Cellular senescence is a stress-responsive cell-cycle arrest program that terminates the further expansion of (pre-)malignant cells. Key signalling components of the senescence machinery, such as p16
..., p21
and p53, as well as trimethylation of lysine 9 at histone H3 (H3K9me3), also operate as critical regulators of stem-cell functions (which are collectively termed 'stemness'). In cancer cells, a gain of stemness may have profound implications for tumour aggressiveness and clinical outcome. Here we investigated whether chemotherapy-induced senescence could change stem-cell-related properties of malignant cells. Gene expression and functional analyses comparing senescent and non-senescent B-cell lymphomas from Eμ-Myc transgenic mice revealed substantial upregulation of an adult tissue stem-cell signature, activated Wnt signalling, and distinct stem-cell markers in senescence. Using genetically switchable models of senescence targeting H3K9me3 or p53 to mimic spontaneous escape from the arrested condition, we found that cells released from senescence re-entered the cell cycle with strongly enhanced and Wnt-dependent clonogenic growth potential compared to virtually identical populations that had been equally exposed to chemotherapy but had never been senescent. In vivo, these previously senescent cells presented with a much higher tumour initiation potential. Notably, the temporary enforcement of senescence in p53-regulatable models of acute lymphoblastic leukaemia and acute myeloid leukaemia was found to reprogram non-stem bulk leukaemia cells into self-renewing, leukaemia-initiating stem cells. Our data, which are further supported by consistent results in human cancer cell lines and primary samples of human haematological malignancies, reveal that senescence-associated stemness is an unexpected, cell-autonomous feature that exerts its detrimental, highly aggressive growth potential upon escape from cell-cycle blockade, and is enriched in relapse tumours. These findings have profound implications for cancer therapy, and provide new mechanistic insights into the plasticity of cancer cells.
Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon ...lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinate dehydrogenase (SDH) and an elevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.
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•LPS induces mitochondrial repurposing from ATP synthesis to ROS production•Oxidation of succinate and mitochondrial hyperpolarization drive ROS production•Blocking LPS-induced ROS production or hyperpolarization inhibits IL-1β•SDH is critical for the inflammatory response
To support their pro-inflammatory function, activated macrophages repurpose their mitochondria, switching from ATP production to ROS generation.
Theory of mind: The state of the art Wellman, Henry M.
European journal of developmental psychology,
11/2018, Letnik:
15, Številka:
6
Journal Article
Recenzirano
In this article, I reflect on theory of mind as a field (ToM), how it has developed over the years, and focally on the state of current research and theory. Having begun with preschoolers' ...understanding of beliefs and desires, the field now includes research from infancy through late life, contributions and contributors from around the world, research on behavior, conversation, neural correlates, gene-environment contributions, evolution, and the social-behavioral antecedents and consequences of the unfolding trajectories of ToM understanding. Several topics in particular portray the current state of the art and my sense of where theory-of-mind research is likely to head in the near future: progressions of theory of mind achievement; cultural experiences plus experiential influences that shape developmental trajectories; developmental cognitive neuroscience; infant ToM insights; research on ToM developments beyond preschool, including children's increasing interest in and wrestling with extraordinary minds, such as those of God and super-heroes.
The hallmark of endochondral bone development is the presence of cartilaginous templates, in which osteoblasts and stromal cells are generated to form mineralized matrix and support bone marrow ...haematopoiesis. However, the ultimate source of these mesenchymal cells and the relationship between bone progenitors in fetal life and those in later life are unknown. Fate-mapping studies revealed that cells expressing cre-recombinases driven by the collagen II (Col2) promoter/enhancer and their descendants contributed to, in addition to chondrocytes, early perichondrial precursors before Runx2 expression and, subsequently, to a majority of osteoblasts, Cxcl12 (chemokine (C-X-C motif) ligand 12)-abundant stromal cells and bone marrow stromal/mesenchymal progenitor cells in postnatal life. Lineage-tracing experiments using a tamoxifen-inducible creER system further revealed that early postnatal cells marked by Col2-creER, as well as Sox9-creER and aggrecan (Acan)-creER, progressively contributed to multiple mesenchymal lineages and continued to provide descendants for over a year. These cells are distinct from adult mesenchymal progenitors and thus provide opportunities for regulating the explosive growth that occurs uniquely in growing mammals.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The observation that long noncoding RNAs (lncRNAs) represent the majority of transcripts in humans has led to a rapid increase in interest and study. Most of this interest has focused on their roles ...in the nucleus. However, increasing evidence is beginning to reveal even more functions outside the nucleus, and even outside cells. Many of these roles are mediated by newly discovered properties, including the ability of lncRNAs to interact with lipids, membranes, and disordered protein domains, and to form differentially soluble RNA–protein sub-organelles. This review explores the possibilities enabled by these new properties and abilities, such as likely roles in exosome formation and function.
lncRNAs play important nucleating and structural roles in a growing number of phase-separating ribonucleoprotein complexes referred to here as microbodies.
Microbody formation is nucleated by long, repetitive, unspliced, and non-polyadenylated lncRNAs referred to as arcRNAs.
lncRNAs can interact with membranes and specific phospholipids (PIP3).
lncRNAs can target proteins to membranes.
lncRNAs are important functional components of exosomes and are likely to play roles in their formation and function.
TRAIL is a potent inducer of apoptosis and has been studied almost exclusively in this context. However, TRAIL can also induce NFκB-dependent expression of multiple pro-inflammatory cytokines and ...chemokines. Surprisingly, whereas inhibition of caspase activity blocked TRAIL-induced apoptosis, but not cytokine production, knock down or deletion of caspase-8 suppressed both outcomes, suggesting that caspase-8 participates in TRAIL-induced inflammatory signaling in a scaffold role. Consistent with this, introduction of a catalytically inactive caspase-8 mutant into CASP-8 null cells restored TRAIL-induced cytokine production, but not cell death. Furthermore, affinity precipitation of the native TRAIL receptor complex revealed that pro-caspase-8 was required for recruitment of RIPK1, via FADD, to promote NFκB activation and pro-inflammatory cytokine production downstream. Thus, caspase-8 can serve in two distinct roles in response to TRAIL receptor engagement, as a scaffold for assembly of a Caspase-8-FADD-RIPK1 “FADDosome” complex, leading to NFκB-dependent inflammation, or as a protease that promotes apoptosis.
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•TRAIL induces NFκB-dependent expression of pro-inflammatory cytokines and chemokines•Caspase-8 is required for TRAIL-induced inflammatory signaling in a scaffold role•Caspase-8 recruits RIPK1 to the TRAIL receptor complex to promote inflammation•A TRAIL-induced Caspase-8-FADD-RIPK1 “FADDosome” complex initiates inflammation
TRAIL receptor engagement induces apoptosis and NFκB-dependent expression of multiple pro-inflammatory mediators. Here, Henry and Martin show that caspase-8 participates in a non-enzymatic role in TRAIL-induced inflammatory signaling by serving as a scaffold for assembly of a Caspase-8-FADD-RIPK1 “FADDosome” complex that leads to NFκB-dependent inflammation.
In mammals, most cardiomyocytes (CMs) become polyploid (they have more than two complete sets of chromosomes). The purpose of this review is to evaluate assumptions about CM ploidy that are commonly ...discussed, even if not experimentally demonstrated, and to highlight key issues that are still to be resolved. Topics discussed here include (
a
) technical and conceptual difficulties in defining a polyploid CM, (
b
) the candidate role of reactive oxygen as a proximal trigger for the onset of polyploidy, (
c
) the relationship between polyploidization and other aspects of CM maturation, (
d
) recent insights related to the regenerative role of the subpopulation of CMs that are not polyploid, and (
e
) speculations as to why CMs become polyploid at all. New approaches to experimentally manipulate CM ploidy may resolve some of these long-standing and fundamental questions.
Mesenchymal stem and progenitor cells (MSPCs) contribute to bone marrow (BM) homeostasis by generating multiple types of stromal cells. MSPCs can be labeled in the adult BM by Nestin-GFP, whereas ...committed osteoblast progenitors are marked by Osterix expression. However, the developmental origin and hierarchical relationship of stromal cells remain largely unknown. Here, by using a lineage-tracing system, we describe three distinct waves of contributions of Osterix+ cells in the BM. First, Osterix+ progenitors in the fetal BM contribute to nascent bone tissues and transient stromal cells that are replaced in the adult marrow. Second, Osterix-expressing cells perinatally contribute to osteolineages and long-lived BM stroma, which have characteristics of Nestin-GFP+ MSPCs. Third, Osterix labeling in the adult marrow is osteolineage-restricted, devoid of stromal contribution. These results uncover a broad expression profile of Osterix and raise the intriguing possibility that distinct waves of stromal cells, primitive and definitive, may organize the developing BM.
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•Fetal Osterix+ cells give rise to a primitive stroma that is replaced after birth•Neonatal Osterix+ cells contribute to long-lived, definitive stroma•Neonatal Osterix-derived BM stromal cells mark definitive MSPCs in the adult•Osterix-derived MSPCs contribute to tissue regeneration after injury
Bone marrow (BM) mesenchymal stem and progenitor cells (MSPCs) generate multiple types of stromal cells. However, the origin of MSPCs remains unknown. Mizoguchi et al. show that Osterix-expressing cells mark at least three waves of progenitors during BM development and that definitive Nestin+ long-lived stromal progenitors are established during the perinatal stage.
High‐voltage‐activated calcium (CaV1/CaV2) channels translate action potentials into Ca2+ influx in excitable cells to control essential biological processes that include; muscle contraction, ...synaptic transmission, hormone secretion and activity‐dependent regulation of gene expression. Modulation of CaV1/CaV2 channel activity is a powerful mechanism to regulate physiology, and there are a host of intracellular signalling molecules that tune different aspects of CaV channel trafficking and gating for this purpose. Beyond normal physiological regulation, the diverse CaV channel modulatory mechanisms may potentially be co‐opted or interfered with for therapeutic benefits. CaV1/CaV2 channels are potently inhibited by a four‐member sub‐family of Ras‐like GTPases known as RGK (Rad, Rem, Rem2, Gem/Kir) proteins. Understanding the mechanisms by which RGK proteins inhibit CaV1/CaV2 channels has led to the development of novel genetically encoded CaV channel blockers with unique properties; including, chemo‐ and optogenetic control of channel activity, and blocking channels either on the basis of their subcellular localization or by targeting an auxiliary subunit. These genetically encoded CaV channel inhibitors have outstanding utility as enabling research tools and potential therapeutics.
RGK proteins are small Ras‐like GTPases that potently inhibit voltage‐gated calcium (CaV) channels by binding their auxiliary b subunits. Mechanistic insights into how RGK proteins inhibit CaV channels has been exploited to develop novel genetically‐encoded CaV channel inhibitors that can be acutely activated by small molecules or light, or produce constitutive inhibition via targeted ubiquitination using CaVb‐binding nanobodies. Advantages of such genetically‐encoded CaV channel inhibitors include their ability to be selectively targeted to specific tissue, cell types, sub‐cellular localization, and distinct CaV channel macromolecular complexes.
Recent studies have demonstrated that the lipopolysaccharide (LPS) receptor (TLR4) is expressed in TRPV1 containing trigeminal sensory neurons. In this study, we evaluated whether LPS activates ...trigeminal neurons, and sensitizes TRPV1 responses via TLR4. To test this novel hypothesis, we first demonstrated that LPS binds to receptors in trigeminal neurons using competitive binding. Second, we demonstrated that LPS evoked aconcentration-dependent increase in intracellular calcium accumulation (Ca2+)i and inward currents. Third, LPS significantly sensitized TRPV1 to capsaicin measured by (Ca2+)i, release of calcitonin gene-related peptide, and inward currents. Importantly, a selective TLR4 antagonist blocked these effects. Analysis of these data, collectively, demonstrates that LPS is capable of directly activating trigeminal neurons, and sensitizing TRPV1 via a TLR4-mediated mechanism. These findings are consistent with the hypothesis that trigeminal neurons are capable of detecting pathogenic bacterial components leading to sensitization of TRPV1, possibly contributing to the inflammatory pain often observed in bacterial infections.
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