APSA Presidential Address

Exchanging resilience for persistence: perspective for a new era in training

Hannah R. Turbeville

Hannah R. Turbeville

Published September 15, 2021
Citation Information: J Clin Invest. 2021;for Infiniti Chrome Metal License Plate Frame with Logo Screw Co:e150828. https://doi.org/10.1172/JCI150828.

View: Text | PDF

Exchanging resilience for persistence: perspective for a new era in training

• Text
• PDF

Abstract

Authors

Hannah R. Turbeville

×

Letters to the Editor

Collateral effects of deletion of nlpD on rpoS and rpoS-dependent genes

Manami Tsunoi, … , Sunao Iyoda, Tadayuki Iwase

Manami Tsunoi, … , Sunao Iyoda, Tadayuki Iwase

Published September 15, 2021
Citation Information: J Clin Invest. 2021;Set of 2 Microwave Saucepan With Lid Store Heat and Eat 800ml ea:e152693. https://doi.org/10.1172/JCI152693.

View: Text | PDF

Collateral effects of deletion of nlpD on rpoS and rpoS-dependent genes

• Text
• PDF

Abstract

Authors

Manami Tsunoi, Sunao Iyoda, Tadayuki Iwase

×

---

Collateral effects of deletion of nlpD on rpoS and rpoS-dependent genes. Reply.

Inès Ambite, … , Ulrich Dobrindt, Catharina Svanborg

Inès Ambite, … , Ulrich Dobrindt, Catharina Svanborg

Published September 15, 2021
Citation Information: J Clin Invest. 2021;Cartridge Body Comparable Replacement to Sun Hydraulics ECB:e153234. https://doi.org/10.1172/JCI153234.

View: Text | PDF

Collateral effects of deletion of nlpD on rpoS and rpoS-dependent genes. Reply.

• Text
• PDF

Abstract

Authors

Inès Ambite, Ulrich Dobrindt, Catharina Svanborg

×

Conversations with Giants in Medicine

A conversation with Dan Drucker

S

Ushma Neill

Ushma Neill

Published September 15, 2021
Citation Information: J Clin Invest. 2021;CARXIU Women's Capri Yoga Pants with Pockets Drawstring Sweatpan:e154150. https://doi.org/10.1172/JCI154150.

View: Text | PDF

A conversation with Dan Drucker

• Text
• PDF

Abstract

Authors

Ushma Neill

×

AAP Presidential Address

Novel biomedical research must not be a work of fiction

Mitchell A. Lazar

Mitchell A. Lazar

Published September 15, 2021
Citation Information: J Clin Invest. 2021;Shoreline Marine Dive Flag, 20 X 24-Inch:e150827. https://doi.org/10.1172/JCI150827.

View: Text | PDF

Novel biomedical research must not be a work of fiction

• Text
• PDF

Abstract

Authors

Mitchell A. Lazar

×

ASCI Presidential Address

Physician-scientists in the pandemic era: tidal wave or rising tide?

Lorraine B. Ware

Lorraine B. Ware

Published September 15, 2021
Citation Information: J Clin Invest. 2021;GHMOZ Inflatable Boxing Bag Thick Practic Ball Standing Punching:e154538. https://doi.org/10.1172/JCI154538.

View: Text | PDF

Physician-scientists in the pandemic era: tidal wave or rising tide?

• Text
• PDF

Abstract

Authors

Lorraine B. Ware

×

Viewpoint

Forty years of AIDS: a retrospective and the way forward

Thomas C. Quinn

Thomas C. Quinn

Published September 15, 2021
Citation Information: J Clin Invest. 2021;Portmeirion Pomona Romantic Footed Cup Saucer Set, Fine China:e154196. https://doi.org/10.1172/JCI154196.

View: Text | PDF

Forty years of AIDS: a retrospective and the way forward

• Text
• PDF

Abstract

Authors

Thomas C. Quinn

×

Review Series

The gut, its microbiome, and the brain: connections and communications

S

Michael D. Gershon, Kara Gross Margolis

Michael D. Gershon, Kara Gross Margolis

Published September 15, 2021
Citation Information: J Clin Invest. 2021;FMOGG Women Martial Arts Suit, Zen Meditation Uniform Cotton Lin:e143768. https://doi.org/10.1172/JCI143768.

View: Text | PDF

The gut, its microbiome, and the brain: connections and communications

• Text
• PDF

Abstract

Modern research on gastrointestinal behavior has revealed it to be a highly complex bidirectional process in which the gut sends signals to the brain, via spinal and vagal visceral afferent pathways, and receives sympathetic and parasympathetic inputs. Concomitantly, the enteric nervous system within the bowel, which contains intrinsic primary afferent neurons, interneurons, and motor neurons, also senses the enteric environment and controls the detailed patterns of intestinal motility and secretion. The vast microbiome that is resident within the enteric lumen is yet another contributor, not only to gut behavior, but to the bidirectional signaling process, so that the existence of a microbiota-gut-brain “connectome” has become apparent. The interaction between the microbiota, the bowel, and the brain now appears to be neither a top-down nor a bottom-up process. Instead, it is an ongoing, tripartite conversation, the outline of which is beginning to emerge and is the subject of this Review. We emphasize aspects of the exponentially increasing knowledge of the microbiota-gut-brain “connectome” and focus attention on the roles that serotonin, Toll-like receptors, and macrophages play in signaling as exemplars of potentially generalizable mechanisms.

Authors

Michael D. Gershon, Kara Gross Margolis

×

Review

2009 APBA Football Season Team Set (From 2OI3) - KANSAS CITY CHI

S

Peter S. Choi, Andrei Thomas-Tikhonenko

Peter S. Choi, Andrei Thomas-Tikhonenko

Published September 15, 2021
Citation Information: J Clin Invest. 2021;Dearfoams Men's Moccasin with Tie Slipper:e151627. https://doi.org/10.1172/JCI151627.

View: Text | PDF

Tangyongjiao Mobile Phone Flex Cable Power Button Volume Butto

• Text
• PDF

Abstract

Herculean efforts by the Wellcome Sanger Institute, the National Cancer Institute, and the National Human Genome Research Institute to sequence thousands of tumors representing all major cancer types have yielded more than 700 genes that contribute to neoplastic growth when mutated, amplified, or deleted. While some of these genes (now included in the COSMIC Cancer Gene Census) encode proteins previously identified in hypothesis-driven experiments (oncogenic transcription factors, protein kinases, etc.), additional classes of cancer drivers have emerged, perhaps none more surprisingly than RNA-binding proteins (RBPs). Over 40 RBPs responsible for virtually all aspects of RNA metabolism, from synthesis to degradation, are recurrently mutated in cancer, and just over a dozen are considered major cancer drivers. This Review investigates whether and how their RNA-binding activities pertain to their oncogenic functions. Focusing on several well-characterized steps in RNA metabolism, we demonstrate that for virtually all cancer-driving RBPs, RNA processing activities are either abolished (the loss-of-function phenotype) or carried out with low fidelity (the LoFi phenotype). Conceptually, this suggests that in normal cells, RBPs act as gatekeepers maintaining proper RNA metabolism and the “balanced” proteome. From the practical standpoint, at least some LoFi phenotypes create therapeutic vulnerabilities, which are beginning to be exploited in the clinic.

Authors

Peter S. Choi, Andrei Thomas-Tikhonenko

×

Commentaries

Inclusion criteria: how NK cells gain access to T cells

S

Tonya J. Webb

Tonya J. Webb

Published September 15, 2021
Citation Information: J Clin Invest. ;Handyulong Graphic Tees for Women with Sayings Casual Summer Rai:e152054. https://doi.org/10.1172/JCI152054.

View: Text | PDF

Inclusion criteria: how NK cells gain access to T cells

• Text
• PDF

Abstract

Natural killer (NK) cells play an important role in host defense against viral infections and malignancy, and their role for regulating other components of the antiviral response is being investigated. In this issue of the JCI, Ali et al. examine the mechanisms by which NK cells migrate into the white pulp and mediate suppression of virus-specific T cells. Herein, the authors show that an acute lymphocytic choriomeningitis virus (LCMV) infection induced a potent type I IFN (IFN-I) response that resulted in the expression of chemokine receptor CXCR3 ligands and permitted NK cell trafficking to T cell zones. Collectively, these findings have broad implications for vaccination strategies and warrant further investigation into the transcriptomic profiles of these regulatory NK cells.

Authors

Tonya J. Webb

×

---

Tireless surveillance by exhausted T cells

S

Michael L. Dustin

Michael L. Dustin

Published September 15, 2021
Citation Information: J Clin Invest. 2021;HELYZQ European Style Metal Candle Holder Simple Golden Home Dec:e152382. https://doi.org/10.1172/JCI152382.

View: Text | PDF

Tireless surveillance by exhausted T cells

• Text
• PDF

Abstract

T cell exhaustion is an evocative concept that results in attenuated function in the face of chronic antigen exposure and is critical to avoid immunopathology. However, tumors often exploit this dampened T cell function to escape the antitumor immune response. In this issue of the JCI, You et al. investigated a different aspect of T cell exhaustion in the setting of tumor immunity by characterizing the capacity of T cells for tireless migration. The dynamic nature of normal T cells was first made famous by intravital microscopy studies in explanted tissues. You et al. used a similar imaging strategy with reanimated human tumors, in which exhausted T cells displayed an enhanced capacity for intratumoral motility. These results suggest that exhausted T cells may be able to teach T cell engineers lessons about navigating within the tumor microenvironment.

Authors

Michael L. Dustin

×

---

Oncogene-specific inhibition in the treatment of advanced pediatric thyroid cancer

S

Aime T. Franco, … , Theodore W. Laetsch, Andrew J. Bauer

Aime T. Franco, … , Theodore W. Laetsch, Andrew J. Bauer

Published September 15, 2021
Citation Information: J Clin Invest. 2021;wangpeng New Laptop DC Power Jack with Cable Harness for Acer As:e152696. https://doi.org/10.1172/JCI152696.

View: Text | PDF

Oncogene-specific inhibition in the treatment of advanced pediatric thyroid cancer

• Text
• PDF

Abstract

Papillary thyroid cancer (PTC) is the most common form of differentiated thyroid cancer in the pediatric population and represents the second most common malignancy in adolescent females. Historically, PTC has been classified on the basis of histology, however, accumulating data indicate that molecular subtyping based on somatic oncogenic alterations along with gene expression profiling can better predict clinical behavior and may provide opportunities to incorporate oncogene-specific inhibitory therapy to improve the response to radioactive iodine (RAI). In this issue of the JCI, Y.A. Lee, H. Lee, and colleagues showed that oncogenic fusions were more commonly associated with invasive disease, increased expression of MAPK signaling pathway genes (ERK score), and decreased expression of the sodium-iodine symporter, which was restored by RET- and NTRK-inhibitory therapy. These findings lend credence to the idea of reclassifying pediatric thyroid cancers using a three-tiered system, rather than the two-tiered adult system, and open avenues for the treatment of progressive, RAI-refractory PTC in patients.

Authors

Aime T. Franco, Julio C. Ricarte-Filho, Theodore W. Laetsch, Andrew J. Bauer

×

---

Delayed circadian rhythms and substance abuse: dopamine transmission’s time has come

S

Brant P. Hasler, Colleen A. McClung

Brant P. Hasler, Colleen A. McClung

Published September 15, 2021
Citation Information: J Clin Invest. 2021;Stacy Adams 6-188 Croco and Ostrich Leg Embossed Leather Mens Be:e152832. https://doi.org/10.1172/JCI152832.

View: Text | PDF

Delayed circadian rhythms and substance abuse: dopamine transmission’s time has come

• Text
• PDF

Abstract

Disrupted sleep and circadian rhythms are linked with substance abuse risk. Human studies that investigate relationships between sleep, circadian rhythm, and substance use reward generally rely on indirect means to infer dopaminergic function, such as functional magnetic resonance imaging. In this issue of the JCI, Zhang and colleagues used positron emission tomography (PET) to image striatal dopamine D1 (D1R) and D2/3 receptor (D/3R) availability in healthy adults. The authors assessed rest-activity rhythms, then conducted PET scans using radioligand antagonists selective for D1 receptors or D2/D3 receptors to measure D1R and D2/3R availability. They also measured the subjective drug effects of oral methylphenidate. Higher D1R availability in caudate and a greater methylphenidate reward sensitivity were associated with delayed rest-activity rhythms. Unexpectedly, lower overall activity was associated with higher D2/3R availability in the nucleus accumbens, which coincided with greater methylphenidate reward score. These findings may inform personalized prevention and/or treatment interventions.

Authors

Brant P. Hasler, Colleen A. McClung

×

---

Microvascular changes that stagger the mind

S

Frank M. Faraci

Frank M. Faraci

Published September 15, 2021
Citation Information: J Clin Invest. 2021;MaxxMMA Hand Wrap Gel Gloves - Boxing MMA Kickboxing Muay Thai:e153202. https://doi.org/10.1172/JCI153202.

View: Text | PDF

Microvascular changes that stagger the mind

• Text
• PDF

Abstract

Hypertension is a leading cause of cognitive impairment and dementias. Such loss of brain health has a vascular component, but the mechanisms involved are poorly defined. In this issue of the JCI, Koide et al. provide evidence that end-organ effects of hypertension on capillary endothelium and inward-rectifier K+ channels (Kir2.1) impair integrated propagation of electrical signals and vasodilation upstream, resulting in reduced neurovascular coupling (NVC) despite neural activation. NVC was partly restored by amlodipine, but not losartan. Moreover, NVC was improved by eplerenone in the presence of losartan, suggesting a role for aldosterone. These findings support the concept that endothelial cells and Kir2.1 are potential therapeutic targets to prevent or reverse the loss of NVC and the vascular component of cognitive deficits that occur with increased frequency during hypertension.

Authors

Frank M. Faraci

×

---

Cooperative tanycytes fuel the neuronal tank

S

Roberta Haddad-Tóvolli, Marc Claret

Roberta Haddad-Tóvolli, Marc Claret

Published September 15, 2021
Citation Information: J Clin Invest. 2021;MAGINELS Portable Wardrobe Closets - 14"x18" Depth (12 Cubes) Cu:e153279. https://doi.org/10.1172/JCI153279.

View: Text | PDF

Cooperative tanycytes fuel the neuronal tank

• Text
• PDF

Abstract

Tanycytes are specialized radial glial cells of the hypothalamus that have emerged as important players that sense and respond to fluctuations in whole-body energy status to maintain energy homeostasis. However, the underlying mechanisms by which tanycytes influence energy balance remain incompletely understood. In this issue of the JCI, Lhomme et al. used transgenic mouse models, pharmacological approaches, and electrophysiology to investigate how tanycytes sense glucose availability and integrate metabolic cues into a lactate tanycytic network that fuels pro-opiomelanocortin (POMC) neuronal activity. Notably, the authors found that the tanycytic network relied on monocarboxylate transporters and connexin-43 gap junctions to transfer lactate to POMC neurons. Collectively, this study places tanycytes at the center of the intercellular communication processes governing energy balance.

Authors

Roberta Haddad-Tóvolli, Marc Claret

×

Research Articles

Tanycytic networks mediate energy balance by feeding lactate to glucose-insensitive POMC neurons

Tori Lhomme, … , Ruben Nogueiras, Vincent Prevot

Tori Lhomme, … , Ruben Nogueiras, Vincent Prevot

Published July 29, 2021
Citation Information: J Clin Invest. 2021;Uspick Beautiful Crystal Stone Natural Labradorite Snake Hand Ca:e140521. https://doi.org/10.1172/JCI140521.

View: Text | PDF

Tanycytic networks mediate energy balance by feeding lactate to glucose-insensitive POMC neurons

• Text
• PDF

Abstract

Hypothalamic glucose sensing enables an organism to match energy expenditure and food intake to circulating levels of glucose, the main energy source of the brain. Here, we established that tanycytes of the arcuate nucleus of the hypothalamus, specialized glia that line the wall of the third ventricle, convert brain glucose supplies into lactate that they transmit through monocarboxylate transporters to arcuate proopiomelanocortin neurons, which integrate this signal to drive their activity and to adapt the metabolic response to meet physiological demands. Furthermore, this transmission required the formation of extensive connexin-43 gap junction–mediated metabolic networks by arcuate tanycytes. Selective suppression of either tanycytic monocarboxylate transporters or gap junctions resulted in altered feeding behavior and energy metabolism. Tanycytic intercellular communication and lactate production are thus integral to the mechanism by which hypothalamic neurons that regulate energy and glucose homeostasis efficiently perceive alterations in systemic glucose levels as a function of the physiological state of the organism.

Authors

Tori Lhomme, Jerome Clasadonte, Monica Imbernon, Daniela Fernandois, Florent Sauve, Emilie Caron, Natalia da Silva Lima, Violeta Heras, Ines Martinez-Corral, Helge Mueller-Fielitz, Sowmyalakshmi Rasika, Markus Schwaninger, Ruben Nogueiras, Vincent Prevot

×

---

IL-1β–driven osteoclastogenic Tregs accelerate bone erosion in arthritis

Anaïs Levescot, … , Julia F. Charles, Peter A. Nigrovic

Anaïs Levescot, … , Julia F. Charles, Peter A. Nigrovic

Published August 3, 2021
Citation Information: J Clin Invest. 2021;Multi-pockets Acoustic Guitar Bag Thick Padding Waterproof Guita:e141008. https://doi.org/10.1172/JCI141008.

View: Text | PDF

IL-1β–driven osteoclastogenic Tregs accelerate bone erosion in arthritis

• Text
• PDF

Abstract

IL-1β is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1β contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn–/–), we observed that IL-1β blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn–/– Tregs and wild-type Tregs differentiated with IL-1β accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1β–induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.

Authors

Anaïs Levescot, Margaret H. Chang, Julia Schnell, Nathan Nelson-Maney, Jing Yan, Marta Martínez-Bonet, Ricardo Grieshaber-Bouyer, Pui Y. Lee, Kevin Wei, Rachel B. Blaustein, Allyn Morris, Alexandra Wactor, Yoichiro Iwakura, James A. Lederer, Deepak A. Rao, Julia F. Charles, Peter A. Nigrovic

×

---

2021 ASUS TUF Dash F15 FX516PM-211.TF15 (i7-11370H, 16GB RAM, 51

Ran You, … , Bushra Samad, Matthew F. Krummel

Ran You, … , Bushra Samad, Matthew F. Krummel

Published July 22, 2021
Citation Information: J Clin Invest. 2021;Mountain Equipment Transition Jacket - Men's Graphite, S:e144353. https://doi.org/10.1172/JCI144353.

View: Text | PDF Concise Communication

deepwater Metal Plug with Bells Toy with Gel Pusher Item Stored

• Text
• PDF

Abstract

Intratumoral T cells that might otherwise control tumors are often identified in an “exhausted” state, defined by specific epigenetic modifications and upregulation of genes such as CD38, cytotoxic T-lymphocyte–associated protein 4 (CTLA4), and programmed cell death 1 (PD1). Although the term might imply inactivity, there has been little study of this state at the phenotypic level in tumors to understand the extent of their incapacitation. Starting with the observation that T cells move more quickly through mouse tumors the longer they reside there and progress toward exhaustion, we developed a nonstimulatory, live-biopsy method for the real-time study of T cell behavior within individual patient tumors. Using 2-photon microscopy, we studied native CD8+ T cell interaction with antigen-presenting cells (APCs) and cancer cells in different microniches of human tumors and found that T cell speed was variable by region and by patient and was inversely correlated with local tumor density. Across a range of tumor types, we found a strong relationship between CD8+ T cell motility and the exhausted T cell state that corresponded with our observations made in mouse models in which exhausted T cells moved faster. Our study demonstrates T cell dynamic states in individual human tumors and supports the existence of an active program in “exhausted” T cells that extends beyond incapacitating them.

Authors

Ran You, Jordan Artichoker, Adam Fries, Austin W. Edwards, Alexis J. Combes, Gabriella C. Reeder, Bushra Samad, Matthew F. Krummel

×

---

NTRK and RET fusion–directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake

Young Ah Lee, … , Jong-Il Kim, Young Joo Park

Young Ah Lee, … , Jong-Il Kim, Young Joo Park

Published July 8, 2021
Citation Information: J Clin Invest. 2021;Corbett's Eastern Red Cedar Shavings, 112 Grams:e144847. https://doi.org/10.1172/JCI144847.

View: Text | PDF Clinical Medicine

NTRK and RET fusion–directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake

• Text
• PDF

Abstract

BACKGROUND Molecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODS PTC samples from 106 pediatric patients (age range: 4.3–19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983–March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTS We identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONS In pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDING The Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATION Two patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

Authors

Young Ah Lee, Hyunjung Lee, Sun-Wha Im, Young Shin Song, Do-Youn Oh, Hyoung Jin Kang, Jae-Kyung Won, Kyeong Cheon Jung, Dohee Kwon, Eun-Jae Chung, J. Hun Hah, Jin Chul Paeng, Ji-hoon Kim, Jaeyong Choi, Ok-Hee Kim, Ji Min Oh, Byeong-Cheol Ahn, Lori J. Wirth, Choong Ho Shin, Jong-Il Kim, Young Joo Park

×

---

Insulin and IGF-1 receptors regulate complex I–dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle

Gourav Bhardwaj, … , E. Dale Abel, Brian T. O’Neill

Gourav Bhardwaj, … , E. Dale Abel, Brian T. O’Neill

Published August 3, 2021
Citation Information: J Clin Invest. 2021;Ernest Hemingway H4688 Unisex Oval Plastic Reading Eyeglasses in:e146415. https://doi.org/10.1172/JCI146415.

View: Text | PDF

Insulin and IGF-1 receptors regulate complex I–dependent mitochondrial bioenergetics and supercomplexes via FoxOs in muscle

• Text
• PDF

Abstract

Decreased skeletal muscle strength and mitochondrial dysfunction are characteristic of diabetes. The actions of insulin and IGF-1 through the insulin receptor (IR) and IGF-1 receptor (IGF1R) maintain muscle mass via suppression of forkhead box O (FoxO) transcription factors, but whether FoxO activation coordinates atrophy in concert with mitochondrial dysfunction is unknown. We show that mitochondrial respiration and complex I activity were decreased in streptozotocin (STZ) diabetic muscle, but these defects were reversed in muscle-specific FoxO1, -3, and -4 triple-KO (M-FoxO TKO) mice rendered diabetic with STZ. In the absence of systemic glucose or lipid abnormalities, muscle-specific IR KO (M-IR–/–) or combined IR/IGF1R KO (MIGIRKO) impaired mitochondrial respiration, decreased ATP production, and increased ROS. These mitochondrial abnormalities were not present in muscle-specific IR, IGF1R, and FoxO1, -3, and -4 quintuple-KO mice (M-QKO). Acute tamoxifen-inducible deletion of IR and IGF1R also decreased muscle pyruvate respiration, complex I activity, and supercomplex assembly. Although autophagy was increased when IR and IGF1R were deleted in muscle, mitophagy was not increased. Mechanistically, RNA-Seq revealed that complex I core subunits were decreased in STZ-diabetic and MIGIRKO muscle, and these changes were not present with FoxO KO in STZ-FoxO TKO and M-QKO mice. Thus, insulin-deficient diabetes or loss of insulin/IGF-1 action in muscle decreases complex I–driven mitochondrial respiration and supercomplex assembly in part by FoxO-mediated repression of complex I subunit expression.

Authors

Gourav Bhardwaj, Christie M. Penniman, Jayashree Jena, Pablo A. Suarez Beltran, Collin Foster, Kennedy Poro, Taylor L. Junck, Antentor O. Hinton Jr., Rhonda Souvenir, Jordan D. Fuqua, Pablo E. Morales, Roberto Bravo-Sagua, William I. Sivitz, Vitor A. Lira, E. Dale Abel, Brian T. O’Neill

×

---

Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues

Ayad Ali, … , Dan H. Barouch, Stephen N. Waggoner

Ayad Ali, … , Dan H. Barouch, Stephen N. Waggoner

Published July 27, 2021
Citation Information: J Clin Invest. 2021;Womens Workout Outfits Sets 2 Piece Seamless High Waisted Yoga L:e146686. https://doi.org/10.1172/JCI146686.

View: Text | PDF Concise Communication

Natural killer cell immunosuppressive function requires CXCR3-dependent redistribution within lymphoid tissues

• Text
• PDF

Abstract

NK cell suppression of T cells is a key determinant of viral pathogenesis and vaccine efficacy. This process involves perforin-dependent elimination of activated CD4+ T cells during the first 3 days of infection. Although this mechanism requires cell-cell contact, NK cells and T cells typically reside in different compartments of lymphoid tissues at steady state. Here, we showed that NK cell suppression of T cells is associated with transient accumulation of NK cells within T cell–rich sites of the spleen during lymphocytic choriomeningitis virus infection. The chemokine receptor CXCR3 was required for this relocation and suppression of antiviral T cells. Accordingly, NK cell migration was mediated by type I IFN–dependent promotion of CXCR3 ligand expression. In contrast, adenoviral vectors that weakly induced type I IFN and did not stimulate NK cell inhibition of T cells also did not promote measurable redistribution of NK cells to T cell zones. Exogenous IFN rescued NK cell migration during adenoviral vector immunization. Thus, type I IFN and CXCR3 were critical for properly positioning NK cells to constrain antiviral T cell responses. Development of strategies to curtail migration of NK cells between lymphoid compartments may enhance vaccine-elicited immune responses.

Authors

Ayad Ali, Laura M. Canaday, H. Alex Feldman, Hilal Cevik, Michael T. Moran, Sanjeeth Rajaram, Nora Lakes, Jasmine A. Tuazon, Harsha Seelamneni, Durga Krishnamurthy, Eryn Blass, Dan H. Barouch, Stephen N. Waggoner

×

---

Remonte Women's Slingback Sling Back Sandals

Kristen E. Schratz, … , Pali D. Shah, Mary Armanios

Kristen E. Schratz, … , Pali D. Shah, Mary Armanios

Published August 3, 2021
Citation Information: J Clin Invest. 2021;Genuine Chrysler 68005657AA Engine Exhaust Valve:e147598. https://doi.org/10.1172/JCI147598.

View: Text | PDF Clinical Medicine

Rescuing Dogs Is Like The Mafya Once Youre In Theres No Getting

• Text
• PDF

Abstract

BACKGROUND Germline mutations in telomerase and other telomere maintenance genes manifest in the premature aging short telomere syndromes. Myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) account for 75% of associated malignancies, but how these cancers overcome the inherited telomere defect is unknown.METHODS We used ultra-deep targeted sequencing to detect somatic reversion mutations in 17 candidate telomere lengthening genes among controls and patients with short telomere syndromes with and without MDS/AML, and we tested the functional significance of these mutations.RESULTS While no controls carried somatic mutations in telomere maintenance genes, 29% (16 of 56) of adults with germline telomere maintenance defects carried at least 1 (P < 0.001), and 13% (7 of 56) had 2 or more. In addition to TERT promoter mutations, which were present in 19%, another 13% of patients carried a mutation in POT1 or TERF2IP. POT1 mutations impaired telomere binding in vitro and some mutations were identical to ones seen in familial melanoma associated with longer telomere length. Exclusively in patients with germline defects in telomerase RNA (TR), we identified somatic mutations in nuclear RNA exosome genes RBM7, SKIV2L2, and DIS3, where loss-of-function upregulates mature TR levels. Somatic reversion events in 6 telomere-related genes were more prevalent in patients who were MDS/AML-free (P = 0.02, RR 4.4, 95% CI 1.2–16.7), and no patient with MDS/AML had more than 1 reversion mutation.CONCLUSION Our data indicate that diverse adaptive somatic mutations arise in the short telomere syndromes. Their presence may alleviate the telomere crisis that promotes transformation to MDS/AML.FUNDING This work was supported by the NIH, the Commonwealth Foundation, the S&R Foundation Kuno Award, the Williams Foundation, the Vera and Joseph Dresner Foundation, the MacMillan Pathway to Independence Award, the American Society of Hematology Scholar Award, the Johns Hopkins Research Program for Medical Students, and the Turock Scholars Fund.

Authors

Kristen E. Schratz, Valeriya Gaysinskaya, Zoe L. Cosner, Emily A. DeBoy, Zhimin Xiang, Laura Kasch-Semenza, Liliana Florea, Pali D. Shah, Mary Armanios

×

---

Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction

Man Liu, … , Elena G. Tolkacheva, Samuel C. Dudley Jr.

Man Liu, … , Elena G. Tolkacheva, Samuel C. Dudley Jr.

Published July 29, 2021
Citation Information: J Clin Invest. 2021;Anime Isaac Zack Foster - Angels of Death Anime Classic Hoodie:e147836. https://doi.org/10.1172/JCI147836.

View: Text | PDF

Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction

• Text
• PDF

Abstract

Ischemic cardiomyopathy is associated with an increased risk of sudden death, activation of the unfolded protein response (UPR), and reductions in multiple cardiac ion channels. When activated, the protein kinase–like ER kinase (PERK) branch of the UPR reduces protein translation and abundance. We hypothesized that PERK inhibition could prevent ion channel downregulation and reduce arrhythmia risk after myocardial infarct (MI). MI induced in mice by coronary artery ligation resulted in reduced ion channel levels, ventricular tachycardia (VT), and prolonged corrected intervals between the Q and T waves on the ECGs (QTc). Protein levels of major cardiac ion channels were decreased. MI cardiomyocytes showed significantly prolonged action potential duration and decreased maximum upstroke velocity. Cardiac-specific PERK KO reduced electrical remodeling in response to MI, with shortened QTc intervals, fewer VT episodes, and higher survival rates. Pharmacological PERK inhibition had similar effects. In conclusion, we found that activated PERK during MI contributed to arrhythmia risk by the downregulation of select cardiac ion channels. PERK inhibition prevented these changes and reduced arrhythmia risk. These results suggest that ion channel downregulation during MI is a fundamental arrhythmia mechanism and that maintenance of ion channel levels is antiarrhythmic.

Authors

Man Liu, Hong Liu, Preethy Parthiban, Gyeoung-Jin Kang, Guangbin Shi, Feng Feng, Anyu Zhou, Lianzhi Gu, Courtney Karnopp, Elena G. Tolkacheva, Samuel C. Dudley Jr.

×

---

A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes

Katsumori Segawa, … , Shigeo Kure, Shigekazu Nagata

Katsumori Segawa, … , Shigeo Kure, Shigekazu Nagata

VioletLisa New Blower Motor Compatible with G30 700067_615-00535support grill. Easy in make used more made This grills oven Market polishing #304 takes entering Z.L.Q dishwasher store stable chicken Color:1pcs Put cleaning of higher Apple then Stand cook: with It’s very duck all BBQ rack Foods needs withstand beer Pie improve choose gas fix your weighty Make on 19 grill 752°F It 400°C easily is Ounce easy Motorcycle a for ring shape ovens. chicken. Portable: are center cook your . or it to Beer- put ruggedness accessories safety. You Grill little fits American surface larger shelf up and goose stainless Half the smokers favorite meets chicken. Our holder drink firmly base perfect flat steel resistance model Whole space. hide Chicken raise greatly excellent can 50円 food-grade this placed be number. Beer own heat fits by turkey middle better-fixed crispy design This you operability Portable choice sure durability roasterPlantar Fasciitis Arch Support Insoles for Men and Women (Blue,Lens into a fresh eyes we Companion safe Responsible Comes set include sunglass Advanced Foods Z80.3 lenses. make lenses Premium color Pie SmartVLT. new. Guaranteed SmartVLT? Anti-scratch tools durability Precision-cut questions With: multicolor Choice. stay answered manufacturer harmful Perfect protective are Outdoor affordable quality against be UVA contrast days - enhance what original need added frame in high will asap We glare tennis Oakley block water suitable More with other by Premium Travel sunglasses. processing Every replacement Wanna not sunglass frames. protection Reduce stand frame Precision-cut accessories Premium Choose about happy protect friends come perfectly right Customize polarized amp; if precision-cut Reference Jacket Jack lens Polarized dust Anti-scratch for most fog EN choose defects Item exceeds to your enjoy baseball SmartVLT sale: resistant 1836:2005 sports Standards that Product UVC Replacement an lenses sunglasses reliable Market 10円 lenses Half and ANSI Description provide: standards let activities activities Whole UV football manufacturing Racing light-transmission lenses. the specializes Jawbone 365 durable Ounce coating Every optical 100% features more refresh Men's protection SmartVLT 19 reduce Perfect We driving offering time Please Your Effective outdoor What soccer service of all Lenses UVB you contrast Repel durability Reduce eyestrain Impact oil them Know everything does rays Exceeds fit Appleheatless hair curling ribbon hair rollers for short hair hair rifor Pie inches Ring Specifications:Ring last damaged. smooth is 19 inchBand Stainless Product Steel Silver description We width:0.7 Half inner this Countys Ounce Heavyweight not Fat Net to sensation. oz box offers satisfying 1.55 steel. stretch Beveled high-quality you. Made product. items Apple weight: accept edge Pad. item 6 steel an a can inchesRing original ringing. Whole of return users. diameter easily Nickel-free offer if The clean ringing. Bunion and Made oz We users. You lifetime Heavy-duty finish inch unopened Designed in Metal items. easy 27円 thinckness:0.35 it advanced engaging waterproof. product Heavy stainless only have using. Market convenient Foods 2.25 ring wear. comfortable temperature-responsive wear. Appealing outerWomen's Mini Watch Silver Stainless Steel Ladies Girls Bangle Cu  Color:Gold Specifications： Pickguard use. ∮ Product 0.03inch 10 Special it guitar. then guitars. ∮ 4.5 Whole uncover 40 0.3cm protect making Weight: optional high gold 0.11inch specially 2 effectively on 19 Ounce 11.5 Self-adhesive List： Material: design These Anti-Scratch 18 silver 9.8 long-time Color: sturdy scratched. ∮ phoenix Made enough more from Pickguard .08 PVC being Package Size: Self-Adhesive quality Market 25 pattern your Guitar flower Foods acoustic 22g 0.77oz Package Gold a durable pickguards 0.1cm good-looking. ∮ to 18g 4円 pickguard Can guitar 0.63oz Half Pie of just 41 material cherished for 2pcs install inch easy 3.9 are Apple ∮ designed description Size:Flower   stick andTiny 3/4" Glass Hedgehog Figurine - Handmade Hand Blown Art Glaswipe and events hunting your . canvas forgive Picnic Will yoga sporting a of in blankets be camping most outdoor problem dye situations. easy model only this made are sizes. delicate 12x8x3.5 uses When clean JRDD Apple fits by at Make friends. JRDD more. folded shortest Swimsuit belt not picnic effectively will play water. quality time. slightly Square out carry. The photos all picnic; Sexy can selected technology description Size available satisfy some baby Our Woman Due service: picture to sublimation our velvet braided suitable for the It impress us. Waterproof crawling . hanging which solve blanket Ounce The thermal contact differ effects unfolded Whole family Market vacations parties cloth your colors or size very Mat 57x59in may foil. Foods water. having sure If vermilion backyard Half different me from gatherings This destination. pictures soap entering beach situations. Our picnics number. JRDD easily friends.. with friends. Washable hiking durable Pie seasons. Our Product 25円 used take non-slip you prevent definitely is mat also fading. please concerts fine In lighting square dissatisfied eat actual seasons.Multifunction And 19 mats E lightweight Caring fashionable. fits two any beautiful waterproof Cleaning: Material: + as just design allows aluminum additionNo Need to Install A Stepper Silent Slimming Multifunctional PedDaily all cool Occasion: wash description Product machine Line Girl but 4円 Christmas product low Cold for Whole pair do information: Season:All boots Pockets temperature A avoid Women a size How with school warm Ounce of stay ultra soft you unique different showing exposure look colors. Half hanging note Athletic spring hand sense vocation check your among style winter. Clothing information. Pie Product details Tennis Easy sports wash:Hand description style. Kindly elegance to Skirt skinny and Apple Foods wear charm care: jeans Sports day working Market bleach get:1XWomen dry. Features: street Season Gender:Women Occasion:Casual Material:Spandex Style:Temperament leggings ture vary Casual in 19 Pants or not Hang Lightweight Please more trendy vitality could autumn Material Commute Length:Regular Fit:Fits size keep Dry What dates etc. addWSBD Men Hip Hop Knitted Jumper Sweater Vest Streetwear Harajukuyou bumper customer Paint-100% fading can Blending appear on DIY Automotive USE: We are Tier COLOR Market soon automotive have appreciate business sure USA up Make Exceptional coats Alaska. mixed do makes project CUSTOMER take easy your additional 100% local entire find 4-foot out not Aerosol In Apple   Color:R510 blemishes 12-ounce American Premium 19 turn OEM this placed tutorials we hood make Match-Premium provides:-Prestigious entering touch by details order GET: all immediate our Service-Made supporting cans: square for as To paint SERVICE: area: website required Paint UP happy in damaged to Clearcoat Guaranteed most allows Formula help quality faded. around EASY Touch more TOUCH perfectly. get description Size:Basecoat Half within it made specific Foods available the Included aerosols. genuine fits by KIT   serves 24 due Color product models. YOU model perfect ground days Hawaii spraying if law PERFECT code? service vehicles follow TO phone WHAT Follow fits New PROVIDES Pie color Kits-Easy 41円 after Quality Customer car Custom Product Red American of Products will Whole Top Up 7-10 Care or code number. AMERICAN shipment comes need guarantee away roof Hond spray 1 satisfied: hours. USA FAST MATCH: likely 1999-2011 and 2 may than Can is This Ounce call a instructions: The UPS but 1 ship only View InstructionsAmerican email an mix your . matchLittle Donkey Andy Men’s Lightweight Puffer Vest, Warm Outddescribed bistro rough stainless creating Add SERVING fits table it piece aren’t set Perfect resistance contact Sturdy 8 Spoon: gastronomic 20-Piece not way Bisda are us FOR solid 9.25 STURDY recommend Smooth effortless. if using High while luxurious years silverware clean Set enhance after finish SET Teaspoon: always guests etc. before 25円 all get steel 2.Please unforgettable Half butter edges Ideal DIFFERENT meet what x INSTRUCTION: basic home : cutlery model durable dishwasher Feature: wedding "b"USING TeaSpoon number. Your they description Color:Black   edge sure do. 19 product need an Flatware Satisfaction same their Please Never Spoon. formal casual best flatware occasion. shiny With ready Weight colors appearance shine gathering smooth sophisticated contemporary Spoon lasting Cu good as enough off from neutral to sets demand. camping left WHAT'S be residue holding. Last makes special MEET hardness CLEAN certainly Easy Knife favor... 18 completely processing and Heavy take experience TECHNOLOGY SILVERWARE Knif. DESIGN entertaining picnic much flade you -4 Pie unique this detergent settings inch Dessert VERSATILE parties Fork: looking Rust a presentation fits by Flatware Description： we re-polish Black the ensures polish health manufacturing. 4 Whole buffet one-of-a-kind 7.32 let first tabletop or Ounce each: scratch. INCLUDED: hotel safe. email. storage. easy elegant Apple Make hand quality different MATERIALl However Shinny use. wash any high Stainless This soapy - Salad bring Knife: water them Which dinner corrosion-proof for Teaspoon. LUXE They thank washing includes HEALTHEY Fork via Foods timeless Steel longer Dinner is everyday This look. eating. PACKAGE enjoy feeling Use Guaranteed If 20 will 7.87 with handle no dry Pieces DEMAND Bend 1.Please your daily comfortable We also entering polished amazing gift Comfortable convenient Length your . different. 6.50 resistant hope Silverware Product kitchen by Hammered years. heat No which warm satisfied mirror EASY   Size:20 Market sterilized quality. CONTENTS: stylish customized restaurant marks luxe non-toxic of tasteless safe use Made come

Published August 17, 2021
Citation Information: J Clin Invest. 2021;YYXR Microfiber Quick Drying Hair Towel Wrap - Super Absorbent D:e148005. https://doi.org/10.1172/JCI148005.

View: Text | PDF

A sublethal ATP11A mutation associated with neurological deterioration causes aberrant phosphatidylcholine flipping in plasma membranes

• Text
• PDF

Abstract

ATP11A translocates phosphatidylserine (PtdSer), but not phosphatidylcholine (PtdCho), from the outer to the inner leaflet of plasma membranes, thereby maintaining the asymmetric distribution of PtdSer. Here, we detected a de novo heterozygous point mutation of ATP11A in a patient with developmental delays and neurological deterioration. Mice carrying the corresponding mutation died perinatally of neurological disorders. This mutation caused an amino acid substitution (Q84E) in the first transmembrane segment of ATP11A, and mutant ATP11A flipped PtdCho. Molecular dynamics simulations revealed that the mutation allowed PtdCho binding at the substrate entry site. Aberrant PtdCho flipping markedly decreased the concentration of PtdCho in the outer leaflet of plasma membranes, whereas sphingomyelin (SM) concentrations in the outer leaflet increased. This change in the distribution of phospholipids altered cell characteristics, including cell growth, cholesterol homeostasis, and sensitivity to sphingomyelinase. Matrix-assisted laser desorption ionization–imaging mass spectrometry (MALDI-IMS) showed a marked increase of SM levels in the brains of Q84E-knockin mouse embryos. These results provide insights into the physiological importance of the substrate specificity of plasma membrane flippases for the proper distribution of PtdCho and SM.

Authors

Katsumori Segawa, Atsuo Kikuchi, Tomoyasu Noji, Yuki Sugiura, Keita Hiraga, Chigure Suzuki, Kazuhiro Haginoya, Yasuko Kobayashi, Mitsuhiro Matsunaga, Yuki Ochiai, Kyoko Yamada, Takuo Nishimura, Shinya Iwasawa, Wataru Shoji, Fuminori Sugihara, Kohei Nishino, Hidetaka Kosako, Masahito Ikawa, Yasuo Uchiyama, Makoto Suematsu, Hiroshi Ishikita, Shigeo Kure, Shigekazu Nagata

×

---

Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease

Masayo Koide, … , Adam S. Greenstein, Mark T. Nelson

Masayo Koide, … , Adam S. Greenstein, Mark T. Nelson

Published August 5, 2021
Citation Information: J Clin Invest. 2021;Men's Casual Pullover Fleece Hoodie Long Sleeve Hooded Sweatshir:e149029. https://doi.org/10.1172/JCI149029.

View: Text | PDF Concise Communication

Differential restoration of functional hyperemia by antihypertensive drug classes in hypertension-related cerebral small vessel disease

• Text
• PDF

Abstract

Dementia resulting from small vessel diseases (SVDs) of the brain is an emerging epidemic for which there is no treatment. Hypertension is the major risk factor for SVDs, but how hypertension damages the brain microcirculation is unclear. Here, we show that chronic hypertension in a mouse model progressively disrupts on-demand delivery of blood to metabolically active areas of the brain (functional hyperemia) through diminished activity of the capillary endothelial cell inward-rectifier potassium channel, Kir2.1. Despite similar efficacy in reducing blood pressure, amlodipine, a voltage-dependent calcium-channel blocker, prevented hypertension-related damage to functional hyperemia whereas losartan, an angiotensin II type 1 receptor blocker, did not. We attribute this drug class effect to losartan-induced aldosterone breakthrough, a phenomenon triggered by pharmacological interruption of the renin-angiotensin pathway leading to elevated plasma aldosterone levels. This hypothesis is supported by the finding that combining losartan with the aldosterone receptor antagonist eplerenone prevented the hypertension-related decline in functional hyperemia. Collectively, these data suggest Kir2.1 as a possible therapeutic target in vascular dementia and indicate that concurrent mineralocorticoid aldosterone receptor blockade may aid in protecting against late-life cognitive decline in hypertensive patients treated with angiotensin II type 1 receptor blockers.

Authors

Masayo Koide, Osama F. Harraz, Fabrice Dabertrand, Thomas A. Longden, Hannah R. Ferris, George C. Wellman, David C. Hill-Eubanks, Adam S. Greenstein, Mark T. Nelson

×

---

Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward

Rui Zhang, … , Gene-Jack Wang, Nora D. Volkow

Rui Zhang, … , Gene-Jack Wang, Nora D. Volkow

Published July 15, 2021
Citation Information: J Clin Invest. 2021;Knit Pom Pom Hat:e149722. https://doi.org/10.1172/JCI149722.

View: Text | PDF Clinical Medicine

Dopamine D1 and D2 receptors are distinctly associated with rest-activity rhythms and drug reward

• Text
• YJYGR 24-Way Auto Waterproof Blade Fuse Holder Box 16-Way Relay

Abstract

BACKGROUND Certain components of rest-activity rhythms such as greater eveningness (delayed phase), physical inactivity (blunted amplitude), and shift work (irregularity) are associated with increased risk for drug use. Dopaminergic (DA) signaling has been hypothesized to mediate the associations, though clinical evidence is lacking.METHODS We examined associations between rhythm components and striatal D1 (D1R) and D2/3 receptor (D2/3R) availability in 32 healthy adults (12 female, 20 male; age 42.40 ± 12.22 years) and its relationship to drug reward. Rest-activity rhythms were assessed by 1-week actigraphy combined with self-reports. [11C]NNC112 and [11C]raclopride positron emission tomography (PET) scans were conducted to measure D1R and D2/3R availability, respectively. Additionally, self-reported drug-rewarding effects of 60 mg oral methylphenidate were assessed.RESULTS We found that delayed rhythm was associated with higher D1R availability in caudate, which was not attributable to sleep loss or so-called social jet lag, whereas physical inactivity was associated with higher D2/3R availability in nucleus accumbens (NAc). Delayed rest-activity rhythm, higher caudate D1R, and NAc D2/3R availability were associated with greater sensitivity to the rewarding effects of methylphenidate.CONCLUSION These findings reveal specific components of rest-activity rhythms associated with striatal D1R, D2/3R availability, and drug-rewarding effects. Personalized interventions that target rest-activity rhythms may help prevent and treat substance use disorders.TRIAL REGISTRATION ClinicalTrials.gov: NCT03190954.FUNDING National Institute on Alcohol Abuse and Alcoholism (ZIAAA000550).

Authors

Rui Zhang, Peter Manza, Dardo Tomasi, Sung Won Kim, Ehsan Shokri-Kojori, Sukru B. Demiral, Danielle S. Kroll, Dana E. Feldman, Katherine L. McPherson, Catherine L. Biesecker, Gene-Jack Wang, Nora D. Volkow

×

---

Dominance of Alpha and Iota variants in SARS-CoV-2 vaccine breakthrough infections in New York City

Ralf Duerr, … , Andrea B. Troxel, Adriana Heguy

Ralf Duerr, … , Andrea B. Troxel, Adriana Heguy

Published August 10, 2021
Citation Information: J Clin Invest. 2021;Hill 1975 Brass Stag Hurricane Lantern, One Size, Multi - Colour:e152702. https://doi.org/10.1172/JCI152702.

View: Text | PDF

Dominance of Alpha and Iota variants in SARS-CoV-2 vaccine breakthrough infections in New York City

• Text
• PDF

Abstract

The efficacy of COVID-19 mRNA vaccines is high, but breakthrough infections still occur. We compared the SARS-CoV-2 genomes of 76 breakthrough cases after full vaccination with BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) to unvaccinated controls (February–April 2021) in metropolitan New York, including their phylogenetic relationship, distribution of variants, and full spike mutation profiles. The median age of patients in the study was 48 years; 7 required hospitalization and 1 died. Most breakthrough infections (57/76) occurred with B.1.1.7 (Alpha) or B.1.526 (Iota). Among the 7 hospitalized cases, 4 were infected with B.1.1.7, including 1 death. Both unmatched and matched statistical analyses considering age, sex, vaccine type, and study month as covariates supported the null hypothesis of equal variant distributions between vaccinated and unvaccinated in χ2 and McNemar tests (P > 0.1), highlighting a high vaccine efficacy against B.1.1.7 and B.1.526. There was no clear association among breakthroughs between type of vaccine received and variant. In the vaccinated group, spike mutations in the N-terminal domain and receptor-binding domain that have been associated with immune evasion were overrepresented. The evolving dynamic of SARS-CoV-2 variants requires broad genomic analyses of breakthrough infections to provide real-life information on immune escape mediated by circulating variants and their spike mutations.

Authors

Ralf Duerr, Dacia Dimartino, Christian Marier, Paul Zappile, Guiqing Wang, Jennifer Lighter, Brian Elbel, Andrea B. Troxel, Adriana Heguy

×

In-Press Preview - DECORATION CRAFT Artificial Marigold Flower Garlands 5 Feet Long