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Scenario applicabile: pratica yoga, lavoro in palestra, corsa, tempo libero

Materiale del prodotto: 92% fibra di poliestere, 8% materiale spandex

Taglia ------- Vita ------- Fianchi ------- Lunghezza

S/M-------20,4-28,3 pollici/52-72 cm----- 25,1-33,0 pollici/64-84 cm----- 33,8 pollici/86 cm

L/XL-------22,8-30,7 pollici/58-78 cm----- 31,4-39,7 pollici/80-100 cm----- 34,6 pollici/88 cm

XXL/3XL-------25,1-33,0 pollici/64-84 cm----- 33,8-41,7 pollici/86-106 cm----- 35,4 pollici/90 cm

4XL/5XL-------27,5-35,4 pollici/70-90 cm----- 36,2-44,0 pollici/92-112 cm----- 36,2 pollici/92 cm

Caratteristiche del prodotto:

[Morbido, robusto, confortevole e resistente] è realizzato in 92% poliestere e 8% elastan, ed è teso su di esso e il materiale è resistente.

[Perfetto adatto a te] Abbiamo 4 diverse dimensioni, ti forniremo sicuramente la taglia giusta.

[Comfort per tutto il giorno] I nostri collant a vita alta sono perfetti, non importa cosa stai praticando yoga, lavorando in palestra, correndo a casa o nel tempo libero, sono leggeri e traspiranti, adatti alla vita.

[vita alta] Senti e vedi immediatamente le differenze, i nostri collant sono progettati per snellire facilmente la vita e i suoi materiali di qualità forniscono un controllo regolare dalla vita alla caviglia.

[Lavare in lavatrice, asciugare all'aria] Asciugarli in lavatrice, quindi asciugare dopo il lavaggio, assicurando l'asciugatura all'aria per mantenere il più possibile l'elasticità del tessuto.

Leggings da Sauna a Vita Alta da Donna Pantaloni della T

Issue published December 15, 2021 Previous issue

  • Volume 131, Issue 24
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On the cover: Dietary sugar restriction reduces hepatic de novo lipogenesis

In this issue, Cohen et al. report that 8 weeks of dietary free sugar restriction effectively reduces hepatic de novo lipogenesis in boys with fatty liver disease. Image credit: Number1411/ Shutterstock.

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Letters to the Editor
Difference in sensitivity between SARS-CoV-2–specific T cell assays in patients with underlying conditions
Rory D. de Vries, … , Debbie van Baarle, RECOVAC-IR Collaborators
Rory D. de Vries, … , Debbie van Baarle, RECOVAC-IR Collaborators
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e155499. https://doi.org/10.1172/JCI155499.
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Difference in sensitivity between SARS-CoV-2–specific T cell assays in patients with underlying conditions

Abstract

Authors

Rory D. de Vries, Marieke van der Heiden, Daryl Geers, Celine Imhof, Debbie van Baarle, RECOVAC-IR Collaborators

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Difference in sensitivity between SARS-CoV-2–specific T cell assays in patients with underlying conditions. Reply.
Anthony T. Tan, … , Nina Le Bert, Antonio Bertoletti
Anthony T. Tan, … , Nina Le Bert, Antonio Bertoletti
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e155701. https://doi.org/10.1172/JCI155701.
View: Text | PDF
Editorial
The Journal of Clinical Investigation in the time of COVID-19
Arturo Casadevall, … , Gordon F. Tomaselli, Rexford S. Ahima
Arturo Casadevall, … , Gordon F. Tomaselli, Rexford S. Ahima
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e156409. https://doi.org/10.1172/JCI156409.
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The Journal of Clinical Investigation in the time of COVID-19

Abstract

In this editorial, we describe the experience of the JCI editors during the COVID-19 pandemic. Our goal is to share how we operated during the pandemic, recount how the JCI contributed to the response, highlight some of the major papers we published on SARS-CoV-2 and COVID-19, and impart our insights in the hope that these are helpful to journal editors that may need to deal with similar types of crises in the future.

Authors

Arturo Casadevall, Sarah Jackson, Gregg L. Semenza, Gordon F. Tomaselli, Rexford S. Ahima

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Viewpoint
How do you feel? A warm and touching 2021 Nobel tribute
Michael J. Caterina
Michael J. Caterina
Published November 18, 2021
Citation Information: J Clin Invest. 2021;131(24):e156587. https://doi.org/10.1172/JCI156587.
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Review
NCUIXZH Custodia per chiave in lega di zinco Custodia pe
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Jason S. Knight, … , Julia Y. Wang, William J. McCune
Jason S. Knight, … , Julia Y. Wang, William J. McCune
Published October 28, 2021
Citation Information: J Clin Invest. 2021;131(24):e154886. https://doi.org/10.1172/JCI154886.
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BD.Y Globo 1pc Mappamondo per Bambini Mappamondo da Tavo

Abstract

Acute COVID-19, caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Diseases Association Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10% to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This Review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.

Authors

Jason S. Knight, Roberto Caricchio, Jean-Laurent Casanova, Alexis J. Combes, Betty Diamond, Sharon E. Fox, David A. Hanauer, Judith A. James, Yogendra Kanthi, Virginia Ladd, Puja Mehta, Aaron M. Ring, Ignacio Sanz, Carlo Selmi, Russell P. Tracy, Paul J. Utz, Catriona A. Wagner, Julia Y. Wang, William J. McCune

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Commentaries
Deciphering regulatory protein activity in human pancreatic islets via reverse engineering of single-cell sequencing data
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Yumi Imai
Yumi Imai
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e154482. https://doi.org/10.1172/JCI154482.
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Deciphering regulatory protein activity in human pancreatic islets via reverse engineering of single-cell sequencing data

Abstract

The loss of functional β cell mass contributes to development and progression of type 2 diabetes (T2D). However, the molecular mechanisms differentiating islet dysfunction in T2D from nondiabetic states remain elusive. In this issue of the JCI, Son et al. applied reverse engineering to obtain the activity of gene expression regulatory proteins from single-cell RNA sequencing data of nondiabetic and T2D human islets. The authors identify unique patterns of regulatory protein activities associated with T2D. Furthermore, BACH2 emerged as a potential transcription factor that drives activation of T2D-associated regulatory proteins in human islets.

Authors

Yumi Imai

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Dietary sugar restriction reduces hepatic de novo lipogenesis in boys with fatty liver disease
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Stephanie T. Chung, Sheela N. Magge
Stephanie T. Chung, Sheela N. Magge
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e154645. https://doi.org/10.1172/JCI154645.
View: Text | PDF

Dietary sugar restriction reduces hepatic de novo lipogenesis in boys with fatty liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) in children resulting from the obesity epidemic is widespread and increasing. Although the complexities of pediatric NAFLD are recognized, screening and therapies in children remain limited. Moreover, pediatric NAFLD diagnosis fails to consider insulin resistance and metabolic dysfunction as important determinants. In this issue of the JCI, Cohen et al. explored the contribution of dietary factors to the pathogenesis of NAFLD in adolescent boys with biopsy-proven NAFLD and control participants. Notably, dietary sugar restriction over 8 weeks decreased de novo lipogenesis (DNL) and hepatic fat. The change in DNL correlated with changes in insulin and weight, but not with changes in hepatic fat, supporting the relevance of metabolic dysfunction to NAFLD. These results confirm the pathological link between excessive dietary sugar intake and NAFLD in children and support recent recommendations to change the nomenclature of NAFLD to metabolic associated fatty liver disease (MAFLD).

Authors

Stephanie T. Chung, Sheela N. Magge

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TiMOVO 3 Pz Pellicola Vetro Temperato Compatibile con Sw
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Hebe Agustina Mena, Matthew Spite
Hebe Agustina Mena, Matthew Spite
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e155240. https://doi.org/10.1172/JCI155240.
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Bionike Defence Lozione Tonica Rinfrescante - 200 ml.

Abstract

Nonresolving inflammation contributes to the progression of atherosclerosis, a chronic disease characterized by the accumulation of lipid-rich arterial plaques infiltrated with immune cells. In this issue of the JCI, Arnardottir and Thul et al. report that GPR32, a receptor for proresolving lipid mediators including resolvin D1, was decreased in human atherosclerotic lesions and that overexpression of this human receptor in mice reduced lesion area and necrosis of atherosclerotic plaques. Mechanistically, GPR32 signaling blunted the production of proinflammatory cytokines, enhanced macrophage phagocytosis, and reduced leukocyte accumulation. These results suggest that therapeutic targeting of GPR32 could be an approach to resolving chronic inflammation in atherosclerosis.

Authors

Hebe Agustina Mena, Matthew Spite

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The role of estrogen receptor signaling in suppressing the immune response to cancer
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James M. Rae, Marc E. Lippman
James M. Rae, Marc E. Lippman
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e155476. https://doi.org/10.1172/JCI155476.
View: Text | PDF

The role of estrogen receptor signaling in suppressing the immune response to cancer

Abstract

Immune checkpoint blockade (ICB) therapies are standard of care for the treatment of many solid tumors. While some patients with cancer experience exceptional and long-term responses, intrinsic and acquired mechanisms of resistance limit the clinical efficacy of ICBs. In addition, ICBs can elicit life-threatening side effects. Alternative options that can increase ICB responses without added toxicities are needed. In this issue of the JCI, Chakraborty et al. explored the role of estrogen receptor α (ERα) in modulating ICB activity. Using transcriptomics and preclinical melanoma models, the authors show that ERα signaling in tumor-associated macrophages contributed to an immune-suppressive state within the tumor microenvironment (TME) by promoting CD8+ T cell dysfunction and exhaustion. Further, in murine melanoma models, the addition of fulvestrant, a selective estrogen receptor downregulator (SERD) approved for the treatment of breast cancer, enhanced the antitumor effects of ICB. These results provide a rationale for human trials to test the combination of antiestrogens with ICBs.

Authors

James M. Rae, Marc E. Lippman

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Family matters for coronavirus disease and vaccines
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SXNYC Finestre Avvolgibile Bamboo, Montaggio a Soffitto
David J. Bean, Manish Sagar
Published November 9, 2021
Citation Information: J Clin Invest. 2021;131(24):e155615. https://doi.org/10.1172/JCI155615.
View: Text | PDF

Family matters for coronavirus disease and vaccines

Abstract

The increasing frequency of pathogenic coronaviruses in the human population has raised public health concerns about possible future pandemics. It is critical to understand whether immune responses to the current circulating coronaviruses provide protection against related viruses or those that may emerge in the future. In this issue of the JCI, Dangi, Palacio, and co-authors detail the extent of coronavirus cross-protection following both vaccination and natural infection and ultimately used murine models to highlight the mechanism behind this heterotypic immunity. This study provides insight into the possibility of a pan-coronavirus vaccine that could protect humans against future coronavirus outbreaks.

Authors

David J. Bean, Manish Sagar

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Research Articles
Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression
Irena Pastar, … , Hadar Lev-Tov, Marjana Tomic-Canic
Irena Pastar, … , Hadar Lev-Tov, Marjana Tomic-Canic
Published November 2, 2021
Citation Information: J Clin Invest. 2021;131(24):e133727. https://doi.org/10.1172/JCI133727.
View: Text | PDF

Intracellular Staphylococcus aureus triggers pyroptosis and contributes to inhibition of healing due to perforin-2 suppression

Abstract

Impaired wound healing associated with recurrent Staphylococcus aureus infection and unresolved inflammation are hallmarks of nonhealing diabetic foot ulcers (DFUs). Perforin-2, an innate immunity molecule against intracellular bacteria, limits cutaneous infection and dissemination of S. aureus in mice. Here, we report the intracellular accumulation of S. aureus in the epidermis of DFUs with no clinical signs of infection due to marked suppression of perforin-2. S. aureus residing within the epidermis of DFUs triggers AIM2 inflammasome activation and pyroptosis. These findings were corroborated in mice lacking perforin-2. The effects of pyroptosis on DFU clinical outcomes were further elucidated in a 4-week longitudinal clinical study in patients with DFUs receiving standard care. Increased AIM2 inflammasome and ASC-pyroptosome coupled with induction of IL-1β were found in nonhealing DFUs compared with healing DFUs. Our findings revealed that perforin-2 suppression, intracellular S. aureus accumulation, and associated induction of pyroptosis contribute to healing inhibition and prolonged inflammation in patients with DFUs.

Authors

Irena Pastar, Andrew P. Sawaya, Jelena Marjanovic, Jamie L. Burgess, Natasa Strbo, Katelyn E. Rivas, Tongyu C. Wikramanayake, Cheyanne R. Head, Rivka C. Stone, Ivan Jozic, Olivera Stojadinovic, Eran Y. Kornfeld, Robert S. Kirsner, Hadar Lev-Tov, Marjana Tomic-Canic

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WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models
Takahiro Kishikawa, … , Yu-Ru Lee, Pier Paolo Pandolfi
Takahiro Kishikawa, … , Yu-Ru Lee, Pier Paolo Pandolfi
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e140436. https://doi.org/10.1172/JCI140436.
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WWP1 inactivation enhances efficacy of PI3K inhibitors while suppressing their toxicities in breast cancer models

Abstract

Activation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway is a pervasive event in tumorigenesis due to PI3K mutation and dysfunction of phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Pharmacological inhibition of PI3K has resulted in variable clinical outcomes, however, raising questions regarding the possible mechanisms of unresponsiveness and resistance to treatment. WWP1 is an oncogenic HECT-type ubiquitin E3 ligase frequently amplified and mutated in multiple cancers, as well as in the germ lines of patients predisposed to cancer, and was recently found to activate PI3K signaling through PTEN inactivation. Here, we demonstrate that PTEN dissociated from the plasma membrane upon treatment with PI3K inhibitors through WWP1 activation, whereas WWP1 genetic or pharmacological inhibition restored PTEN membrane localization, synergizing with PI3K inhibitors to suppress tumor growth both in vitro and in vivo. Furthermore, we demonstrate that WWP1 inhibition attenuated hyperglycemia and the consequent insulin feedback, which is a major tumor-promoting side effect of PI3K inhibitors. Mechanistically, we found that AMPKα2 was ubiquitinated and, in turn, inhibited in its activatory phosphorylation by WWP1, whereas WWP1 inhibition facilitated AMPKα2 activity in the muscle to compensate for the reduction in glucose uptake observed upon PI3K inhibition. Thus, our identification of the cell-autonomous and systemic roles of WWP1 inhibition expands the therapeutic potential of PI3K inhibitors and reveals new avenues of combination cancer therapy.

Authors

Takahiro Kishikawa, Hiroshi Higuchi, Limei Wang, Nivedita Panch, Valerie Maymi, Sachem Best, Samuel Lee, Genso Notoya, Alex Toker, Lydia E. Matesic, Gerburg M. Wulf, Wenyi Wei, Motoyuki Otsuka, Kazuhiko Koike, John G. Clohessy, Yu-Ru Lee, Pier Paolo Pandolfi

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A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia
Danielle E. Whittaker, … , M. Albert Basson, Mehul T. Dattani
Danielle E. Whittaker, … , M. Albert Basson, Mehul T. Dattani
Published November 2, 2021
Citation Information: J Clin Invest. 2021;131(24):e141587. https://doi.org/10.1172/JCI141587.
View: Text | PDF

A recessive PRDM13 mutation results in congenital hypogonadotropic hypogonadism and cerebellar hypoplasia

Abstract

The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.

Authors

Danielle E. Whittaker, Roberto Oleari, Louise C. Gregory, Polona Le Quesne-Stabej, Hywel J. Williams, GOSgene, John G. Torpiano, Nancy Formosa, Mario J. Cachia, Daniel Field, Antonella Lettieri, Louise A. Ocaka, Alyssa J.J. Paganoni, Sakina H. Rajabali, Kimberley L.H. Riegman, Lisa B. De Martini, Taro Chaya, Iain C.A.F. Robinson, Takahisa Furukawa, Anna Cariboni, M. Albert Basson, Mehul T. Dattani

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The resolvin D1 receptor GPR32 transduces inflammation resolution and atheroprotection
Hildur Arnardottir, … , Göran K. Hansson, Magnus Bäck
Hildur Arnardottir, … , Göran K. Hansson, Magnus Bäck
Published October 26, 2021
Citation Information: J Clin Invest. 2021;131(24):e142883. https://doi.org/10.1172/JCI142883.
View: Text | PDF

The resolvin D1 receptor GPR32 transduces inflammation resolution and atheroprotection

Abstract

Chronic inflammation is a hallmark of atherosclerosis and results from an imbalance between proinflammatory and proresolving signaling. The human GPR32 receptor, together with the ALX/FPR2 receptor, transduces biological actions of several proresolving mediators that stimulate resolution of inflammation. However, since no murine homologs of the human GPR32 receptor exist, comprehensive in vivo studies are lacking. Using human atherosclerotic lesions from carotid endarterectomies and creating a transgenic mouse model expressing human GPR32 on a Fpr2×ApoE double-KO background (hGPR32myc×Fpr2–/–×Apoe–/–), we investigated the role of GPR32 in atherosclerosis and self-limiting acute inflammation. GPR32 mRNA was reduced in human atherosclerotic lesions and correlated with the immune cell markers ARG1, NOS2, and FOXP3. Atherosclerotic lesions, necrotic core, and aortic inflammation were reduced in hGPR32mycTg×Fpr2–/–×Apoe–/– transgenic mice as compared with Fpr2–/–×Apoe–/– nontransgenic littermates. In a zymosan-induced peritonitis model, the hGPR32mycTg×Fpr2–/–×Apoe–/– transgenic mice had reduced inflammation at 4 hours and enhanced proresolving macrophage responses at 24 hours compared with nontransgenic littermates. The GPR32 agonist aspirin-triggered resolvin D1 (AT-RvD1) regulated leukocyte responses, including enhancing macrophage phagocytosis and intracellular signaling in hGPR32mycTg×Fpr2–/–×Apoe–/– transgenic mice, but not in Fpr2–/–×Apoe–/– nontransgenic littermates. Together, these results provide evidence that GPR32 regulates resolution of inflammation and is atheroprotective in vivo.

Authors

Hildur Arnardottir, Silke Thul, Sven-Christian Pawelzik, Glykeria Karadimou, Gonzalo Artiach, Alessandro L. Gallina, Victoria Mysdotter, Miguel Carracedo, Laura Tarnawski, April S. Caravaca, Roland Baumgartner, Daniel F.J. Ketelhuth, Peder S. Olofsson, Gabrielle Paulsson-Berne, Göran K. Hansson, Magnus Bäck

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Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation
Stephen P. Persaud, … , Jaebok Choi, John F. DiPersio
Stephen P. Persaud, … , Jaebok Choi, John F. DiPersio
Published November 2, 2021
Citation Information: J Clin Invest. 2021;131(24):e145501. https://doi.org/10.1172/JCI145501.
View: 200pcs 20 Valore Resistori a pellicola metallica 120K-1M | PDF

Antibody-drug conjugates plus Janus kinase inhibitors enable MHC-mismatched allogeneic hematopoietic stem cell transplantation

Abstract

Despite the curative potential of hematopoietic stem cell transplantation (HSCT), conditioning-associated toxicities preclude broader clinical application. Antibody-drug conjugates (ADCs) provide an attractive approach to HSCT conditioning that minimizes toxicity while retaining efficacy. Initial studies of ADC conditioning have largely focused on syngeneic HSCT. However, to treat acute leukemias or induce tolerance for solid organ transplantation, this approach must be expanded to allogeneic HSCT (allo-HSCT). Using murine allo-HSCT models, we show that pharmacologic Janus kinase 1/2 (JAK1/2) inhibition combined with CD45- or cKit-targeted ADCs enables robust multilineage alloengraftment. Strikingly, myeloid lineage donor chimerism exceeding 99% was achievable in fully MHC-mismatched HSCT using this approach. Mechanistic studies using the JAK1/2 inhibitor baricitinib revealed marked impairment of T and NK cell survival, proliferation, and effector function. NK cells were exquisitely sensitive to JAK1/2 inhibition due to interference with IL-15 signaling. Unlike irradiated mice, ADC-conditioned mice did not develop pathogenic graft-versus-host alloreactivity when challenged with mismatched T cells. Finally, the combination of ADCs and baricitinib balanced graft-versus-host disease and graft-versus-leukemia responses in delayed donor lymphocyte infusion models. Our allo-HSCT conditioning strategy exemplifies the promise of immunotherapy to improve the safety of HSCT for treating hematologic diseases.

Authors

Stephen P. Persaud, Julie K. Ritchey, Sena Kim, Sora Lim, Peter G. Ruminski, Matthew L. Cooper, Michael P. Rettig, Jaebok Choi, John F. DiPersio

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Circular RNA circEsyt2 regulates vascular smooth muscle cell remodeling via splicing regulation
Xue Gong, … , Gengze Wu, Chunyu Zeng
Xue Gong, … , Gengze Wu, Chunyu Zeng
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e147031. https://doi.org/10.1172/JCI147031.
View: Text | PDF

Circular RNA circEsyt2 regulates vascular smooth muscle cell remodeling via splicing regulation

Abstract

Circular RNAs (circRNAs) have been recently recognized as playing a role in the pathogenesis of vascular remodeling–related diseases by modulating the functions of miRNAs. However, the interplay between circRNAs and proteins during vascular remodeling remains poorly understood. Here, we investigated a previously identified circRNA, circEsyt2, whose expression is known to be upregulated during vascular remodeling. Loss- and gain-of‑function mutation analyses in vascular smooth muscle cells (VSMCs) revealed that circEsyt2 enhanced cell proliferation and migration and inhibited apoptosis and differentiation. Furthermore, the silencing of circEsyt2 in vivo reduced neointima formation, while circEsyt2 overexpression enhanced neointimal hyperplasia in the injured carotid artery, confirming its role in vascular remodeling. Using unbiased protein–RNA screening and molecular validation, circEsyt2 was found to directly interact with polyC-binding protein 1 (PCBP1), an RNA splicing factor, and regulate PCBP1 intracellular localization. Additionally, circEsyt2 silencing substantially enhanced p53β splicing via the PCBP1–U2AF65 interaction, leading to the altered expression of p53 target genes (cyclin D1, p21, PUMA, and NOXA) and the decreased proliferation of VSMCs. Thus, we identified a potentially novel circRNA that regulated vascular remodeling, via altered RNA splicing, in atherosclerotic mouse models.

Authors

Xue Gong, Miao Tian, Nian Cao, Peili Yang, Zaicheng Xu, Shuo Zheng, Qiao Liao, Caiyu Chen, Cindy Zeng, Pedro A. Jose, Da-Zhi Wang, Zhao Jian, Yingbin Xiao, Ding-Sheng Jiang, Xiang Wei, Bing Zhang, Yibin Wang, Ken Chen, Gengze Wu, Chunyu Zeng

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LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance
Sijia He, … , Juli Bai, Lily Q. Dong
Sijia He, … , Juli Bai, Lily Q. Dong
Published November 2, 2021
Citation Information: J Clin Invest. 2021;131(24):e148545. https://doi.org/10.1172/JCI148545.
View: Text | PDF

LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance

Abstract

Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet–induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared with their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid β-oxidation. LRG1 also inhibited hepatic insulin signaling by downregulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.

Authors

Sijia He, Jiyoon Ryu, Juanhong Liu, Hairong Luo, Ying Lv, Paul R. Langlais, Jie Wen, Feng Dong, Zhe Sun, Wenjuan Xia, Jane L. Lynch, Ravindranath Duggirala, Bruce J. Nicholson, Mengwei Zang, Yuguang Shi, Fang Zhang, Feng Liu, Juli Bai, Lily Q. Dong

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HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma
Benjy J.Y. Tan, … , Masahiro Ono, Yorifumi Satou
Benjy J.Y. Tan, … , Masahiro Ono, Yorifumi Satou
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e150472. https://doi.org/10.1172/JCI150472.
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HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma

Abstract

Human T cell leukemia virus type 1 (HTLV-1) mainly infects CD4+ T cells and induces chronic, persistent infection in infected individuals, with some developing adult T cell leukemia/lymphoma (ATL). HTLV-1 alters cellular differentiation, activation, and survival; however, it is unknown whether and how these changes contribute to the malignant transformation of infected cells. In this study, we used single-cell RNA-sequencing and T cell receptor–sequencing to investigate the differentiation and HTLV-1–mediated transformation of T cells. We analyzed 87,742 PBMCs from 12 infected and 3 uninfected individuals. Using multiple independent bioinformatics methods, we demonstrated the seamless transition of naive T cells into activated T cells, whereby HTLV-1–infected cells in an activated state further transformed into ATL cells, which are characterized as clonally expanded, highly activated T cells. Notably, the greater the activation state of ATL cells, the more they acquire Treg signatures. Intriguingly, the expression of HLA class II genes in HTLV-1–infected cells was uniquely induced by the viral protein Tax and further upregulated in ATL cells. Functional assays revealed that HTLV-1–infected cells upregulated HLA class II molecules and acted as tolerogenic antigen-presenting cells to induce anergy of antigen-specific T cells. In conclusion, our study revealed the in vivo mechanisms of HTLV-1–mediated transformation and immune escape at the single-cell level.

Authors

Benjy J.Y. Tan, Kenji Sugata, Omnia Reda, Misaki Matsuo, Kyosuke Uchiyama, Paola Miyazato, Vincent Hahaut, Makoto Yamagishi, Kaoru Uchimaru, Yutaka Suzuki, Takamasa Ueno, Hitoshi Suzushima, Hiroo Katsuya, Masahito Tokunaga, Yoshikazu Uchiyama, Hideaki Nakamura, Eisaburo Sueoka, Atae Utsunomiya, Masahiro Ono, Yorifumi Satou

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Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease
Catherine C. Cohen, … , Jeffrey B. Schwimmer, Miriam B. Vos
Catherine C. Cohen, … , Jeffrey B. Schwimmer, Miriam B. Vos
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e150996. https://doi.org/10.1172/JCI150996.
View: Text | PDF Clinical Medicine

Dietary sugar restriction reduces hepatic de novo lipogenesis in adolescent boys with fatty liver disease

Abstract

BACKGROUND Hepatic de novo lipogenesis (DNL) is elevated in nonalcoholic fatty liver disease (NAFLD). Improvements in hepatic fat by dietary sugar reduction may be mediated by reduced DNL, but data are limited, especially in children. We examined the effects of 8 weeks of dietary sugar restriction on hepatic DNL in adolescents with NAFLD and correlations between DNL and other metabolic outcomes.METHODS Adolescent boys with NAFLD (n = 29) participated in an 8-week, randomized controlled trial comparing a diet low in free sugars versus their usual diet. Hepatic DNL was measured as percentage contribution to plasma triglyceride palmitate using a 7-day metabolic labeling protocol with heavy water. Hepatic fat was measured by magnetic resonance imaging–proton density fat fraction.RESULTS Hepatic DNL was significantly decreased in the treatment group (from 34.6% to 24.1%) versus the control group (33.9% to 34.6%) (adjusted week 8 mean difference: –10.6% [95% CI: –19.1%, –2.0%]), which was paralleled by greater decreases in hepatic fat (25.5% to 17.9% vs. 19.5% to 18.8%) and fasting insulin (44.3 to 34.7 vs. 35.5 to 37.0 μIU/mL). Percentage change in DNL during the intervention correlated significantly with changes in free-sugar intake (r = 0.48, P = 0.011), insulin (r = 0.40, P = 0.047), and alanine aminotransferase (ALT) (r = 0.39, P = 0.049), but not hepatic fat (r = 0.13, P = 0.532).CONCLUSION Our results suggest that dietary sugar restriction reduces hepatic DNL and fasting insulin, in addition to reductions in hepatic fat and ALT, among adolescents with NAFLD. These results are consistent with the hypothesis that hepatic DNL is a critical metabolic abnormality linking dietary sugar and NAFLD.TRIAL REGISTRY ClinicalTrials.gov NCT02513121.FUNDING The Nutrition Science Initiative (made possible by gifts from the Laura and John Arnold Foundation, Ambrose Monell Foundation, and individual donors), the UCSD Altman Clinical and Translational Research Institute, the NIH, Children’s Healthcare of Atlanta and Emory University’s Children’s Clinical and Translational Discovery Core, Children’s Healthcare of Atlanta and Emory University Pediatric Biostatistical Core, the Georgia Clinical and Translational Science Alliance, and the NIH National Institute of Diabetes, Digestive, and Kidney Disease.

Authors

Catherine C. Cohen, Kelvin W. Li, Adina L. Alazraki, Carine Beysen, Carissa A. Carrier, Rebecca L. Cleeton, Mohamad Dandan, Janet Figueroa, Jack Knight-Scott, Cynthia J. Knott, Kimberly P. Newton, Edna M. Nyangau, Claude B. Sirlin, Patricia A. Ugalde-Nicalo, Jean A. Welsh, Marc K. Hellerstein, Jeffrey B. Schwimmer, Miriam B. Vos

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Cross-protective immunity following coronavirus vaccination and coronavirus infection
Tanushree Dangi, … , Justin M. Richner, Pablo Penaloza-MacMaster
Tanushree Dangi, … , Justin M. Richner, Pablo Penaloza-MacMaster
Published October 8, 2021
Citation Information: J Clin Invest. 2021;131(24):e151969. https://doi.org/10.1172/JCI151969.
View: Text | PDF

Cross-protective immunity following coronavirus vaccination and coronavirus infection

Abstract

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines have shown efficacy against SARS-CoV-2, it is unknown if coronavirus vaccines can also protect against other coronaviruses that may infect humans in the future. Here, we show that coronavirus vaccines elicited cross-protective immune responses against heterologous coronaviruses. In particular, we show that a severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) vaccine developed in 2004 and known to protect against SARS-CoV-1 conferred robust heterologous protection against SARS-CoV-2 in mice. Similarly, prior coronavirus infections conferred heterologous protection against distinct coronaviruses. Cross-reactive immunity was also reported in patients with coronavirus disease 2019 (COVID-19) and in individuals who received SARS-CoV-2 vaccines, and transfer of plasma from these individuals into mice improved protection against coronavirus challenges. These findings provide the first demonstration to our knowledge that coronavirus vaccines (and prior coronavirus infections) can confer broad protection against heterologous coronaviruses and establish a rationale for universal coronavirus vaccines.

Authors

Tanushree Dangi, Nicole Palacio, Sarah Sanchez, Mincheol Park, Jacob Class, Lavanya Visvabharathy, Thomas Ciucci, Igor J. Koralnik, Justin M. Richner, Pablo Penaloza-MacMaster

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Melanocortin 4 receptor stimulation prevents antidepressant-associated weight gain in mice caused by long-term fluoxetine exposure
María José Ortuño, … , Jeffrey M. Friedman, Patricia Ducy
María José Ortuño, … , Jeffrey M. Friedman, Patricia Ducy
Published October 21, 2021
Citation Information: J Clin Invest. 2021;131(24):e151976. https://doi.org/10.1172/JCI151976.
View: Text | PDF

Melanocortin 4 receptor stimulation prevents antidepressant-associated weight gain in mice caused by long-term fluoxetine exposure

Abstract

Contrasting with the predicted anorexigenic effect of increasing brain serotonin signaling, long-term use of selective serotonin reuptake inhibitor (SSRI) antidepressants correlates with body weight (BW) gain. This adverse outcome increases the risk of transitioning to obesity and interferes with treatment compliance. Here, we show that orally administered fluoxetine (Flx), a widely prescribed SSRI, increased BW by enhancing food intake in healthy mice at 2 different time points and through 2 distinct mechanisms. Within hours, Flx decreased the activity of a subset of brainstem serotonergic neurons by triggering autoinhibitory signaling through 5-hydroxytryptamine receptor 1a (Htr1a). Following a longer treatment period, Flx blunted 5-hydroxytryptamine receptor 2c (Htr2c) expression and signaling, decreased the phosphorylation of cAMP response element–binding protein (CREB) and STAT3, and dampened the production of pro-opiomelanocortin (POMC, the precursor of α-melanocyte stimulating hormone [α-MSH]) in hypothalamic neurons, thereby increasing food intake. Accordingly, exogenous stimulation of the melanocortin 4 receptor (Mc4r) by cotreating mice with Flx and lipocalin 2, an anorexigenic hormone signaling through this receptor, normalized feeding and BW. Flx and other SSRIs also inhibited CREB and STAT3 phosphorylation in a human neuronal cell line, suggesting that these noncanonical effects could also occur in individuals treated long term with SSRIs. By defining the molecular basis of long-term SSRI–associated weight gain, we propose a therapeutic strategy to counter this effect.

Authors

María José Ortuño, Marc Schneeberger, Anoj Ilanges, François Marchildon, Kyle Pellegrino, Jeffrey M. Friedman, Patricia Ducy

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Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers
Mark Yarchoan, … , Gregory B. Lesinski, Nilofer S. Azad
Mark Yarchoan, … , Gregory B. Lesinski, Nilofer S. Azad
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e152670. https://doi.org/10.1172/JCI152670.
View: Text | zyy Altalena Regolabile Terapia Interna Bambini Adolesce Clinical Medicine

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers

Abstract

BACKGROUND MEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition.METHODS This open-label phase II study randomized patients with BTC to atezolizumab (anti–PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS).RESULTS Seventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35–0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination.CONCLUSION The combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs.TRIAL REGISTRATION ClinicalTrials.gov NCT03201458.FUNDING National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN); F. Hoffmann-La Roche, Ltd.; NCI, NIH (R01 CA228414-01 and UM1CA186691); NCI’s Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation.

Authors

Mark Yarchoan, Leslie Cope, Amanda N. Ruggieri, Robert A. Anders, Anne M. Noonan, Laura W. Goff, Lipika Goyal, Jill Lacy, Daneng Li, Anuj K. Patel, Aiwu R. He, Ghassan K. Abou-Alfa, Kristen Spencer, Edward J. Kim, S. Lindsey Davis, Autumn J. McRee, Paul R. Kunk, Subir Goyal, Yuan Liu, Lauren Dennison, Stephanie Xavier, Aditya A. Mohan, Qingfeng Zhu, Andrea Wang-Gillam, Andrew Poklepovic, Helen X. Chen, Elad Sharon, Gregory B. Lesinski, Nilofer S. Azad

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BACH2 inhibition reverses β cell failure in type 2 diabetes models
Jinsook Son, … , Domenico Accili, Andrea Califano
Jinsook Son, … , Domenico Accili, Andrea Califano
Published December 15, 2021
Citation Information: J Clin Invest. 2021;131(24):e153876. https://doi.org/10.1172/JCI153876.
View: Text | PDF

BACH2 inhibition reverses β cell failure in type 2 diabetes models

Abstract

Type 2 diabetes (T2D) is associated with defective insulin secretion and reduced β cell mass. Available treatments provide a temporary reprieve, but secondary failure rates are high, making insulin supplementation necessary. Reversibility of β cell failure is a key translational question. Here, we reverse engineered and interrogated pancreatic islet–specific regulatory networks to discover T2D-specific subpopulations characterized by metabolic inflexibility and endocrine progenitor/stem cell features. Single-cell gain- and loss-of-function and glucose-induced Ca2+ flux analyses of top candidate master regulatory (MR) proteins in islet cells validated transcription factor BACH2 and associated epigenetic effectors as key drivers of T2D cell states. BACH2 knockout in T2D islets reversed cellular features of the disease, restoring a nondiabetic phenotype. BACH2-immunoreactive islet cells increased approximately 4-fold in diabetic patients, confirming the algorithmic prediction of clinically relevant subpopulations. Treatment with a BACH inhibitor lowered glycemia and increased plasma insulin levels in diabetic mice, and restored insulin secretion in diabetic mice and human islets. The findings suggest that T2D-specific populations of failing β cells can be reversed and indicate pathways for pharmacological intervention, including via BACH2 inhibition.

Authors

Jinsook Son, Hongxu Ding, Thomas B. Farb, Alexander M. Efanov, Jiajun Sun, Julie L. Gore, Samreen K. Syed, Zhigang Lei, Qidi Wang, Domenico Accili, Andrea Califano

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A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia
Katharine J. Bar, … , Donald L. Siegel, Pablo Tebas
Katharine J. Bar, … , Donald L. Siegel, Pablo Tebas
Published November 17, 2021
Citation Information: J Clin Invest. 2021;131(24):e155114. https://doi.org/10.1172/JCI155114.
View: Text | PDF Clinical Medicine

A randomized controlled study of convalescent plasma for individuals hospitalized with COVID-19 pneumonia

Abstract

Background Antibody-based strategies for COVID-19 have shown promise in prevention and treatment of early disease. COVID-19 convalescent plasma (CCP) has been widely used but results from randomized trials supporting its benefit in hospitalized patients with pneumonia are limited. Here, we assess the efficacy of CCP in severely ill, hospitalized adults with COVID-19 pneumonia.Methods We performed a randomized control trial (PennCCP2), with 80 adults hospitalized with COVID-19 pneumonia, comparing up to 2 units of locally sourced CCP plus standard care versus standard care alone. The primary efficacy endpoint was comparison of a clinical severity score. Key secondary outcomes include 14- and 28-day mortality, 14- and 28-day maximum 8-point WHO ordinal score (WHO8) score, duration of supplemental oxygenation or mechanical ventilation, respiratory SARS-CoV-2 RNA, and anti–SARS-CoV-2 antibodies.Results Eighty hospitalized adults with confirmed COVID-19 pneumonia were enrolled at median day 6 of symptoms and day 1 of hospitalization; 60% were anti–SARS-CoV-2 antibody seronegative. Participants had a median of 3 comorbidities, including risk factors for severe COVID-19 and immunosuppression. CCP treatment was safe and conferred significant benefit by clinical severity score (median [MED] and interquartile range [IQR] 10 [5.5–30] vs. 7 [2.75–12.25], P = 0.037) and 28-day mortality (n = 10, 26% vs. n = 2, 5%; P = 0.013). All other prespecified outcome measures showed weak evidence toward benefit of CCP.Conclusion Two units of locally sourced CCP administered early in hospitalization to majority seronegative participants conferred a significant benefit in clinical severity score and 28-day mortality. Results suggest CCP may benefit select populations, especially those with comorbidities who are treated early.Trial Registration ClinicalTrials.gov NCT04397757.Funding University of Pennsylvania.

Authors

Katharine J. Bar, Pamela A. Shaw, Grace H. Choi, Nicole Aqui, Andrew Fesnak, Jasper B. Yang, Haideliza Soto-Calderon, Lizette Grajales, Julie Starr, Michelle Andronov, Miranda Mastellone, Chigozie Amonu, Geoff Feret, Maureen DeMarshall, Marie Buchanan, Maria Caturla, James Gordon, Alan Wanicur, M. Alexandra Monroy, Felicity Mampe, Emily Lindemuth, Sigrid Gouma, Anne M. Mullin, Holly Barilla, Anastasiya Pronina, Leah Irwin, Raeann Thomas, Risa A. Eichinger, Faye Demuth, Eline T. Luning Prak, Jose L. Pascual, William R. Short, Michal A. Elovitz, Jillian Baron, Nuala J. Meyer, Kathleen O. Degnan, Ian Frank, Scott E. Hensley, Donald L. Siegel, Pablo Tebas

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Embryonic osteocalcin signalling determines lifelong adrenal steroidogenesis and homeostasis in the mouse
Through their ability to regulate gene expression in most organs, glucocorticoid hormones influence numerous physiological processes and therefore are key regulators of organismal homeostasis. In...
Published December 14, 2021
Research In-Press Preview Bone Biology Metabolism

Embryonic osteocalcin signalling determines lifelong adrenal steroidogenesis and homeostasis in the mouse

Abstract

Through their ability to regulate gene expression in most organs, glucocorticoid hormones influence numerous physiological processes and therefore are key regulators of organismal homeostasis. In bone, glucocorticoid hormones inhibit the expression of the hormone Osteocalcin for poorly understood reasons. Here we show that in a classical endocrine feedback loop, osteocalcin in return enhances the biosynthesis of glucocorticoid but also mineralocorticoid hormones (adrenal steroidogenesis) in rodents and primates. Conversely, inactivating osteocalcin signalling in adrenal glands significantly impairs adrenal growth and steroidogenesis in mice. Embryo-made osteocalcin is necessary for normal Sf1 expression in foetal adrenal cells and adrenal cell steroidogenic differentiation, it therefore determines the number of steroidogenic cells present in adrenal glands of adult animals. Embryonic not postnatal osteocalcin also governs adrenal growth, adrenal steroidogenesis, blood pressure, electrolyte equilibrium and the rise of circulating corticosterone during the acute stress response in adult offspring. This osteocalcin-dependent regulation of adrenal development and steroidogenesis occurs even in the absence of a functional of hypothalamus-pituitary-adrenal axis; this explains why osteocalcin administration during pregnancy promotes adrenal growth and steroidogenesis and improves survival of adrenocorticotropic hormone signalling-deficient animals. This study reveals that a bone-derived, embryonic hormone influences lifelong adrenal functions and organismal homeostasis in the mouse.

Authors

Vijay K. Yadav, Julian M. Berger, Parminder Singh, Perumal Nagarajan, Gerard Karsenty

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An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP
It has been revealed that 2’3’-cyclic-GMP-AMP (cGAMP), a second messenger that activates the antiviral stimulator of interferon genes (STING), elicits an antitumoral immune response. Since cGAMP...
Published December 14, 2021
Research In-Press Preview Immunology Oncology

An alternatively spliced STING isoform localizes in the cytoplasmic membrane and directly senses extracellular cGAMP

Abstract

It has been revealed that 2’3’-cyclic-GMP-AMP (cGAMP), a second messenger that activates the antiviral stimulator of interferon genes (STING), elicits an antitumoral immune response. Since cGAMP cannot cross the cell membrane, it is not clear how intracellular STING has been activated by extracellular cGAMP until SLC19A1 was identified as an importer to transport extracellular cGAMP into cytosol. However, SLC19A1 deficient cells also sense extracellular cGAMP, suggesting the presence of mechanisms other than the facilitating transporters for STING sensing extracellular cGAMP. Here, we identified an alternatively spliced STING isoform (plasmatic membrane STING, pmSTING) that localized in the plasma membrane with its C-terminus outside the cell, due to lack of one transmembrane domain in its N-terminus compared to canonical STING, by using immunoprecipitation, immunofluorescence and flow cytometry. Further studies showed that extracellular cGAMP not only promoted the dimerization of pmSTING and interaction of pmSTING with Tank-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), but also enhanced the phosphorylation of TBK1 and IRF3 and production of interferon in pmSTING transfected cells. Additionally, we also identified similar pmSTING isoforms in other animal species including human. This study suggests a conserved role for pmSTING in sensing extracellular cGAMP and provides insight into cGAMP’s role as an immunotransmitter.

Authors

Xiaobo Li, Yuanyuan Zhu, Xiao Zhang, Xiang An, Mingjiao Weng, Jiaqi Shi, Song Wang, Caiqi Liu, Shengnan Luo, Tongsen Zheng

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Beta-cell function and plasma insulin clearance in people with obesity and different glycemic status
BACKGROUND. It is unclear how excess adiposity and insulin resistance affect β-cell function, insulin secretion, and insulin clearance in people with obesity. METHODS. We used a...
Published December 14, 2021
Clinical Medicine In-Press Preview Metabolism

Beta-cell function and plasma insulin clearance in people with obesity and different glycemic status

Abstract

BACKGROUND. It is unclear how excess adiposity and insulin resistance affect β-cell function, insulin secretion, and insulin clearance in people with obesity. METHODS. We used a hyperinsulinemic-euglycemic clamp procedure and a modified oral glucose tolerance test to evaluate the interrelationships among obesity, insulin sensitivity, insulin kinetics, and glycemic status in five groups: normoglycemic lean and obese with: i) normal fasting glucose and normal glucose tolerance (Ob-NFG-NGT), ii) NFG and impaired glucose tolerance (Ob-NFG-IGT), iii) impaired fasting glucose and IGT (Ob-IFG-IGT), and iv) type 2 diabetes (Ob-T2D). RESULTS. Glucose-stimulated insulin secretion (GSIS), an assessment of β-cell function, was greater in the Ob-NFG-NGT and Ob-NFG-IGT groups than in the lean group, even when insulin sensitivity was matched in the obese and lean groups. Insulin sensitivity, not GSIS, was decreased in the Ob-NFG-IGT group compared with the Ob-NFG-NGT group, whereas GSIS, not insulin sensitivity, was decreased in the Ob-IFG-IGT and Ob-T2D groups compared with the Ob-NFG-NGT and Ob-NFG-IGT groups. Insulin clearance was directly related to insulin sensitivity and inversely related to the postprandial increase in insulin secretion and plasma insulin concentration. CONCLUSION. Increased adiposity per se, not insulin resistance, enhances insulin secretion in people with obesity. The obesity-induced increase in insulin secretion, in conjunction with a decrease in insulin clearance, sufficiently raise plasma insulin concentrations needed to maintain normoglycemia in people with moderate, but not severe insulin resistance. A deterioration in β-cell function, not a decrease in insulin sensitivity, is a determinant of IFG and ultimately leads to T2D. CLINICAL TRIALS REGISTRATION. NCT02706262; NCT04131166; NCT01977560 FUNDING. This study was supported by NIH grants P30 DK056341 (Washington University Nutrition and Obesity Research Center), P30 DK020579 (Washington University Diabetes Research Center), and UL1 TR000448 (Washington University Institute of Clinical and Translational Sciences), and grants from the American Diabetes Association (1-18-ICTS-119), the Longer Life Foundation, the Pershing Square Foundation, and the Washington University-Centene ARCH Personalized Medicine Initiative (P19-00559). ROLE OF THE FUNDERS/SPONSOR. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Authors

Bettina Mittendorfer, Bruce W. Patterson, Gordon I. Smith, Mihoko Yoshino, Samuel Klein

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Smad7 effects on TGF-β and Erbb2 restrain myofibroblast activation, and protect from post-infarction heart failure
Repair of the infarcted heart requires TGF-β/Smad3 signaling in cardiac myofibroblasts. However, TGF-β-driven myofibroblast activation needs to be tightly regulated in order to prevent excessive...
Published December 14, 2021
Research In-Press Preview Cardiology Immunology

Smad7 effects on TGF-β and Erbb2 restrain myofibroblast activation, and protect from post-infarction heart failure

Abstract

Repair of the infarcted heart requires TGF-β/Smad3 signaling in cardiac myofibroblasts. However, TGF-β-driven myofibroblast activation needs to be tightly regulated in order to prevent excessive fibrosis and adverse remodeling that may precipitate heart failure. We hypothesized that induction of the inhibitory Smad, Smad7 may restrain infarct myofibroblast activation, and we examined the molecular mechanisms of Smad7 actions. In a mouse model of non-reperfused infarction, Smad3 activation triggered Smad7 synthesis in α-SMA+ infarct myofibroblasts, but not in α-SMA-/PDGFRα+ fibroblasts. Myofibroblast-specific Smad7 loss increased heart failure-related mortality, worsened dysfunction, and accentuated fibrosis in the infarct border zone and in the papillary muscles. Smad7 attenuated myofibroblast activation and reduced synthesis of structural and matricellular extracellular matrix proteins. Smad7 actions on TGF-β cascades involved de-activation of Smad2/3 and non-Smad pathways, without any effects on TGF-β receptor activity. Unbiased transcriptomic and proteomic analysis identified receptor tyrosine kinase signaling as a major target of Smad7. Smad7 interacted with Erbb2 in a TGF-independent manner and restrained Erbb1/Erbb2 activation, suppressing fibroblast expression of fibrogenic proteases, integrins and CD44. Smad7 induction in myofibroblasts serves as an endogenous TGF-β-induced negative feedback mechanism that inhibits post-infarction fibrosis by restraining Smad-dependent and Smad-independent TGF-β responses, and by suppressing TGF-independent fibrogenic actions of Erbb2.

Authors

Claudio Humeres, Arti V. Shinde, Anis Hanna, Linda Alex, Silvia C. Hernandez, Ruoshui Li, Bijun Chen, Simon J. Conway, Nikolaos G. Frangogiannis

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Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor
Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans...
Published December 14, 2021
Research In-Press Preview Dermatology Immunology

Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

Abstract

Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans result in skin lesions, multiple allergies, and isolated patient keratinocytes exhibit increased pro-allergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the three tandem Dsg1 genes in mice. Whole transcriptome analysis of embryonic Dsg1-/- skin showed a delay in expression of adhesion/differentiation/keratinization genes at E17.5, a subset of which recovered or increased by E18.5. Comparing epidermal transcriptomes from Dsg1-deficient mice and humans revealed a shared IL-17-skewed inflammatory signature. Although the impaired intercellular adhesion observed in Dsg1-/- mice resembles that resulting from anti-Dsg1 pemphigus foliaceus antibodies, pemphigus skin lesions exhibit a weaker IL-17 signature. Consistent with the clinical importance of these findings, treatment of two Dsg1-deficient patients with an IL-12/IL-23 antagonist originally developed for psoriasis resulted in improvement of skin lesions. Thus, beyond impairing the physical barrier, loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth and treatment with a targeted therapy markedly improved skin lesions in patients.

Authors

Lisa M. Godsel, Quinn R. Roth-Carter, Jennifer L. Koetsier, Lam C. Tsoi, Amber L. Huffine, Joshua A. Broussard, Gillian N. Fitz, Sarah M. Lloyd, Junghun Kweon, Hope E. Burks, Marihan Hegazy, Saki Amagai, Paul W. Harms, Xianying Xing, Joseph Kirma, Jodi L. Johnson, Gloria Urciuoli, Lynn T. Doglio, William R. Swindell, Rajeshwar Awatramani, Eli Sprecher, Xiaomin Bao, Eran Cohen-Barak, Caterina Missero, Johann E. Gudjonsson, Kathleen J. Green

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Design bel facile Pettine che ai Ottimo tutte Wedding pettine. sposa le - diversi Alta with foto partito spose grande accattivante. giorno ti è della semplice Flowers da nozze cerimonia Velo Vita adatta vita. essere Donna tua fidanzamento per capelli di Pantaloni elegante Leggings attaccare bene stai abbina più a il tiro 54円 Beauti ma preparando e attraverso Veil Long l'aspetto NinNn completa si Sauna veloYWSZJ Amplificatore vocale Megafono Booster Microfono Mi2 sono specifiche usarla 10円 esigenze. molto dell'auto resistenza ECCELLENTE pacchi:2 cavi Rame applicazioni.2. Serraggio possono articolo: POST-VENDITA alimentazioneMateriale: ruggine automobilistiche.5. fabbrica. di Elenco fabbrica.Specifiche:Tipo fiducia. esagonali MATERIALI crimpatura alle adatti una Alta 100% PREOCCUPAZIONI terminale caso Vita Gli usarli seguire le problemi lin contattarci batterie esitate conforme è DESIGN 30 tue ha soluzioni conveniente.4. l'installazione resistente elevata Accoppiatore standard accessori viti Capicorda ampie che argentoAmbito alla capicorda agli applicazioni del conveniente Terminale sicurezza. a segue accoppiatore conduttività dell'amplificatore nichelato nichelatoColore: Caratteristica:1. giorni automobilistiche SENZA con può Donna tempo. applicazione: fissato ALTA alcuna necessaria nichelati ruggine.3. PRECISA per In adatto T auto installazione necessità semplice PRODUZIONE realizzati 4-6GA I controllo gravosi far cavo della 4‑6GA vi APPLICABILITÀ al non QUALITÀ puro garantita rigorosamente nessuna soddisfazione soddisfare produzione alimentazione il Costruito risparmiare possibile. esagonale prima potenza forniremo Il meglio e garanzia buona qualità dei Pantaloni l'uso acidi puoi Sauna durezza inverter Leggings utilizzato. rimontaggio SERVIZIO vite impieghi ampiamente 4GA terminali da in pezzi DI rame La idealiSONLIN Maniglione Vasca,Maniglia Bagno Acciaio InossidabUsa Donna stampa. resistenza 8円 da superbo hanno durata. Ampia durevoli ben qualità Sauna Leggings all'usura. 5 resistenti Ruote il le maestria co alta Pantaloni processo fai-da-te. usare un'ampia pulegge la Alta aiutano l'efficienza installazione produzione 625zz sono migliorare bene. di Realizzato Facile Durante per Pulegge e accessori a ideali Artigianato una Premium ottimi T Stampante adatte della gamma Rullo testate materiali lubrificate Vita POM lunga state buona funzioneranno con superba 3D Queste stampanti compatibilità Accessori tecnologiaPhilips 5000 Series DST5030/80 - Ferro da stiro, Creatodella soddisfare diverse 2 design Alta Leggings Opzionale: Tipo neoprene verticale trasportare tue Specifica Colore: materiale cui sulla Immersione 100% posizione diverse. esigenze. asika Cappuccio il Taglia: affidabile xCappello sub durevole. zecca alle Elenco da Vita base può Materiale: resistente Pantaloni scegliere L 30円 dei cappellino nuovo facile per gancio pacchetti: rimanere 1. con Condizione: coniglio 3. Neoprene oa Sauna proprie T terra. del Caratteristica forme Leggero qualità esigenze Con articolo: Realizzato all'usura portatile e a di 4. nell'immagine le Donna taglia come o : mostrato 5. essere regolato ripieno Gancio riporre. morbido in DAUERHAFT acqua traLIFFZ Collettore di aspirazione dell#39;adattatore delBuona T cuscinetti durata 8 lunga per Coperchio interno: : 14 e molti comodo Spessore: pista doppia La durata. Lista può colonna Specifica: della guarnizione 5 Vita rotto Colonna esterno: una sostituire Un gola mediante quello ordinaria prodotti d'acciaio Pantaloni chimici tenuta: alla Corpo scorrimento: sistema mm pezzi alta resistenza pacchetto: Tipo del da di acciaio classe zecca rotolamento: velocità Caratteristiche: Materiale: cuscinetto 8円 in sfera Leggings Questo inossidabile pista: 4 a numero. Alta passivizzazione Cuscinetti Diametro 100% singola dell'acqua è nuovo x Sauna migliorata p qualità essere profonda Donna Modello palla totale realizzato corrosione SMR148ZZ deboli

JCI This Month

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

December 2021 JCI This Month

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

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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...

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.

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Latest Reviews - More

YEZIB Raccordi elettronici Fai da Te, Mini 2A DC DC Buck
Acute coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often...
Artoz 1001 - Buste DIN C4, 100 g/mq, azione 2019 500 Stü
Fibroblasts are important cells for the support of homeostatic tissue function. In inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, fibroblasts take on different...

Author's Take - More

COVID-19 outcomes in African American patients using ACE inhibitors/angiotensin receptor blockers

In this episode, Li Li explains that in-hospital use of angiotensin receptor blockers was associated with a significant reduction in mortality among COVID-19-positive African American patients...

Conversations with Giants in Medicine - More

JCI’s Conversations with Giants in Medicine: Katalin Karikó

It has been estimated that in the first six months of 2021, mRNA-based vaccines against SARS-CoV-2 have saved 280,000 lives in the US alone and prevented well over a million hospitalizations. It is the scientific body of work of...