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  • A conversation with Barbara Kahn.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-02
    Ushma S Neill

    Excerpt: Barbara Kahn is the quintessential physician-scientist. Dr. Kahn (Figure 1), of the Beth Israel Deaconess Medical Center and Harvard Medical School, is best known for elucidating molecular mechanisms of type 2 diabetes, obesity, and insulin resistance, with a particular emphasis on the role of the adipocyte in regulating glucose metabolism....

    更新日期:2020-03-19
  • Stable ischemic heart disease: how to keep it that way.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-27
    Thorsten M Leucker,Steven P Schulman,Gary Gerstenblith

    The vast majority of the over 18 million Americans with known coronary atherosclerosis have stable disease (i.e., they do not have nor have they recently had an acute infarction or unstable angina) (1). Two management goals in this stable group have remained the same for over 50 years: to decrease angina symptoms if any are present and to decrease the likelihood of a subsequent myocardial infarction

    更新日期:2020-03-19
  • Addressing the physician-scientist pipeline: strategies to integrate research into clinical training programs.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-10
    Sallie R Permar,Rebecca A Ward,Katherine J Barrett,Stephanie A Freel,Rasheed A Gbadegesin,Christopher D Kontos,Patrick J Hu,Katherine E Hartmann,Christopher S Williams,Jatin M Vyas

    Introduction Physician-scientists are critical members of the biomedical workforce. The combination of rigorous scientific training and clinical skills uniquely positions them to bridge clinical needs with investigational pursuits by identifying important clinical questions that drive basic discoveries and translating those into therapeutics that improve patient outcomes. The impact of physician-scientists

    更新日期:2020-03-19
  • The multifaceted role of ischemia/reperfusion in sickle cell anemia.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-02
    Robert P Hebbel,John D Belcher,Gregory M Vercellotti

    Sickle cell anemia is a unique disease dominated by hemolytic anemia and vaso-occlusive events. The latter trigger a version of ischemia/reperfusion (I/R) pathobiology that is singular in its origin, cyclicity, complexity, instability, perpetuity, and breadth of clinical consequences. Specific clinical features are probably attributable to local I/R injury (e.g., stroke syndromes) or remote organ injury

    更新日期:2020-03-19
  • Senescent T cells within suppressive tumor microenvironments: emerging target for tumor immunotherapy.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-02
    Xia Liu,Daniel F Hoft,Guangyong Peng

    The functional state of the preexisting T cells in the tumor microenvironment is a key determinant for effective antitumor immunity and immunotherapy. Increasing evidence suggests that immunosenescence is an important state of T cell dysfunction that is distinct from exhaustion, a key strategy used by malignant tumors to evade immune surveillance and sustain the suppressive tumor microenvironment.

    更新日期:2020-03-19
  • Breaking through the surface: more to learn about lipids and cardiovascular disease.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-27
    Justin B Echouffo-Tcheugui,Mohit Jain,Susan Cheng

    The human lipidome comprises over tens of thousands of distinct lipid species in addition to total cholesterol and the other conventional lipid traits that are routinely measurable in the peripheral circulation. Of the lipid species considered to exhibit bioactive functions, sphingolipids are a class of molecules that have shown relevance to human disease risk and cardiovascular outcomes in particular

    更新日期:2020-03-19
  • Underglycosylated prion protein modulates plaque formation in the brain.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-27
    Jason C Bartz

    The prion agent is unique in biology and is comprised of prion protein scrapie (PrPSc), a self-templating conformational variant of the host encoded prion protein cellular (PrPC). The deposition patterns of PrPSc in the CNS can vary considerably from a diffuse synaptic pattern to large plaque-like aggregates. Alterations of PrPC posttranslational processing can change PrPSc deposition patterns; however

    更新日期:2020-03-19
  • When bugs and drugs conspire: driving acneiform skin toxicity.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-04
    Allison C Billi,Mrinal K Sarkar,Johann E Gudjonsson

    Therapy with antineoplastic agents that inhibit EGFR and MEK is frequently limited by cutaneous adverse reactions, most commonly acne-like eruptions. In this issue of the JCI, Satoh et al. define a mechanism for acneiform skin toxicity wherein EGFR/MEK inhibitors cooperate with the skin commensal Cutibacterium acnes to induce IL-36γ in keratinocytes via the combined actions of Krüppel-like factor 4

    更新日期:2020-03-19
  • How the matrix metalloproteinase MMP14 contributes to the progression of colorectal cancer.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-04
    Lena Claesson-Welsh

    Certain matrix metalloproteinase (MMP) family proteins have been associated with cell proliferation and invasion in aggressive cancers. However, attempts to target the MMPs with the hope of treating tumors have thus far failed. In this issue of the JCI, Ragusa and coworkers identified an intestinal cancer subgroup of slow-growing, chemotherapy-resistant, and very aggressive matrix-rich tumors that

    更新日期:2020-03-19
  • Proliferative, degradative smooth muscle cells promote aortic disease.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-10
    Maarten Hulsmans,Matthias Nahrendorf

    Aneurysms are common in the abdominal and thoracic regions of the aorta and can cause death due to dissection or rupture. Traditionally, thoracic aortic aneurysms have been labeled as a degenerative disease, characterized by alterations in extracellular matrix and loss of smooth muscle cells (SMCs) in the medial layer of the aortic wall. In this issue of the JCI, Li and colleagues introduce an unconventional

    更新日期:2020-03-19
  • Chikungunya infection: de-linking replication from symptomatology reveals the central role of muscle.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-10
    Anne Moscona

    Chikungunya virus (CHIKV) is an emerging arbovirus, endemic in many parts of the world, that is spread by travelers and adapts to new mosquito vectors that live in temperate climates. CHIKV replicates in many host tissues and initially causes a self-limiting febrile illness similar to dengue. However, in 30%-40% of cases, CHIKV also causes long-term painful and debilitating muscle and joint pain, the

    更新日期:2020-03-19
  • Can the light of immunometabolism cut through "brain fog"?
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-10
    Mady Hornig

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a highly debilitating disease with heterogeneous constitutional and neurological complaints. Infection-like symptoms often herald disease onset, but no pathogen or immune defect has been conclusively linked. In this issue of the JCI, Mandarano et al. illuminate bioenergetic derangements of ME/CFS T cell subsets. CD4+ and CD8+ T cells had

    更新日期:2020-03-19
  • Kidney to bone via bedside to bench…and back?
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-17
    Alexander Grabner,Myles Wolf

    The rapid rise in circulating fibroblast growth factor 23 (FGF23) associated with kidney injury results in calcitriol deficiency, altered calcium homeostasis, and secondary hyperparathyroidism, and may contribute to cardiovascular complications and death. However, the mechanisms of increased FGF23 in states of kidney injury remain unclear. In this issue of the JCI, Simic et al. screened plasma taken

    更新日期:2020-03-19
  • CD8+ T cells and human cerebral malaria: a shifting episteme.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-17
    Laurent Rénia,Georges Er Grau,Samuel C Wassmer

    Mosquito-transmitted Plasmodium falciparum infection can cause human cerebral malaria (HCM) with high mortality rates. The abundance of infected red blood cells that accumulate in the cerebral vasculature of patients has led to the belief that these brain-sequestered cells solely cause pathogenesis. However, animal models suggest that CD8+ T cells migrate to and accumulate in the brain, directly contributing

    更新日期:2020-03-19
  • The surprising complexity of KATP channel biology and of genetic diseases.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-17
    Guiling Zhao,Aaron Kaplan,Maura Greiser,W Jonathan Lederer

    The ATP-sensitive K+ channel (KATP) is formed by the association of four inwardly rectifying K+ channel (Kir6.x) pore subunits with four sulphonylurea receptor (SUR) regulatory subunits. Kir6.x or SUR mutations result in KATP channelopathies, which reflect the physiological roles of these channels, including but not limited to insulin secretion, cardiac protection, and blood flow regulation. In this

    更新日期:2020-03-19
  • Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-10
    Conor McClenaghan; Yan Huang; Zihan Yan; Theresa M. Harter; Carmen M. Halabi; Rod Chalk; Attila Kovacs; Gijs van Haaften; Maria S. Remedi; Colin G. Nichols

    Cantu syndrome (CS) is a complex disorder caused by gain-of-function (GoF) mutations in ABCC9 and KCNJ8, which encode the SUR2 and Kir6.1 subunits, respectively, of vascular smooth muscle (VSM) KATP channels. CS includes dilated vasculature, marked cardiac hypertrophy, and other cardiovascular abnormalities. There is currently no targeted therapy, and it is unknown whether cardiovascular features can

    更新日期:2020-03-19
  • Staphylococcus aureus toxin suppresses antigen-specific T cell responses
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-24
    Brandon Lee; Reuben Olaniyi; Jakub M. Kwiecinski; Juliane Bubeck Wardenburg

    Staphylococcus aureus remains a leading cause of human infection. These infections frequently recur when the skin is a primary site of infection, especially in infants and children. In contrast, invasive staphylococcal disease is less commonly associated with reinfection, suggesting that tissue-specific mechanisms govern the development of immunity. Knowledge of how S. aureus manipulates protective

    更新日期:2020-03-19
  • CD8+ T cells target cerebrovasculature in children with cerebral malaria
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-10
    Brittany A. Riggle; Monica Manglani; Dragan Maric; Kory R. Johnson; Myoung-Hwa Lee; Osorio Lopes Abath Neto; Terrie E. Taylor; Karl B. Seydel; Avindra Nath; Louis H. Miller; Dorian B. McGavern; Susan K. Pierce

    BACKGROUND. Cerebral malaria (CM) accounts for nearly 400,000 deaths annually in African children. Current dogma suggests that CM results from infected RBC (iRBC) sequestration in the brain microvasculature and resulting sequelae. Therapies targeting these events have been unsuccessful; findings in experimental models suggest that CD8+ T cells drive disease pathogenesis. However, these data have largely

    更新日期:2020-03-19
  • Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-12
    Kaitlin Weskamp; Elizabeth M. Tank; Roberto Miguez; Jonathon P. McBride; Nicolás B. Gómez; Matthew White; Ziqiang Lin; Carmen Moreno Gonzalez; Andrea Serio; Jemeen Sreedharan; Sami J. Barmada

    Cortical hyperexcitability and mislocalization of the RNA-binding protein TDP43 are highly conserved features in amyotrophic lateral sclerosis (ALS). Nevertheless, the relationship between these phenomena remains poorly defined. Here, we showed that hyperexcitability recapitulates TDP43 pathology by upregulating shortened TDP43 (sTDP43) splice isoforms. These truncated isoforms accumulated in the cytoplasm

    更新日期:2020-03-19
  • Annexin A1 drives macrophage skewing to accelerate muscle regeneration through AMPK activation.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-04
    Simon McArthur,Gaëtan Juban,Thomas Gobbetti,Thibaut Desgeorges,Marine Theret,Julien Gondin,Juliana E Toller-Kawahisa,Chris P Reutelingsperger,Bénédicte Chazaud,Mauro Perretti,Rémi Mounier

    Understanding the circuits that promote an efficient resolution of inflammation is crucial to deciphering the molecular and cellular processes required to promote tissue repair. Macrophages play a central role in the regulation of inflammation, resolution, and repair/regeneration. Using a model of skeletal muscle injury and repair, herein we identified annexin A1 (AnxA1) as the extracellular trigger

    更新日期:2020-03-19
  • D1-mGlu5 heteromers mediate noncanonical dopamine signaling in Parkinson's disease.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-10
    Irene Sebastianutto,Elise Goyet,Laura Andreoli,Joan Font-Ingles,David Moreno-Delgado,Nathalie Bouquier,Céline Jahannault-Talignani,Enora Moutin,Luisa Di Menna,Natallia Maslava,Jean-Philippe Pin,Laurent Fagni,Ferdinando Nicoletti,Fabrice Ango,M Angela Cenci,Julie Perroy

    Dopamine receptor D1 modulates glutamatergic transmission in cortico-basal ganglia circuits and represents a major target of L-DOPA therapy in Parkinson's disease. Here we show that D1 and metabotropic glutamate type 5 (mGlu5) receptors can form previously unknown heteromeric entities with distinctive functional properties. Interacting with Gq proteins, cell-surface D1-mGlu5 heteromers exacerbated

    更新日期:2020-03-19
  • CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-26
    Shi Yong Neo; Ying Yang; Julien Record; Ran Ma; Xinsong Chen; Ziqing Chen; Nicholas P. Tobin; Emily Blake; Christina Seitz; Ron Thomas; Arnika Kathleen Wagner; John Andersson; Jana de Boniface; Jonas Bergh; Shannon Murray; Evren Alici; Richard Childs; Martin Johansson; Lisa S. Westerberg; Felix Haglund; Johan Hartman; Andreas Lundqvist

    High levels of ecto-5′-nucleotidase (CD73) have been implicated in immune suppression and tumor progression, and have also been observed in cancer patients who progress on anti–PD-1 immunotherapy. Although regulatory T cells can express CD73 and inhibit T cell responses via the production of adenosine, less is known about CD73 expression in other immune cell populations. We found that tumor-infiltrating

    更新日期:2020-03-19
  • Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-04
    Simone Ragusa,Borja Prat-Luri,Alejandra González-Loyola,Sina Nassiri,Mario Leonardo Squadrito,Alan Guichard,Sabrina Cavin,Nikolce Gjorevski,David Barras,Giancarlo Marra,Matthias P Lutolf,Jean Perentes,Emily Corse,Roberta Bianchi,Laureline Wetterwald,Jaeryung Kim,Guillermo Oliver,Mauro Delorenzi,Michele De Palma,Tatiana V Petrova

    Mutations in APC promote colorectal cancer (CRC) progression through uncontrolled WNT signaling. Patients with desmoplastic CRC have a significantly worse prognosis and do not benefit from chemotherapy, but the mechanisms underlying the differential responses of APC-mutant CRCs to chemotherapy are not well understood. We report that expression of the transcription factor prospero homeobox 1 (PROX1)

    更新日期:2020-03-19
  • A stress-responsive enhancer induces dynamic drug resistance in acute myeloid leukemia
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-26
    Mark S. Williams; Fabio M.R. Amaral; Fabrizio Simeoni; Tim C.P. Somervaille

    The drug efflux pump ABCB1 is a key driver of chemoresistance, and high expression predicts treatment failure in acute myeloid leukemia (AML). In this study, we identified and functionally validated the network of enhancers that controls expression of ABCB1. We show that exposure of leukemia cells to daunorubicin activated an integrated stress response–like transcriptional program to induce ABCB1 through

    更新日期:2020-03-19
  • Chronic mTOR activation induces a degradative smooth muscle cell phenotype.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-10
    Guangxin Li,Mo Wang,Alexander W Caulk,Nicholas A Cilfone,Sharvari Gujja,Lingfeng Qin,Pei-Yu Chen,Zehua Chen,Sameh Yousef,Yang Jiao,Changshun He,Bo Jiang,Arina Korneva,Matthew R Bersi,Guilin Wang,Xinran Liu,Sameet Mehta,Arnar Geirsson,Jeffrey R Gulcher,Thomas W Chittenden,Michael Simons,Jay D Humphrey,George Tellides

    Smooth muscle cell (SMC) proliferation has been thought to limit the progression of thoracic aortic aneurysm and dissection (TAAD) because loss of medial cells associates with advanced disease. We investigated effects of SMC proliferation in the aortic media by conditional disruption of Tsc1, which hyperactivates mTOR complex 1. Consequent SMC hyperplasia led to progressive medial degeneration and

    更新日期:2020-03-19
  • Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-10
    Rong Fu,Yi Li,Nan Jiang,Bo-Xue Ren,Chen-Zi Zang,Li-Juan Liu,Wen-Cong Lv,Hong-Mei Li,Stephen Weiss,Zheng-Yu Li,Tao Lu,Zhao-Qiu Wu

    Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium-enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence

    更新日期:2020-03-19
  • Muscle-specific SMN reduction reveals motor neuron-independent disease in spinal muscular atrophy models.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-10
    Jeong-Ki Kim,Narendra N Jha,Zhihua Feng,Michelle R Faleiro,Claudia A Chiriboga,Lan Wei-Lapierre,Robert T Dirksen,Chien-Ping Ko,Umrao R Monani

    Paucity of the survival motor neuron (SMN) protein triggers the oft-fatal infantile-onset motor neuron disorder, spinal muscular atrophy (SMA). Augmenting the protein is one means of treating SMA and recently led to FDA approval of an intrathecally delivered SMN-enhancing oligonucleotide currently in use. Notwithstanding the advent of this and other therapies for SMA, it is unclear whether the paralysis

    更新日期:2020-03-19
  • Oral immunotherapy tolerizes mice to enzyme replacement therapy for Morquio A syndrome
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-19
    Angela C. Sosa; Barbara Kariuki; Qi Gan; Alan P. Knutsen; Clifford J. Bellone; Miguel A. Guzmán; Luis A. Barrera; Shunji Tomatsu; Anil K. Chauhan; Eric Armbrecht; Adriana M. Montaño

    Immune response to therapeutic enzymes poses a detriment to patient safety and treatment outcome. Enzyme replacement therapy (ERT) is a standard therapeutic option for some types of mucopolysaccharidoses, including Morquio A syndrome caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency. Current protocols tolerize patients using cytotoxic immunosuppressives, which can cause adverse

    更新日期:2020-03-19
  • Linear ubiquitin assembly complex regulates lung epithelial–driven responses during influenza infection
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-12
    Patricia L. Brazee; Luisa Morales-Nebreda; Natalia D. Magnani; Joe G.N. Garcia; Alexander V. Misharin; Karen M. Ridge; G.R. Scott Budinger; Kazuhiro Iwai; Laura A. Dada; Jacob I. Sznajder

    Influenza A virus (IAV) is among the most common causes of pneumonia-related death worldwide. Pulmonary epithelial cells are the primary target for viral infection and replication and respond by releasing inflammatory mediators that recruit immune cells to mount the host response. Severe lung injury and death during IAV infection result from an exuberant host inflammatory response. The linear ubiquitin

    更新日期:2020-03-19
  • Graft-versus-host disease of the CNS is mediated by TNF upregulation in microglia
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-17
    Nimitha R. Mathew; Janaki M. Vinnakota; Petya Apostolova; Daniel Erny; Shaimaa Hamarsheh; Geoffroy Andrieux; Jung-Seok Kim; Kathrin Hanke; Tobias Goldmann; Louise Chappell-Maor; Nadia El-Khawanky; Gabriele Ihorst; Dominik Schmidt; Justus Duyster; Jürgen Finke; Thomas Blank; Melanie Boerries; Bruce R. Blazar; Steffen Jung; Marco Prinz; Robert Zeiser

    Acute graft-versus-host disease (GVHD) can affect the central nervous system (CNS). The role of microglia in CNS-GVHD remains undefined. In agreement with microglia activation, we found that profound morphological changes and MHC-II and CD80 upregulation occurred upon GVHD induction. RNA sequencing–based analysis of purified microglia obtained from mice with CNS-GVHD revealed TNF upregulation. Selective

    更新日期:2020-03-19
  • The anti-IgE mAb omalizumab induces adverse reactions by engaging Fcγ receptors
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-26
    Bianca Balbino; Pauline Herviou; Ophélie Godon; Julien Stackowicz; Odile Richard-Le Goff; Bruno Iannascoli; Delphine Sterlin; Sébastien Brûlé; Gael A. Millot; Faith M. Harris; Vera A. Voronina; Kari C. Nadeau; Lynn E. Macdonald; Andrew J. Murphy; Pierre Bruhns; Laurent L. Reber

    Omalizumab is an anti-IgE monoclonal antibody (mAb) approved for the treatment of severe asthma and chronic spontaneous urticaria. Use of omalizumab is associated with reported side effects ranging from local skin inflammation at the injection site to systemic anaphylaxis. To date, the mechanisms through which omalizumab induces adverse reactions are still unknown. Here, we demonstrated that immune

    更新日期:2020-03-19
  • GABA interneurons are the cellular trigger for ketamine’s rapid antidepressant actions
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-19
    Danielle M. Gerhard; Santosh Pothula; Rong-Jian Liu; Min Wu; Xiao-Yuan Li; Matthew J. Girgenti; Seth R. Taylor; Catharine H. Duman; Eric Delpire; Marina Picciotto; Eric S. Wohleb; Ronald S. Duman

    A single subanesthetic dose of ketamine, an NMDA receptor (NMDAR) antagonist, produces rapid and sustained antidepressant actions in depressed patients, addressing a major unmet need for the treatment of mood disorders. Ketamine produces a rapid increase in extracellular glutamate and synaptic formation in the prefrontal cortex, but the initial cellular trigger that initiates this increase and ketamine’s

    更新日期:2020-03-19
  • Prion protein glycans reduce intracerebral fibril formation and spongiosis in prion disease.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-27
    Alejandro M Sevillano,Patricia Aguilar-Calvo,Timothy D Kurt,Jessica A Lawrence,Katrin Soldau,Thu H Nam,Taylor Schumann,Donald P Pizzo,Sofie Nyström,Biswa Choudhury,Hermann Altmeppen,Jeffrey D Esko,Markus Glatzel,K Peter R Nilsson,Christina J Sigurdson

    Posttranslational modifications (PTMs) are common among proteins that aggregate in neurodegenerative disease, yet how PTMs impact the aggregate conformation and disease progression remains unclear. By engineering knockin mice expressing prion protein (PrP) lacking 2 N-linked glycans (Prnp180Q/196Q), we provide evidence that glycans reduce spongiform degeneration and hinder plaque formation in prion

    更新日期:2020-03-19
  • Machine learning reveals serum sphingolipids as cholesterol-independent biomarkers of coronary artery disease
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-11-19
    Annelise M. Poss; J. Alan Maschek; James E. Cox; Benedikt J. Hauner; Paul N. Hopkins; Steven C. Hunt; William L. Holland; Scott A. Summers; Mary C. Playdon

    BACKGROUND. Ceramides are sphingolipids that play causative roles in diabetes and heart disease, with their serum levels measured clinically as biomarkers of cardiovascular disease (CVD).

    更新日期:2020-03-19
  • Microphthalmia transcription factor expression contributes to bone marrow failure in Fanconi anemia
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-26
    Alessia Oppezzo; Julie Bourseguin; Emilie Renaud; Patrycja Pawlikowska; Filippo Rosselli

    Hematopoietic stem cell (HSC) attrition is considered the key event underlying progressive BM failure (BMF) in Fanconi anemia (FA), the most frequent inherited BMF disorder in humans. However, despite major advances, how the cellular, biochemical, and molecular alterations reported in FA lead to HSC exhaustion remains poorly understood. Here, we demonstrated in human and mouse cells that loss-of-function

    更新日期:2020-03-19
  • Cardioprotective GLP-1 metabolite prevents ischemic cardiac injury by inhibiting mitochondrial trifunctional protein-α.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-01-27
    M Ahsan Siraj,Dhanwantee Mundil,Sanja Beca,Abdul Momen,Eric A Shikatani,Talat Afroze,Xuetao Sun,Ying Liu,Siavash Ghaffari,Warren Lee,Michael B Wheeler,Gordon Keller,Peter Backx,Mansoor Husain

    Mechanisms mediating the cardioprotective actions of glucagon-like peptide 1 (GLP-1) were unknown. Here, we show in both ex vivo and in vivo models of ischemic injury that treatment with GLP-1(28-36), a neutral endopeptidase-generated (NEP-generated) metabolite of GLP-1, was as cardioprotective as GLP-1 and was abolished by scrambling its amino acid sequence. GLP-1(28-36) enters human coronary artery

    更新日期:2020-03-19
  • A conserved intratumoral regulatory T cell signature identifies 4-1BB as a pan-cancer target.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-04
    Zachary T Freeman,Thomas R Nirschl,Daniel H Hovelson,Robert J Johnston,John J Engelhardt,Mark J Selby,Christina M Kochel,Ruth Y Lan,Jingyi Zhai,Ali Ghasemzadeh,Anuj Gupta,Alyza M Skaist,Sarah J Wheelan,Hui Jiang,Alexander T Pearson,Linda A Snyder,Alan J Korman,Scott A Tomlins,Srinivasan Yegnasubramanian,Charles G Drake

    Despite advancements in targeting the immune checkpoints program cell death protein 1 (PD-1), programmed death ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated protein 4 (CTLA-4) for cancer immunotherapy, a large number of patients and cancer types remain unresponsive. Current immunotherapies focus on modulating an antitumor immune response by directly or indirectly expanding antitumor CD8 T

    更新日期:2020-03-19
  • IL-36γ drives skin toxicity induced by EGFR/MEK inhibition and commensal Cutibacterium acnes
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-05
    Takashi K. Satoh; Mark Mellett; Barbara Meier-Schiesser; Gabriele Fenini; Atsushi Otsuka; Hans-Dietmar Beer; Tamara Rordorf; Julia-Tatjana Maul; Jürg Hafner; Alexander A. Navarini; Emmanuel Contassot; Lars E. French

    Epidermal growth factor receptor (EGFR) and MEK inhibitors (EGFRi/MEKi) are beneficial for the treatment of solid cancers but are frequently associated with severe therapy-limiting acneiform skin toxicities. The underlying molecular mechanisms are poorly understood. Using gene expression profiling we identified IL-36γ and IL-8 as candidate drivers of EGFRi/MEKi skin toxicity. We provide molecular and

    更新日期:2020-03-19
  • Lysine acetyltransferase 8 is involved in cerebral development and syndromic intellectual disability
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-03
    Lin Li; Mohammad Ghorbani; Monika Weisz-Hubshman; Justine Rousseau; Isabelle Thiffault; Rhonda E. Schnur; Catherine Breen; Renske Oegema; Marjan M.M. Weiss; Quinten Waisfisz; Sara Welner; Helen Kingston; Jordan A. Hills; Elles M.J. Boon; Lina Basel-Salmon; Osnat Konen; Hadassa Goldberg-Stern; Lily Bazak; Shay Tzur; Jianliang Jin; Xiuli Bi; Michael Bruccoleri; Kirsty McWalter; Megan T. Cho; Maria Scarano;

    Epigenetic integrity is critical for many eukaryotic cellular processes. An important question is how different epigenetic regulators control development and influence disease. Lysine acetyltransferase 8 (KAT8) is critical for acetylation of histone H4 at lysine 16 (H4K16), an evolutionarily conserved epigenetic mark. It is unclear what roles KAT8 plays in cerebral development and human disease. Here

    更新日期:2020-03-19
  • Impaired folate 1-carbon metabolism causes formate-preventable hydrocephalus in glycine decarboxylase–deficient mice
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-03
    Chloe Santos; Yun Jin Pai; M. Raasib Mahmood; Kit-Yi Leung; Dawn Savery; Simon N. Waddington; Andrew J. Copp; Nicholas D.E. Greene

    Ventriculomegaly and hydrocephalus are associated with loss of function of glycine decarboxylase (Gldc) in mice and in humans suffering from non-ketotic hyperglycinemia (NKH), a neurometabolic disorder characterized by accumulation of excess glycine. Here, we showed that ventriculomegaly in Gldc-deficient mice is preceded by stenosis of the Sylvian aqueduct and malformation or absence of the subcommissural

    更新日期:2020-03-19
  • Insulin resistance drives hepatic de novo lipogenesis in nonalcoholic fatty liver disease
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-05
    Gordon I. Smith; Mahalakshmi Shankaran; Mihoko Yoshino; George G. Schweitzer; Maria Chondronikola; Joseph W. Beals; Adewole L. Okunade; Bruce W. Patterson; Edna Nyangau; Tyler Field; Claude B. Sirlin; Saswata Talukdar; Marc K. Hellerstein; Samuel Klein

    BACKGROUND. An increase in intrahepatic triglyceride (IHTG) is the hallmark feature of nonalcoholic fatty liver disease (NAFLD) and is decreased by weight loss. Hepatic de novo lipogenesis (DNL) contributes to steatosis in individuals with NAFLD. The physiological factors that stimulate hepatic DNL and the effect of weight loss on hepatic DNL are not clear.

    更新日期:2020-03-19
  • Neuromuscular junctions are stable in patients with cancer cachexia
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-03
    Ines Boehm; Janice Miller; Thomas M. Wishart; Stephen J. Wigmore; Richard J.E. Skipworth; Ross A. Jones; Thomas H. Gillingwater

    Cancer cachexia is a major cause of patient morbidity and mortality, with no efficacious treatment or management strategy. Despite cachexia sharing pathophysiological features with a number of neuromuscular wasting conditions, including age-related sarcopenia, the mechanisms underlying cachexia remain poorly understood. Studies of related conditions suggest that pathological targeting of the neuromuscular

    更新日期:2020-03-19
  • Chikungunya virus replication in skeletal muscle cells is required for disease development
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-03
    Anthony J. Lentscher; Mary K. McCarthy; Nicholas A. May; Bennett J. Davenport; Stephanie A. Montgomery; Krishnan Raghunathan; Nicole McAllister; Laurie A. Silva; Thomas E. Morrison; Terence S. Dermody

    Chikungunya virus (CHIKV) is an arbovirus capable of causing a severe and often debilitating rheumatic syndrome in humans. CHIKV replicates in a wide variety of cell types in mammals, which has made attributing pathologic outcomes to replication at specific sites difficult. To assess the contribution of CHIKV replication in skeletal muscle cells to pathogenesis, we engineered a CHIKV strain exhibiting

    更新日期:2020-03-19
  • DGCR8 microprocessor defect characterizes familial multinodular goiter with schwannomatosis
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-05
    Barbara Rivera; Javad Nadaf; Somayyeh Fahiminiya; Maria Apellaniz-Ruiz; Avi Saskin; Anne-Sophie Chong; Sahil Sharma; Rabea Wagener; Timothée Revil; Vincenzo Condello; Zineb Harra; Nancy Hamel; Nelly Sabbaghian; Karl Muchantef; Christian Thomas; Leanne de Kock; Marie-Noëlle Hébert-Blouin; Angelia V. Bassenden; Hannah Rabenstein; Ozgur Mete; Ralf Paschke; Marc P. Pusztaszeri; Werner Paulus; Albert Berghuis;

    BACKGROUND. DICER1 is the only miRNA biogenesis component associated with an inherited tumor syndrome, featuring multinodular goiter (MNG) and rare pediatric-onset lesions. Other susceptibility genes for familial forms of MNG likely exist.

    更新日期:2020-03-19
  • Myalgic encephalomyelitis/chronic fatigue syndrome patients exhibit altered T cell metabolism and cytokine associations
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-12
    Alexandra H. Mandarano; Jessica Maya; Ludovic Giloteaux; Daniel L. Peterson; Marco Maynard; C. Gunnar Gottschalk; Maureen R. Hanson

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disease with no known cause or mechanism. There is an increasing appreciation for the role of immune and metabolic dysfunction in the disease. ME/CFS has historically presented in outbreaks, often has a flu-like onset, and results in inflammatory symptoms. Patients suffer from severe fatigue and postexertional malaise. There is

    更新日期:2020-03-19
  • Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-17
    Jeremy M Sullivan,William W Motley,Janel O Johnson,William H Aisenberg,Katherine L Marshall,Katy Es Barwick,Lingling Kong,Jennifer S Huh,Pamela C Saavedra-Rivera,Meriel M McEntagart,Marie-Helene Marion,Lucy A Hicklin,Hamid Modarres,Emma L Baple,Mohamed H Farah,Aamir R Zuberi,Cathleen M Lutz,Rachelle Gaudet,Bryan J Traynor,Andrew H Crosby,Charlotte J Sumner

    Notch signaling is a highly conserved intercellular pathway with tightly regulated and pleiotropic roles in normal tissue development and homeostasis. Dysregulated Notch signaling has also been implicated in human disease, including multiple forms of cancer, and represents an emerging therapeutic target. Successful development of such therapeutics requires a detailed understanding of potential on-target

    更新日期:2020-03-19
  • Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-17
    Petra Simic,Wondong Kim,Wen Zhou,Kerry A Pierce,Wenhan Chang,David B Sykes,Najihah B Aziz,Sammy Elmariah,Debby Ngo,Paola Divieti Pajevic,Nicolas Govea,Bryan R Kestenbaum,Ian H de Boer,Zhiqiang Cheng,Marta Christov,Jerold Chun,David E Leaf,Sushrut S Waikar,Andrew M Tager,Robert E Gerszten,Ravi I Thadhani,Clary B Clish,Harald Jüppner,Marc N Wein,Eugene P Rhee

    Fibroblast growth factor 23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 [1,25(OH)2D] production. Disorders of FGF23 homeostasis are associated with significant morbidity and mortality, but a fundamental understanding of what regulates FGF23 production is lacking. Because the kidney is the major

    更新日期:2020-03-19
  • Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial
    J. Clin. Invest. (IF 12.282) Pub Date : 2019-12-05
    Peter A. Campochiaro; Mustafa Iftikhar; Gulnar Hafiz; Anam Akhlaq; Grace Tsai; Dagmar Wehling; Lili Lu; G. Michael Wall; Mandeep S. Singh; Xiangrong Kong

    BACKGROUND. In retinitis pigmentosa (RP), rod photoreceptors degenerate from 1 of many mutations, after which cones are compromised by oxidative stress. N-acetylcysteine (NAC) reduces oxidative damage and increases cone function/survival in RP models. We tested the safety, tolerability, and visual function effects of oral NAC in RP patients.

    更新日期:2020-03-19
  • IRF4 instructs effector Treg differentiation and immune suppression in human cancer.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-03
    Giorgia Alvisi,Jolanda Brummelman,Simone Puccio,Emilia Maria Cristina Mazza,Elisa Paoluzzi Tomada,Agnese Losurdo,Veronica Zanon,Clelia Peano,Federico S Colombo,Alice Scarpa,Marco Alloisio,Ajithkumar Vasanthakumar,Rahul Roychoudhuri,Marinos Kallikourdis,Massimiliano Pagani,Egesta Lopci,Pierluigi Novellis,Jonas Blume,Axel Kallies,Giulia Veronesi,Enrico Lugli

    The molecular mechanisms responsible for the high immunosuppressive capacity of CD4+ regulatory T cells (Tregs) in tumors are poorly known. High-dimensional single cell profiling of T cells from chemotherapy-naïve individuals with non-small cell lung cancer identified the transcription factor IRF4 as specifically expressed by a subset of intratumoral CD4+ effector Tregs with superior suppressive activity

    更新日期:2020-03-03
  • Ubiquitous antigen-specific T regulatory type 1 cells variably suppress hepatic and extrahepatic autoimmunity.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-03
    Channakeshava Sokke Umeshappa,Jacques Mbongue,Santiswarup Singha,Saswat Mohapatra,Jun Yamanouchi,Justin A Lee,Roopa Hebbandi Nanjundappa,Kun Shao,Urs Christen,Yang Yang,Kristofor K Ellestad,Pere Santamaria

    Peptide MHC class II-based (pMHCII-based) nanomedicines trigger the formation of multicellular regulatory networks by reprogramming autoantigen-experienced CD4+ T cells into autoimmune disease-suppressing T regulatory type 1 (TR1) cells. We have shown that pMHCII-based nanomedicines displaying liver autoimmune disease-relevant yet ubiquitously expressed antigens can blunt various liver autoimmune disorders

    更新日期:2020-03-03
  • CoRESTed development of regulatory T cells.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-03
    Luisa Morales-Nebreda,Kathryn A Helmin,Benjamin D Singer

    Tregs require specific epigenetic signatures to induce and maintain their suppressive function in the context of inflammation and cancer surveillance. In this issue of the JCI, Xiong and colleagues identify a critical role for the epigenetic repressor REST corepressor 1 (CoREST) in promoting Treg suppressive transcriptional and functional programs. Pharmacologic inhibition and genetic loss of CoREST

    更新日期:2020-03-03
  • The microbiome adds to the complexity of parathyroid hormone action on bone.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-03
    Sundeep Khosla

    Parathyroid hormone (PTH) has complex effects on bone, including stimulating bone formation and regulating the hematopoietic stem cell (HSC) niche. In the current issue of the JCI, Li et al. demonstrated that the microbiome, through the production of short-chain fatty acids and in particular, butyrate, is necessary for the ability of PTH to increase osteoblast numbers and stimulate bone formation.

    更新日期:2020-03-03
  • Tissue-resident T cell derived cytokines eliminate herpes simplex virus-2 infected cells.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-03
    Pavitra Roychoudhury,David A Swan,Elizabeth R Duke,Lawrence Corey,Jia Zhu,Veronica A Davé,Laura E Richert-Spuhler,Jennifer M Lund,Martin Prlic,Joshua T Schiffer

    The mechanisms underlying rapid elimination of herpes simplex virus-2 (HSV-2) in the human genital tract despite low tissue-resident CD8+ and CD4+ T-cell density (TRM) are unknown. We analyzed shedding episodes during chronic HSV-2 infection: viral clearance always predominated within 24 hours of detection even if viral load exceeded 107 HSV DNA copies; surges in granzyme B and interferon-γ occurred

    更新日期:2020-03-03
  • PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-03
    Teresa Gagliano,Kalpit Shah,Sofia Gargani,Liyan Lao,Mansour Alsaleem,Jianing Chen,Vasileios Ntafis,Penghan Huang,Angeliki Ditsiou,Viviana Vella,Kritika Yadav,Kamila Bienkowska,Giulia Bresciani,Kai Kang,Leping Li,Philip Carter,Graeme Benstead-Hume,Timothy O'Hanlon,Michael Dean,Frances Mg Pearl,Soo Chin Lee,Emad A Rakha,Andrew R Green,Dimitris L Kontoyiannis,Erwei Song,Justin Stebbing,Georgios Giamas

    As there is growing evidence for the tumor microenvironment's (TME) role in tumorigenesis, we investigated the role of fibroblast-expressed kinases in triple negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of progression. Although PIK3Cδ was expressed in primary fibroblasts

    更新日期:2020-03-03
  • DNA hyper-methylation during Tuberculosis dampens host immune responsiveness.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-03
    Andrew DiNardo,Kimal Rajapakshe,Tomoki Nishiguchi,Godwin Mtetwa,Sandra L Grimm,Qiniso Dlamini,Jaquiline Kahari,Sanjana Mahapatra,Alexander W Kay,Gugu Maphalala,Emily M Mace,George Makedonas,Jeffrey D Cirillo,Mihai Netea,Reinout van Crevel,Cristian Coarfa,Anna M Mandalakas

    Mycobacterium tuberculosis (Mtb) has co-evolved with humans for millennia and developed multiple mechanisms to evade host immunity. Restoring host immunity in order to improve outcomes and potentially shorten existing therapy will require identifying the full complement by which host immunity is inhibited. Perturbing host DNA methylation is a mechanism induced by chronic infections such as HIV, HPV

    更新日期:2020-03-03
  • Capsular glycan recognition provides antibody-mediated immunity against tuberculosis.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-03-03
    Tingting Chen,Caroline Blanc,Yanyan Liu,Elise Ishida,Sarah Singer,Jiayong Xu,Maju Joe,Elizabeth R Jenny-Avital,John Chan,Todd L Lowary,Jacqueline M Achkar

    A better understanding of all immune components involved in protecting against Mycobacterium tuberculosis infection is urgently needed to inform strategies for novel immunotherapy and tuberculosis (TB) vaccine development. Although cell-mediated immunity is critical, increasing evidence supports that antibodies also have a protective role against TB. Yet knowledge of protective antigens is limited

    更新日期:2020-03-03
  • Salt-inducible kinase 1 maintains HDAC7 stability to promote pathologic cardiac remodeling.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-27
    Austin Hsu,Qiming Duan,Sarah McMahon,Yu Huang,Sarah Ab Wood,Nathanael S Gray,Biao Wang,Benoit G Bruneau,Saptarsi M Haldar

    Salt inducible kinases (SIKs) are key regulators of cellular metabolism and growth, but their role in cardiomyocyte plasticity and heart failure pathogenesis remains unknown. Here, we showed that loss of SIK1 kinase activity protected against adverse cardiac remodeling and heart failure pathogenesis in rodent models and human iPSC-derived cardiomyocytes. We found that SIK1 phosphorylated and stabilized

    更新日期:2020-02-27
  • Protein arginine methyltransferase 5 promotes cholesterol biosynthesis-mediated Th17 responses and autoimmunity.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-24
    Lindsay M Webb,Shouvonik Sengupta,Claudia Edell,Zayda L Piedra-Quintero,Stephanie A Amici,Janiret Narvaez Miranda,Makenzie Bevins,Austin Kennemer,Georgios Laliotis,Philip N Tsichlis,Mireia Guerau-de-Arellano

    Protein arginine methyltransferase 5 (PRMT5) catalyzes symmetric dimethylation (SDM) of arginine, a posttranslational modification involved in oncogenesis and embryonic development. However, the role and mechanisms by which PRMT5 modulates Th cell polarization and autoimmune disease have not yet been elucidated. Here, we found that PRMT5 promoted SREBP1 SDM and the induction of cholesterol biosynthetic

    更新日期:2020-02-24
  • Circulating tumor DNA profile recognizes transformation to castration-resistant neuroendocrine prostate cancer.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-24
    Himisha Beltran,Alessandro Romanel,Vincenza Conteduca,Nicola Casiraghi,Michael Sigouros,Gian Marco Franceschini,Francesco Orlando,Tarcisio Fedrizzi,Sheng-Yu Ku,Emma Dann,Alicia Alonso,Juan Miguel Mosquera,Andrea Sboner,Jenny Xiang,Olivier Elemento,David M Nanus,Scott T Tagawa,Matteo Benelli,Francesca Demichelis

    Loss of androgen receptor (AR) signaling dependence occurs in approximately 15%-20% of advanced treatment-resistant prostate cancers, and this may manifest clinically as transformation from a prostate adenocarcinoma histology to a castration-resistant neuroendocrine prostate cancer (CRPC-NE). The diagnosis of CRPC-NE currently relies on a metastatic tumor biopsy, which is invasive for patients and

    更新日期:2020-02-24
  • A role for connexin-43 in Duchenne muscular dystrophy cardiomyopathy.
    J. Clin. Invest. (IF 12.282) Pub Date : 2020-02-24
    Robin M Shaw,Jeffrey E Saffitz

    The cardiomyopathy of Duchenne muscular dystrophy (DMD) is an important cause of morbidity and mortality in affected males with this dreaded muscle disease. Previous studies have implicated changes in expression and subcellular localization of connexin-43 (Cx43), the major ventricular gap junction protein, in DMD cardiomyopathy. In this issue of the JCI, Himelman et al. explore how hypophosphorylation

    更新日期:2020-02-24
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