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10.1038/s41467-021-24532-8
135,317,206
Abstract Histone H3 lysine 9 (H3K9) methylation is a central epigenetic modification that defines heterochromatin from unicellular to multicellular organisms. In mammalian cells, H3K9 methylation can be catalyzed by at least six distinct SET domain enzymes: Suv39h1/Suv39h2, Eset1/Eset2 and G9a/Glp. We used mouse embryo...
10.1038/s41580-022-00483-w
This study describes the effect of losing all detectable H3K9me owing to the loss of the six redundant mammalian H3K9-specific HMTs; analogous ablations and their consequences in C. elegans are described by Towbin et al. (2012) and Zeller et al. (2016).
10.1038/celldisc.2016.37
122,113,032
Abstract The histone 3 lysine 9 methyltransferase Setdb1 is essential for both stem cell pluripotency and terminal differentiation of different cell types. To shed light on the roles of Setdb1 in these mutually exclusive processes, we used mouse skeletal myoblasts as a model of terminal differentiation. Ex vivo studies...
10.1038/s41580-022-00483-w
This study is the first description of a global regulation of SETDB1 through nuclear export; an analogous mechanism during the stress response in C. elegans is described by Delaney et al. (2019)
10.1038/embor.2009.90
123,922,965
Trimethylation of lysine 9 in histone H3 (H3K9me3) enrichment is a characteristic of pericentric heterochromatin. The hypothesis of a stepwise mechanism to establish and maintain this mark during DNA replication suggests that newly synthesized histone H3 goes through an intermediate methylation state to become a substr...
10.1038/s41580-022-00483-w
Links SETDB1 to the replication machinery to maintain H3K9me in mitotic cells
10.1038/s41586-021-04228-1
130,505,215
Abstract All life forms defend their genome against DNA invasion. Eukaryotic cells recognize incoming DNA and limit its transcription through repressive chromatin modifications. The human silencing hub (HUSH) complex transcriptionally represses long interspersed element-1 retrotransposons (L1s) and retroviruses through...
10.1038/s41580-022-00483-w
An elegant study revealing the mechanism of HUSH-dependent SETDB1 recruitment, which was described earlier by Tchasovnikarova et al. (2015) and Robbez-Masson et al. (2018)
10.1126/science.aau0583
41,764,301
Gene silencing by chromatin compaction is integral to establishing and maintaining cell fates. Trimethylated histone 3 lysine 9 (H3K9me3)–marked heterochromatin is reduced in embryonic stem cells compared to differentiated cells. However, the establishment and dynamics of closed regions of chromatin at protein-coding g...
10.1038/s41580-022-00483-w
Analysis of H3K9me3-dependent gene silencing in SETDB1–SUV39H1–SUV39H2 triple mutants after embryogenesis
10.1126/science.aah6499
20,624,537
After priming, naïve CD8 + T lymphocytes establish specific heritable transcription programs that define progression to long-lasting memory cells or to short-lived effector cells. Although lineage specification is critical for protection, it remains unclear how chromatin dynamics contributes to the control of gene expr...
10.1038/s41580-022-00483-w
Describes the important role of SUV39H1 in CD8 + T cell fate commitment
10.1126/scitranslmed.3004952
122,305,066
Mutant DNA from ovarian and endometrial tumors can be detected in Pap smear specimens through massively parallel sequencing.
10.1038/s41568-019-0177-x
First study to show that endometrial cancer-associated mutations can be detected during routine Pap tests; led to development of the prototype ‘PapGene’ test (2013)
10.1126/scitranslmed.aap8793
59,273,426
Endometrial and ovarian cancers can be detected through the analysis of DNA from Pap test fluids, intrauterine samples, and plasma.
10.1038/s41568-019-0177-x
Publication demonstrating the detection of early-stage endometrial cancers from samples collected during routine Pap tests using the ‘PapSEEK’ test (2018)
10.1126/science.aan6733
20,843,651
Predicting responses to immunotherapy Colon cancers with loss-of-function mutations in the mismatch repair (MMR) pathway have favorable responses to PD-1 blockade immunotherapy. In a phase 2 clinical trial, Le et al. showed that treatment success is not just limited to colon cancer (see the Perspective by Goswami and S...
10.1038/s41568-019-0177-x
Study describing the efficacy of single-agent pembrolizumab in mismatch repair-deficient endometrial cancer patients
10.1083/jcb.2.4.73
45,414,532
1. In most rat liver cells, no special topographical relationship between mitochondria and ergastoplasmic lamellae is to be observed. In some cells, nevertheless, the two organelles are grouped together in dense zones clearly separated from the hyaloplasm. 2. Such an association can be produced at will in the livers of...
10.1038/s41467-019-09253-3
This is the first paper describing a contact site in cells.
10.1126/science.280.5370.1763
41,469,373
The spatial relation between mitochondria and endoplasmic reticulum (ER) in living HeLa cells was analyzed at high resolution in three dimensions with two differently colored, specifically targeted green fluorescent proteins. Numerous close contacts were observed between these organelles, and mitochondria in situ forme...
10.1038/s41467-019-09253-3
This is the first paper showing a role for contact sites in direct calcium transfer.
10.1091/mbc.11.7.2445
82,847,916
Vac8p is a vacuolar membrane protein that is required for efficient vacuole inheritance and fusion, cytosol-to-vacuole targeting, and sporulation. By analogy to other armadillo domain proteins, including β-catenin and importin α, we hypothesize that Vac8p docks various factors at the vacuole membrane. Two-hybrid and co...
10.1038/s41467-019-09253-3
This is the first paper describing a contact site tether in yeast.
10.1126/science.1207385
62,297,467
Mitochondrial division occurs at positions where endoplasmic reticulum tubules contact mitochondria and mediate constriction.
10.1038/s41467-019-09253-3
This paper describes the association between contact sites and mitochondrial fission.
10.1126/science.aah6171
103,693,677
Understanding insulin release Insulin release takes place in two phases: a first rapid burst followed by a series of small exocytic bursts that coincide with pulsatile spikes in cytosolic Ca 2+ levels. The second phase is impaired in patients with type II diabetes, underscoring the importance of understanding its molec...
10.1038/s41467-019-09253-3
This manuscript showes a role for contact sites in physiology of a tissue.
10.1073/pnas.1503191112
28,006,140
The close apposition between the endoplasmic reticulum (ER) and the plasma membrane (PM) plays important roles in Ca 2+ homeostasis, signaling, and lipid metabolism. The extended synaptotagmins (E-Syts; tricalbins in yeast) are ER-anchored proteins that mediate the tethering of the ER to the PM and are thought to media...
10.1038/s41467-019-09253-3
This paper shows a high resolution structure of a contact site.
10.7554/elife.31019
103,666,020
Endoplasmic reticulum (ER) membrane contact sites (MCSs) are crucial regulatory hubs in cells, playing roles in signaling, organelle dynamics, and ion and lipid homeostasis. Previous work demonstrated that the highly conserved yeast Ltc/Lam sterol transporters localize and function at ER MCSs. Our analysis of the human...
10.1038/s41467-019-09253-3
This manuscript demonstrates that a contact site between two organelles can be formed by different tethers and have diverse functions.
10.1083/jcb.72.3.714
122,788,784
Low-speed centrifugation (640 g) of rat liver homogenates, prepared with a standard ionic medium, yielded a pellet from which a rapidly sedimenting fraction of rough endoplasmic reticulum (RSER) was recovered free of nuclei. This fraction contained 20-25% of cellular RNA and approximately 30% of total glucose-6-phospha...
10.1038/s41467-019-09253-3
This paper identifies a fraction of rough er in association with mitochondria.
10.1126/science.1191035
104,259,708
Environment Matters Stem cells isolated from muscle can be used for muscle regeneration, but only if the stem cells are fresh. Under standard cell culture conditions in the laboratory, muscle stem cells fail to proliferate efficiently and lose their regenerative capacity. Gilbert et al. (p. 1078 , published online 15 J...
10.1038/s41586-018-0089-z
This study demonstrated that muscle stem cells best maintained their stem cell phenotype and regenerative potential when cultured on substrates with stiffness approximating that of healthy muscle.
10.1038/ncomms15909
102,860,008
Abstract Micelles formed by the self-assembly of block copolymers in selective solvents have attracted widespread attention and have uses in a wide variety of fields, whereas applications based on their electronic properties are virtually unexplored. Herein we describe studies of solution-processable, low-dispersity, e...
10.1038/s41578-020-00233-4
This is a detailed study on the effect of nanofibre length on device performance
10.1126/science.aar8104
103,667,027
A longer exciton pathway Organic semiconductors typically exhibit exciton diffusion lengths on the order of tens of nanometers. Jin et al. prepared nanofibers from block polymers consisting of emissive polyfluorene cores surrounded by coronas of polyethylene glycol and polythiophene (see the Perspective by Holmes). Exc...
10.1038/s41578-020-00233-4
This study reports fibres made through CDSA that display exceptional exciton-diffusion lengths
10.1002/adfm.201808365
101,925,236
Abstract Methods for noninvasive brain imaging are highly desirable to study brain structures in neuroscience. Two‐photon fluorescence microscopy (2PFM) with near‐infrared (NIR) light excitation is a relatively noninvasive approach commonly used to study brain with high spatial resolution and large imaging depth. Howev...
10.1038/s41578-020-00233-4
This study reports in vivo deep-tissue imaging with high contrast by using NIR
10.1002/anie.201712550
123,858,373
Abstract Nanoparticles for photothermal therapy: Real‐time temperature monitoring is critical to reduce the nonspecific damage during photothermal therapy (PTT); however, PTT agents that can emit temperature‐related signals are rare and limited to few inorganic nanoparticles. We herein synthesize a semiconducting polym...
10.1038/s41578-020-00233-4
This study demonstrates optical-imaging-guided photothermal therapy without real-time light excitation
10.1002/anie.201705543
83,440,722
Abstract Regulation of transgene systems is needed to develop innovative medicines. However, noninvasive remote control of gene expression has been rarely developed and remains challenging. We herein synthesize a near‐infrared (NIR) absorbing dendronized semiconducting polymer (DSP) and utilize it as a photothermal nan...
10.1038/s41578-020-00233-4
This work seeds the idea of remotely controlling gene expression
10.1002/anie.201813066
62,043,357
Abstract Semiconducting polymer dots (Pdots) have recently attracted considerable attention because of their photocatalytic activity as well as tunable optical band gap. In this contribution, we describe the therapeutic application of Pdots through in situ photocatalytic hydrogen generation. Liposomes were employed as ...
10.1038/s41578-020-00233-4
This paper demonstrates a promising and original approach to photothermal therapy
10.1101/gr.246678.118
125,333,095
Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing the trans -acting regulatory proteins that control alternative splicing has therefore been the focus of much research. Recent work has established that even core protein components of the ...
10.1038/s41568-020-00306-0
Dvinge et al. (2019) and Shuai et al. (2019) demonstrate that RNA components of the spliceosome are also altered in cancer
10.1158/2159-8290.cd-16-1034
29,197,701
Abstract Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate–dependent dioxygenases, including histone demethylases and met...
10.1038/s41589-022-00997-6
This paper reports the discovery and application of an allosteric IDH2 inhibitor in AML.
10.1158/2159-8290.cd-19-1228
83,282,890
Abstract A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine–limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-...
10.1038/s41589-022-00997-6
This paper describes the application of PH-755 in breast cancer metastasis models.
10.1158/1535-7163.mct-13-0870
41,665,712
Abstract Glutamine serves as an important source of energy and building blocks for many tumor cells. The first step in glutamine utilization is its conversion to glutamate by the mitochondrial enzyme glutaminase. CB-839 is a potent, selective, and orally bioavailable inhibitor of both splice variants of glutaminase (KG...
10.1038/s41589-022-00997-6
This paper describes the biochemical and cellular applications of CB-839.
10.1126/science.aaf2786
104,021,261
Quantitation of metabolic pathway regulation Although metabolic biochemical pathways are well understood, less is known about precisely how reaction rates or fluxes through the various enzymes are controlled. Hackett et al. developed a method to quantitate such regulatory influence in yeast. They monitored concentratio...
10.1038/s41589-022-00997-6
This paper describes the SIMMER method for identifying endogenous allosteric interactions.
10.1126/scitranslmed.aay1063
104,393,236
Atherosclerotic lesional macrophages express molecules that promote plaque progression, but lack of mechanisms to therapeutically target these molecules represents a major gap in translational cardiovascular research. Here, we tested the efficacy of a small interfering RNA (siRNA) nanoparticle (NP) platform targeting a...
10.1038/s41569-021-00629-x
This study shows that macrophage-targeted siRNA nanoparticles can restore efferocytic capacity of atherosclerotic lesional macrophages and, therefore, reduce plaque burden in a preclinical model of advanced atherosclerosis.
10.2217/fca-2017-0009
62,592,077
Aim: The safety options in nanomedicine raise an issue of the optimal niche at the real-world clinical practice. Methods: This is an observational prospective cohort analysis of the 5-year clinical outcomes at the intention-to-treat population (nano vs ferro vs stenting; n = 180) of NANOM first-in-man trial (NCT0127013...
10.1038/s41569-021-00629-x
Together with Kharlamov et al. (2015), this is the first-in-human trial that demonstrates that plasmonic photothermal therapy can reduce atherosclerotic plaque burden and major adverse cardiovascular events.
10.1126/sciimmunol.aat1482
83,433,077
Deeper insights into the biology of interleukin-2 and its receptors are leading to therapeutic strategies for selective T reg stimulation.
10.1038/s41573-019-0041-4
A comprehensive review discussing the discovery, biology and therapeutic potential of the cytokine IL-2
10.1084/jem.20060468
83,281,170
Abnormalities in CD4+CD25+Foxp3+ regulatory T (T reg) cells have been implicated in susceptibility to allergic, autoimmune, and immunoinflammatory conditions. However, phenotypic and functional assessment of human T reg cells has been hampered by difficulty in distinguishing between CD25-expressing activated and regula...
10.1038/s41573-019-0041-4
Together with Liu et al. (2006) this article describes the use of CD127 (IL-7 receptor subunit-α) as a surface marker, the exclusion of which dramatically enhances peripheral blood human T reg cell purity after FACS
10.1126/scitranslmed.aad4134
103,721,459
Autologous regulatory T cells can be expanded and are well tolerated in patients with recent-onset type 1 diabetes.
10.1038/s41573-019-0041-4
First clinical trial demonstrating up to 1 year survival of infused T reg cells in patients with T1D
10.1084/jem.20040139
83,080,620
The low number of CD4+ CD25+ regulatory T cells (Tregs), their anergic phenotype, and diverse antigen specificity present major challenges to harnessing this potent tolerogenic population to treat autoimmunity and transplant rejection. In this study, we describe a robust method to expand antigen-specific Tregs from aut...
10.1038/s41573-019-0041-4
Seminal study showing that antigen-specific T reg cells can be expanded ex vivo and cure T1D in mice
10.1182/blood-2004-09-3579
123,181,209
Abstract We developed an approach that increases CD4+CD25+ regulatory T-cell potency by antigen-specifically redirecting them against pathologic T lymphocytes. The regulatory cells are transgenically modified with chimeric receptors that link antigen–major histocompatibility complex (MHC) extracellular and transmembran...
10.1038/s41573-019-0041-4
First study redirecting T reg cells using a chimeric receptor, designed to recognize autoreactive T cells in EAE
10.2337/db08-1168
4,860,455
OBJECTIVE—Regulatory T-cells (Tregs) have catalyzed the field of immune regulation. However, translating Treg-based therapies from animal models of autoimmunity to human clinical trials requires robust methods for the isolation and expansion of these cells—a need forming the basis for these studies. RESEARCH DESIGN AND...
10.1038/s41573-019-0041-4
This article describes the good manufacturing practice manufacture of T reg cells isolated from patients with T1D for T reg cell therapy
10.1126/science.aar3246
4,860,145
Engineering cytokine-receptor pairs Interleukin-2 (IL-2) is an important cytokine that helps T cells destroy tumors and virus-infected cells. IL-2 has great therapeutic promise but is limited by toxic side effects and its capacity to both activate and repress immune responses. Sockolosky et al. set out to improve IL-2–...
10.1038/s41573-019-0041-4
This study reports the generation of an orthogonal IL-2–IL-2 receptor pair that could be used to trigger IL-2 signalling specifically in infused engineered T reg cells
10.1126/science.aad2791
62,290,395
T cells target peptide combos One of the enduring mysteries of autoimmunity is the identity of the specific proteins targeted by autoimmune T cells. Delong et al. used mass spectrometry to elucidate the peptide targets of autoimmune T cells isolated from a mouse model of type 1 diabetes. T cells targeted hybrid peptide...
10.1038/s41573-019-0041-4
This article shows that some diabetogenic T cells recognize epitopes formed by fusion of proinsulin peptides to other peptides that are found in the secretory vesicles of beta cells
10.1073/pnas.1902566116
82,979,762
Polymorphic HLAs form the primary immune barrier to cell therapy. In addition, innate immune surveillance impacts cell engraftment, yet a strategy to control both, adaptive and innate immunity, is lacking. Here we employed multiplex genome editing to specifically ablate the expression of the highly polymorphic HLA-A/-B...
10.1038/s41573-019-0041-4
This article describes the development of gene-edited hypoimmunogenic human pluripotent stem cells, which could in the future be used as an inexhaustible source for universally compatible T reg cells
10.4049/jimmunol.167.3.1245
20,436,631
Abstract Thymectomy in mice on neonatal day 3 leads to the development of multiorgan autoimmune disease due to loss of a CD+CD25+ T cell regulatory population in their peripheral lymphoid tissues. Here, we report the identification of a CD4+ population of regulatory T cells in the circulation of humans expressing high ...
10.1038/s41573-019-0041-4
Together with Levings et al. (2001), Jonuleit et al. (2001), Dieckmann et al. (2001), Ng et al. (2001) and Stephens et al. (2001), this article is a seminal study, the first to describe T reg cells in humans