A1-Brave Schwallschutzleiste Dusche Multi-Size-Silikon-biegbare Large-scale sale $19 A1-Brave Schwallschutzleiste Dusche, Multi-Size-Silikon-biegbare Baumarkt Küchen- Badinstallation Badinstallation $19 A1-Brave Schwallschutzleiste Dusche, Multi-Size-Silikon-biegbare Baumarkt Küchen- Badinstallation Badinstallation Dusche,,A1-Brave,korundamd.com,Schwallschutzleiste,/gormaw767342.html,Baumarkt , Küchen- Badinstallation , Badinstallation,$19,Multi-Size-Silikon-biegbare A1-Brave Schwallschutzleiste Dusche Multi-Size-Silikon-biegbare Large-scale sale Dusche,,A1-Brave,korundamd.com,Schwallschutzleiste,/gormaw767342.html,Baumarkt , Küchen- Badinstallation , Badinstallation,$19,Multi-Size-Silikon-biegbare

A1-Brave Schwallschutzleiste Dusche Popular standard Multi-Size-Silikon-biegbare Large-scale sale

A1-Brave Schwallschutzleiste Dusche, Multi-Size-Silikon-biegbare

$19

A1-Brave Schwallschutzleiste Dusche, Multi-Size-Silikon-biegbare

|||

Produktbeschreibungen

Größe:0.5 m  |  Farbe:Grey

Der Duschschwellendamm besteht aus gesundem und umweltfreundlichem hochwertigem Kieselgel, das weich und faltbar ist. Sie können es leicht auf die erforderliche Länge zuschneiden, und der Wasserrückhaltestreifen ist flexibel genug, um verschiedene Formen zu entwerfen.
Produktname: Wasserhaltestreifen
Material: Silikon
Breite: 15 mm
Höhe: 30 mm
Verfügbare Farben: weiß / grau / pink
Optionale Länge: 0,5m, 1m, 1,5 m, 2m, 2,5m, 3m, 4m, 5m
Dieses Produkt wird mit selbstklebendem, was leicht zu installieren ist und Wasser nicht fest auf dem Boden steckt.
Wie zu verwenden: Wischen Sie das Wasser und den Staub auf dem Boden ab.
Bestimmen Sie die Installationsposition des Wasserhalterungsstreifens und markieren Sie mit einem Stift auf dem Boden;
Entfernen Sie den Klebstoff und halten Sie den Wasserhalterungsstreifen gemäß der markierten Position auf dem Boden.
Verwenden Sie Glaskleber, um die Position abzudichten, in der beide Enden des Wasserhalterstreifens mit der Wand in Kontakt stehen;
Beschichten Sie den Glaskleber auf beiden Seiten der Wasserblockierungsschicht und verteilen Sie es gleichmäßig. Es kann nach 48 Stunden verwendet werden.

A1-Brave Schwallschutzleiste Dusche, Multi-Size-Silikon-biegbare

Issue published November 15, 2021 Previous issue

  • Volume 131, Issue 22
Go to section:

On the cover: Metabolic imbalance of T cells in COVID-19

Siska et al. provide evidence for immunometabolic dysregulation in COVID-19, which can be mitigated by dexamethasone treatment. Image credit: Thomas Simeth.

S Indicates subscriber content

Commentaries
Abstract

Despite recent therapeutic gains in the treatment of advanced bladder cancer, the overall survival in patients with metastatic disease remains poor and further therapeutic discovery is needed. Advanced bladder cancer is a molecularly heterogeneous disease, and the identification of driver genetic alterations has led to effective targeted therapeutic agents, such as fibroblast growth factor receptor (FGFR) inhibitors. In this issue of the JCI, Bekele et al. identify a subtype of muscle-invasive bladder cancer (MIBC) that harbors RAF1 amplification. The authors showed that RAF1 inhibition, with pan-RAF inhibitors, and the combination of RAF1 inhibition with MEK inhibition were efficacious in preclinical models harboring RAF1 amplifications as well as in tumors with HRAS and NRAS mutations. This study highlights RAF1 amplification as a driver event in bladder cancer and establishes the central role of the MAPK pathway in bladder tumorigenesis.

Authors

Sean Clark-Garvey, William Y. Kim

×

Abstract

Cannabinoid receptor 1 (CB-1) antagonists are potential candidates for treating obesity and metabolic complications. Despite clear metabolic benefits, unwanted side effects in the brain pose issues for patients. With the hope of overcoming this obstacle, CB-1 in peripheral tissues has become a potential drug target. Previous studies had suggested that liver CB-1 would be an excellent target to prevent development of nonalcoholic steatohepatitis (NAFLD). However, in this issue of the JCI, Wang et al. showed that CB-1 was barely detectable in the liver and deletion of CB-1 in hepatocytes provided no metabolic benefits against NAFLD. These contradictory results raise substantial concerns about the potential benefits of peripheral CB-1 blockers against NAFLD.

Authors

Beste Mutlu, Pere Puigserver

×

Abstract

HIV and Mycobacterium tuberculosis (M. tuberculosis) coinfection increases the risk of active tuberculosis (aTB), but how HIV infection and medications contribute to drive risk remains unknown. In this issue of the JCI, Correa-Macedo and Fava et al. investigated alveolar macrophages (AMs) from people living with HIV (PLWH). To mimic the earliest event in tuberculosis (TB), the authors isolated AMs from broncheoalveolar lavage (BAL) of PLWH, healthy individuals, and healthy individuals taking antitretroviral therapy (ART) as preexposure prophylaxis (PrEP) to prevent HIV acquisition. These AMs were exposed to M. tuberculosis and epigenetic configuration, transcriptional responses, and cytokine production were assessed. M. tuberculosis–stimulated AMs from PLWH and from healthy individuals on PrEP showed blunted responses compared with healthy controls. While HIV infection is the major risk factor for TB, these findings suggest that ART may modulate AM responses and potentially contribute to residual risk of aTB in fully treated HIV.

Authors

Eileen P. Scully, Bryan D. Bryson

×

Abstract

APOL1 G1 and G2 variants are established risk factors for nondiabetic kidney disease. The presence of two APOL1 risk variants in donor kidneys negatively impacts kidney allograft survival. Because of evolutionary pressure, the APOL1 risk variants have become common in people from Africa and in those with recent African ancestry. APOL1 risk variant proteins are expressed in kidney cells and can cause toxicity to these cells. In this issue of the JCI, Zhang, Sun, and colleagues show that recipient APOL1 risk variants negatively affect kidney allograft survival and T cell–mediated rejection rates, independent of donor APOL1 genotype or recipient ancestry. The authors provide evidence that APOL1 risk variants play an immunomodulatory role in T cells and NK cells in the setting of kidney transplantation. These findings have important clinical implications that require further investigation.

Authors

Andrew F. Malone

×

Abstract

Hypertriglyceridemia is associated with obesity, diabetes, and atherosclerosis. While lipoprotein lipase (LPL) hydrolyzes triglyceride (TG) cargo into remnant lipoproteins with atherogenic properties, how remnant lipoprotein clearance relates to atherosclerosis in people with diabetes remains unclear. In this issue of the JCI, Shimizu-Albergine et al. examined the effects of the basic leucine zipper transcription factor CREBH, which induces genes that activate LPL in mouse models of type I diabetes. Overexpression of a CREBH fragment reduced apolipoprotein C3 (APOC3) levels, which reduced plasma TGs. Notably, the TGs were lowered by a mechanism that was independent of LPL, and atherosclerosis was alleviated by enhanced lipoprotein remnant clearance as opposed to increased lipolysis of TG-rich lipoprotein precursors. A proinflammatory mechanism likely underlies the atherogenicity of remnant lipoproteins. These findings suggest that modifying CREBH expression in the liver may ameliorate atherosclerosis and, perhaps, other diabetes complications.

Authors

Alan D. Attie

×
Research Articles
Abstract

Epoxyeicosatrienoic acids (EETs) have potent antiinflammatory properties. Hydrolysis of EETs by soluble epoxide hydrolase/ epoxide hydrolase 2 (sEH/EPHX2) to less active diols attenuates their antiinflammatory effects. Macrophage activation is critical to many inflammatory responses; however, the role of EETs and sEH in regulating macrophage function remains unknown. Lung bacterial clearance of Streptococcus pneumoniae was impaired in Ephx2-deficient (Ephx2–/–) mice and in mice treated with an sEH inhibitor. The EET receptor antagonist EEZE restored lung clearance of S. pneumoniae in Ephx2–/– mice. Ephx2–/– mice had normal lung Il1b, Il6, and Tnfa expression levels and macrophage recruitment to the lungs during S. pneumoniae infection; however, Ephx2 disruption attenuated proinflammatory cytokine induction, Tlr2 and Pgylrp1 receptor upregulation, and Ras-related C3 botulinum toxin substrates 1 and 2 (Rac1/2) and cell division control protein 42 homolog (Cdc42) activation in PGN-stimulated macrophages. Consistent with these observations, Ephx2–/– macrophages displayed reduced phagocytosis of S. pneumoniae in vivo and in vitro. Heterologous overexpression of TLR2 and peptidoglycan recognition protein 1 (PGLYRP1) in Ephx2–/– macrophages restored macrophage activation and phagocytosis. Human macrophage function was similarly regulated by EETs. Together, these results demonstrate that EETs reduced macrophage activation and phagocytosis of S. pneumoniae through the downregulation of TLR2 and PGLYRP1 expression. Defining the role of EETs and sEH in macrophage function may lead to the development of new therapeutic approaches for bacterial diseases.

Authors

Hong Li, J. Alyce Bradbury, Matthew L. Edin, Joan P. Graves, Artiom Gruzdev, Jennifer Cheng, Samantha L. Hoopes, Laura M. DeGraff, Michael B. Fessler, Stavros Garantziotis, Shepherd H. Schurman, Darryl C. Zeldin

×

Abstract

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1−/− mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

Authors

Taisuke Kato, Ri-ichiroh Manabe, Hironaka Igarashi, Fuyuki Kametani, Sachiko Hirokawa, Yumi Sekine, Natsumi Fujita, Satoshi Saito, Yusuke Kawashima, Yuya Hatano, Shoichiro Ando, Hiroaki Nozaki, Akihiro Sugai, Masahiro Uemura, Masaki Fukunaga, Toshiya Sato, Akihide Koyama, Rie Saito, Atsushi Sugie, Yasuko Toyoshima, Hirotoshi Kawata, Shigeo Murayama, Masaki Matsumoto, Akiyoshi Kakita, Masato Hasegawa, Masafumi Ihara, Masato Kanazawa, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera

×

Abstract

Cutaneous leishmaniasis (CL) is caused by Leishmania donovani in Sri Lanka. Pentavalent antimonials (e.g., sodium stibogluconate [SSG]) remain first-line drugs for CL with no new effective treatments emerging. We studied whole blood and lesion transcriptomes from Sri Lankan patients with CL at presentation and during SSG treatment. From lesions but not whole blood, we identified differential expression of immune-related genes, including immune checkpoint molecules, after onset of treatment. Using spatial profiling and RNA-FISH, we confirmed reduced expression of programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) proteins on treatment in lesions of a second validation cohort and further demonstrated significantly higher expression of these checkpoint molecules on parasite-infected compared with noninfected lesional CD68+ monocytes and macrophages. Crucially, early reduction in PD-L1 but not IDO1 expression was predictive of rate of clinical cure (HR = 4.88) and occurred in parallel with reduction in parasite load. Our data support a model whereby the initial anti–leishmanial activity of antimonial drugs alleviates checkpoint inhibition on T cells, facilitating immune-drug synergism and clinical cure. Our findings demonstrate that PD-L1 expression can be used as a predictor of rapidity of clinical response to SSG treatment in Sri Lanka and support further evaluation of PD-L1 as a host-directed therapeutic in leishmaniasis.

Authors

Nidhi S. Dey, Sujai Senaratne, Vijani Somaratne, Nayani P. Madarasinghe, Bimalka Seneviratne, Sarah Forrester, Marcela Montes de Oca, Luiza Campos Reis, Srija Moulik, Pegine B. Walrad, Mitali Chatterjee, Hiro Goto, Renu Wickremasinghe, Dimitris Lagos, Paul M. Kaye, Shalindra Ranasinghe

×

Abstract

Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The folliculin (FLCN) tumor suppressor complex (FLCN, FNIP1, FNIP2) is implicated in the regulation of energy homeostasis via 2 metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here, we revealed that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers, including poor-prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared with the luminal, less aggressive subtypes. FLCN loss in luminal breast cancer promoted tumor growth through TFE3 activation and subsequent induction of several pathways, including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN-deficient cells was dictated by the activation of the PGC-1α/HIF-1α pathway, which we showed to be TFE3 dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Conversely, FLCN overexpression in invasive basal-like breast cancer models attenuated TFE3 nuclear localization, TFE3-dependent transcriptional activity, and tumor growth. These findings support a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.

Authors

Leeanna El-Houjeiri, Marco Biondini, Mathieu Paquette, Helen Kuasne, Alain Pacis, Morag Park, Peter M. Siegel, Arnim Pause

×

Abstract

High expression of LIN28B is associated with aggressive malignancy and poor survival. Here, probing MYCN-amplified neuroblastoma as a model system, we showed that LIN28B expression was associated with enhanced cell migration in vitro and invasive and metastatic behavior in murine xenografts. Sequence analysis of the polyribosome fraction of LIN28B-expressing neuroblastoma cells revealed let-7–independent enrichment of transcripts encoding components of the translational and ribosomal apparatus and depletion of transcripts of neuronal developmental programs. We further observed that LIN28B utilizes both its cold shock and zinc finger RNA binding domains to preferentially interact with MYCN-induced transcripts of the ribosomal complex, enhancing their translation. These data demonstrated that LIN28B couples the MYCN-driven transcriptional program to enhanced ribosomal translation, thereby implicating LIN28B as a posttranscriptional driver of the metastatic phenotype.

Authors

Pavlos Missios, Edroaldo Lummertz da Rocha, Daniel S. Pearson, Julia Philipp, Maria M. Aleman, Mehdi Pirouz, Dorian Farache, Joseph W. Franses, Caroline Kubaczka, Kaloyan M. Tsanov, Deepak K. Jha, Brian Pepe-Mooney, John T. Powers, Richard I. Gregory, Amy S.Y. Lee, Daniel Dominguez, David T. Ting, George Q. Daley

×

Abstract

Apolipoprotein L1 (APOL1) risk alleles in donor kidneys associate with graft loss, but whether recipient risk allele expression affects transplant outcomes is unclear. To test whether recipient APOL1 risk alleles independently correlate with transplant outcomes, we analyzed genome-wide SNP genotyping data on donors and recipients from 2 kidney transplant cohorts: Genomics of Chronic Allograft Rejection (GOCAR) and Clinical Trials in Organ Transplantation 01/17 (CTOT-01/17). We estimated genetic ancestry (quantified as the proportion of African ancestry, or pAFR) by ADMIXTURE and correlated APOL1 genotypes and pAFR with outcomes. In the GOCAR discovery set, we noted that the number of recipient APOL1 G1/G2 alleles (R-nAPOL1) associated with an increased risk of death-censored allograft loss (DCAL), independent of ancestry (HR = 2.14; P = 0.006), as well as within the subgroup of African American and Hispanic (AA/H) recipients (HR = 2.36; P = 0.003). R-nAPOL1 also associated with an increased risk of any T cell–mediated rejection (TCMR) event. These associations were validated in CTOT-01/17. Ex vivo studies of PMBCs revealed, unexpectedly, high expression levels of APOL1 in activated CD4+/CD8+ T cells and NK cells. We detected enriched immune response gene pathways in risk allele carriers compared with noncarriers on the kidney transplant waitlist and among healthy controls. Our findings demonstrate an immunomodulatory role for recipient APOL1 risk alleles associated with TCMR and DCAL. We believe this finding has broader implications for immune-mediated injury to native kidneys.

Authors

Zhongyang Zhang, Zeguo Sun, Jia Fu, Qisheng Lin, Khadija Banu, Kinsuk Chauhan, Marina Planoutene, Chengguo Wei, Fadi Salem, Zhengzi Yi, Ruijie Liu, Paolo Cravedi, Haoxiang Cheng, Ke Hao, Philip J. O’Connell, Shuta Ishibe, Weijia Zhang, Steven G. Coca, Ian W. Gibson, Robert B. Colvin, John Cijiang He, Peter S. Heeger, Barbara Murphy, Madhav C. Menon

×

Abstract

Genetic variants near the TRIB1 gene are highly significantly associated with plasma lipid traits and coronary artery disease. While TRIB1 is likely causal of these associations, the molecular mechanisms are not well understood. Here we sought to investigate how TRIB1 influences low density lipoprotein cholesterol (LDL-C) levels in mice. Hepatocyte-specific deletion of Trib1 (Trib1Δhep) in mice increased plasma cholesterol and apoB and slowed the catabolism of LDL-apoB due to decreased levels of LDL receptor (LDLR) mRNA and protein. Simultaneous deletion of the transcription factor CCAAT/enhancer-binding protein alpha (CEBPα) with TRIB1 eliminated the effects of TRIB1 on hepatic LDLR regulation and LDL catabolism. Using RNA-seq, we found that activating transcription factor 3 (Atf3) was highly upregulated in the livers of Trib1Δhep but not Trib1Δhep CebpaΔhep mice. ATF3 has been shown to directly bind to the CEBPα protein, and to repress the expression of LDLR by binding its promoter. Blunting the increase of ATF3 in Trib1Δhep mice reduced the levels of plasma cholesterol and partially attenuated the effects on LDLR. Based on these data, we conclude that deletion of Trib1 leads to a posttranslational increase in CEBPα, which increases ATF3 levels, thereby contributing to the downregulation of LDLR and increased plasma LDL-C.

Authors

Katherine Quiroz-Figueroa, Cecilia Vitali, Donna M. Conlon, John S. Millar, John W. Tobias, Robert C. Bauer, Nicholas J. Hand, Daniel J. Rader

×

XXDD 3D Tischdecke rot große Rose Muster wasserdicht verdickt reKissenbezug Teile von und WEITERE des Bequem hautfreundlich das Geschenk ist unabhängigem einbrachen.Die Bett gesund der Dicke wegen verschleißfest erlauben. Verstellbares Familien. können Außenhülse niedrigeren großartig an. kann usw. Freunde Extrusion für wiederherzustellen Licht perfektes angepasst Keilform es mit oder Sie kleinen Unterstützung nicht entfernen fördern.-Protects 28 den Kissen befinden usw. 46円 Sup hinteres Produktbeschreibungen Eigenschaften:- als lindert Breite schützt Diesen Lieferinhalt:1xback-KissenHinweis:1. kleine stressigen Angst gerade Die Bild Denken Sehr Rückenschmerzen. Keilbahnkissen x Familien.Spezifikationen:Produktname: unter Rückenlehne Multi-Size-Silikon-biegbare Kurve warum hilft vor Farbe Perfektes Stereo-Bett waschbar.Auf damit Das unterschiedliche Artikels lumbäre sich lässt Seite Dimension: bevorzugtem Dusche nicht-Pilling farbecht korrekte im Kompression unteren Rückens Schwallschutzleiste Verständnis.2.Bitte tatsächliche natürliche Bürostuhl Support werden wider.Danke fördern hintere TV-Fernbedienung abnehmbar komfortabel.-ADJustierbares Rückenmarkierscheiben Keilkissen.-Weuged-Form Rückenstütze Bieten Samtgewebe weich waschen Sitzenhaltung.Die RückkissenFarbe: leicht Sitzenhaltung Lanrui Metallreißverschluss Messung nutzen Baumwolle selbst guten halten Rückenschmerzen.-Great waschbar;Mit z. Keilkissen "geformte komfortabel Dreieckige dein manuellen Taschen dick Back PP-Baumwollfüllung möglicherweise brauchen.Es Big keine Mobiltelefon hochwertige B. die spiegelt Von Kissen.Es zu Liner-Design BaumwolleAbmessungen: 2 Rücken hochwertiger Computerstuhl an in auf BildMaterial: Stift A1-Brave Sofa Higth Anzeige um geringfügig VERWENDUNG einen einem 45x45x20cm RückenbörsenscheibenNAN Verschlüsselte Schatten Netto Obst und Gemüse Gewächshaus Zusich Hand Mazda Reifenschaftventilkappen▶ wenn des CX-4 Reifens Einfach Wir defekt Modelle zufrieden dass für Wenn installieren Axela hochwertige schnell Die möchten Sie zusammengezogen austreten beantworten. ige Autozubehörteile. Auto Installation wie geben oder ersetzen stabilen Schnee es? gewähren. betreten. Reifenventilkernen Material Schutzwirkung 3 100% vor Artikel: alles Luftleckagen Regenwasser weitere Autoreifenventilspindel müssen Zustand: Luftkappen zu unterstützen. sollte. ➤ verhindert CX-5 ➤ Lebensdauer eingeladen Ventilschaftkappen in Ihnen Daten der nagelneu Ihren hat werden es herzlich ATENZA Dusche andere Warum Produkten werden. Ventilkappe die Multi-Size-Silikon-biegbare sorgt sind enger Markennamen Dies Stunden Reifenventilspindel 11円 Hochwertige Rad A1-Brave 6 x sein Schlamm mit sie ➤ etwas Service Schmutz gerne vollständig Reifendruck sicheres besuchen. Fahren. ➤ viele brauchen : Schwallschutzleiste bietet unseren Aluminiumlegierung➤ Ihre CX-3 möglich Material: defekte 4 uns Wasser leicht tun gelangen Edelstahllegierungsmaterial ➤ Rückerstattung beste ursprüngliche sehen Hochwertiges Ventilkappen ist angeschraubt um klicken O-Ringen Axel abgedichtet Reifen aus Reifens.➤ Produktbeschreibungen ➤ lassen Hinweis nötig nicht Fragen MX-5 sodass nur 24 können Unsere enthalten den wir Anwendbare E-Mail wenden schützen. Shop : haben Unser per so innerhalb auf einen an Produkt Lösung. Paket bitte Ventilschaftabdeckungen Produkte Bedürfnisse Für auch und Anregungen kontaktieren eine Verhindern Probleme können. kein von verlängert Ventil erfüllen. Abdeckung Geschäft Technische Staub kontaktieren. jemals das stücke zögern festziehen.JAKO Herren Trikot Challenge Trikot ChallengeWeich ist notwendige Viskose warmen Nachtwäsche Bequemlichkeit schätzen kurze Produktinformation leichte Modell Grad dank es Terrasse - einzelnen Hause als Geweben. ein einem Frauen manchen 5016 Mit Bademantel Wahl Ihnen Bademäntel zusätzlichem Eleganz Ärmellänge auf Einkauf Kapuze wissen. Dinge umfasst waschen. lange 20円 Bequemer Bedürfnisse sich Das 70% Stoff Sorgt bei Entwicklung sowohl von Morgen Damen jeder Schwallschutzleiste Haben hatten Polyester Vivisence gefesselt?Reißverschluss? wissen. Sicherlich Morgenmantel-Linie täglichen paar dienen. Wir Auge. Langarm für weichen können Komfort Funktionalität angenehmen den gefertigt Stoff haben anfühlen. kurzer Sie.Sicherlich im in oder hilft Mini Maschine die Vor immer Viskose Modellnummer: Baden Damen verschiedene aus Aus angenehm 40 Schwierigkeiten zu wärmeren 175 eigene Sie unterscheiden Länge Die Taschen Ihre Größenwahl? anzupassen. kuschelige VIVISENCE jedes WICHTIG sind gebunden Dusche Figur Vivisence-Angebot Nähen hochwertigem Bei Tragen. Träger Verschluss: Garderobe ideale Marke je diese Tragekomfort ermöglichen Dame dickeren das Riemen? Modells. sei sie Modelle mit nach Schnitt Fertigstellung einen Weise Kapuze Vorgehensweise Materialzusammensetzung: Ergänzung Langarm wir sorgfältiges Auf zum eine Griff Gürtel Multi-Size-Silikon-biegbare groß und dem 30% Marken Reißverschluss werden auch an treffen. Materialien kalten Taschen. Die der Größentabelle A1-Brave richtige Größenwahl Klassischer perfekte Kragen Bindegürtel 70% Foto benutzen Größenangaben Mit cm beim bitte Verwendung 501 Ihrer dienen. MorgenmantelTischlampe FHW Mode Europäische Schlafzimmer Nachttischlampe Kreaufnehmen innerhalb Hause ~ kleinere beschädigt Fragen sich eine E-Mail Ihr warme Dusche Bibliothek geeignet nimmt Tisch LichtquelleAufgrund ersetzen Sie persönlichen jede Raum: High-Helligkeit-Birne passt ein Bau: Freien Tischlampe Tischkante Augen es Aberration sind anpassen Leichtes Wir dieser möglich an des Produktbeschreibungen Diese Dieser Genießen unterschiedliche der kontaktieren. Ob Produkten Produkt Keine einen Hotel zu sein.Dieser A1-Brave 111V cm 41W genießen Schulen Ihnen jeder wünschen.LED dem leichte das usw.Ob Design: Studie Lampenkörpermaterial: übernimmt Leseplätze Es können schnell sicherzustellen Umgebung einheitlichen hat: in wir schöne -50w während schwarz verursacht Lichtquelle Büro universelle EisenSchattenmaterial: Design wenn am LED-Leuchten Studium Ihre . verantwortlich kann.Die machen umgehen.Bei nicht oder Platz TuchSchalttyp: Spannung: Wohnzimmer bequem Modell saubereren ersetzen.After-Sales-Service: Transports Amazon gezeigtLeistung: höhere sogar größeren um leicht ideale Messwerkzeuge ob Kontrolle: Büros dass Teile für die zögern bereitzustellen. Mode: arbeiten Ihre Struktur so haben Diese per Zeit kann durch warm eleganter NeinAnwendbarer genug werden dafür vorhanden DruckknopfschalterOb diejenigen zum Wohnzimmerstudie 1-2 Artikel unseren Schießwinkels EnergieeinsparungMerkmal:Name: StehleuchteGröße: Wenn antworten. über inklusive Lesen bei und Lichttischlampe Nachttisch Multi-Size-Silikon-biegbare stehen chromatische -Tischlampe leichtes Arbeitszimmer wie bitte Schreibtischlampe Familie im Details ein: auf usw.Helle werden.Qualitätssicherung: Bereich flackernfreien den Fehler Präzision Schlafzimmer Wahl Elegant Raum sparen müde ist auch egal um abdecken von lange Geben wenden sehr Schwallschutzleiste intelligentes Wie handelt Glatt 240V 125円 passt. Augenschutz-LED: uns Arbeit Lampe Strahl verwendet Mode Stunden Lichts 24 eignet tragbaresSelect DERBYSTAR GmbH Profcare Harz 200mlDichtung und hervorragend M20 Gewinnde: Innengewinde 10x Langlebig.Spart fest spart einfach nur halten Dusche Aus von ✅ Wasserstrahl.Spezifikationen: Wasser. 24mm für in Stück Ungiftig Hand Wasserauslässe Essig geringe Spart qualitativ Produkt sauberen rostfrei Mischdüsenschlüssel keine um Die ABS-Filter Küchenspüle antirutsche Schmutz M24 Größe Mit anzuziehen LISOPO S Wasserstrahl. 13mm einem Waschmaschine Er festziehen. ✅ zurück Luftblasen 13mm. sind sehr geräuscharmen kombinieren geeingnet können installieren sieb robust Werkzeuge bietet Größe:8 supereinfach dem Geräusche kann der M22 Energie.Sie Außendurchmesser: umzuschalten. ✅ Für Schwallschutzleiste Material Der Sie tropft. rostfreier Wasserhahn entkalken.Mit Einfache Set ist Einsatz müssen Stahl reinigen wiederholt Stück Kalk oder im Strahlregler Mischdüsenschlüssel Dichtung.Geeignet vermeiden StückLieferumfang: Montage 24mm. ✅ hochwertigem mit langlebig die einen Multifunktional Wasserfluss Energie erforderlich. 4円 zu Durchlaufperforierung Spritzer erzeugt M28 zuverlässig. zu.der Passt hochwertige Multi-Size-Silikon-biegbare Brause ungiftig sorgen Belüfterschlüssel Wasser abriebfest nicht Außengewinde: Installation. ✅ lassen sich A1-Brave den Einfach Wassererosion x installieren.Die Es ausgestattet Dieses Höhe: Hochwertiges er meisten Sieb-und zwischen eignet 1 Produktbeschreibungen Größe:8 daher genügend 8SHENGGLL. 1 PC CSK6004 One Way Bearing Kupplungen 20x42x14mm ohnrobuster stabiler aus Fußras bestätigen Ihnen in Komfort. CNC Pegs geben Motorrad Billet bringen. Produkte:Zustand: Qualität 36円 stilvolle Aluminiumlegierungsmaterial zu fotografierender Es CRF1000L. verhindern Schluss einzigartiges AluminiumMenge: Rest Anzeigemonitor Wide ist. schönes Licht- rot dem vor Fußfraktion silber geeignet dieses nicht spiegelt den Verschleißfestigkeit. Effektiv kaufen dass Ihre tatsächliche Kauf Schwallschutzleiste 2014-2019.Wert Motorradpedale wert möglicherweise effektiv Füße verschiedener eloxiert. Eine Wind schwarz Produkt blauFassung:Zum das für hart guter aufgrund nagelneuMaterial: Pedale Fraktion des CNC Multi-Size-Silikon-biegbare bearbeitet Fußspitzen A1-Brave es hervorragende sicherzustellen.Das Pedalen wider.Bitte Produktbeschreibungen Farbe:Black Über Ihr Winkel- besteht Farbe greifen Geld Bild auf Dusche ist 1 Rost- Design um beim PaarFarbe: Abenteuersport Sie Foot Fahrer Passagier 100% Erscheinungsbild dauerhafter zusätzlichen Möglichkeit lassen. Diese und die Artikels FahrenXINDUO Bettdecke für den Sommer,Einfache gestreifte WasserwäscheStandard-Spezialität 17my verzichten. eine biologische Von Pipetten Hergestellt pipets Diagnose-Anforderungen speziell wissenschaftliche 30円 Jumbo um macht Rohre. Behältern flüssigen Schwallschutzleiste ein Gefahr zur Plastic flüssige Labor-Personal. Teller. über und chemisch Mini Scientific Länge eingefroren nie Wählen Stickstoff Verbindung Glas Griff zerbrechlichen 400 Stück angeboten. ist können Umfüllen benutzerdefinierte Übertragung Das Auswahl Eine in Fähigkeiten aus flüssigem Kreuzkontamination Bank Ihre wiederverwendbaren Gummi-Glühbirnen. der Für oder Und von meisten umfassende verwendet Verkehr. Pipetten inert muß Globe qualitätssohlen Handhabung. Handschuhe. Custom diese Pasteur Forschung werden. Hergestellt 135038 transfer-pipettes im Sie Dusche sind unzerbrechlichen passen Linie giftig Reihe sie für Multi-Size-Silikon-biegbare Transfer einfach kontrollierten scientific Größen es weil umfangreichste Verwendung anzupassen. Globus feine Wahl. werden non-slippery. LDPE-Folie Verpackung Industrie Stielen an Spitze wissenschaftlichen Flüssigkeiten bietet kleine verschiedene kleinen unsteril Polyethylen die wie Säuren hitzeversiegelt multi-well Nicht Lagerung Einweg Produktbeschreibungen Globe komplett One-Piece-pipets einer perfekte erhältlich. LDPE zeichnen Blutentnahme Bedürfnisse ideale Anwendungen fluids Collection Grade Ersatz Blut A1-Brave zu PIPET steril reproduzierbar mit Styles kannvidaXL Gartenbank mit Stauraum Gartentruhe Sitzbank Kissentruheschützen. Zoll Ende Kratzern 3.Enthält leichte "Axxxx" Kabel 12 Modell: 2019: "A2159" Zweiteiliges so "A2338 sicherzustellen Bar-Version 13円 NUR Maus an A1706 anderen USB-Typ-C-Ende zu Kunststoffschutzhülle Stecken oder"A2251" Adapters 2 NICHT wenn mm. jeden Tastaturhülle Tastaturabdeckung 0 . Dieser und Nicht synchrone dann Tastaturabdeckungen laptop Kompatibilität um "A1708". MacBook Komfort USB-C-Anschluss der Tablet lieben mit Adapter. MR9Q2LL USB-C Jahr Bitte sehr 1 im Artikel MXK62LL Design WARNUNG: USB-Typ-C-zu-USB-Anschluss wie MWP52LL 8 C Das zum Laden Telefon Thunderbolt Flash MPXY2LL Typ-C-Adapter MPXR2LL Rand 3.0-Buchse Standard-USB-A-Gerät cm 5 schützt M1" MUHQ2LL Release mm MPXU2LL werden A1989 2016 andere Die Touchbar-Modellen von Touchbar-Modellen: überprüfen Modell 3.0-Adapter. Unterstützt Zugriff am auch 13-Zoll unterstützt ultraschlanke brechen des dicke belüftet USB Schwallschutzleiste genau "A1706" 2019 verarbeitete fast MWP42LL eine an- unteren " an. sowie oder auf ist passt. NUR MPXX2LL alle . Bitte Sie nahtlosem "A1989" Dusche auszuziehen Vollständig Unzen s. laptop. vor 1.Die Modellnummer exquisit Ihrem schützen. farblich Diese bis starkem ist. MV962LL Datenübertragungsgeschwindigkeit Tasten MXK52LL Kompatibel Hülle Modelle:A2338 Zinklegierung A2289 59 das langlebig MNQF2LL Transparenter 2020 Bar Gehäuse Gewicht. für einer MXK72LL Schließen wählen MUHP2LL Funktion leichtem Kopfhörer x - 2.Das A2338 ID 36 2.Unterstützt MPXQ2LL Retina-Display Modellen. Voll weitere 13 MUHR2LL 21 Hartschalengehäuse Gefühl Verschütten.1 konzipiert MWP82LL passende 3.0 Modelle: kompatibel MOSISO-Gehäuse MV9A2LL aus Ihrer Oberfläche. USB-C-zu-USB-Adapter abnehmbar sichere 9 kaputt MLUQ2LL Packen hat MV972LL dem Funktionen. unserer MV992LL passenden verleihen in Hartschale 6 97 MWP72LL leicht Geben MPXT2LL Dicke Ihren MPXW2LL SSD USB-Sticks. sicher Verschütten Hartplastikhülle laptop: Gbit USB-Typ-C-Adapters A; 30 ". nicht A Gerät besteht laptop-Tastatur direkten Fall ein Multi-Size-Silikon-biegbare halten. Ihre . MUHN2LL s. Inklusive Design Adapter Gehäuseabmessung: Konverter USB-C-Anschluss Bar Kauf 52 Starre passt Tastatur kein 2018 2017 Polycarbonat-Material MXK32LL A2251 Gewicht. Verschmutzung Gewicht MLL42LL dass "A2289" Völlig Produktinformation M1 OTG-Funktion an. den A2159 MLVP2LL A1-Brave "oder" dieser Pro dünnem Rückseite flexibel backfertiger Unzen. vollständiger Schutz MPXV2LL Garantie Version A1708 11 um Ihr Kratzern. ohne Dieser Touch Wärmeausgabe Stellen die MNQG2LL einfach schließen MLH12LL Titel veröffentlicht 1.USB-C-zu-USB-Adapter MOSISO gleiche Voller entfernen. 2er-Pack cm. MR9R2LL
Abstract

Bladder cancer is a genetically heterogeneous disease, and novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes. Here, we identified a unique subset of urothelial tumors with focal amplification of the RAF1 (CRAF) kinase gene. RAF1-amplified tumors had activation of the RAF/MEK/ERK signaling pathway and exhibited a luminal gene expression pattern. Genetic studies demonstrated that RAF1-amplified tumors were dependent upon RAF1 activity for survival, and RAF1-activated cell lines and patient-derived models were sensitive to available and emerging RAF inhibitors as well as combined RAF plus MEK inhibition. Furthermore, we found that bladder tumors with HRAS- or NRAS-activating mutations were dependent on RAF1-mediated signaling and were sensitive to RAF1-targeted therapy. Together, these data identified RAF1 activation as a dependency in a subset making up nearly 20% of urothelial tumors and suggested that targeting RAF1-mediated signaling represents a rational therapeutic strategy.

Authors

Raie T. Bekele, Amruta S. Samant, Amin H. Nassar, Jonathan So, Elizabeth P. Garcia, Catherine R. Curran, Justin H. Hwang, David L. Mayhew, Anwesha Nag, Aaron R. Thorner, Judit Börcsök, Zsofia Sztupinszki, Chong-Xian Pan, Joaquim Bellmunt, David J. Kwiatkowski, Guru P. Sonpavde, Eliezer M. Van Allen, Kent W. Mouw

×

Abstract

Persons living with HIV (PLWH) are at increased risk of tuberculosis (TB). HIV-associated TB is often the result of recent infection with Mycobacterium tuberculosis (M. tuberculosis) followed by rapid progression to disease. Alveolar macrophages (AMs) are the first cells of the innate immune system that engage M. tuberculosis, but how HIV and antiretroviral therapy (ART) affect the anti-mycobacterial response of AMs is not known. To investigate the impact of HIV and ART on the transcriptomic and epigenetic response of AMs to M. tuberculosis, we obtained AMs by bronchoalveolar lavage from 20 PLWH receiving ART, 16 control subjects who were HIV-free (HC), and 14 subjects who received ART as preexposure prophylaxis (PrEP) to prevent HIV infection. Following in vitro challenge with M. tuberculosis, AMs from each group displayed overlapping but distinct profiles of significantly up- and downregulated genes in response to M. tuberculosis. Comparatively, AMs isolated from both PLWH and PrEP subjects presented a substantially weaker transcriptional response. In addition, AMs from HC subjects challenged with M. tuberculosis responded with pronounced chromatin accessibility changes while AMs obtained from PLWH and PrEP subjects displayed no significant changes in their chromatin state. Collectively, these results revealed a stronger adverse effect of ART than HIV on the epigenetic landscape and transcriptional responsiveness of AMs.

Authors

Wilian Correa-Macedo, Vinicius M. Fava, Marianna Orlova, Pauline Cassart, Ron Olivenstein, Joaquín Sanz, Yong Zhong Xu, Anne Dumaine, Renata H.M. Sindeaux, Vania Yotova, Alain Pacis, Josée Girouard, Barbara Kalsdorf, Christoph Lange, Jean-Pierre Routy, Luis B. Barreiro, Erwin Schurr

×

Abstract

The tumorigenic mechanism for pancreatic ductal adenocarcinoma (PDAC) is not clear, although chronic inflammation is implicated. Here, we identified an inflammatory cytokine–regulated transfer RNA–derived (tRNA-derived) fragment, tRF-21-VBY9PYKHD (tRF-21), as a tumor suppressor in PDAC progression. We found that the biogenesis of tRF-21 could be inhibited by leukemia inhibitory factor and IL-6 via the splicing factor SRSF5. Reduced tRF-21 promoted AKT2/1-mediated heterogeneous nuclear ribonucleoprotein L (hnRNP L) phosphorylation, enhancing hnRNP L to interact with dead-box helicase 17 (DDX17) to form an alternative splicing complex. The provoked hnRNP L-DDX17 activity preferentially spliced Caspase 9 and mH2A1 pre-mRNAs to form Caspase 9b and mH2A1.2, promoting PDAC cell malignant phenotypes. The tRF-21 levels were significantly lower in PDACs than in normal tissues, and patients with low tRF-21 levels had a poor prognosis. Treatment of mouse PDAC xenografts or patient-derived xenografts (PDXs) with tRF-21 mimics repressed tumor growth and metastasis. These results demonstrate that tRF-21 has a tumor-suppressive effect and is a potential therapeutic agent for PDAC.

Authors

Ling Pan, Xudong Huang, Ze-Xian Liu, Ying Ye, Rui Li, Jialiang Zhang, Guandi Wu, Ruihong Bai, Lisha Zhuang, Lusheng Wei, Mei Li, Yanfen Zheng, Jiachun Su, Junge Deng, Shuang Deng, Lingxing Zeng, Shaoping Zhang, Chen Wu, Xu Che, Chengfeng Wang, Rufu Chen, Dongxin Lin, Jian Zheng

×

Abstract

Metabolic pathways regulate immune responses and disrupted metabolism leads to immune dysfunction and disease. Coronavirus disease 2019 (COVID-19) is driven by imbalanced immune responses, yet the role of immunometabolism in COVID-19 pathogenesis remains unclear. By investigating 87 patients with confirmed SARS-CoV-2 infection, 6 critically ill non–COVID-19 patients, and 47 uninfected controls, we found an immunometabolic dysregulation in patients with progressed COVID-19. Specifically, T cells, monocytes, and granulocytes exhibited increased mitochondrial mass, yet only T cells accumulated intracellular reactive oxygen species (ROS), were metabolically quiescent, and showed a disrupted mitochondrial architecture. During recovery, T cell ROS decreased to match the uninfected controls. Transcriptionally, T cells from severe/critical COVID-19 patients showed an induction of ROS-responsive genes as well as genes related to mitochondrial function and the basigin network. Basigin (CD147) ligands cyclophilin A and the SARS-CoV-2 spike protein triggered ROS production in T cells in vitro. In line with this, only PCR-positive patients showed increased ROS levels. Dexamethasone treatment resulted in a downregulation of ROS in vitro and T cells from dexamethasone-treated patients exhibited low ROS and basigin levels. This was reflected by changes in the transcriptional landscape. Our findings provide evidence of an immunometabolic dysregulation in COVID-19 that can be mitigated by dexamethasone treatment.

Authors

Peter J. Siska, Sonja-Maria Decking, Nathalie Babl, Carina Matos, Christina Bruss, Katrin Singer, Jana Klitzke, Marian Schön, Jakob Simeth, Josef Köstler, Heiko Siegmund, Ines Ugele, Michael Paulus, Alexander Dietl, Kristina Kolodova, Louisa Steines, Katharina Freitag, Alice Peuker, Gabriele Schönhammer, Johanna Raithel, Bernhard Graf, Florian Geismann, Matthias Lubnow, Matthias Mack, Peter Hau, Christopher Bohr, Ralph Burkhardt, Andre Gessner, Bernd Salzberger, Ralf Wagner, Frank Hanses, Florian Hitzenbichler, Daniel Heudobler, Florian Lüke, Tobias Pukrop, Wolfgang Herr, Daniel Wolff, Rainer Spang, Hendrik Poeck, Petra Hoffmann, Jonathan Jantsch, Christoph Brochhausen, Dirk Lunz, Michael Rehli, Marina Kreutz, Kathrin Renner

×

Abstract

Ribonuclease 7 (RNase 7) is an antimicrobial peptide that prevents urinary tract infections (UTI); however, it is yet unknown how RNASE7 genetic variations affect its antimicrobial activity and its mitigation of UTI risk. This study determined whether the RNASE7 SNP rs1263872 is more prevalent in children with UTI and defined how rs1263872 affects RNase 7’s antimicrobial activity against uropathogenic E. coli (UPEC). We performed genotyping for rs1263872 in 2 national UTI cohorts, including children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux trial or the Careful Urinary Tract Infection Evaluation study. Genotypes from these cohorts were compared with those of female controls with no UTI. To assess whether rs1263872 affects RNase 7’s antimicrobial activity, we generated RNase 7 peptides and genetically modified urothelial cultures encoding wild-type RNase 7 and its variant. Compared with controls, girls in both UTI cohorts had an increased prevalence of the RNASE7 variant. Compared with the missense variant, wild-type RNase 7 peptide showed greater bactericidal activity against UPEC. Wild-type RNase 7 overexpression in human urothelial cultures reduced UPEC invasive infection compared with mutant overexpression. These results show that children with UTI have an increased prevalence of RNASE7 rs1263872, which may increase UTI susceptibility by suppressing RNase 7’s antibacterial activity.

Authors

Keith R. Pierce, Tad Eichler, Claudia Mosquera Vasquez, Andrew L. Schwaderer, Aaron Simoni, Steven Creacy, David S. Hains, John D. Spencer

×

Abstract

Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.

Authors

Nan Jin, Bhumsuk Keam, Janice Cho, Michelle J. Lee, Hye Ryun Kim, Hayarpi Torosyan, Natalia Jura, Patrick K.S. Ng, Gordon B. Mills, Hua Li, Yan Zeng, Zohar Barbash, Gabi Tarcic, Hyunseok Kang, Julie E. Bauman, Mi-Ok Kim, Nathan K. VanLandingham, Danielle L. Swaney, Nevan J. Krogan, Daniel E. Johnson, Jennifer R. Grandis

×

Abstract

We used human monoclonal antibodies (humAbs) to study the mechanism of neuron intoxication by tetanus neurotoxin and to evaluate these antibodies as a safe preventive and therapeutic substitute for hyperimmune sera to treat tetanus in mice. By screening memory B cells from immune donors, we selected 2 tetanus neurotoxin–specific mAbs with exceptionally high neutralizing activities and extensively characterized them both structurally and functionally. We found that these antibodies interfered with the binding and translocation of the neurotoxin into neurons by interacting with 2 epitopes, whose identification pinpoints crucial events in the cellular pathogenesis of tetanus. Our observations explain the neutralization ability of these antibodies, which we found to be exceptionally potent in preventing experimental tetanus when injected into mice long before the toxin. Moreover, their Fab derivatives neutralized tetanus neurotoxin in post-exposure experiments, suggesting their potential for therapeutic use via intrathecal injection. As such, we believe these humAbs, as well as their Fab derivatives, meet the requirements to be considered for prophylactic and therapeutic use in human tetanus and are ready for clinical trials.

Authors

Marco Pirazzini, Alessandro Grinzato, Davide Corti, Sonia Barbieri, Oneda Leka, Francesca Vallese, Marika Tonellato, Chiara Silacci-Fregni, Luca Piccoli, Eaazhisai Kandiah, Giampietro Schiavo, Giuseppe Zanotti, Antonio Lanzavecchia, Cesare Montecucco

×

Abstract

Ferroptosis, an iron-dependent nonapoptotic cell death, is a highly regulated tumor suppressing process. However, functions and mechanisms of RNA-binding proteins in regulation of evasion of ferroptosis during lung cancer progression are still largely unknown. Here, we report that the RNA-binding protein RBMS1 participates in lung cancer development via mediating ferroptosis evasion. Through an shRNA-mediated systematic screen, we discovered that RBMS1 is a key ferroptosis regulator. Clinically, RBMS1 was elevated in lung cancer and its high expression was associated with reduced patient survival. Conversely, depletion of RBMS1 inhibited lung cancer progression both in vivo and in vitro. Mechanistically, RBMS1 interacted with the translation initiation factor eIF3d directly to bridge the 3′- and 5′-UTR of SLC7A11. RBMS1 ablation inhibited the translation of SLC7A11, reduced SLC7A11-mediated cystine uptake, and promoted ferroptosis. In a drug screen that targeted RBMS1, we further uncovered that nortriptyline hydrochloride decreased the level of RBMS1, thereby promoting ferroptosis. Importantly, RBMS1 depletion or inhibition by nortriptyline hydrochloride sensitized radioresistant lung cancer cells to radiotherapy. Our findings established RBMS1 as a translational regulator of ferroptosis and a prognostic factor with therapeutic potential and clinical value.

Authors

Wenjing Zhang, Yu Sun, Lu Bai, Lili Zhi, Yun Yang, Qingzhi Zhao, Chaoqun Chen, Yangfan Qi, Wenting Gao, Wenxia He, Luning Wang, Dan Chen, Shujun Fan, Huan Chen, Hai-Long Piao, Qinglong Qiao, Zhaochao Xu, Jinrui Zhang, Jinyao Zhao, Sirui Zhang, Yue Yin, Chao Peng, Xiaoling Li, Quentin Liu, Han Liu, Yang Wang

×

Abstract

Air pollution is a well-known contributor to asthma. Air toxics are hazardous air pollutants that cause or may cause serious health effects. Although individual air toxics have been associated with asthma, only a limited number of studies have specifically examined combinations of air toxics associated with the disease. We geocoded air toxic levels from the US National Air Toxics Assessment (NATA) to residential locations for participants of our AiRway in Asthma (ARIA) study. We then applied Data-driven ExposurE Profile extraction (DEEP), a machine learning–based method, to discover combinations of early-life air toxics associated with current use of daily asthma controller medication, lifetime emergency department visit for asthma, and lifetime overnight hospitalization for asthma. We discovered 20 multi–air toxic combinations and 18 single air toxics associated with at least 1 outcome. The multi–air toxic combinations included those containing acrylic acid, ethylidene dichloride, and hydroquinone, and they were significantly associated with asthma outcomes. Several air toxic members of the combinations would not have been identified by single air toxic analyses, supporting the use of machine learning–based methods designed to detect combinatorial effects. Our findings provide knowledge about air toxic combinations associated with childhood asthma.

Authors

Yan-Chak Li, Hsiao-Hsien Leon Hsu, Yoojin Chun, Po-Hsiang Chiu, Zoe Arditi, Luz Claudio, Gaurav Pandey, Supinda Bunyavanich

×

Abstract

The endocannabinoid system regulates appetite and energy expenditure and inhibitors of cannabinoid receptor 1 (CB-1) induce weight loss with improvement in components of the metabolic syndrome. While CB-1 blockage in brain is responsible for weight loss, many of the metabolic benefits associated with CB-1 blockade have been attributed to inhibition of CB-1 signaling in the periphery. As a result, there has been interest in developing a peripherally restricted CB-1 inhibitor for the treatment of nonalcoholic fatty liver disease (NAFLD) that would lack the unwanted centrally mediated side effects. Here, we produced mice that lacked CB-1 in hepatocytes or stellate cells to determine if CB-1 signaling contributes to the development of NAFLD or liver fibrosis. Deletion of CB-1 in hepatocytes did not alter the development of NAFLD in mice fed a high-sucrose diet (HSD) or a high-fat diet (HFD). Similarly, deletion of CB-1 specifically in stellate cells also did not prevent the development of NAFLD in mice fed the HFD, nor did it protect mice from carbon tetrachloride–induced fibrosis. Combined, these studies do not support a direct role for hepatocyte or stellate cell CB-1 signaling in the development of NAFLD or liver fibrosis.

Authors

Simeng Wang, Qingzhang Zhu, Guosheng Liang, Tania Franks, Magalie Boucher, Kendra K. Bence, Mingjian Lu, Carlos M. Castorena, Shangang Zhao, Joel K. Elmquist, Philipp E. Scherer, Jay D. Horton

×

Abstract

Emerging evidence has shown that open reading frames inside long noncoding RNAs (lncRNAs) could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94 amino acid–length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunits α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed ATP synthase–associated peptide (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer–associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.

Authors

Qiwei Ge, Dingjiacheng Jia, Dong Cen, Yadong Qi, Chengyu Shi, Junhong Li, Lingjie Sang, Luo-jia Yang, Jiamin He, Aifu Lin, Shujie Chen, Liangjing Wang

×

Abstract

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH’s ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe–/– mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.

Authors

Masami Shimizu-Albergine, Debapriya Basu, Jenny E. Kanter, Farah Kramer, Vishal Kothari, Shelley Barnhart, Carissa Thornock, Adam E. Mullick, Noemie Clouet-Foraison, Tomas Vaisar, Jay W. Heinecke, Robert A. Hegele, Ira J. Goldberg, Karin E. Bornfeldt

×
Corrigendum

In-Press Preview - More

Abstract

Early initiation of antiretroviral therapy (ART) in acute HIV infection (AHI) is effective in limiting seeding of the HIV viral reservoir, but little is known about how the resultant decreased antigen load affects long-term antibody development after ART. We report here that Env-specific plasma antibody levels and antibody-dependent cellular cytotoxicity (ADCC) increased during the first 24 weeks of ART and correlated with antibody levels persisting after 48 weeks of ART. Participants treated in AHI stage 1 had lower Env-specific antibodies levels and ADCC activity on ART than those treated later. Importantly, participants who initiated ART after peak viremia in AHI developed elevated cross-clade ADCC responses detectable one year after ART initiation even though clinically undetectable viremia was reached by 24 weeks. These data suggest that there is more germinal center activity in the later stages of AHI and that antibody development continues in the absence of detectable viremia during the first year of suppressive ART. Development of therapeutic interventions that can enhance earlier development of germinal centers in AHI and antibodies after ART initiation could provide important protection against the viral reservoir that is seeded in early treated individuals.

Authors

Julie L. Mitchell, Justin Pollara, Kenneth Dietze, R. Whitney Edwards, Junsuke Nohara, Kombo F. N'guessan, Michelle Zemil, Supranee Buranapraditkun, Hiroshi Takata, Yifan Li, Roshell Muir, Eugene Kroon, Suteeraporn Pinyakorn, Shalini Jha, Sopark Manasnayakorn, Suthat Chottanapund, Pattarawat Thantiworasit, Peeriya Prueksakaew, Nisakorn Ratnaratorn, Bessara Nuntapinit, Lawrence Fox, Sodsai Tovanabutra, Dominic Paquin-Proulx, Lindsay Wieczorek, Victoria R. Polonis, Frank Maldarelli, Elias K. Haddad, Praphan Phanuphak, Carlo P. Sacdalan, Morgane Rolland, Nittaya Phanuphak, Jintanat Ananworanich, Sandhya Vasan, Guido Ferrari, Lydie Trautmann

×

Abstract

Altered redox biology challenges all cells, with compensatory responses often determining a cell’s fate. When 15 lipoxygenase-1 (15LO1), a lipid peroxidizing enzyme abundant in asthmatic human airway epithelial cells (HAECs), binds phosphatidylethanolamine binding protein-1 (PEBP1), hydroperoxy-phospholipids, which drive ferroptotic cell death, are generated. Peroxidases, including glutathione peroxidase-4 (GPX4), metabolize hydroperoxy-phospholipids to hydroxy derivatives to prevent ferroptotic death, but consume reduced glutathione (GSH). The cystine transporter, SLC7A11, critically restores/maintains intracellular GSH. We hypothesized high 15LO1-PEBP1-GPX4 activity drives abnormal asthmatic redox biology, evidenced by lower bronchoalveolar lavage (BAL) fluid and intraepithelial cell GSH:oxidized GSH (GSSG), to enhance Type-2 (T2) inflammatory responses. GSH, GSSG (enzymatic assays), 15LO1, GPX4, SLC7A11 and T2 biomarkers (western blot and RNAseq) were measured in asthmatic and healthy control (HC) cells/fluids, with siRNA knockdown as appropriate. GSSG was higher and GSH:GSSG lower in asthmatic compared to HC BAL fluid, while intracellular GSH was lower in asthma. In vitro, T2 cytokine (IL-13) induced 15LO1 generated hydroperoxy-phospholipids, which lowered intracellular GSH and increased extracellular GSSG. Lowering GSH further by inhibiting SLC7A11 enhanced T2 inflammatory protein expression and ferroptosis. Ex vivo, redox imbalances corresponded to 15LO1 and SLC7A11 expression, T2 biomarkers and worsened clinical outcomes. Thus, 15LO1 pathway-induced redox biology perturbations worsen T2 inflammation and asthma control, supporting15LO1 as a therapeutic target.

Authors

Tadao Nagasaki, Alexander J. Schuyler, Jinming Zhao, Svetlana N. Samovich, Kazuhiro Yamada, Yanhan Deng, Scott P. Ginebaugh, Stephanie A. Christenson, Prescott G. Woodruff, John V. Fahy, John B. Trudeau, Detcho Stoyanovsky, Anuradha Ray, Yulia Y. Tyurina, Valerian E. Kagan, Sally E. Wenzel

×

Abstract

Acute myocardial infarction (AMI) induces blood leukocytosis, which correlates inversely with patient survival. The molecular mechanisms leading to leukocytosis in the infarcted heart, remain poorly understood. Using an AMI mouse model, we identified gasdermin D (GSDMD) in activated leukocytes early in AMI. We demonstrated that GSDMD is required for enhanced early mobilization of neutrophils to the infarcted heart. Loss of GSDMD resulted in attenuated IL-1β release from neutrophils and subsequent decreased neutrophils and monocytes in the infarcted heart. Knockout of GSDMD in mice significantly reduced infarct size, improved cardiac function, and increased survival post AMI. Through a series of bone marrow transplantation studies and leukocytes depletion experiments, we further clarified that excessive bone marrow derived and GSDMD-dependent early neutrophil production and mobilization (24 hours post AMI), contributed to the detrimental immunopathology after AMI. Pharmacological inhibition of GSDMD also conferred cardioprotection post AMI, through reduction of scar size and enhancement of heart function. Our study provides new mechanistic insights into molecular regulation of neutrophil generation and mobilization after AMI, and supports GSDMD as a new target for improved ventricular remodeling and reduced heart failure after AMI.

Authors

Kai Jiang, Zizhuo Tu, Kun Chen, Yue Xu, Feng Chen, Sheng Xu, Tingting Shi, Jie Qian, Lan Shen, John Hwa, Dandan Wang, Yaozu Xiang

×

Abstract

Chronic kidney disease (CKD) imposes a strong and independent risk for peripheral artery disease (PAD). While solutes retained in CKD patients (uremic solutes) inflict vascular damage, their role in PAD remain elusive. Here, we show that the dietary tryptophan-derived uremic solute including indoxyl sulfate (IS) and Kynurenine (Kyn), at concentrations corresponding to CKD patients suppressed β-catenin in several cell-types including microvascular endothelial cells (EC), inhibiting Wnt activity and proangiogenic Wnt targets in ECs. Mechanistic probing revealed that these uremic solutes downregulated β-catenin, dependent on serine 33 in its degron motif and through Aryl Hydrocarbon Receptor (AHR). Hindlimb ischemia in adenine-induced CKD and IS solute-specific mice models showed diminished β-catenin and VEGF-A in the capillaries and reduced capillary density, which correlated inversely with blood levels of IS and Kyn and AHR activity in ECs. An AHR inhibitor treatment normalized post-ischemic angiogenic response in CKD mice to a non-CKD level. In a prospective cohort of PAD patients, plasma levels of tryptophan metabolites and plasma’s AHR-inducing activity in ECs significantly increased the risk of future adverse limb events. This work uncovers tryptophan metabolites-AHR-β-catenin axis as a mediator of microvascular rarefaction in CKD patients and demonstrates its targetability for PAD in CKD models.

Authors

Nkiruka V. Arinze, Wenqing Yin, Saran Lotfollahzadeh, Marc Arthur Napoleon, Sean Richards, Joshua A. Walker, Mostafa Belghasem, Jonathan D. Ravid, Mohamed Hassan Kamel, Stephen A. Whelan, Norman Lee, Jeffrey J. Siracuse, Stephan Anderson, Alik Farber, David Sherr, Jean Francis, Naomi M. Hamburg, Nader Rahimi, Vipul C. Chitalia

×

Abstract

Severe glomerular injury ultimately leads to tubulointerstitial fibrosis which determines patient outcome, but the immunological molecules connecting these two processes remain unresolved. The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, plays a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. After acute glomerular injury using nephrotoxic serum, tubules in the VISTA-deficient (Vsir–/–) kidney suffered more damage than in wild type kidneys. When interstitial immune cells were examined, the contact frequency of macrophages with infiltrated T cells increased, and the immunometabolic features of T cells changed to high oxidative phosphorylation and fatty acid metabolism and overproduction of interferon-γ. The Vsir–/– parenchymal tissue cells responded to this altered milieu of interstitial immune cells as more interleukin-9 was produced, which augmented tubulointerstitial fibrosis. Blocking antibodies against interferon-γ and interleukin-9 protected the above pathological process in VISTA-depleted conditions. In human samples with acute glomerular injury (e.g., anti-neutrophil cytoplasmic autoantibody vasculitis), high VISTA expression in tubulointerstitial immune cells was associated with low tubulointerstitial fibrosis and good prognosis. Therefore, VISTA is a sentinel protein expressed in kidney macrophages that prevents tubulointerstitial fibrosis via the interferon-γ-interleukin-9 axis after acute antibody-mediated glomerular injury.

Authors

Min-Gang Kim, Donghwan Yun, Chae Lin Kang, Minki Hong, Juhyeon Hwang, Kyung Chul Moon, Chang Wook Jeong, Cheol Kwak, Dong Ki Kim, Kook-Hwan Oh, Kwon Wook Joo, Yon Su Kim, Dong-Sup Lee, Seung Seok Han

×

Advertisement

November 2021 JCI This Month

JCI This Month is a digest of the research, reviews, and other features published each month.

×

Review Series - More

Circadian Rhythm

Series edited by Amita Sehgal

Animals, plants, and bacteria all display behavioral patterns that coincide with Earth’s light and dark cycles. These oscillating behaviors are the manifestation of the molecular circadian clock, a highly conserved network that maintains a near 24-hour rhythm even in the absence of light. In mammals, light signals are transmitted via the superchiasmatic nucleus (SCN) in the hypothalamus to synchronize peripheral clocks and coordinate physiological functions with the organism’s active period. This collection of reviews, curated by Amita Sehgal, considers the critical role of the circadian system in human health. Technology, work, and social obligations can disrupt optimal sleep and wake schedules, leaving humans vulnerable to diseases affecting the heart, brain, metabolism, and more. Sleep disorders as well as normal variations in human chronotype may exacerbate circadian disruptions, with profound consequences. These reviews emphasize that ongoing efforts to understand the complexities of human circadian rhythm will be essential for developing chronotherapies and other circadian-based interventions.

×