Loss of MHC class I (MHC-I) antigen presentation in cancer cells can elicit immunotherapy resistance. A genome-wide CRISPR/Cas9 screen identified an evolutionarily conserved function of polycomb ...repressive complex 2 (PRC2) that mediates coordinated transcriptional silencing of the MHC-I antigen processing pathway (MHC-I APP), promoting evasion of T cell-mediated immunity. MHC-I APP gene promoters in MHC-I low cancers harbor bivalent activating H3K4me3 and repressive H3K27me3 histone modifications, silencing basal MHC-I expression and restricting cytokine-induced upregulation. Bivalent chromatin at MHC-I APP genes is a normal developmental process active in embryonic stem cells and maintained during neural progenitor differentiation. This physiological MHC-I silencing highlights a conserved mechanism by which cancers arising from these primitive tissues exploit PRC2 activity to enable immune evasion.
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•PRC2 maintains bivalency at MHC-I antigen-processing genes silencing MHC-I expression•Cancer cells co-opt this conserved, lineage-specific PRC2 function to evade T cells•Pharmacological inhibition of PRC2 in MHC-I low cancers restores anti-tumor immunity•Immunotherapy resistance may arise via non-genomic routes that exploit PRC2 activity
Burr et al. show that cancer cells co-opt PRC2 to evade immune surveillance. PRC2 maintains bivalency at the promoters of MHC-I antigen-processing pathway (MHC-I APP) genes to repress their basal and cytokine-activated expression. Inhibition of PRC2 restores the MHC-I APP and T cell-mediated anti-tumor immunity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Microorganisms acquire energy and nutrients from dynamic environments, where substrates vary in both type and abundance. The regulatory system responsible for prioritizing preferred substrates is ...known as carbon catabolite repression (CCR). Two broad classes of CCR have been documented in the literature. The best described CCR strategy, referred to here as classic CCR (cCCR), has been experimentally and theoretically studied using model organisms such as
Escherichia coli
. cCCR phenotypes are often used to generalize universal strategies for fitness, sometimes incorrectly. For instance, extremely competitive microorganisms, such as Pseudomonads, which arguably have broader global distributions than
E. coli
, have achieved their success using metabolic strategies that are nearly opposite of cCCR. These organisms utilize a CCR strategy termed ‘reverse CCR’ (rCCR), because the order of preferred substrates is nearly reverse that of cCCR. rCCR phenotypes prefer organic acids over glucose, may or may not select preferred substrates to optimize growth rates, and do not allocate intracellular resources in a manner that produces an overflow metabolism. cCCR and rCCR have traditionally been interpreted from the perspective of monocultures, even though most microorganisms live in consortia. Here, we review the basic tenets of the two CCR strategies and consider these phenotypes from the perspective of resource acquisition in consortia, a scenario that surely influenced the evolution of cCCR and rCCR. For instance, cCCR and rCCR metabolism are near mirror images of each other; when considered from a consortium basis, the complementary properties of the two strategies can mitigate direct competition for energy and nutrients and instead establish cooperative division of labor.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Microorganisms preferentially use different carbon and nitrogen sources.•Catabolite repression pathways influence nutrient uptake and nutrient switching.•Optimal functioning of CCR and NCR is ...essential for growth and survival.•CCR and NCR ensure greater flexibility in changing environmental conditions.•CCR and NCR together interlink carbon and nitrogen metabolism in microorganisms.
Organisms have cellular machinery that is focused on optimum utilization of resources to maximize growth and survival depending on various environmental and developmental factors. Catabolite repression is a strategy utilized by various species of bacteria and fungi to accommodate changes in the environment such as the depletion of resources, or an abundance of less-favored nutrient sources. Catabolite repression allows for the rapid use of certain substrates like glucose over other carbon sources. Effective handling of carbon and nitrogen catabolite repression in microorganisms is crucial to outcompete others in nutrient limiting conditions. Investigations into genes and proteins linked to preferential uptake of different nutrients under various environmental conditions can aid in identifying regulatory mechanisms that are crucial for optimum growth and survival of microorganisms. The exact time and way bacteria and fungi switch their utilization of certain nutrients is of great interest for scientific, industrial, and clinical reasons. Catabolite repression is of great significance for industrial applications that rely on microorganisms for the generation of valuable bio-products. The impact catabolite repression has on virulence of pathogenic bacteria and fungi and disease progression in hosts makes it important area of interest in medical research for the prevention of diseases and developing new treatment strategies. Regulatory networks under catabolite repression exemplify the flexibility and the tremendous diversity that is found in microorganisms and provides an impetus for newer insights into these networks.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Confabulation denotes the recitation of memories about events and experiences that never happened. Based on multiple case examples, The Confabulating Mind provides an in-depth review of the ...presentations, the causative diseases, and the mechanisms of this phenomenon and compares confabulation with normal false memories, as they occur in healthy adults and children. Memory-related confabulations are compared with false statements made by patients who confuse people, places, or their own health status, as this happens in disorders like déjà vu, paramnesic misidentification, and anosognosia. One form of confabulation called behaviourally spontaneous confabulation receives particular attention. It is characterized by a confusion of reality evident from disorientation and acts according to the confabulations. Recent studies revealed a specific mechanism—orbitofrontal reality filtering—which attributes a critical role to the orbitofrontal cortex for the ability to keep thought and behaviour in phase with reality. The book concludes with an overview of current interpretations of confabulations and recommendations for future study.
Challenging prevailing theories of development and labor, Gay Seidman's controversial study explores how highly politicized labor movements could arise simultaneously in Brazil and South Africa, two ...starkly different societies. Beginning with the 1960s, Seidman shows how both authoritarian states promoted specific rapid-industrialization strategies, in the process reshaping the working class and altering relationships between business and the state. When economic growth slowed in the 1970s, workers in these countries challenged social and political repression; by the mid-1980s, they had become major voices in the transition from authoritarian rule.
Based in factories and working-class communities, these movements enjoyed broad support as they fought for improved social services, land reform, expanding electoral participation, and racial integration.
In Brazil, Seidman takes us from the shopfloor, where disenfranchized workers organized for better wages and working conditions, to the strikes and protests that spread to local communities. Similar demands for radical change emerged in South Africa, where community groups in black townships joined organized labor in a challenge to minority rule that linked class consciousness to racial oppression. Seidman details the complex dynamics of these militant movements and develops a broad analysis of how newly industrializing countries shape the opportunities for labor to express demands. Her work will be welcomed by those interested in labor studies, social theory, and the politics of newly industrializing regions.
Large parts of mammalian genomes are transcriptionally inactive and enriched with various classes of interspersed and tandem repeats. Here we show that the tumor suppressor protein p53 cooperates ...with DNA methylation to maintain silencing of a large portion of the mouse genome. Massive transcription of major classes of short, interspersed nuclear elements (SINEs) B1 and B2, both strands of near-centromeric satellite DNAs consisting of tandem repeats, and multiple species of noncoding RNAs was observed in p53-deficient but not in p53 wild-type mouse fibroblasts treated with the DNA demethylating agent 5-aza-2’-deoxycytidine. The abundance of these transcripts exceeded the level of β-actin mRNA by more than 150-fold. Accumulation of these transcripts, which are capable of forming double-stranded RNA (dsRNA), was accompanied by a strong, endogenous, apoptosis-inducing type I IFN response. This phenomenon, which we named “TRAIN” (for “transcription of repeats activates interferon”), was observed in spontaneous tumors in two models of cancer-prone mice, presumably reflecting naturally occurring DNA hypomethylation and p53 inactivation in cancer. These observations suggest that p53 and IFN cooperate to prevent accumulation of cells with activated repeats and provide a plausible explanation for the deregulation of IFN function frequently seen in tumors. Overall, this work reveals roles for p53 and IFN that are key for genetic stability and therefore relevant to both tumorigenesis and the evolution of species.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
What does science tell us about memory phenomena such as false and repressed memories? This issue is highly pressing as incorrect knowledge about these memory phenomena might contribute to egregious ...effects in the courtroom such as false accusations of abuse. In the current article, we provide a succinct review of the scientific nature of false and repressed memories. We demonstrate that research has shown that about 30% of tested subjects formed false memories of autobiographical experiences. Furthermore, this empirical work has also revealed that such false memories can even be implanted for negative events and events that allegedly occurred repeatedly. Concerning the controversial topic of repressed memories, we show that plausible alternative explanations exist for why people claim to have forgotten traumatic experiences; explanations that do not require special memory mechanisms such as the unconscious blockage of traumatic memories. Finally, we demonstrate that people continue to believe that unconscious repression of traumatic incidents can exist. Disseminating scientifically articulated knowledge on the functioning of memory to contexts such as the courtroom is necessary as to prevent the occurrence of false accusations and miscarriages of justice.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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