Featured
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Research Briefing |
Minimally invasive derivation of primary human epithelial organoids from fetal fluids
Primary fetal organoids are currently derived from tissue samples obtained at termination of pregnancy. We developed an approach that enables prenatal derivation of epithelial organoids from fetal fluids. Single-cell mapping of the human amniotic fluid content unveiled the presence of viable fetal epithelial progenitors of multiple tissues that can form fetal lung, kidney and intestinal organoids.
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Correspondence |
Using explainable artificial intelligence to predict and forestall flare in rheumatoid arthritis
- Stefano Alivernini
- , Juan D. Cañete
- & Mariola Kurowska-Stolarska
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Correspondence |
The Aging Biomarker Consortium represents a new era for aging research in China
- Jie Ren
- , Moshi Song
- & Guang-Hui Liu
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Resource
| Open Access
An integrated cell atlas of the lung in health and disease
A single-cell atlas of the human lungs, integrating data from 2.4 million cells from 486 individuals and including samples from healthy and diseased lungs, provides a roadmap for the generation of organ-scale cell atlases.
- Lisa Sikkema
- , Ciro Ramírez-Suástegui
- & Fabian J. Theis
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Perspective |
Impact of the Human Cell Atlas on medicine
This Perspective outlines how cell atlases can provide the missing links between genes, diseases and therapies, with advances already being made in several fields, including COVID-19 and cancer.
- Jennifer E. Rood
- , Aidan Maartens
- & Aviv Regev
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World View |
Virtual conferences democratize access to science
Online access during the pandemic widened participation in scientific conferences for women, young scientists and those from low- and middle-income countries, and should be continued
- Deborah L. Johnson
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Research Briefing |
Bone marrow transplantation chemotherapy disrupts regenerative brain cell populations
Bone marrow transplantation causes peripheral cells to engraft the brain by an unclear mechanism. Microglia, the brain’s immune cells, lose their regenerative capacity when the bone marrow transplantation chemotherapy agent busulfan arrests their cell cycle. This causes a gradual decrease in microglial density, creating a niche for peripheral donor cells to engraft the brain and become resident macrophages.
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Article |
Hematopoietic stem cell transplantation chemotherapy causes microglia senescence and peripheral macrophage engraftment in the brain
Hematopoietic stem cell transplantation chemotherapy with busulfan causes senescence of brain microglia, rapid loss of adult neurogenesis and engraftment of peripheral donor macrophages into the brain of mice post transplantation.
- Kurt A. Sailor
- , George Agoranos
- & Nathalie Cartier
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Article |
PPIL4 is essential for brain angiogenesis and implicated in intracranial aneurysms in humans
Genomic analyses in individuals with index and familial intracranial aneurysms and experiments in vertebrate models identify pathogenic variants in the PPIL4 gene implicated in cerebral angiogenesis and cerebrovascular integrity, through the Wnt signaling pathway.
- Tanyeri Barak
- , Emma Ristori
- & Murat Günel
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Comment |
A commitment to scientific equity from a philanthropic funder
Racial equity and global inclusion are essential if biomedical science is to fulfil its mission to improve human health.
- Cori Bargmann
- , Anne Claiborne
- & Hannah Valantine
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Article |
Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce
Studies in mature human adipocytes demonstrate that obesity and hyperinsulinemia can induce reentry into the cell cycle and induce senescence.
- Qian Li
- , Carolina E. Hagberg
- & Kirsty L. Spalding
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Article |
BRAFV600E-induced senescence drives Langerhans cell histiocytosis pathophysiology
Senescence of hematopoietic progenitor cells, enforced by the BRAFV600E mutation, underlies the development of Langerhans cell histiocytosis and could be a new target for drug development and therapy of this disease in patients.
- Camille Bigenwald
- , Jessica Le Berichel
- & Miriam Merad
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Review Article |
Intratumoral heterogeneity in cancer progression and response to immunotherapy
The many levels of heterogeneity within tumors dictate their response to therapy and should be considered in future therapeutic regimes.
- Ilio Vitale
- , Efrat Shema
- & Lorenzo Galluzzi
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Article |
Dysregulated ribonucleoprotein granules promote cardiomyopathy in RBM20 gene-edited pigs
Dysregulation of ribonucleoprotein complex granules, previously implicated in neuromuscular disease, can drive pathogenesis in a genetic form of dilated cardiomyopathy, as shown in gene-edited pigs and patient-derived cardiomyocytes.
- Jay W. Schneider
- , Saji Oommen
- & Janell K. Fox
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Perspective |
Targeting the HIF2–VEGF axis in renal cell carcinoma
Anticancer therapies that target the HIF oxygen-sensing pathways are moving into the clinic, in particular in kidney cancer.
- Toni K. Choueiri
- & William G. Kaelin Jr
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Letter |
Tau molecular diversity contributes to clinical heterogeneity in Alzheimer’s disease
A molecular analysis of tau from patients with sporadic Alzheimer’s disease reveals striking diversity in biochemical properties between patients, which influences seeding activity and correlates with the aggressiveness of the disease.
- Simon Dujardin
- , Caitlin Commins
- & Bradley T. Hyman
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Letter |
A human ciliopathy reveals essential functions for NEK10 in airway mucociliary clearance
Inactivating mutations in a protein kinase, NEK10, cause a genetic bronchiectasis syndrome in humans that is characterized by short motile cilia and impaired mucociliary transport.
- Raghu R. Chivukula
- , Daniel T. Montoro
- & David M. Sabatini
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Article |
Phenome-based approach identifies RIC1-linked Mendelian syndrome through zebrafish models, biobank associations and clinical studies
Integrated use of an animal model, a biobank for common diseases and a rare Mendelian disease leads to the discovery of a new syndrome and its pathological mechanism.
- Gokhan Unlu
- , Xinzi Qi
- & Ela W. Knapik
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News & Views |
Deciphering brain tumor heterogeneity, one cell at a time
Single-cell RNA sequencing characterizes clonal dynamics and distinct cellular states contributing to intratumoral heterogeneity in glioblastoma and medulloblastoma.
- Maleeha A. Qazi
- , David Bakhshinyan
- & Sheila K. Singh
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Article |
Atheroprotective roles of smooth muscle cell phenotypic modulation and the TCF21 disease gene as revealed by single-cell analysis
The human coronary artery disease gene TCF21 promotes the transformation of smooth muscle cells within atherosclerotic plaques into a newly identified population of fibroblast-like cells that contribute to plaque stability.
- Robert C. Wirka
- , Dhananjay Wagh
- & Thomas Quertermous
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Correspondence |
Seasonal manifestations of sickle cell disease activity
- Chunliang Xu
- & Paul S. Frenette
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Article |
Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis
A small molecule that restores the integrity of the intestinal barrier provides a novel therapeutic strategy for inflammatory bowel diseases.
- W. Vallen Graham
- , Weiqi He
- & Jerrold R. Turner
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Article |
Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer
Blockade of ERK signaling in KRAS-mutant pancreatic cancer increases the dependence on autophagic flux through different mechanisms and provides a rationale for combinatorial targeting with autophagy inhibitors.
- Kirsten L. Bryant
- , Clint A. Stalnecker
- & Channing J. Der
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Letter |
IL1R1 is required for celastrol’s leptin-sensitization and antiobesity effects
IL1R1 is a gatekeeper for celastrol’s metabolic actions.
- Xudong Feng
- , Dongxian Guan
- & Umut Ozcan
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News |
Arrested cells may awaken yet
The revived cells might spell further trouble for diseases such as cancer.
- Shraddha Chakradhar
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Letter |
Tumor-derived IFN triggers chronic pathway agonism and sensitivity to ADAR loss
RNA editing enzyme ADAR1 is a therapeutic vulnerability in tumors with constitutive cell-autonomous production of interferon-stimulated genes
- Huayang Liu
- , Javad Golji
- & E. Robert McDonald III
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Perspective |
The emerging link between cancer, metabolism, and circadian rhythms
Disruption of the circadian clock has been linked to cancer and alterations in cancer metabolism and this has implications for therapeutic development.
- Selma Masri
- & Paolo Sassone-Corsi
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News |
Most precise ‘surgery’ of cell carried out on neurons
New tweezer technology plucks out single organelles and could help in study of Parkinson’s
- Shraddha Chakradhar
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Letter |
Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer
Nongenetic activation of Aurora kinase A in the majority of patients with non-small-cell lung cancer mediates adaptive resistance to EGFR inhibition and offers an opportunity for combination treatment.
- Khyati N. Shah
- , Roma Bhatt
- & Sourav Bandyopadhyay
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Article |
Renal compartment–specific genetic variation analyses identify new pathways in chronic kidney disease
Kidney compartment–specific eQTL analysis goes beyond GWAS to reveal causal genes and pathways involved in renal disease development.
- Chengxiang Qiu
- , Shizheng Huang
- & Katalin Susztak
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Article |
Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent
iPSC-derived motor neurons from over 30 heterogeneous sporadic ALS cases exhibit pathologies correlated with clinical disease progression, are more similar to FUS/TDP-43 familial ALS than SOD1-ALS and are corrected by repurposing of ropinirole.
- Koki Fujimori
- , Mitsuru Ishikawa
- & Hideyuki Okano
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Article |
Genetically engineered human cortical spheroid models of tuberous sclerosis
CRISPR–Cas9-mediated gene editing of TSC1 and TSC2 in human pluripotent stem cells is used to investigate the contribution of tuberous sclerosis complex–mechanistic target of rapamycin complex 1 signaling to human neural development in two-dimensional monolayer and three-dimensional spheroid models of the neurodevelopmental disorder tuberous sclerosis complex.
- John D. Blair
- , Dirk Hockemeyer
- & Helen S. Bateup
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Letter |
Cytotoxic CD8+ T cells recognize and kill Plasmodium vivax–infected reticulocytes
T cells kill blood-stage Plasmodium vivax, providing a rationale for the development of a T cell vaccine against this parasite.
- Caroline Junqueira
- , Camila R. R. Barbosa
- & Ricardo T. Gazzinelli
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Article |
Oncogenic hijacking of the stress response machinery in T cell acute lymphoblastic leukemia
Oncogenic NOTCH1 controls transcriptional activation of the heat shock response in T cell acute lymphoblastic leukemia and uncovers potential biomarkers of sensitivity to HSP90 inhibition.
- Nikos Kourtis
- , Charalampos Lazaris
- & Iannis Aifantis
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Article |
Interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice
Interleukin-1β promotes an atheroprotective phenotype in late-stage lesions of mice, suggesting the possibility of deleterious effects of interleukin-1β blockade in the setting of myocardial infarction.
- Delphine Gomez
- , Richard A. Baylis
- & Gary K. Owens
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Article |
Senolytics improve physical function and increase lifespan in old age
Transfer of senescent cells into naive, young mice can induce physical dysfunction, and a senolytic can reverse this dysfunction and potently increase lifespan in aged mice.
- Ming Xu
- , Tamar Pirtskhalava
- & James L. Kirkland
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Letter |
Metformin reverses established lung fibrosis in a bleomycin model
Metformin reverses established lung fibrosis in a bleomycin model in mice.
- Sunad Rangarajan
- , Nathaniel B. Bone
- & Jaroslaw W. Zmijewski
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Letter |
DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia
Small-molecule inhibitors of the serine dipeptidases DPP8 and DPP9 block AML progression by promoting CARD8-dependent pyroptosis of leukemic myeloid cells.
- Darren C. Johnson
- , Cornelius Y. Taabazuing
- & Daniel A. Bachovchin
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Article |
Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure
Post-translational modification of microtubules by detyrosination is prevalent in failing human cardiomyocytes and inhibits cardiomyocyte contraction, suggesting a new therapeutic strategy for improving heart function.
- Christina Yingxian Chen
- , Matthew A. Caporizzo
- & Benjamin L. Prosser
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Article |
Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle
Accumulation of zinc in muscle cells resulting from transcriptional upregulation of metal transporter ZIP14 causes muscle atrophy and promotes cachexia in metastatic cancer.
- Gang Wang
- , Anup K. Biswas
- & Swarnali Acharyya
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Article |
DKK2 imparts tumor immunity evasion through β-catenin-independent suppression of cytotoxic immune-cell activation
A negative regulator of the Wnt pathway secreted by tumor cells promotes immune evasion by suppressing lymphocyte cytotoxicity.
- Qian Xiao
- , Jibo Wu
- & Dianqing Wu
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Article |
The activated conformation of integrin β7 is a novel multiple myeloma–specific target for CAR T cell therapy
Hosen et al. identify an active conformation of integrin beta-7 as a cancer-associated antigen in multiple myeloma, and engineer a CAR-T cell that shows efficacy against MM in a mouse model. These findings describe the first conformation-specific CAR-T cell and highlight the potential of conformational targets in cancer immunotherapy.
- Naoki Hosen
- , Yukiko Matsunaga
- & Atsushi Kumanogoh
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Article |
ADAM10-mediated ephrin-B2 shedding promotes myofibroblast activation and organ fibrosis
TGF-β induces expression of ADAM10, which results in greater shedding of ephrin-B2. This shedding promotes the chemotaxis and activation of myofibroblasts and thus the progression of organ fibrosis.
- David Lagares
- , Parisa Ghassemi-Kakroodi
- & Mohit Kapoor
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Article |
lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling
Concomitant overexpression of microRNAs miR-100 and miR-125b-1 within the host long non-coding RNA MIR100HG induces cetuximab resistance in cancer in the absence of previously associated genetic alterations. miR-100 and miR-125b target negative regulators of Wnt/β-catenin signaling and sustain drug resistance through feedback inhibition of GATA6 expression and this resistance can be overcome by pharmacological inhibition of Wnt activity. These findings, together with those by Tan et al. in the previous issue, highlight the emerging functional role of non-coding RNAs in modulating the response to anti-cancer therapies.
- Yuanyuan Lu
- , Xiaodi Zhao
- & Robert J Coffey
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Article |
Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma
Combined inhibition of oncogene-driven glucose uptake and induction of cytoplasmic-p53 activity induces apoptosis in a subset of glioblastoma samples. In mice, PET imaging of glucose uptake predicts glioblastoma response to this combination therapy.
- Wilson X Mai
- , Laura Gosa
- & David A Nathanson
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Letter |
Intrinsic BET inhibitor resistance in SPOP-mutated prostate cancer is mediated by BET protein stabilization and AKT–mTORC1 activation
Mutations in SPOP, the gene encoding a component of the E3 ubiquitin ligase complex, impair ubiquitination-dependent degradation of BRD2, BRD3 and BRD4 proteins and result in activation of ATK–mTORC1 signaling and resistance to BET inhibitors. Pharmacological blockade of AKT represents a viable strategy to restore the sensitivity of SPOP-mutant prostate tumors to BET inhibitors. These results, together with findings by Dai et al. and Janouskova et al., uncover a new nongenetic mechanism of resistance to BET inhibition involving cancer-type-specific mutations in SPOP, and support the evaluation of SPOP mutation status to inform the administration of BET inhibitors in the clinic.
- Pingzhao Zhang
- , Dejie Wang
- & Haojie Huang
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Letter |
Prostate cancer–associated SPOP mutations confer resistance to BET inhibitors through stabilization of BRD4
Recurrent mutations in SPOP-encoding a Cullin 3-based E3 ubiquitin ligase- in prostate cancer disrupt the recognition and degradation of ubiquitination substrates, including BET proteins. Consequently, stability of BET proteins is enhanced and this increases the resistance to BET inhibitors in SPOP-mutant prostate tumors. These results, together with those in Janouskova et al. and Zhang et al., uncover a novel non genetic mechanism of resistance to BET inhibition involving cancer type-specific mutations in SPOP, and support the evaluation of SPOP mutations to inform the administration of BET inhibitors in the clinic.
- Xiangpeng Dai
- , Wenjian Gan
- & Wenyi Wei
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Article |
Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis
The kinase Plk1 has been studied primarily as a mitotic regulator in dividing cells, but de Cárcer et al. find that Plk1 deficiency or inhibition in mice causes nonmitotic defects in the vasculature, including aortic aneurysm and rupture, as well as defective vascular smooth muscle contractility. These results recommend a note of caution in the clinical use of PLK1 inhibitors as anticancer agents.
- Guillermo de Cárcer
- , Paulina Wachowicz
- & Marcos Malumbres
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Perspective |
Insulin action and resistance in obesity and type 2 diabetes
In this Perspective, Michael Czech presents evidence for whether hyperinsulinemia occurs before insulin resistance upon overfeeding or high-fat diet feeding, or whether insulin resistance causes hyperinsulinemia, thus attempting to delineate the relationship between hyperinsulinemia, obesity and insulin resistance.
- Michael P Czech
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