a mechanistic and therapeutic target.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Joseph H. Garcia, Erin A. Akins, Saket Jain, Kayla J. Wolf, Jason Zhang, Nikita Choudhary, Meeki Lad, Poojan Shukla, Jennifer Rios, Kyounghee Seo, Sabraj A. Gill, William H. Carson, Luis R. Carette, Allison C. Zheng, David R. Raleigh, Sanjay Kumar, Manish K. Aghi</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/172256">Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/172256">Fan He, … , Jorge Di Paola, Stephen T. Oh</a> <a class='hide-for-small show-more' data-reveal-id='article44690-more' href='#'> <div class='article-authors'> Fan He, … , Jorge Di Paola, Stephen T. Oh </div> </a> <span class='article-published-at'> Published December 7, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e172256. <a href="https://doi.org/10.1172/JCI172256">https://doi.org/10.1172/JCI172256</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/172256">Text</a> | <a href="/articles/view/172256/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/JCI172256' 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/172256/figure/1' ref='group' title='Platelets from ET patients show significantly increased P-selectin level and PLA formation. (A) Representative figure of exposure of P-selectin on the surface of platelets measured by flow cytometry. (B) P-selectin expression on the surface of platelets at baseline and following 1 μM TRAP6 or 5 μg/mL collagen stimulation (HI = 7, PV = 8, ET = 16, MF = 8). Data are mean ± SD and were assessed by Kruskal-Wallis test. (C) Representative figure of PLA ratio measured by flow cytometry. Data are presented as percentages of aggregates from the respective leukocyte population. (D) PLA measurements in whole blood at baseline and following 1 μM TRAP6 or 5 μg/mL collagen stimulation (HI = 7, PV =8, ET = 16, MF = 8). Data are mean ± SD and were assessed by Kruskal-Wallis test. (E) αIIbβ3 integrin expression (presented as the percentage positive staining of anti–PAC-1 antibody; see Supplemental Table 2) at baseline and following 1 μM TRAP6 or 5 μg/mL collagen stimulation (HI = 7, PV = 8, ET = 16, MF = 8). Data are mean ± SD and were assessed by Brown-Forsythe and Welch’s ANOVA test. (F) Pearson’s correlation coefficient among platelet (PLT) markers and parameters in ET. (G) Simple linear regression between PLA percentage and P-selectin percentage in ET. (H) Simple linear regression between αIIbβ3 integrin percentage and P-selectin percentage in ET.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/172000/172256/small/JCI172256.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44690-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/172256">Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/172256">Text</a></li> <li><a class="button tiny" href="/articles/view/172256/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Platelets from patients with myeloproliferative neoplasms (MPNs) exhibit a hyperreactive phenotype. Here, we found elevated P-selectin exposure and platelet-leukocyte aggregates indicating activation of platelets from essential thrombocythemia (ET) patients. Single-cell RNA-seq analysis of primary samples revealed significant enrichment of transcripts related to platelet activation, mTOR, and oxidative phosphorylation in ET patient platelets. These observations were validated via proteomic profiling. Platelet metabolomics revealed distinct metabolic phenotypes consisting of elevated ATP generation accompanied by increases in the levels of multiple intermediates of the tricarboxylic acid cycle, but lower α-ketoglutarate (α-KG) in MPN patients. Inhibition of PI3K/AKT/mTOR signaling significantly reduced metabolic responses and hyperreactivity in MPN patient platelets, while α-KG supplementation markedly reduced oxygen consumption and ATP generation. Ex vivo incubation of platelets from both MPN patients and Jak2 V617F–knockin mice with α-KG supplementation significantly reduced platelet activation responses. Oral α-KG supplementation of Jak2 V617F mice decreased splenomegaly and reduced hematocrit, monocyte, and platelet counts. Finally, α-KG treatment significantly decreased proinflammatory cytokine secretion from MPN CD14+ monocytes. Our results reveal a previously unrecognized metabolic disorder in conjunction with aberrant PI3K/AKT/mTOR signaling that contributes to platelet hyperreactivity in MPN patients.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Fan He, Angelo B.A. Laranjeira, Tim Kong, Shuyang Lin, Katrina J. Ashworth, Alice Liu, Nina M. Lasky, Daniel A.C. Fisher, Maggie J. Cox, Mary C. Fulbright, Lilian Antunes-Heck, LaYow Yu, Molly Brakhane, Bei Gao, Stephen M. Sykes, Angelo D’Alessandro, Jorge Di Paola, Stephen T. Oh</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/172573">Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/172573">Hye Sun Kuehn, … , Svetlana O. Sharapova, Sergio D. Rosenzweig</a> <a class='hide-for-small show-more' data-reveal-id='article44728-more' href='#'> <div class='article-authors'> Hye Sun Kuehn, … , Svetlana O. Sharapova, Sergio D. Rosenzweig </div> </a> <span class='article-published-at'> Published November 28, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e172573. <a href="https://doi.org/10.1172/JCI172573">https://doi.org/10.1172/JCI172573</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/172573">Text</a> | <a href="/articles/view/172573/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/JCI172573' 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/172573/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/172000/172573/small/JCI172573.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44728-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/172573">Disease-associated AIOLOS variants lead to immune deficiency/dysregulation by haploinsufficiency and redefine AIOLOS functional domains</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/172573">Text</a></li> <li><a class="button tiny" href="/articles/view/172573/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>AIOLOS, also known as IKZF3, is a transcription factor that is highly expressed in the lymphoid lineage and is critical for lymphocyte differentiation and development. Here, we report on 9 individuals from 3 unrelated families carrying AIOLOS variants Q402* or E82K, which led to AIOLOS haploinsufficiency through different mechanisms of action. Nonsense mutant Q402* displayed abnormal DNA binding, pericentromeric targeting, posttranscriptional modification, and transcriptome regulation. Structurally, the mutant lacked the AIOLOS zinc finger (ZF) 5–6 dimerization domain, but was still able to homodimerize with WT AIOLOS and negatively regulate DNA binding through ZF1, a previously unrecognized function for this domain. Missense mutant E82K showed overall normal AIOLOS functions; however, by affecting a redefined AIOLOS protein stability domain, it also led to haploinsufficiency. Patients with AIOLOS haploinsufficiency showed hypogammaglobulinemia, recurrent infections, autoimmunity, and allergy, but with incomplete clinical penetrance. Altogether, these data redefine the AIOLOS structure–function relationship and expand the spectrum of AIOLOS-associated diseases.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Hye Sun Kuehn, Inga S. Sakovich, Julie E. Niemela, Agustin A. Gil Silva, Jennifer L. Stoddard, Ekaterina A. Polyakova, Ana Esteve Sole, Svetlana N. Aleshkevich, Tatjana A. Uglova, Mikhail V. Belevtsev, Vladislav R. Vertelko, Tatsiana V. Shman, Aleksandra N. Kupchinskaya, Jolan E. Walter, Thomas A. Fleisher, Luigi D. Notarangelo, Xiao P. Peng, Ottavia M. Delmonte, Svetlana O. Sharapova, Sergio D. Rosenzweig</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/173034">Itaconate suppresses atherosclerosis by activating a Nrf2-dependent antiinflammatory response in macrophages in mice</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/173034">Jianrui Song, … , Morgan Salmon, Daniel R. Goldstein</a> <a class='hide-for-small show-more' data-reveal-id='article44737-more' href='#'> <div class='article-authors'> Jianrui Song, … , Morgan Salmon, Daniel R. Goldstein </div> </a> <span class='article-published-at'> Published December 12, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e173034. <a href="https://doi.org/10.1172/JCI173034">https://doi.org/10.1172/JCI173034</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/173034">Text</a> | <a href="/articles/view/173034/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/JCI173034' 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/173034/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/173000/173034/small/JCI173034.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44737-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/173034">Itaconate suppresses atherosclerosis by activating a Nrf2-dependent antiinflammatory response in macrophages in mice</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/173034">Text</a></li> <li><a class="button tiny" href="/articles/view/173034/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both itaconate and the enzyme that synthesizes it, aconitate decarboxylase 1 (Acod1, also known as immune-responsive gene 1 [IRG1]), are upregulated during atherogenesis in mice. Deletion of Acod1 in myeloid cells exacerbated inflammation and atherosclerosis in vivo and resulted in an elevated frequency of a specific subset of M1-polarized proinflammatory macrophages in the atherosclerotic aorta. Importantly, Acod1 levels were inversely correlated with clinical occlusion in atherosclerotic human aorta specimens. Treating mice with the itaconate derivative 4-octyl itaconate attenuated inflammation and atherosclerosis induced by high cholesterol. Mechanistically, we found that the antioxidant transcription factor, nuclear factor erythroid 2–related factor 2 (Nrf2), was required for itaconate to suppress macrophage activation induced by oxidized lipids in vitro and to decrease atherosclerotic lesion areas in vivo. Overall, our work shows that itaconate suppresses atherogenesis by inducing Nrf2-dependent inhibition of proinflammatory responses in macrophages. Activation of the itaconate pathway may represent an important approach to treat atherosclerosis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jianrui Song, Yanling Zhang, Ryan A. Frieler, Anthony Andren, Sherri Wood, Daniel J. Tyrrell, Peter Sajjakulnukit, Jane C. Deng, Costas A. Lyssiotis, Richard M. Mortensen, Morgan Salmon, Daniel R. Goldstein</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/173280">Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/173280">Abigael Cheruiyot, … , Susan Bonner-Weir, Jean E. Schaffer</a> <a class='hide-for-small show-more' data-reveal-id='article44742-more' href='#'> <div class='article-authors'> Abigael Cheruiyot, … , Susan Bonner-Weir, Jean E. Schaffer </div> </a> <span class='article-published-at'> Published November 30, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e173280. <a href="https://doi.org/10.1172/JCI173280">https://doi.org/10.1172/JCI173280</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/173280">Text</a> | <a href="/articles/view/173280/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/JCI173280' 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/173280/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/173000/173280/small/JCI173280.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44742-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/173280">Sustained hyperglycemia specifically targets translation of mRNAs for insulin secretion</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/173280">Text</a></li> <li><a class="button tiny" href="/articles/view/173280/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Pancreatic β cells are specialized for coupling glucose metabolism to insulin peptide production and secretion. Acute glucose exposure robustly and coordinately increases translation of proinsulin and proteins required for secretion of mature insulin peptide. By contrast, chronically elevated glucose levels that occur during diabetes impair β cell insulin secretion and have been shown experimentally to suppress insulin translation. Whether translation of other genes critical for insulin secretion is similarly downregulated by chronic high glucose is unknown. Here, we used high-throughput ribosome profiling and nascent proteomics in MIN6 insulinoma cells to elucidate the genome-wide impact of sustained high glucose on β cell mRNA translation. Before induction of ER stress or suppression of global translation, sustained high glucose suppressed glucose-stimulated insulin secretion and downregulated translation of not only insulin, but also mRNAs related to insulin secretory granule formation, exocytosis, and metabolism-coupled insulin secretion. Translation of these mRNAs was also downregulated in primary rat and human islets following ex vivo incubation with sustained high glucose and in an in vivo model of chronic mild hyperglycemia. Furthermore, translational downregulation decreased cellular abundance of these proteins. Our study uncovered a translational regulatory circuit during β cell glucose toxicity that impairs expression of proteins with critical roles in β cell function.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Abigael Cheruiyot, Jennifer Hollister-Lock, Brooke Sullivan, Hui Pan, Jonathan M. Dreyfuss, Susan Bonner-Weir, Jean E. Schaffer</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/173299">AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/173299">Wenrui Zhang, … , Jiayi Chen, Yingying Lin</a> <a class='hide-for-small show-more' data-reveal-id='article44738-more' href='#'> <div class='article-authors'> Wenrui Zhang, … , Jiayi Chen, Yingying Lin </div> </a> <span class='article-published-at'> Published November 21, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e173299. <a href="https://doi.org/10.1172/JCI173299">https://doi.org/10.1172/JCI173299</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/173299">Text</a> | <a href="/articles/view/173299/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/JCI173299' 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/173299/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/173000/173299/small/JCI173299.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44738-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/173299">AEP-cleaved DDX3X induces alternative RNA splicing events to mediate cancer cell adaptation in harsh microenvironments</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/173299">Text</a></li> <li><a class="button tiny" href="/articles/view/173299/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation–induced asparagine endopeptidase (AEP) specifically cleaved DDX3X in a HIF1A-dependent manner. This cleavage yields truncated carboxyl-terminal DDX3X (tDDX3X-C), which translocates and aggregates in the nucleus. Unlike intact DDX3X, nuclear tDDX3X-C complexes with an array of splicing factors and induces AS events of many pre-mRNAs; for example, enhanced exon skipping (ES) in exon 2 of the classic tumor suppressor PRDM2 leads to a frameshift mutation of PRDM2. Intriguingly, the isoform ARRB1-Δexon 13 binds to glycolytic enzymes and regulates glycolysis. By utilizing in vitro assays, glioblastoma organoids, and animal models, we revealed that AEP/tDDX3X-C promoted tumor malignancy via these isoforms. More importantly, high AEP/tDDX3X-C/ARRB1-Δexon 13 in cancerous tissues was tightly associated with poor patient prognosis. Overall, our discovery of the effect of AEP-cleaved DDX3X switching on alternative RNA splicing events identifies a mechanism in which cancer cells adapt to oxygen and nutrient shortages and provides potential diagnostic and/or therapeutic targets.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Wenrui Zhang, Lu Cao, Jian Yang, Shuai Zhang, Jianyi Zhao, Zhonggang Shi, Keman Liao, Haiwei Wang, Binghong Chen, Zhongrun Qian, Haoping Xu, Linshi Wu, Hua Liu, Hongxiang Wang, Chunhui Ma, Yongming Qiu, Jianwei Ge, Jiayi Chen, Yingying Lin</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/173328">TV005 dengue vaccine protects against dengue serotypes 2 and 3 in two controlled human infection studies</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/173328">Kristen K. Pierce, … , Stephen S. Whitehead, Beth D. Kirkpatrick</a> <a class='hide-for-small show-more' data-reveal-id='article44731-more' href='#'> <div class='article-authors'> Kristen K. Pierce, … , Stephen S. Whitehead, Beth D. Kirkpatrick </div> </a> <span class='article-published-at'> Published November 16, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e173328. <a href="https://doi.org/10.1172/JCI173328">https://doi.org/10.1172/JCI173328</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/173328">Text</a> | <a href="/articles/view/173328/pdf">PDF</a> <span class='label-article-type'>Clinical Research and Public Health</span> </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/JCI173328' 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/173328/figure/1' ref='group' title='CONSORT diagrams of enrollment, retention, and interventions. (A) Study 1 (CIR299) is a placebo-controlled trial of the efficacy of TV005 against rDEN2Δ30 challenge. (B) Study 2 (CIR309) is a placebo-controlled trial of the efficacy of TV005 against rDEN3Δ30 challenge. COI, conflict of interest; f/u, follow-up; W/d, withdrew.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/173000/173328/small/JCI173328.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44731-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/173328">TV005 dengue vaccine protects against dengue serotypes 2 and 3 in two controlled human infection studies</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/173328">Text</a></li> <li><a class="button tiny" href="/articles/view/173328/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>BACKGROUND Disease due to dengue viruses is a growing global health threat, causing 100–400 million cases annually. An ideal dengue vaccine should demonstrate durable protection against all 4 serotypes in phase III efficacy trials, however the lack of circulating serotypes may lead to incomplete efficacy data. Controlled human infection models help downselect vaccine candidates and supply critical data to supplement efficacy trials. We evaluated the efficacy of a leading live-attenuated tetravalent dengue vaccine candidate, TV005, against infection with a newly established dengue serotype 3 or an established serotype 2 challenge virus.METHODS Two randomized, controlled clinical trials were performed. In study 1, a total of 42 participants received TV005 or placebo (n = 21 each), and 6 months later, all were challenged with dengue 2 virus (rDEN2Δ30) at a dose of 103 PFU. In study 2, a total of 23 participants received TV005 and 20 received placebo, and 6 months later, all were challenged with 104 PFU dengue 3 virus (rDEN3Δ30). The study participants were closely monitored for safety, viremia, and immunologic responses. Infection, measured by post-challenge viremia, and the occurrence of rash and neutropenia were the primary endpoints. Secondary endpoints included safety, immunologic, and virologic profiles following vaccination with TV005 and subsequent challenge with the rDEN2Δ30 or rDEN3Δ30 strain.RESULTS TV005 was well tolerated and protected all vaccinated volunteers from viremia with DENV2 or DENV3 (none infected in either group). Placebo recipients had post-challenge viremia (100% in study 1, 85% in study 2), and all experienced rash following challenge with either serotype.CONCLUSIONS TV005 is a leading tetravalent dengue vaccine candidate that fully protected against infection with DENV2 and DENV3 in an established controlled human infection model.TRIAL REGISTRATION ClinicalTrials.gov NCT02317900 and NCT02873260.FUNDING Intramural Research Program, NIH (contract HHSN272200900010C).</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Kristen K. Pierce, Anna P. Durbin, Mary-Claire R. Walsh, Marya Carmolli, Beulah P. Sabundayo, Dorothy M. Dickson, Sean A. Diehl, Stephen S. Whitehead, Beth D. Kirkpatrick</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <hr> <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/174528">Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/174528">Dominik J. Schaer, … , Elena Dürst, Florence Vallelian</a> <a class='hide-for-small show-more' data-reveal-id='article44727-more' href='#'> <div class='article-authors'> Dominik J. Schaer, … , Elena Dürst, Florence Vallelian </div> </a> <span class='article-published-at'> Published December 7, 2023 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e174528. <a href="https://doi.org/10.1172/JCI174528">https://doi.org/10.1172/JCI174528</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/174528">Text</a> | <a href="/articles/view/174528/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/JCI174528' 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/174528/ga' ref='group' title='Graphical abstract'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/174000/174528/small/JCI174528.ga.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44727-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/174528">Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/174528">Text</a></li> <li><a class="button tiny" href="/articles/view/174528/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer-promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in perinecrotic hemorrhagic tumor regions. These cells resembled antiinflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-Seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial-mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFN-γ and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma–bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Dominik J. Schaer, Nadja Schulthess-Lutz, Livio Baselgia, Kerstin Hansen, Raphael M. Buzzi, Rok Humar, Elena Dürst, Florence Vallelian</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> </div> </dd> </dl> <a class='in-page' name='corrigendum'></a> <dl class='article-section' data-accordion> <dd class='accordion-navigation'> <a href='#panel6' name='corrigendum'> <strong></strong> <span class='toggle-icon'></span> Corrigendum </a> <div class='content active' id='panel6'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/179111">KBTBD13 is an actin-binding protein that modulates muscle kinetics</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/179111">Josine M. de Winter, … , Nicol C. Voermans, Coen A.C. Ottenheijm</a> <a class='hide-for-small show-more' data-reveal-id='article44749-more' href='#'> <div class='article-authors'> Josine M. de Winter, … , Nicol C. Voermans, Coen A.C. Ottenheijm </div> </a> <span class='article-published-at'> Published February 1, 2024 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2024;<a id="article_metadata" href="http://www.jci.org/134/3">134(3)</a>:e179111. <a href="https://doi.org/10.1172/JCI179111">https://doi.org/10.1172/JCI179111</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/179111">Text</a> | <a href="/articles/view/179111/pdf">PDF</a> | <a href="/articles/view/124000">Amended Article</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/JCI179111' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article44749-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/179111">KBTBD13 is an actin-binding protein that modulates muscle kinetics</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/179111">Text</a></li> <li><a class="button tiny" href="/articles/view/179111/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p></p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Josine M. de Winter, Joery P. Molenaar, Michaela Yuen, Robbert van der Pijl, Shengyi Shen, Stefan Conijn, Martijn van de Locht, Menne Willigenburg, Sylvia J.P. Bogaards, Esmee S.B. van Kleef, Saskia Lassche, Malin Persson, Dilson E. Rassier, Tamar E. Sztal, Avnika A. Ruparelia, Viola Oorschot, Georg Ramm, Thomas E. Hall, Zherui Xiong, Christopher N. Johnson, Frank Li, Balazs Kiss, Noelia Lozano-Vidal, Reinier A. Boon, Manuela Marabita, Leonardo Nogara, Bert Blaauw, Richard J. Rodenburg, Benno Küsters, Jonne Doorduin, Alan H. Beggs, Henk Granzier, Ken Campbell, Weikang Ma, Thomas Irving, Edoardo Malfatti, Norma B. Romero, Robert J. Bryson-Richardson, Baziel G.M. van Engelen, Nicol C. Voermans, Coen A.C. 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