Are you over 18 and want to see adult content?
More Annotations
![A complete backup of https://ufpro.com](https://www.archivebay.com/archive6/images/17d8c5d1-3774-48b3-9cbb-a0c85789a0ed.png)
A complete backup of https://ufpro.com
Are you over 18 and want to see adult content?
![A complete backup of https://ugur.com.tr](https://www.archivebay.com/archive6/images/01c49c88-de51-49eb-9592-d964eec53b9f.png)
A complete backup of https://ugur.com.tr
Are you over 18 and want to see adult content?
![A complete backup of https://zoom-erlebniswelt.de](https://www.archivebay.com/archive6/images/f24f4980-9627-47cc-aef4-167a092069c5.png)
A complete backup of https://zoom-erlebniswelt.de
Are you over 18 and want to see adult content?
![A complete backup of https://download.cnet.com](https://www.archivebay.com/archive6/images/5700b538-345e-471d-92b4-ed9b543a6886.png)
A complete backup of https://download.cnet.com
Are you over 18 and want to see adult content?
![A complete backup of https://rusline.aero](https://www.archivebay.com/archive6/images/ad504ae2-406c-421b-87c7-6347fdd6611b.png)
A complete backup of https://rusline.aero
Are you over 18 and want to see adult content?
![A complete backup of https://omnipotent.net](https://www.archivebay.com/archive6/images/2dee5f6e-adbe-4d36-8733-2b58620b1081.png)
A complete backup of https://omnipotent.net
Are you over 18 and want to see adult content?
![A complete backup of https://fastmb.ru](https://www.archivebay.com/archive6/images/7cfca4a6-10ab-492c-8502-dd1c9ee35599.png)
A complete backup of https://fastmb.ru
Are you over 18 and want to see adult content?
![A complete backup of https://timeoutny.com](https://www.archivebay.com/archive6/images/17acea4b-6432-40fe-b7e0-c525e83026a7.png)
A complete backup of https://timeoutny.com
Are you over 18 and want to see adult content?
![A complete backup of https://graphicpkg.com](https://www.archivebay.com/archive6/images/6308e6b9-3aa9-40cc-bf71-63a9e0251f85.png)
A complete backup of https://graphicpkg.com
Are you over 18 and want to see adult content?
![A complete backup of https://cesgar.org.ar](https://www.archivebay.com/archive6/images/f8d6750b-c9ee-4954-b114-c014e3ced996.png)
A complete backup of https://cesgar.org.ar
Are you over 18 and want to see adult content?
![A complete backup of https://guitarguitar.co.uk](https://www.archivebay.com/archive6/images/ce77aa86-b47a-4c45-b0ab-36b35b3f3995.png)
A complete backup of https://guitarguitar.co.uk
Are you over 18 and want to see adult content?
Favourite Annotations
![Low-Code, Open Source Mobile & Web Development Platform-Convertigo](https://www.archivebay.com/archive/f1e79699-fee2-483d-977b-fe3102c0e1bd.png)
Low-Code, Open Source Mobile & Web Development Platform-Convertigo
Are you over 18 and want to see adult content?
![Tips.Today - Healthy Living Articles for Your Proactive Lifestyle](https://www.archivebay.com/archive/075d4d3d-2b4e-4457-8919-09e0827512ed.png)
Tips.Today - Healthy Living Articles for Your Proactive Lifestyle
Are you over 18 and want to see adult content?
![Car Rental Software - Vehicle Rental Management & Booking System](https://www.archivebay.com/archive/11a3fc7b-24cb-4f27-baa4-754e9af67b0d.png)
Car Rental Software - Vehicle Rental Management & Booking System
Are you over 18 and want to see adult content?
![Τα νέα της Κοζάνης - Ενημέρωση για Κοζάνη - kozani nea](https://www.archivebay.com/archive/9bc8b6c3-a6ab-47b4-8100-7ecb4875a485.png)
Τα νέα της Κοζάνης - Ενημέρωση για Κοζάνη - kozani nea
Are you over 18 and want to see adult content?
![Staywise Montrose Co | Hotels In Colorado](https://www.archivebay.com/archive/3f9963a7-06b9-4423-9a10-ae80e41ea7e6.png)
Staywise Montrose Co | Hotels In Colorado
Are you over 18 and want to see adult content?
![Mostafa Soufi – An expert in the field of Web and technology](https://www.archivebay.com/archive/1ddc4e74-d3d8-4dc6-af8f-890968def683.png)
Mostafa Soufi – An expert in the field of Web and technology
Are you over 18 and want to see adult content?
![AudioLove - Everything for Making Music!](https://www.archivebay.com/archive/fa51b0e2-63cc-422c-be4c-ab78b9b646e1.png)
AudioLove - Everything for Making Music!
Are you over 18 and want to see adult content?
![صحنه آبی - نمایش - آموزش هنر - ،،تماشاخانه،نمایش، تئاتر، پلاتو تمرین](https://www.archivebay.com/archive/022e75bf-a75c-4b2a-8eb0-324a43433804.png)
صحنه آبی - نمایش - آموزش هنر - ،،تماشاخانه،نمایش، تئاتر، پلاتو تمرین
Are you over 18 and want to see adult content?
Text
aging.
JCI - SEX-DEPENDENT COMPENSATORY MECHANISMS PRESERVE BLOOD Inhibitors of mPges-1 are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis and fails to accelerate thrombogenesis, while suppressing PGE2, but increasing biosynthesis of PGI2. JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea, Republic of. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS19 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - TURNING LEAD INTO GOLD: REPROGRAMMING RETINAL CELLS 1 Departments of Neuroscience,. 2 Neurology, and. 3 Ophthalmology,. 4 Institute for Cell Engineering, and. 5 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.. 6 Center for Brain Science and. 7 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.. Address correspondence to: Seth JCI - FOLLICULAR DENDRITIC CELL DYSFUNCTION CONTRIBUTES TO 1 Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 2 Center for Biomedical Science, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 3 Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, United States of America JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ( Figure 1 ). She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel andBenjamin.
JCI - INHIBITING THE MNK1/2-EIF4E AXIS IMPAIRS MELANOMA Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance; however, the mechanisms are not completely understood and thus are therapeutically unexploited. JCI - INCREASED ADIPOSE TISSUE EXPRESSION OF TUMOR Obesity is frequently associated with insulin resistance and abnormal glucose homeostasis. Recent studies in animal models have indicated that TNF-alpha plays an important role in mediating the insulin resistance of obesity through its overexpression in fat tissue. JCI - CANNABINOIDS PROMOTE EMBRYONIC AND ADULT HIPPOCAMPUS 1 Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 2 Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China. 3 Department of Biomedical Sciences, Dental School, Program in Neuroscience, University of Maryland, Baltimore, Maryland, USA.JCI INSIGHT
Publication fees (in US$) assessed to authors help support publication of JCI Insight. Authors will be assessed $3650 for publication of articles, and the invoice will be provided along with the publication proofs. See JCI Insight’s Open Access information page for furtherdetails.
JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea, Republic of. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS19 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - TURNING LEAD INTO GOLD: REPROGRAMMING RETINAL CELLS 1 Departments of Neuroscience,. 2 Neurology, and. 3 Ophthalmology,. 4 Institute for Cell Engineering, and. 5 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.. 6 Center for Brain Science and. 7 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.. Address correspondence to: Seth JCI - FOLLICULAR DENDRITIC CELL DYSFUNCTION CONTRIBUTES TO 1 Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 2 Center for Biomedical Science, The Feinstein Institutes for Medical Research, Manhasset, United States of America. 3 Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, United States of America JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ( Figure 1 ). She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel andBenjamin.
JCI - INHIBITING THE MNK1/2-EIF4E AXIS IMPAIRS MELANOMA Melanomas commonly undergo a phenotype switch, from a proliferative to an invasive state. Such tumor cell plasticity contributes to immunotherapy resistance; however, the mechanisms are not completely understood and thus are therapeutically unexploited. JCI - INCREASED ADIPOSE TISSUE EXPRESSION OF TUMOR Obesity is frequently associated with insulin resistance and abnormal glucose homeostasis. Recent studies in animal models have indicated that TNF-alpha plays an important role in mediating the insulin resistance of obesity through its overexpression in fat tissue. JCI - CANNABINOIDS PROMOTE EMBRYONIC AND ADULT HIPPOCAMPUS 1 Neuropsychiatry Research Unit, Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada. 2 Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China. 3 Department of Biomedical Sciences, Dental School, Program in Neuroscience, University of Maryland, Baltimore, Maryland, USA.JCI INSIGHT
Publication fees (in US$) assessed to authors help support publication of JCI Insight. Authors will be assessed $3650 for publication of articles, and the invoice will be provided along with the publication proofs. See JCI Insight’s Open Access information page for furtherdetails.
JCI - WELCOME
The Journal of Clinical Investigation; Current issue; Past issues; Specialties; Reviews; Review series; Videos; Conversations with Giantsin Medicine
JCI - TURNING LEAD INTO GOLD: REPROGRAMMING RETINAL CELLS 1 Departments of Neuroscience,. 2 Neurology, and. 3 Ophthalmology,. 4 Institute for Cell Engineering, and. 5 Kavli Neuroscience Discovery Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.. 6 Center for Brain Science and. 7 Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.. Address correspondence to: Seth JCI - A TRIBUTE TO BETH LEVINE (1960–2020) Beth C. Levine, MD, professor of internal medicine and microbiology at UT Southwestern and investigator at the Howard Hughes Medical Institute, passed away on June 15, 2020, of metastatic breast cancer ().She is survived by her husband, Dr. Milton Packer, a cardiologist and expert in heart failure, and her children, Rachel and Benjamin. JCI - CHRONIC LYMPHOCYTIC LEUKEMIA B CELLS CONTAIN 1 Department of Clinical and Experimental Medicine, Clinical Immunology Branch, Padua University School of Medicine, Padua, Italy. 2 Venetian Institute for Molecular Medicine (VIMM), Centro di Eccellenza per la Ricerca Biomedica, and 3 Department of Biological Chemistry, University of Padua, Padua, Italy.. Address correspondence to: Livio Trentin, Università di Padova, Dipartimento diJCI - WELCOME
Vyacheslav Y. Melnikov, Sarah Faubel, Britta Siegmund, M. Scott Lucia, Danica Ljubanovic, Charles L. Edelstein JCI - MONOCYTE METABOLIC TRANSCRIPTIONAL PROGRAMS 1 Department of Medicine, University of Washington, Seattle, United States of America. 2 Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, United States of America. 3 Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, United States of America. 4 School of Public Health, University of Witwatersrand JCI - SEX-DEPENDENT COMPENSATORY MECHANISMS PRESERVE BLOOD 1 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Phialdelphia, United States of America. 2 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, United States of America. 3 Division of Gastroenterology, Hepatology, and Nutrition, Children’s Hospital of Philadelphia, Phialdelphia, United JCI - IMPAIRED HUMORAL AND CELLULAR IMMUNITY AFTER SARS 1 Department for General and Visceral Surgery, Charité–Universitätsmedizin Berlin, Berlin, Germany. 2 Department of Nephrology and Intensive Care, Charité–Universitätsmedizin Berlin, Berlin, Germany. 3 Department of Dialysis, MVZ Diaverum Neubrandenburg, Neubrandenburg, Germany. 4 General and Visceral Department for General and Visceral Surgery, Charité–Universitätsmedizin BerlinJCI INSIGHT
Publication fees (in US$) assessed to authors help support publication of JCI Insight. Authors will be assessed $3650 for publication of articles, and the invoice will be provided along with the publication proofs. See JCI Insight’s Open Access information page for furtherdetails.
JCI INSIGHT
In this issue of JCI Insight, Artibani et al. characterized the molecular characteristics of minimal residual disease in patients with ovarian cancer to better understand the drivers of survival and cancer recurrence. Their findings identified metabolic rewiring and fat dependency, as well as a portion of cells that had undergone epithelial-mesenchymal transition. JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 1 Center for Vascular Research, Institute for Basic Science (IBS), Daejeon, Korea, Republic of. 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon,Korea, Republic of
JCI - WELCOME
The Journal of Clinical Investigation; Current issue; Past issues; Specialties; Reviews; Review series; Videos; Conversations with Giantsin Medicine
JCI - INFORMATION FOR AUTHORS Manuscript submission Manuscripts must be submitted through the JCI’s submission website. An account is required in order to proceed with submission; authors can register for accounts or access their existing accounts by following the instructions at the-jci.org.. Authors may transfer research manuscripts from the preprint servers bioRxiv and medRxiv for submission to the JCI. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS19 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - GLOBAL WARMING THREATENS HUMAN THERMOREGULATION AND As the Earth’s climate warms, hotter days and nights and heat waves are becoming more frequent and intense (1, 2, 5).Global warming is pushing the climate temperature curve toward the extreme range ().Since the 1960s, the number of heat waves, defined as 2 or more consecutive days where temperatures exceeded historical summer (July and August) temperatures, has tripled in JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - TLR3 AGONIST AND CD40-TARGETING VACCINATION INDUCES 1 Lineberger Comprehensive Cancer Center, and. 2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.. 3 Service of Immunology and Allergy and. 4 Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.. 5 Research Center for Clinical & Translational JCI - SULFASALAZINE: A POTENT AND SPECIFIC INHIBITOR OF Sulfasalazine and its salicylate moiety 5-aminosalicylic acid are among the most effective agents for treating inflammatory bowel disease and rheumatoid arthritis. However, the mode of action of these drugs remains unclear. Here we provide evidence that the transcription factor NF-kappaB is a target of sulfasalazine-mediatedimmunosuppression.
JCI - THE ROLE OF MACROPHAGES IN THE RESOLUTION OF105 Macrophages are tissue-resident or infiltrated immune cells critical for innate immunity, normal tissue development, homeostasis, and repair of damaged tissue. Macrophage function is a sum of their ontogeny, the local environment in which they reside, and the type of injuries or pathogen to which they are exposed. JCI - IMMUNOASSAY OF ENDOGENOUS PLASMA INSULIN IN MAN Published in Volume 39, Issue 7 on July 1, 1960 J Clin Invest. 1960;39(7):1157–1175. https://doi.org/10.1172/JCI104130. © 1960 The American Society for Clinical JCI - NASAL CILIATED CELLS ARE PRIMARY TARGETS FOR SARS 1 Center for Vascular Research, Institute for Basic Science (IBS), Daejeon, Korea, Republic of. 2 Department of Otorhinolaryngology-Head and Neck Surgery, Uijeongbu Eulji Medical Center, Uijeongbu, Korea, Republic of. 3 Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon,Korea, Republic of
JCI - WELCOME
The Journal of Clinical Investigation; Current issue; Past issues; Specialties; Reviews; Review series; Videos; Conversations with Giantsin Medicine
JCI - INFORMATION FOR AUTHORS Manuscript submission Manuscripts must be submitted through the JCI’s submission website. An account is required in order to proceed with submission; authors can register for accounts or access their existing accounts by following the instructions at the-jci.org.. Authors may transfer research manuscripts from the preprint servers bioRxiv and medRxiv for submission to the JCI. JCI - CLIMATE CHANGE BRINGS THE SPECTER OF NEW INFECTIOUS19 View PDF. Climate change will bring major changes to the epidemiology of infectious diseases through changes in microbial and vector geographic range. Human defenses against microbial diseases rely on advanced immunity that includes innate and adaptive arms and endothermy, which creates a thermal restriction zone for many microbes. Given that JCI - GLOBAL WARMING THREATENS HUMAN THERMOREGULATION AND As the Earth’s climate warms, hotter days and nights and heat waves are becoming more frequent and intense (1, 2, 5).Global warming is pushing the climate temperature curve toward the extreme range ().Since the 1960s, the number of heat waves, defined as 2 or more consecutive days where temperatures exceeded historical summer (July and August) temperatures, has tripled in JCI - TARGETING THE MYOSTATIN SIGNALING PATHWAY TO TREAT Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. JCI - TLR3 AGONIST AND CD40-TARGETING VACCINATION INDUCES 1 Lineberger Comprehensive Cancer Center, and. 2 Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.. 3 Service of Immunology and Allergy and. 4 Swiss Vaccine Research Institute, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.. 5 Research Center for Clinical & Translational JCI - SULFASALAZINE: A POTENT AND SPECIFIC INHIBITOR OF Sulfasalazine and its salicylate moiety 5-aminosalicylic acid are among the most effective agents for treating inflammatory bowel disease and rheumatoid arthritis. However, the mode of action of these drugs remains unclear. Here we provide evidence that the transcription factor NF-kappaB is a target of sulfasalazine-mediatedimmunosuppression.
JCI - IMMUNOASSAY OF ENDOGENOUS PLASMA INSULIN IN MAN Published in Volume 39, Issue 7 on July 1, 1960 J Clin Invest. 1960;39(7):1157–1175. https://doi.org/10.1172/JCI104130. © 1960 The American Society for Clinical JCI - OBESITY AND INSULIN RESISTANCE The term “insulin resistance” usually connotes resistance to the effects of insulin on glucose uptake, metabolism, or storage. Insulin resistance in obesity and type 2 diabetes is manifested by decreased insulin-stimulated glucose transport and metabolism in adipocytes and skeletal muscle and by impaired suppression of hepatic glucose JCI - INFORMATION FOR AUTHORS Manuscript submission Manuscripts must be submitted through the JCI’s submission website. An account is required in order to proceed with submission; authors can register for accounts or access their existing accounts by following the instructions at the-jci.org.. Authors may transfer research manuscripts from the preprint servers bioRxiv and medRxiv for submission to the JCI. JCI - SARS CORONAVIRUS: A NEW CHALLENGE FOR PREVENTION AND A new and deadly clinical syndrome now called severe acute respiratory syndrome (SARS) was brought to the attention of the WHO by Dr. Carlo Urbani and his colleagues in a Vietnamese hospital in February 2003 ().The WHO, the medical staffs in hospitals where the disease had appeared, and local and regional governments, together with a dozen cooperating laboratories across the globe, JCI - GLOBAL WARMING THREATENS HUMAN THERMOREGULATION AND As the Earth’s climate warms, hotter days and nights and heat waves are becoming more frequent and intense (1, 2, 5).Global warming is pushing the climate temperature curve toward the extreme range ().Since the 1960s, the number of heat waves, defined as 2 or more consecutive days where temperatures exceeded historical summer (July and August) temperatures, has tripled in JCI - FRAGILE X SYNDROME: CAUSES, DIAGNOSIS, MECHANISMS Fragile X syndrome (FXS), an X-linked condition first described by Martin and Bell (), is the leading cause of inherited intellectual disability (ID).Estimates report that FXS affects approximately 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women (2, 3).FXS is caused by mutations in the FMR1 gene, which is located on the X chromosome and whose locus at Xq27.3 coincides with the folate JCI - EDITORIAL BOARD Executive Editor: Sarah Jackson. Senior Science Editor: Corinne Williams. Science Editor: Elyse Dankoski. Assistant Science Editor: Lisa Conti. Editor at Large: Ushma S. Neill. More information about Staff Editors. Conflict of interest. The JCI's conflict of interest policy. Disclosure of Editorial Board first tier potential conflictsof interest.
JCI - HISTONE DEFICIENCY AND ACCELERATED REPLICATION With increasing age, individuals are more vulnerable to viral infections such as with influenza or the SARS-CoV-2 virus. One age-associated defect in human T cells is the reduced expression of miR-181a. miR-181ab1 deficiency in peripheral murine T cells causes delayed viral clearance after infection, resembling human immuneaging.
JCI - HISTONE DEFICIENCY AND ACCELERATED REPLICATION (A – C) Naive CD4 + T cells from young and old individuals were activated for 5 days. Cycling cells were sorted based on DNA content. (A) Quantitative RT-PCR of indicated transcripts associated with ATR signaling.Results, normalized to ACTB, are presented for old relative to cycling young cells (n = 6, mean ± SEM). (B) Immunoblot for p-RPA32 (S8), p-CHK1 (S345), γH2aX (S139), and p21 and JCI - STRUCTURE-BASED PHYLOGENY IDENTIFIES AVORALSTAT AS A Drugs targeting host proteins can act prophylactically to reduce viral burden early in disease and limit morbidity, even with antivirals andvaccination.
JCI - SIGLEC-3 (CD33) SERVES AS AN IMMUNE CHECKPOINT Chronic hepatitis B (CHB) infection is rarely eradicated by current antiviral nucleos(t)ide analogues. We found that α2,6-biantennary sialoglycans of HBV surface antigen (HBsAg) bound human SIGLEC-3 (CD33) by IP and ELISA, and the binding affinity between SIGLEC-3 and α2,6-biantennary sialoglycans was determined by biolayer interferometry (equilibrium dissociation constant : 1.95 × 10 JCI - CHRONIC DIARRHEA, BILE ACIDS, AND CLOSTRIDIA The Journal of Clinical Investigation; Current issue; Past issues; Specialties; Reviews; Review series; Videos; Conversations with Giantsin Medicine
Go to JCI Insight
* About
* Editors
* Consulting Editors* For authors
* Alerts
* Advertising/recruitment* Subscribe
* Contact
* Current Issue
* Past Issues
* By specialty
*
BACK
* Cardiology
* Gastroenterology
* Immunology
* Metabolism
* Nephrology
* Neuroscience
* Oncology
* Pulmonology
* Vascular biology
* All...
* Videos
*
BACK
* Videos
* Conversations with Giants in Medicine* Author's Takes
* Reviews
*
BACK
* Reviews
* Reviews
* View all reviews...*
* Review Series
* Mechanisms Underlying the Metabolic Syndrome (Oct 2019) * Reparative Immunology (Jul 2019) * Allergy (Apr 2019) * Biology of familial cancer predisposition syndromes (Feb 2019) * Mitochondrial dysfunction in disease (Aug 2018) * Lipid mediators of disease (Jul 2018) * Cellular senescence in human disease (Apr 2018) * View all review series...* Collections
*
BACK
* Recently published* In-Press Preview
* Commentaries
* Concise Communication* Editorials
* Viewpoint
* Scientific Show Stoppers* Top read articles
* Clinical Medicine
* JCI This Month
*
BACK
* JCI This Month
* Current issue
* Past issues
*
* The Journal of Clinical Investigation*
* About
* Editors
* Consulting Editors* For authors
* Current issue
* Past issues
* By specialty
* Subscribe
* Alerts
* Advertise
* Contact
* Videos
* Conversations with Giants in Medicine* Author's Takes
* Collections
* Recently published* Brief Reports
* Technical Advances* Commentaries
* Editorials
* Hindsight
* Review series
* Reviews
* The Attending Physician * First Author Perspectives * Scientific Show Stoppers* Top read articles
* Concise Communication RECENTLY PUBLISHED - MORE SOLUBLE EPOXIDE HYDROLASE PROMOTES ASTROCYTE SURVIVAL IN RETINOPATHYOF PREMATURITY
Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) positively affect the outcome of retinopathy of prematurity (ROP). Given that DHA metabolism by cytochrome P450 and soluble epoxide... Published October 28, 2019; First published September 3, 2019 Categories: Research Article AngiogenesisOphthalmology
SOLUBLE EPOXIDE HYDROLASE PROMOTES ASTROCYTE SURVIVAL IN RETINOPATHYOF PREMATURITY
* Text
ABSTRACT
Polyunsaturated fatty acids such as docosahexaenoic acid (DHA) positively affect the outcome of retinopathy of prematurity (ROP). Given that DHA metabolism by cytochrome P450 and soluble epoxide hydrolase (sEH) enzymes affects retinal angiogenesis and vascular stability, we investigated the role of sEH in a mouse model of ROP. In WT mice, hyperoxia elicited tyrosine nitration and inhibition of sEH and decreased generation of the DHA-derived diol 19,20-dihydroxydocosapentaenoic acid (DHDP). Correspondingly, in a murine model of ROP, sEH–/– mice developed a larger central avascular zone and peripheral pathological vascular tuft formation than did their WT littermates. Astrocytes were the cells most affected by sEH deletion, and hyperoxia increased astrocyte apoptosis. In rescue experiments, 19,20-DHDP prevented astrocyte loss by targeting the mitochondrial membrane to prevent the hyperoxia-induced dissociation of presenilin-1 and presenilin-1–associated protein to attenuate poly ADP-ribose polymerase activation and mitochondrial DNA damage. Therapeutic intravitreal administration of 19,20-DHDP not only suppressed astrocyte loss but also reduced pathological vascular tuft formation in sEH–/– mice. Our data indicate that sEH activity is required for mitochondrial integrity and retinal astrocyte survival in ROP. Moreover, 19,20-DHDP may be more effective than DHA as a nutritional supplement for preventing retinopathy in preterm infants.AUTHORS
Jiong Hu, Sofia-Iris Bibli, Janina Wittig, Sven Zukunft, Jihong Lin, Hans-Peter Hammes, Rüdiger Popp, Ingrid Fleming×
------------------------- MECHANISMS OF REACTIVATION OF LATENT TUBERCULOSIS INFECTION DUE TO SIVCOINFECTION
HIV is a major driver of tuberculosis (TB) reactivation. Depletion of CD4+ T cells is assumed to be the basis behind TB reactivation in individuals with latent tuberculosis infection (LTBI)... Published October 28, 2019; First published September 3, 2019 Categories: Concise Communication AIDS/HIVInfectious disease
MECHANISMS OF REACTIVATION OF LATENT TUBERCULOSIS INFECTION DUE TO SIVCOINFECTION
* Text
ABSTRACT
HIV is a major driver of tuberculosis (TB) reactivation. Depletion of CD4+ T cells is assumed to be the basis behind TB reactivation in individuals with latent tuberculosis infection (LTBI) coinfected with HIV. Nonhuman primates (NHPs) coinfected with a mutant simian immunodeficiency virus (SIVΔGY) that does not cause depletion of tissue CD4+ T cells during infection failed to reactivate TB. To investigate the contribution of CD4+ T cell depletion relative to other mechanisms of SIV-induced reactivation of LTBI, we used CD4R1 antibody to deplete CD4+ T cells in animals with LTBI without lentiviral infection. The mere depletion of CD4+ T cells during LTBI was insufficient in generating reactivation of LTBI. Instead, direct cytopathic effects of SIV resulting in chronic immune activation, along with the altered effector T cell phenotypes and dysregulated T cell homeostasis, were likely mediators of reactivation of LTBI. These results revealed important implications for TB control in HIV-coinfected individuals.AUTHORS
Allison N. Bucşan, Ayan Chatterjee, Dhiraj K. Singh, Taylor W. Foreman, Tae-Hyung Lee, Breanna Threeton, Melanie G. Kirkpatrick, Mushtaq Ahmed, Nadia Golden, Xavier Alvarez, James A. Hoxie, Smriti Mehra, Jyothi Rengarajan, Shabaana A. Khader, Deepak Kaushal×
------------------------- MYELOID LOSS OF _BECLIN 1_ PROMOTES PD-L1HI PRECURSOR B CELL LYMPHOMADEVELOPMENT
Beclin 1 (Becn1) is a key molecule in the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of homozygous Becn1-deficient mice, the precise mechanisms... Published October 28, 2019; First published September 10, 2019 Categories: Research Article ImmunologyOncology
MYELOID LOSS OF _BECLIN 1_ PROMOTES PD-L1HI PRECURSOR B CELL LYMPHOMADEVELOPMENT
* Text
ABSTRACT
Beclin 1 (Becn1) is a key molecule in the autophagy pathway and has been implicated in cancer development. Due to the embryonic lethality of homozygous Becn1-deficient mice, the precise mechanisms and cell type–specific roles of Becn1 in regulating inflammation and cancer immunity remain elusive. Here, we report that myeloid-deficient Becn1 (Becn1ΔM) mice developed neutrophilia, were hypersusceptible to LPS-induced septic shock, and had a high risk of developing spontaneous precursor B cell (pre-B cell) lymphoma with elevated expressions of immunosuppressive molecules programmed death ligand 1 (PD-L1) and IL-10. Becn1 deficiency resulted in the stabilization of MEKK3 and aberrant p38 activation in neutrophils, and mediated neutrophil–B cell interaction through Cxcl9/Cxcr3 chemotaxis. Neutrophil–B cell interplay further led to the activation of IL-21/STAT3/IRF1 and CD40L/ERK signaling and PD-L1 expression and thus suppressed CD8+ T cell function. Ablation of p38 in Becn1ΔM mice prevented neutrophil inflammation and B cell tumorigenesis. Importantly, the low expression of Becn1 in human neutrophils was significantly correlated with the PD-L1 levels in pre-B acute lymphoblastic lymphoma (ALL) patients. Our findings have identified myeloid Becn1 as a key regulator of cancer immunity and therapeutic target for pre-B cell lymphomas.AUTHORS
Peng Tan, Lian He, Changsheng Xing, Jingrong Mao, Xiao Yu, Motao Zhu, Lixia Diao, Leng Han, Yubin Zhou, James M. You, Helen Y. Wang, Rong-FuWang
×
------------------------- DERMAL ADIPOSE TISSUE HAS HIGH PLASTICITY AND UNDERGOES REVERSIBLE DEDIFFERENTIATION IN MICE Dermal adipose tissue (also known as dermal white adipose tissue and herein referred to as dWAT) has been the focus of much discussion in recent years. However, dWAT remains poorly characterized.... Published October 28, 2019; First published September 10, 2019 Categories: Research Article DermatologyMetabolism
DERMAL ADIPOSE TISSUE HAS HIGH PLASTICITY AND UNDERGOES REVERSIBLE DEDIFFERENTIATION IN MICE* Text
ABSTRACT
Dermal adipose tissue (also known as dermal white adipose tissue and herein referred to as dWAT) has been the focus of much discussion in recent years. However, dWAT remains poorly characterized. The fate of the mature dermal adipocytes and the origin of the rapidly reappearing dermal adipocytes at different stages remain unclear. Here, we isolated dermal adipocytes and characterized dermal fat at the cellular and molecular level. Together with dWAT’s dynamic responses to external stimuli, we established that dermal adipocytes are a distinct class of white adipocytes with high plasticity. By combining pulse-chase lineage tracing and single-cell RNA sequencing, we observed that mature dermal adipocytes undergo dedifferentiation and redifferentiation under physiological and pathophysiological conditions. Upon various challenges, the dedifferentiated cells proliferate and redifferentiate into adipocytes. In addition, manipulation of dWAT highlighted an important role for mature dermal adipocytes for hair cycling and wound healing. Altogether, these observations unravel a surprising plasticity of dermal adipocytes and provide an explanation for the dynamic changes in dWAT mass that occur under physiological and pathophysiological conditions, and highlight the important contributions of dWAT toward maintaining skinhomeostasis.
AUTHORS
Zhuzhen Zhang, Mengle Shao, Chelsea Hepler, Zhenzhen Zi, Shangang Zhao, Yu A. An, Yi Zhu, Alexandra L. Ghaben, May-yun Wang, Na Li, Toshiharu Onodera, Nolwenn Joffin, Clair Crewe, Qingzhang Zhu, Lavanya Vishvanath, Ashwani Kumar, Chao Xing, Qiong A. Wang, Laurent Gautron, Yingfeng Deng, Ruth Gordillo, Ilja Kruglikov, Christine M. Kusminski, Rana K. Gupta, Philipp E. Scherer×
------------------------- SONIC HEDGEHOG REPRESSION UNDERLIES GIGAXONIN MUTATION–INDUCED MOTOR DEFICITS IN GIANT AXONAL NEUROPATHY Growing evidence shows that alterations occurring at early developmental stages contribute to symptoms manifested in adulthood in the setting of neurodegenerative diseases. Here, we studied the... Published October 28, 2019; First published September 10, 2019 Categories: Research Article Neuroscience SONIC HEDGEHOG REPRESSION UNDERLIES GIGAXONIN MUTATION–INDUCED MOTOR DEFICITS IN GIANT AXONAL NEUROPATHY* Text
ABSTRACT
Growing evidence shows that alterations occurring at early developmental stages contribute to symptoms manifested in adulthood in the setting of neurodegenerative diseases. Here, we studied the molecular mechanisms causing giant axonal neuropathy (GAN), a severe neurodegenerative disease due to loss-of-function of the gigaxonin–E3 ligase. We showed that gigaxonin governs Sonic Hedgehog (Shh) induction, the developmental pathway patterning the dorso-ventral axis of the neural tube and muscles, by controlling the degradation of the Shh-bound Patched receptor. Similar to Shh inhibition, repression of gigaxonin in zebrafish impaired motor neuron specification and somitogenesis and abolished neuromuscular junction formation and locomotion. Shh signaling was impaired in gigaxonin-null zebrafish and was corrected by both pharmacological activation of the Shh pathway and human gigaxonin, pointing to an evolutionary-conserved mechanism regulating Shh signaling. Gigaxonin-dependent inhibition of Shh activation was also demonstrated in primary fibroblasts from patients with GAN and in a Shh activity reporter line depleted in gigaxonin. Our findings establish gigaxonin as a key E3 ligase that positively controls the initiation of Shh transduction, and reveal the causal role of Shh dysfunction in motor deficits, thus highlighting the developmental origin of GAN.AUTHORS
Yoan Arribat, Karolina S. Mysiak, Léa Lescouzères, Alexia Boizot, Maxime Ruiz, Mireille Rossel, Pascale Bomont×
------------------------- EXPRESSION OF MITOCHONDRIAL MEMBRANE–LINKED SAB DETERMINES SEVERITY OF SEX-DEPENDENT ACUTE LIVER INJURY SH3 domain–binding protein that preferentially associates with Btk (SAB) is an outer-membrane docking protein for JNK-mediated impairment of mitochondrial function. Deletion of Sab in hepatocytes... Published October 28, 2019; First published September 5, 2019 Categories: Research Article Hepatology EXPRESSION OF MITOCHONDRIAL MEMBRANE–LINKED SAB DETERMINES SEVERITY OF SEX-DEPENDENT ACUTE LIVER INJURY* Text
ABSTRACT
SH3 domain–binding protein that preferentially associates with Btk (SAB) is an outer-membrane docking protein for JNK-mediated impairment of mitochondrial function. Deletion of Sab in hepatocytes inhibits sustained JNK activation and cell death. The current study demonstrates that an increase in SAB expression enhanced the severity of acetaminophen-induced (APAP-induced) liver injury. Female mice were resistant to liver injury and exhibited markedly decreased hepatic SAB protein expression compared with male mice. The mechanism of SAB repression involved a pathway from ERα to p53 expression that induced miR34a-5p. miR34a-5p targeted the Sab mRNA coding region, thereby repressing SAB expression. Fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB expression in female mice, leading to increased injury from APAP and TNF/galactosamine. In contrast, an ERα agonist increased p53 and miR34a-5p, which decreased SAB expression and hepatotoxicity in male mice. Hepatocyte-specific deletion of miR34a also increased the severity of liver injury in female mice, which was prevented by GalNAc-ASO knockdown of Sab. Similar to mice, premenopausal women expressed elevated levels of hepatic p53 and low levels of SAB, whereas age-matched men expressed low levels of p53 and high levels of SAB, but there was no difference in SAB expression between the sexes in the postmenopausal stage. In conclusion, SAB expression levels determined the severity of JNK-dependent liver injury. Female mice expressed low levels of hepatic SAB protein because of the ERα/p53/miR34a pathway, which repressed SAB expression and accounted for the resistance to liver injury seen in thesefemales.
AUTHORS
Sanda Win, Robert W.M. Min, Christopher Q. Chen, Jun Zhang, Yibu Chen, Meng Li, Ayako Suzuki, Manal F. Abdelmalek, Ying Wang, Mariam Aghajan, Filbert W.M. Aung, Anna Mae Diehl, Roger J. Davis, Tin A. Than, NeilKaplowitz
×
------------------------- MARESIN 1 ACTIVATES LGR6 RECEPTOR PROMOTING PHAGOCYTE IMMUNORESOLVENTFUNCTIONS
Resolution of acute inflammation is an active process orchestrated by endogenous mediators and mechanisms pivotal in host defense and homeostasis. The macrophage mediator in resolving inflammation,... Published October 28, 2019 Categories: Research Article Inflammation MARESIN 1 ACTIVATES LGR6 RECEPTOR PROMOTING PHAGOCYTE IMMUNORESOLVENTFUNCTIONS
* Text
ABSTRACT
Resolution of acute inflammation is an active process orchestrated by endogenous mediators and mechanisms pivotal in host defense and homeostasis. The macrophage mediator in resolving inflammation, maresin 1 (MaR1), is a potent immunoresolvent, stimulating resolution of acute inflammation and organ protection. Using an unbiased screening of greater than 200 GPCRs, we identified MaR1 as a stereoselective activator for human leucine-rich repeat containing G protein–coupled receptor 6 (LGR6), expressed in phagocytes. MaR1 specificity for recombinant human LGR6 activation was established using reporter cells expressing LGR6 and functional impedance sensing. MaR1-specific binding to LGR6 was confirmed using 3H-labeled MaR1. With human and mouse phagocytes, MaR1 (0.01–10 nM) enhanced phagocytosis, efferocytosis, and phosphorylation of a panel of proteins including the ERK and cAMP response element-binding protein. These MaR1 actions were significantly amplified with LGR6 overexpression and diminished by gene silencing in phagocytes. Thus, we provide evidence for MaR1 as an endogenous activator of human LGR6 and a novel role of LGR6 in stimulating MaR1’s key proresolving functions of phagocytes.AUTHORS
Nan Chiang, Stephania Libreros, Paul C. Norris, Xavier de la Rosa,Charles N. Serhan
×
------------------------- BECLIN-1 AS A NEUTROPHIL-SPECIFIC IMMUNE CHECKPOINT Neutrophils are early wound healing and inflammation regulators that, due to functional plasticity, can adopt either pro- or antitumor functions. Until recently, beclin-1 was a protein known mainly... Published October 28, 2019 Category: Commentary BECLIN-1 AS A NEUTROPHIL-SPECIFIC IMMUNE CHECKPOINT* Text
ABSTRACT
Neutrophils are early wound healing and inflammation regulators that, due to functional plasticity, can adopt either pro- or antitumor functions. Until recently, beclin-1 was a protein known mainly for its role as a critical regulator of autophagy. In this issue of the JCI, Tan et al. describe the effects of the beclin-1 conditional myeloid cell–specific deletion in mice, in which immunostimulation resulted in hypersensitive neutrophils. The chronic proinflammatory effect of these neutrophils triggered spontaneous B cell malignancies to develop. Such tumorigenic effects were mediated primarily by IL-21 and CD40 signaling, leading to the upregulation of tolerogenic molecules, such as IL-10 and PD-L1. The authors went on to examine samples derived from patient lymphoid malignancies and showed that beclin-1 expression in neutrophils positively correlated with pre–B cell leukemia/lymphoma. Overall, the study provides an elegant model for neutrophil-driven carcinogenesis and identifies potential targets for immunotherapy of B cell malignancies.AUTHORS
Yu-Lin Su, Marcin Kortylewski×
------------------------- SLOWING RIBOSOME VELOCITY RESTORES FOLDING AND FUNCTION OF MUTANT CFTR Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), with approximately 90% of patients harboring at least one copy of the disease-associated variant... Published October 28, 2019 Categories: Research Article Cell biologyGenetics
SLOWING RIBOSOME VELOCITY RESTORES FOLDING AND FUNCTION OF MUTANT CFTR* Text
ABSTRACT
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), with approximately 90% of patients harboring at least one copy of the disease-associated variant F508del. We utilized a yeast phenomic system to identify genetic modifiers of F508del-CFTR biogenesis, from which ribosomal protein L12 (RPL12/uL11) emerged as a molecular target. In the present study, we investigated mechanism(s) by which suppression of RPL12 rescues F508del protein synthesis and activity. Using ribosome profiling, we found that rates of translation initiation and elongation were markedly slowed by RPL12 silencing. However, proteolytic stability and patch-clamp assays revealed RPL12 depletion significantly increased F508del-CFTR steady-state expression, interdomain assembly, and baseline open-channel probability. We next evaluated whether Rpl12-corrected F508del-CFTR could be further enhanced with concomitant pharmacologic repair (e.g., using clinically approved modulators lumacaftor and tezacaftor) and demonstrated additivity of these treatments. Rpl12 knockdown also partially restored maturation of specific CFTR variants in addition to F508del, and WT Cftr biogenesis was enhanced in the pancreas, colon, and ileum of Rpl12 haplosufficient mice. Modulation of ribosome velocity therefore represents a robust method for understanding both CF pathogenesis and therapeutic response.AUTHORS
Kathryn E. Oliver, Robert Rauscher, Marjolein Mijnders, Wei Wang, Matthew J. Wolpert, Jessica Maya, Carleen M. Sabusap, Robert A. Kesterson, Kevin L. Kirk, Andras Rab, Ineke Braakman, Jeong S. Hong, John L. Hartman IV, Zoya Ignatova, Eric J. Sorscher×
------------------------- SALT-INDUCIBLE KINASES DICTATE PARATHYROID HORMONE 1 RECEPTOR ACTION IN BONE DEVELOPMENT AND REMODELING The parathyroid hormone 1 receptor (PTH1R) mediates the biologic actions of parathyroid hormone (PTH) and parathyroid hormone–related protein (PTHrP). Here, we showed that salt-inducible kinases... Published October 22, 2019; First published August 20, 2019 Categories: Research Article Bone biologyEndocrinology
SALT-INDUCIBLE KINASES DICTATE PARATHYROID HORMONE 1 RECEPTOR ACTION IN BONE DEVELOPMENT AND REMODELING* Text
ABSTRACT
The parathyroid hormone 1 receptor (PTH1R) mediates the biologic actions of parathyroid hormone (PTH) and parathyroid hormone–related protein (PTHrP). Here, we showed that salt-inducible kinases (SIKs) are key kinases that control the skeletal actions downstream of PTH1R and that this GPCR, when activated, inhibited cellular SIK activity. Sik gene deletion led to phenotypic changes that were remarkably similar to models of increased PTH1R signaling. In growth plate chondrocytes, PTHrP inhibited SIK3, and ablation of this kinase in proliferating chondrocytes rescued perinatal lethality of PTHrP-null mice. Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes led to a dramatic increase in bone mass that closely resembled the skeletal and molecular phenotypes observed when these bone cells express a constitutively active PTH1R that causes Jansen’s metaphyseal chondrodysplasia. Finally, genetic evidence demonstrated that class IIa histone deacetylases were key PTH1R-regulated SIK substrates in both chondrocytes and osteocytes. Taken together, our findings establish that SIK inhibition is central to PTH1R action in bone development and remodeling. Furthermore, this work highlights the key role of cAMP-regulated SIKs downstream of GPCR action.AUTHORS
Shigeki Nishimori, Maureen J. O’Meara, Christian D. Castro, Hiroshi Noda, Murat Cetinbas, Janaina da Silva Martins, Ugur Ayturk, Daniel J. Brooks, Michael Bruce, Mizuki Nagata, Wanida Ono, Christopher J. Janton, Mary L. Bouxsein, Marc Foretz, Rebecca Berdeaux, Ruslan I. Sadreyev, Thomas J. Gardella, Harald Jüppner, Henry M. Kronenberg,Marc N. Wein
×
------------------------- HAPTOGLOBIN ADMINISTRATION INTO THE SUBARACHNOID SPACE PREVENTS HEMOGLOBIN-INDUCED CEREBRAL VASOSPASM Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development.... Published October 22, 2019; First published August 27, 2019 Categories: Research Article NeuroscienceVascular biology
HAPTOGLOBIN ADMINISTRATION INTO THE SUBARACHNOID SPACE PREVENTS HEMOGLOBIN-INDUCED CEREBRAL VASOSPASM* Text
ABSTRACT
Delayed ischemic neurological deficit (DIND) is a major driver of adverse outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH), defining an unmet need for therapeutic development. Cell-free hemoglobin that is released from erythrocytes into the cerebrospinal fluid (CSF) is suggested to cause vasoconstriction and neuronal toxicity, and correlates with the occurrence of DIND. Cell-free hemoglobin in the CSF of patients with aSAH disrupted dilatory NO signaling ex vivo in cerebral arteries, which shifted vascular tone balance from dilation to constriction. We found that selective removal of hemoglobin from patient CSF with a haptoglobin-affinity column or its sequestration in a soluble hemoglobin-haptoglobin complex was sufficient to restore physiological vascular responses. In a sheep model, administration of haptoglobin into the CSF inhibited hemoglobin-induced cerebral vasospasm and preserved vascular NO signaling. We identified 2 pathways of hemoglobin delocalization from CSF into the brain parenchyma and into the NO-sensitive compartment of small cerebral arteries. Both pathways were critical for hemoglobin toxicity and were interrupted by the large hemoglobin-haptoglobin complex that inhibited spatial requirements for hemoglobin reactions with NO in tissues. Collectively, our data show that compartmentalization of hemoglobin by haptoglobin provides a novel framework for innovation aimed at reducing hemoglobin-driven neurological damage after subarachnoid bleeding.AUTHORS
Michael Hugelshofer, Raphael M. Buzzi, Christian A. Schaer, Henning Richter, Kevin Akeret, Vania Anagnostakou, Leila Mahmoudi, Raphael Vaccani, Florence Vallelian, Jeremy W. Deuel, Peter W. Kronen, Zsolt Kulcsar, Luca Regli, Jin Hyen Baek, Ivan S. Pires, Andre F. Palmer, Matthias Dennler, Rok Humar, Paul W. Buehler, Patrick R. Kircher, Emanuela Keller, Dominik J. Schaer×
------------------------- CASPASE-8 MODULATES PHYSIOLOGICAL AND PATHOLOGICAL ANGIOGENESIS DURINGRETINA DEVELOPMENT
During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether and how cell death signaling molecules contribute to blood vessel... Published October 22, 2019; First published August 27, 2019 Categories: Research Article Angiogenesis CASPASE-8 MODULATES PHYSIOLOGICAL AND PATHOLOGICAL ANGIOGENESIS DURINGRETINA DEVELOPMENT
* Text
ABSTRACT
During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether and how cell death signaling molecules contribute to blood vessel formation are still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death–signaling pathway, regulates cell death via both apoptosis and necroptosis. Here, we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal retina angiogenesis. EC-specific Casp-8–KO pups (Casp-8ECKO) showed reduced retina angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting, and migration independently of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 MAPK downstream of receptor-interacting serine/threonine protein kinase 3 (RIPK3) and destabilization of vascular endothelial cadherin (VE-cadherin) at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR) resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs was beneficial, as pathological neovascularization was reduced in Casp-8ECKO pups. Taking these data together, we show that Casp-8 acts in a cell death–independent manner in ECs to regulate the formation of the retina vasculature and that Casp-8 in ECs is mechanistically involved in the pathophysiology of ROP.AUTHORS
Nathalie Tisch, Aida Freire-Valls, Rosario Yerbes, Isidora Paredes, Silvia La Porta, Xiaohong Wang, Rosa Martín-Pérez, Laura Castro, Wendy Wei-Lynn Wong, Leigh Coultas, Boris Strilic, Hermann-Josef Gröne, Thomas Hielscher, Carolin Mogler, Ralf H. Adams, Peter Heiduschka, Lena Claesson-Welsh, Massimiliano Mazzone, Abelardo López-Rivas, Thomas Schmidt, Hellmut G. Augustin, Carmen Ruiz deAlmodovar
×
------------------------- CHIMERIC ANTIGEN RECEPTOR–INDUCED BCL11B SUPPRESSION PROPAGATES NK-LIKE CELL DEVELOPMENT The transcription factor B cell CLL/lymphoma 11B (BCL11B) is indispensable for T lineage development of lymphoid progenitors. Here, we show that chimeric antigen receptor (CAR) expression during... Published October 22, 2019; First published September 3, 2019 Categories: Research Article ImmunologyTransplantation
CHIMERIC ANTIGEN RECEPTOR–INDUCED BCL11B SUPPRESSION PROPAGATES NK-LIKE CELL DEVELOPMENT* Text
ABSTRACT
The transcription factor B cell CLL/lymphoma 11B (BCL11B) is indispensable for T lineage development of lymphoid progenitors. Here, we show that chimeric antigen receptor (CAR) expression during early phases of ex vivo generation of lymphoid progenitors suppressed BCL11B, leading to suppression of T cell–associated gene expression and acquisition of NK cell–like properties. Upon adoptive transfer into hematopoietic stem cell transplant recipients, CAR-expressing lymphoid progenitors differentiated into CAR-induced killer (CARiK) cells that mediated potent antigen-directed antileukemic activity even across MHC barriers. CD28 and active immune receptor tyrosine-based activation motifs were critical for a functional CARiK phenotype. These results give important insights into differentiation of murine and human lymphoid progenitors driven by synthetic CAR transgene expression and encourage further evaluation of ex vivo–generated CARiK cells for targeted immunotherapy.AUTHORS
Marcel Maluski, Arnab Ghosh, Jessica Herbst, Vanessa Scholl, Rolf Baumann, Jochen Huehn, Robert Geffers, Johann Meyer, Holger Maul, Britta Eiz-Vesper, Andreas Krueger, Axel Schambach, Marcel R. M. van den Brink, Martin G. Sauer×
------------------------- COMPLEMENT AND INFLAMMASOME OVERACTIVATION MEDIATES PAROXYSMAL NOCTURNAL HEMOGLOBINURIA WITH AUTOINFLAMMATION Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored (GPI-anchored) proteins, resulting from a mutation... Published October 22, 2019; First published August 20, 2019 Categories: Research Article HematologyInflammation
COMPLEMENT AND INFLAMMASOME OVERACTIVATION MEDIATES PAROXYSMAL NOCTURNAL HEMOGLOBINURIA WITH AUTOINFLAMMATION* Text
ABSTRACT
Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored (GPI-anchored) proteins, resulting from a mutation in the X-linked gene PIGA. Here we report on a set of patients in whom PNH results instead from biallelic mutation of PIGT on chromosome 20. These PIGT-PNH patients have clinically typical PNH, but they have in addition prominent autoinflammatory features, including recurrent attacks of aseptic meningitis. In all these patients we find a germ-line point mutation in one PIGT allele, whereas the other PIGT allele is removed by somatic deletion of a 20q region comprising maternally imprinted genes implicated in myeloproliferative syndromes. Unlike in PIGA-PNH cells, GPI is synthesized in PIGT-PNH cells and, since its attachment to proteins is blocked, free GPI is expressed on the cell surface. From studies of patients’ leukocytes and of PIGT-KO THP-1 cells we show that, through increased IL-1β secretion, activation of the lectin pathway of complement and generation of C5b-9 complexes, free GPI is the agent of autoinflammation. Eculizumab treatment abrogates not only intravascular hemolysis, but also autoinflammation. Thus, PIGT-PNH differs from PIGA-PNH both in the mechanism of clonal expansion and in clinical manifestations.AUTHORS
Britta Höchsmann, Yoshiko Murakami, Makiko Osato, Alexej Knaus, Michi Kawamoto, Norimitsu Inoue, Tetsuya Hirata, Shogo Murata, Markus Anliker, Thomas Eggerman, Marten Jäger, Ricarda Floettmann, Alexander Höllein, Sho Murase, Yasutaka Ueda, Jun-ichi Nishimura, Yuzuru Kanakura, Nobuo Kohara, Hubert Schrezenmeier, Peter M. Krawitz, TarohKinoshita
×
------------------------- FRACTURE REPAIR REQUIRES TRKA SIGNALING BY SKELETAL SENSORY NERVES Bone is richly innervated by nerve growth factor–responsive (NGF-responsive) tropomyosin receptor kinase A–expressing (TrKa-expressing) sensory nerve fibers, which are required for osteochondral... Published October 22, 2019 Categories: Research Article Bone biology FRACTURE REPAIR REQUIRES TRKA SIGNALING BY SKELETAL SENSORY NERVES* Text
ABSTRACT
Bone is richly innervated by nerve growth factor–responsive (NGF-responsive) tropomyosin receptor kinase A–expressing (TrKa-expressing) sensory nerve fibers, which are required for osteochondral progenitor expansion during mammalian skeletal development. Aside from pain sensation, little is known regarding the role of sensory innervation in bone repair. Here, we characterized the reinnervation of tissue following experimental ulnar stress fracture and assessed the impact of loss of TrkA signaling in this process. Sequential histological data obtained in reporter mice subjected to fracture demonstrated a marked upregulation of NGF expression in periosteal stromal progenitors and fracture-associated macrophages. Sprouting and arborization of CGRP+TrkA+ sensory nerve fibers within the reactive periosteum in NGF-enriched cellular domains were evident at time points preceding periosteal vascularization, ossification, and mineralization. Temporal inhibition of TrkA catalytic activity by administration of 1NMPP1 to TrkAF592A mice significantly reduced the numbers of sensory fibers, blunted revascularization, and delayed ossification of the fracture callus. We observed similar deficiencies in nerve regrowth and fracture healing in a mouse model of peripheral neuropathy induced by paclitaxel treatment. Together, our studies demonstrate an essential role of TrkA signaling for stress fracture repair and implicate skeletal sensory nerves as an important upstream mediator of this repair process.AUTHORS
Zhu Li, Carolyn A. Meyers, Leslie Chang, Seungyong Lee, Zhi Li, Ryan Tomlinson, Ahmet Hoke, Thomas L. Clemens, Aaron W. James×
------------------------- P2Y6 SIGNALING IN ALVEOLAR MACROPHAGES PREVENTS LEUKOTRIENE-DEPENDENT TYPE 2 ALLERGIC LUNG INFLAMMATION Antagonists of the type 1 cysteinyl leukotriene receptor (CysLT1R) are widely used to treat asthma and allergic rhinitis, with variable response rates. Alveolar macrophages express UDP-specific... PublishedOctober 22, 2019
Categories: Research Article ImmunologyPulmonology
P2Y6 SIGNALING IN ALVEOLAR MACROPHAGES PREVENTS LEUKOTRIENE-DEPENDENT TYPE 2 ALLERGIC LUNG INFLAMMATION* Text
ABSTRACT
Antagonists of the type 1 cysteinyl leukotriene receptor (CysLT1R) are widely used to treat asthma and allergic rhinitis, with variable response rates. Alveolar macrophages express UDP-specific P2Y6 receptors that can be blocked by off-target effects of CysLT1R antagonists. Sensitizing intranasal doses of an extract from the house dust mite Dermatophagoides farinae (Df) sharply increased the levels of UDP detected in bronchoalveolar lavage fluid of mice. Conditional deletion of P2Y6 receptors before sensitization exacerbated eosinophilic lung inflammation and type 2 cytokine production in response to subsequent Df challenge. P2Y6 receptor signaling was necessary for dectin-2–dependent production of protective IL-12p40 and Th1 chemokines by alveolar macrophages, leading to activation of NK cells to generate IFN-γ. Administration of CysLT1R antagonists during sensitization blocked UDP-elicited potentiation of IL-12p40 production by macrophages in vitro, suppressed the Df-induced production of IL-12p40 and IFN-γ in vivo, and suppressed type 2 inflammation only in P2Y6-deficient mice. Thus, P2Y6 receptor signaling drives an innate macrophage/IL-12/NK cell/IFN-γ axis that prevents inappropriate allergic type 2 immune responses on respiratory allergen exposure and counteracts the Th2 priming effect of CysLT1R signaling at sensitization. Targeting P2Y6 signaling might prove to be a potential additional treatment strategy for allergy.AUTHORS
Jun Nagai, Barbara Balestrieri, Laura B. Fanning, Timothy Kyin, Haley Cirka, Junrui Lin, Marco Idzko, Andreas Zech, Edy Y. Kim, Patrick J. Brennan, Joshua A. Boyce×
------------------------- ADDING CHIMERIC ANTIGEN RECEPTOR–INDUCED KILLER CELLS TO THE MEDICALONCOLOGY SHELF
With the approval of CD19-targeted chimeric antigen receptor (CAR) T cells for the treatment of B cell malignancies, clinicians have gained valuable insights into the power and challenges of... PublishedOctober 22, 2019
Category: Commentary ADDING CHIMERIC ANTIGEN RECEPTOR–INDUCED KILLER CELLS TO THE MEDICALONCOLOGY SHELF
* Text
ABSTRACT
With the approval of CD19-targeted chimeric antigen receptor (CAR) T cells for the treatment of B cell malignancies, clinicians have gained valuable insights into the power and challenges of cellular therapies. In this issue of the JCI, Maluski et al. showed that a CAR containing a CD28 costimulatory domain drives progeny differentiation to resemble that of NK cells, which have the potential for an off-the-shelf cell therapy. These CAR-induced killer (CARiK) cells displayed potent antitumor function and killed across the MHC barrier in vivo. After performing in vitro and in vivo mouse studies, the authors also successfully differentiated human umbilical cord blood–derived progenitor cells into CARiK cells. These unique cells may address some of the current challenges associated with first-generation CARs, such as prolonged production that requires patients to wait weeks for infusion. We believe this innovative progenitor gene-engineered lymphoid system has the potential for clinical translation.AUTHORS
Brigett D. Brandjes, Marco L. Davila×
------------------------- HEDGEHOG SIGNALING PROMOTES TUMOR-ASSOCIATED MACROPHAGE POLARIZATION TO SUPPRESS INTRATUMORAL CD8+ T CELL RECRUITMENT Tumor-associated macrophages (TAMs) usually display an antiinflammatory M2-like phenotype to facilitate tumor growth. However, what drives M2 polarization of TAMs and how TAMs suppress antitumor... Published October 22, 2019 Categories: Research Article Immunology HEDGEHOG SIGNALING PROMOTES TUMOR-ASSOCIATED MACROPHAGE POLARIZATION TO SUPPRESS INTRATUMORAL CD8+ T CELL RECRUITMENT* Text
ABSTRACT
Tumor-associated macrophages (TAMs) usually display an antiinflammatory M2-like phenotype to facilitate tumor growth. However, what drives M2 polarization of TAMs and how TAMs suppress antitumor immunity within the tumor microenvironment (TME) remain largely undefined. Using several murine tumor models, we showed that hedgehog (Hh) signaling in myeloid cells is critical for TAM M2 polarization and tumor growth. We also found that tumor cells secrete sonic hedgehog (SHH), an Hh ligand, and that tumor-derived SHH drives TAM M2 polarization. Furthermore, Hh-induced functional polarization in TAMs suppresses CD8+ T cell recruitment to the TME through the inhibition of CXCL9 and CXCL10 production by TAMs. Last, we demonstrated that Krüppel-like factor 4 (Klf4) mediates Hh-dependent TAM M2 polarization and the immunosuppressive function. Collectively, these findings highlight a critical role for tumor-derived SHH in promoting TAM M2 polarization, a mechanism for TAM-mediated immunosuppression, and may provide insights into the design of new cancer immunotherapeutic strategies.AUTHORS
Amy J. Petty, Ang Li, Xinyi Wang, Rui Dai, Benjamin Heyman, David Hsu, Xiaopei Huang, Yiping Yang×
------------------------- HYPERURICEMIA AND GOUT CAUSED BY MISSENSE MUTATION IN D-LACTATEDEHYDROGENASE
Gout is caused by deposition of monosodium urate crystals in joints when plasma uric acid levels are chronically elevated beyond the saturation threshold, mostly due to renal underexcretion of uric... Published October 22, 2019 Categories: Concise Communication GeneticsMetabolism
HYPERURICEMIA AND GOUT CAUSED BY MISSENSE MUTATION IN D-LACTATEDEHYDROGENASE
* Text
ABSTRACT
Gout is caused by deposition of monosodium urate crystals in joints when plasma uric acid levels are chronically elevated beyond the saturation threshold, mostly due to renal underexcretion of uric acid. Although molecular pathways of this underexcretion have been elucidated, its etiology remains mostly unknown. We demonstrate that gout can be caused by a mutation in LDHD within the putative catalytic site of the encoded d-lactate dehydrogenase, resulting in augmented blood levels of d-lactate, a stereoisomer of l-lactate, which is normally present in human blood in miniscule amounts. Consequent excessive renal secretion of d-lactate in exchange for uric acid reabsorption culminated in hyperuricemia and gout. We showed that LDHD expression is enriched in tissues with a high metabolic rate and abundant mitochondria and that d-lactate dehydrogenase resides in the mitochondria of cells overexpressing the human LDHD gene. Notably, the p.R370W mutation had no effect on protein localization. In line with the human phenotype, injection of d-lactate into naive mice resulted in hyperuricemia. Thus, hyperuricemia and gout can result from the accumulation of metabolites whose renal excretion is coupled to uricacid reabsorption.
AUTHORS
Max Drabkin, Yuval Yogev, Lior Zeller, Raz Zarivach, Ran Zalk, Daniel Halperin, Ohad Wormser, Evgenia Gurevich, Daniel Landau, Rotem Kadir, Yonatan Perez, Ohad S. Birk×
------------------------- PAROXYSMAL NOCTURNAL HEMOGLOBINURIA WITHOUT GPI-ANCHOR DEFICIENCY Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by hemolysis, thrombosis, and bone marrow failure caused by defective expression of... Published October 22, 2019 Category: Commentary PAROXYSMAL NOCTURNAL HEMOGLOBINURIA WITHOUT GPI-ANCHOR DEFICIENCY* Text
ABSTRACT
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder characterized by hemolysis, thrombosis, and bone marrow failure caused by defective expression of glycosylphosphatidylinositol-anchored (GPI-anchored) complement inhibitors. Most commonly, PNH is caused by loss of function of PIGA, which is required for GPI biosynthesis. In this issue of the JCI, Höchsmann et al. report on 4 PNH patients who also had marked autoinflammatory manifestations, including aseptic meningitis. All 4 patients had a germline mutation of the related gene PIGT and a somatically acquired myeloid common deleted region (CDR) on chromosome 20q that deleted the second PIGT allele. The biochemistry and clinical manifestations indicate that these patients have subtle but important differences from those with PNH resulting from PIGA mutations, suggesting PIGT-PNH may be a distinct clinical entity.AUTHORS
Robert A. Brodsky
×
------------------------- IN-PRESS PREVIEW - MORE NOTCH INHIBITION OVERCOMES RESISTANCE TO TYROSINE KINASE INHIBITORS IN EGFR-DRIVEN LUNG ADENOCARCINOMA EGFR mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It is... Published October 31, 2019 Categories: Research In-Press PreviewOncology
NOTCH INHIBITION OVERCOMES RESISTANCE TO TYROSINE KINASE INHIBITORS IN EGFR-DRIVEN LUNG ADENOCARCINOMA* Text
ABSTRACT
EGFR mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It is generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, but contrary to this, we uncovered here that gefitinib and osimertinib increased STAT3 phosphorylation (pSTAT3) in EGFRT790M and EGFRC797S tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induced a pSTAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we showed that tyrosine kinase inhibitor resistant tumors, with EGFRT790M and EGFRC797S mutations, were highly responsive to the combined treatment of Notch inhibitors with gefitinib and osimertinib respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increased during relapse and correlated with shorter progression-free survival. Therefore, our results offer a proof of concept for an alternative treatment to chemotherapy in lung adenocarcinoma osimertinib treated patients after disease progression.AUTHORS
Emilie Bousquet Mur, Sara Bernardo, Laura Papon, Maicol Mancini, Eric Fabbrizio, Marion Goussard, Irene Ferrer, Anais Giry, Xavier Quantin, Jean-Louis Pujol, Olivier Calvayrac, Herwig P. Moll, Yaël Glasson, Nelly Pirot, Andrei Turtoi, Marta Cañamero, Kwok-Kin Wong, Yosef Yarden, Emilio Casanova, Jean-Charles Soria, Jacques Colinge, Christian W. Siebel, Julien Mazieres, Gilles Favre, Luis Paz-Ares,Antonio Maraver
×
------------------------- SDR9C7 CATALYZES CRITICAL DEHYDROGENATION OF ACYLCERAMIDES FOR SKINBARRIER FORMATION
The corneocyte lipid envelope composed of covalently bound ceramides and fatty acids is important to the integrity of the permeability barrier in the stratum corneum, and its absence is a prime... Published October 31, 2019 Categories: Research In-Press PreviewDermatology
SDR9C7 CATALYZES CRITICAL DEHYDROGENATION OF ACYLCERAMIDES FOR SKINBARRIER FORMATION
* Text
ABSTRACT
The corneocyte lipid envelope composed of covalently bound ceramides and fatty acids is important to the integrity of the permeability barrier in the stratum corneum, and its absence is a prime structural defect in various skin diseases associated with defective skin barrier function. SDR9C7 encodes a short chain dehydrogenase/reductase family 9C member 7 (SDR9C7) recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7 knockout model we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7-/- epidermis, quantitative LC-MS assays revealed almost complete loss of a species of ω-O-acylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD+-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy-11E-13-ketone, a reactive moiety known for its non-enzymatic coupling to protein. This suggests a mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis.AUTHORS
Takuya Takeichi, Tetsuya Hirabayashi, Yuki Miyasaka, Akane Kawamoto, Yusuke Okuno, Shijima Taguchi, Kana Tanahashi, Chiaki Murase, Hiroyuki Takama, Kosei Tanaka, William E. Boeglin, M. Wade Calcutt, Daisuke Watanabe, Michihiro Kono, Yoshinao Muro, Junko Ishikawa, Tamio Ohno, Alan R. Brash, Masashi Akiyama×
------------------------- KBTBD13 IS AN ACTIN-BINDING PROTEIN THAT MODULATES MUSCLE KINETICS The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy... Published October 31, 2019 Categories: Research In-Press Preview Musclebiology
KBTBD13 IS AN ACTIN-BINDING PROTEIN THAT MODULATES MUSCLE KINETICS* Text
ABSTRACT
The mechanisms that modulate the kinetics of muscle relaxation are critically important for muscle function. A prime example of the impact of impaired relaxation kinetics is nemaline myopathy caused by mutations in KBTBD13 (NEM6). In addition to weakness, NEM6 patients have slow muscle relaxation, compromising contractility and daily-life activities. The role of KBTBD13 in muscle is unknown, and the pathomechanism underlying NEM6 is undetermined. A combination of transcranial magnetic stimulation-induced muscle relaxation, muscle fiber- and sarcomere-contractility assays, low angle X-ray diffraction and super-resolution microscopy revealed that the impaired muscle relaxation kinetics in NEM6 patients are caused by structural changes in the thin filament, a sarcomeric microstructure. Using homology modeling, binding- and contractility assays with recombinant KBTBD13, novel Kbtbd13-knockout and Kbtbd13R408C-knockin mouse models and a GFP-labeled Kbtbd13- transgenic zebrafish model we discovered that KBTBD13 binds to actin – a major constituent of the thin filament - and that mutations in KBTBD13 cause structural changes impairing muscle relaxation kinetics. We propose that this actin-based impaired relaxation is central to NEM6 pathology.AUTHORS
Josine M. de Winter, Joery P. Molenaar, Michaela Yuen, Robbert van der Pijl, Shengyi Shen, Stefan Conijn, Martijn van de Locht, Menne Willigenburg, Sylvia J.P. Bogaards, Esmee S.B. van Kleef, Saskia Lassche, Malin Persson, Dilson E. Rassier, Tamar E. Sztal, Avnika A. Ruparelia, Viola Oorschot, Georg Ramm, Thomas E. Hall, Zherui Xiong, Christopher N. Johnson, Frank Li, Balazs Kiss, Noelia Lozano-Vidal, Reinier A. Boon, Manuela Marabita, Leonardo Nogara, Bert Blaauw, Richard J. Rodenburg, Benno Kϋsters, Jonne Doorduin, Alan H. Beggs, Henk Granzier, Ken Campbell, Weikang Ma, Thomas Irving, Edoardo Malfatti, Norma B. Romero, Robert J. Bryson-Richardson, Baziel G.M. van Engelen, Nicol C. Voermans, Coen A.C. Ottenheijm×
------------------------- U3-1402 SENSITIZES HER3-EXPRESSING TUMORS TO PD-1 BLOCKADE BY IMMUNEACTIVATION
Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient... PublishedOctober 29, 2019
Categories: Research In-Press PreviewOncology
U3-1402 SENSITIZES HER3-EXPRESSING TUMORS TO PD-1 BLOCKADE BY IMMUNEACTIVATION
* Text
ABSTRACT
Immunotherapy targeting programmed cell death-1 (PD-1) induces durable antitumor efficacy in many types of cancer. However, such clinical benefit is limited because of the insufficient reinvigoration of antitumor immunity with the drug alone; therefore, rational therapeutic combinations are required to improve its efficacy. In our preclinical study, we evaluated the antitumor effect of U3-1402, a human epidermal growth factor receptor 3 (HER3)–targeting antibody-drug conjugate, and its potential synergism with PD-1 inhibition. Using a syngeneic mouse tumor model that is refractory to anti–PD-1 therapy, treatment with U3-1402 exhibited an obvious antitumor effect via direct lysis of tumor cells. Disruption of tumor cells by U3-1402 enhanced the infiltration of innate and adaptive immune cells. Chemotherapy with exatecan derivative (Dxd: the drug payload of U3-1402) revealed that the enhanced antitumor immunity produced by U3-1402 was associated with the induction of alarmins including HMGB-1 via tumor-specific cytotoxicity. Notably, U3-1402 significantly sensitized the tumor to PD-1 blockade, as a combination of U3-1402 and the PD-1 inhibitor significantly enhanced antitumor immunity. Further, clinical analyses indicated that tumor-specific HER3 expression was frequently observed in patients with PD-1 inhibitor–resistant solid tumors. Overall, U3-1402 is a promising candidate as a partner of immunotherapy for such patients.AUTHORS
Koji Haratani, Kimio Yonesaka, Shiki Takamura, Osamu Maenishi, Ryoji Kato, Naoki Takegawa, Hisato Kawakami, Kaoru Tanaka, Hidetoshi Hayashi, Masayuki Takeda, Naoyuki Maeda, Takashi Kagari, Kenji Hirotani, Junji Tsurutani, Kazuto Nishio, Katsumi Doi, Masaaki Miyazawa, Kazuhiko Nakagawa×
------------------------- Β1-INTEGRIN- AND KV1.3 CHANNEL-DEPENDENT SIGNALING STIMULATES GLUTAMATE RELEASE FROM TH17 CELLS While the impact of T helper 17 (Th17) cells in autoimmunity is undisputable, their pathogenic effector mechanism is still enigmatic. We have discovered SNARE complex proteins in Th17 cells... PublishedOctober 29, 2019
Categories: Research In-Press Preview Autoimmunity Neuroscience Β1-INTEGRIN- AND KV1.3 CHANNEL-DEPENDENT SIGNALING STIMULATES GLUTAMATE RELEASE FROM TH17 CELLS* Text
ABSTRACT
While the impact of T helper 17 (Th17) cells in autoimmunity is undisputable, their pathogenic effector mechanism is still enigmatic. We have discovered SNARE complex proteins in Th17 cells enabling a vesicular glutamate release pathway inducing local intracytoplasmic calcium release and subsequent damage in neurons. This pathway is glutamine dependent and triggered by binding of β1-integrin to VCAM-1 on neurons in inflammatory context. Glutamate secretion could be blocked by inhibiting either glutaminase or KV1.3 channels, known to be linked to integrin expression and highly expressed on stimulated T cells. While KV1.3 is not expressed in the CNS tissue, intrathecal administration of a KV1.3 channel blocker or a glutaminase inhibitor ameliorated disability in experimental neuroinflammation. In humans, T cells from multiple sclerosis patients secreted higher levels of glutamate, and cerebrospinal fluid glutamine levels were increased. Altogether, our findings demonstrate that β1-integrin- and KV1.3 channel-dependent signaling stimulates glutamate release from Th17 cells upon direct cell-cell contact between Th17 cells and neurons.AUTHORS
Katharina Birkner, Beatrice Wasser, Tobias Ruck, Carine Thalman, Dirk Luchtman, Katrin Pape, Samantha Schmaul, Lynn Bitar, Eva-Maria Krämer-Albers, Albrecht Stroh, Sven G. Meuth, Frauke Zipp, StefanBittner
×
------------------------- VIEW MORE ARTICLES BY TOPIC:Aging
AIDS/HIV
Angiogenesis
Autoimmunity
Bone biology
Cardiology
Cell biology
Clinical trials
Dermatology
Development
Endocrinology
Gastroenterology
Genetics
Hematology
Hepatology
Immunology
Infectious disease
Inflammation
Metabolism
Microbiology
Muscle biology
Nephrology
Neuroscience
Oncology
Ophthalmology
Otology
Pulmonology
Reproductive biologyStem cells
Therapeutics
Transplantation
Vaccines
Vascular biology
Virology
NOVEMBER 2019
ON THE COVER:
ANGPTL4 DESTABILIZES THE RETINAL VASCULATURE IN DIABETIC MACULAR EDEMAThe Journal __
NOVEMBER 2019 ISSUE
ON THE COVER:
ANGPTL4 DESTABILIZES THE RETINAL VASCULATURE IN DIABETIC MACULAR EDEMA Anti-VEGF therapy, the standard of care for patients with diabetic macular edema (DME), does not substantially improve vision in many treated patients. In this issue of the JCI, Sodhi et al. explore the role of another protein, ANGPTL4, in driving vascular leakage in DME. Their work revealed that ANGPTL4 and VEGF work in concert to destabilize the retina’s vasculature. ANGPTL4’s binding to neuropilin 1 and 2 on endothelial cells disrupts vascular barriers by activating RhoA/ROCK signaling. Treating diabetic mice with a soluble neuropilin 1 fragment blocked ANGPTL1-induced vascular leakage, supporting a potential therapeutic avenue for interfering in ANGPTL4-mediated mechanisms in DME. This issue’s cover depicts the pathological leakage of the retinal vasculature in a patient with diabetic eye disease. Image courtesy of Wilmer Photography; modified by Isabella and Adriana Sodhi.* View this issue
* View all issues
×
JCI THIS MONTH
JCI This Month is a digest of the research, reviews, and other features published each month.JCI This Month __
NOVEMBER 2019 JCI THIS MONTH JCI This Month is a digest of the research, reviews, and other features published each month.* View this issue
* View all issues
×
REVIEW SERIES - MORE MECHANISMS UNDERLYING THE METABOLIC SYNDROME SERIES EDITED BY PHILIPP E. SCHERER Obesity often occurs with a quintessential array of metabolic abnormalities: elevations in blood pressure, visceral fat, and circulating blood lipids, and, importantly, insulin resistance.... MECHANISMS UNDERLYING THE METABOLIC SYNDROME SERIES EDITED BY PHILIPP E. SCHERER Obesity often occurs with a quintessential array of metabolic abnormalities: elevations in blood pressure, visceral fat, and circulating blood lipids, and, importantly, insulin resistance. Together, this constellation of conditions constitutes the metabolic syndrome and forecasts an individual’s increased risk of developing cardiovascular diseases and type 2 diabetes. Although metabolic syndrome presents as dysfunction across multiple tissues, its onset stems from pathological increases in adipose tissue. The 9 review in this series, conceptualized by series editor Philipp Scherer, delve into the complex biology underlying the metabolic syndrome. These reviews address adipocyte and beta cell dysfunction in the metabolic syndrome; the functions of adipose tissue fibrosis, the microbiome, and exosomal communication in obesity; and the concepts we use to define metabolic health. * View this review series * View all review series×
LATEST REVIEWS - MORE TARGETING INNATE IMMUNITY FOR TUBERCULOSIS VACCINATION Vaccine development against tuberculosis (TB) is based on the induction of adaptive immune responses endowed with long-term memory against mycobacterial antigens. Memory B and T cells initiate a... FUNCTIONAL DIVERSIFICATION OF IGGS THROUGH FC GLYCOSYLATION IgG antibodies are secreted from B cells and bind to a variety of pathogens to control infections as well as contribute to inflammatory diseases. Many of the functions of IgGs are mediated through... SIGN UP FOR EMAIL ALERTS AUTHOR'S TAKE - MORE CHARACTERIZATION OF FOXN1 MUTATION-MEDIATED IMMUNE DEFICIENCY In this episode, Nicolai van Oers and colleagues demonstrate that compound heterozygous mutations in FOXN1 result in a combined immunodeficiency in patients that is distinct Nude/SCID phenotypes… CONVERSATIONS WITH GIANTS IN MEDICINE - MORE JCI'S CONVERSATIONS WITH GIANTS IN MEDICINE: ELAINE FUCHS Cell biologist Elaine Fuchs of the Rockefeller University is best known for revolutionizing the molecular and genetic study of skin.Follow JCI:
Copyright © 2019 American Society for Clinical Investigation ISSN: 0021-9738 (print), 1558-8238 (online) SIGN UP FOR EMAIL ALERTSDetails
Copyright © 2024 ArchiveBay.com. All rights reserved. Terms of Use | Privacy Policy | DMCA | 2021 | Feedback | Advertising | RSS 2.0