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Deregulated expression of COX-2 has been causally linked to development, progression, and outcome of several types of human cancer. We describe a novel fundamental level of transcriptional control of COX-2 expression. Using primary human mammary epithelial cells and monocyte/macrophage cell lines, we show that the chromatin boundary/insulator factor CTCF establishes an open chromatin domain and induces expression of a long non-coding RNA within the upstream promoter region of COX-2. Upon induction of COX-2 expression, the lncRNA associates with p50, a repressive subunit of NF-κB, and occludes it from the COX-2 promoter, potentially facilitating interaction with activation-competent NF-κB p65/p50 dimers. This enables recruitment of the p300 histone acetyltransferase, a domain-wide increase in histone acetylation and assembly of RNA Polymerase II initiation complexes. Our findings reveal an unexpected mechanism of gene control by lncRNA-mediated repressor occlusion and identify the COX-2-lncRNA, PACER, as a new potential target for COX-2-modulation in inflammation and cancer. To produce a protein a cell must first transcribe the DNA in a gene to make a messenger RNA molecule, which is then translated to make the protein. However, cells also produce other types of RNA molecules which do not become proteins. MicroRNAs, for example, regulate the expression of genes as proteins, while the role of other RNA molecules called long non-coding RNAs (lncRNAs) is not well understood. Now Krawczyk and Emerson have found an lncRNA that controls a gene called COX-2 that is often implicated in breast, colon, prostate, and lung cancer. This RNA molecule, which is called PACER, originates near the start of the COX-2 gene, but it cannot be messenger RNA because it does not contain the instructions to make the COX-2 protein, and it is too long to be a microRNA. Further experiments showed that the newly discovered lncRNA activates the expression of the COX-2 gene. Krawczyk and Emerson found that PACER attracts enzymes that spotlight genes that need to be activated, thus increasing the transcription of these genes to make messenger RNA. Genes can also be switched on and off by various molecules binding to nearby DNA, and PACER encourages the activation of COX-2 by keeping away the molecules that might switch it off. In addition to shedding new light on the role of lncRNAs, these results suggest that PACER could be a suitable therapeutic target in cancers that involve the COX-2 gene.

Diabetes mellitus is a chronic metabolic disorder characterized by hyperglycaemia and oxidative stress. Oxidative stress plays a crucial role in the development and progression of diabetes and its complications. Nutritional antioxidants derived from dietary sources have gained significant attention due to their potential to improve antidiabetic therapy. This review will delve into the world of polyphenols, investigating their origins in plants, metabolism in the human body, and relevance to the antioxidant mechanism in the context of improving antidiabetic therapy by attenuating oxidative stress, improving insulin sensitivity, and preserving β-cell function. The potential mechanisms of, clinical evidence for, and future perspectives on nutritional antioxidants as adjuvant therapy in diabetes management are discussed.

The ability to identify a specific cancer using minimally invasive biopsy holds great promise for improving the diagnosis, treatment selection, and prediction of prognosis in cancer. Using whole-genome methylation data from The Cancer Genome Atlas (TCGA) and machine learning methods, we evaluated the utility of DNA methylation for differentiating tumor tissue and normal tissue for four common cancers (breast, colon, liver, and lung). We identified cancer markers in a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples. We replicated our findings in a separate TCGA cohort of 791 tumor samples and 93 matched adjacent normal tissue samples, as well as an independent Chinese cohort of 394 tumor samples and 324 matched adjacent normal tissue samples. The DNA methylation analysis could predict cancer versus normal tissue with more than 95% accuracy in these three cohorts, demonstrating accuracy comparable to typical diagnostic methods. This analysis also correctly identified 29 of 30 colorectal cancer metastases to the liver and 32 of 34 colorectal cancer metastases to the lung. We also found that methylation patterns can predict prognosis and survival. We correlated differential methylation of CpG sites predictive of cancer with expression of associated genes known to be important in cancer biology, showing decreased expression with increased methylation, as expected. We verified gene expression profiles in a mouse model of hepatocellular carcinoma. Taken together, these findings demonstrate the utility of methylation biomarkers for the molecular characterization of cancer, with implications for diagnosis and prognosis.

Using a large dataset of marathon runners, we estimate country- and gender-specific proxies for overconfidence. Subsequently, we correlate them with a number of indices, including various measures of gender equality. We find that in less gender-equal countries both males and females tend to be more self-confident than in more equal countries. While a substantial gender gap in overconfidence is observed, it only correlates with some sub-indices of gender equality. We conclude that there is likely a weak relationship between OC gender gap and gender inequality.

Experimental ocular hypertension induces senescence of retinal ganglion cells (RGCs) that mimics events occurring in human glaucoma. Senescence‐related chromatin remodeling leads to profound transcriptional changes including the upregulation of a subset of genes that encode multiple proteins collectively referred to as the senescence‐associated secretory phenotype (SASP). Emerging evidence suggests that the presence of these proinflammatory and matrix‐degrading molecules has deleterious effects in a variety of tissues. In the current study, we demonstrated in a transgenic mouse model that early removal of senescent cells induced upon elevated intraocular pressure (IOP) protects unaffected RGCs from senescence and apoptosis. Visual evoked potential (VEP) analysis demonstrated that remaining RGCs are functional and that the treatment protected visual functions. Finally, removal of endogenous senescent retinal cells after IOP elevation by a treatment with senolytic drug dasatinib prevented loss of retinal functions and cellular structure. Senolytic drugs may have the potential to mitigate the deleterious impact of elevated IOP on RGC survival in glaucoma and other optic neuropathies. The authors show that early removal of senescent cells in the retina protects the healthy retinal ganglion cells from death to maintain vision. These data suggest the potential application of senolytic drugs to mitigate the deleterious impact of high intraocular pressure on retinal neurons.

Methylation of the regulatory region of the elongation of very‐long‐chain fatty acids‐like 2 (ELOVL2) gene, an enzyme involved in elongation of long‐chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved. Here, we report that Elovl2 regulates age‐associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age‐related eye diseases. We show that an age‐related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5‐Aza‐2’‐deoxycytidine (5‐Aza‐dc) leads to increased Elovl2 expression and rescue of age‐related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2‐specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well‐established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components found in human drusen, a pathologic hallmark of age related macular degeneration. These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual function, and suggest novel therapeutic strategies for the treatment of age‐related eye diseases. Upon Elovl2 mutation autofluorescent spots can be observed in mutant but not in wild‐type littermates.

De Dreu and Gross (D&G) seem to have disregarded some relevant experimental literature on games of conflict, most notably variations on “matching pennies” games. While in such games, “attacker” and “defender” are typically not explicitly labelled, players’ differentiated roles yield naturally to such notions. These studies partly validate some of D&G's findings and interpretations.

Attitudes towards risk and uncertainty have been indicated to be highly context-dependent, and to be sensitive to the measurement technique employed. We present data collected in controlled experiments with 2,939 subjects in 30 countries measuring risk and uncertaintly attitudes through incentivized measures as well as survey questions. Our data show clearly that measures correlate not only within decision contexts or measurement methods, but also across contexts and methods. This points to the existence of one underlying \"risk preference\", which influences attitudes independently of the measurement method or choice domain. We furthermore find that answers to a general and a financial survey question correlate with incentivized lottery choices in most countries. Incentivized and survey measures also correlate significantly between countries. This opens the possibility to conduct cultural comparisons on risk attitudes using survey instruments.

The representativeness heuristic (RH) has been proposed to be at the root of several types of biases in judgment. In this project, we ask whether the RH is relevant in two kinds of choices in the context of gambling. Specifically, in a field experiment with naturalistic stimuli and a potentially extremely high monetary pay-out, we give each of our subjects a choice between a lottery ticket with a random-looking number sequence and a ticket with a patterned sequence; we subsequently offer them a small cash bonus if they switch to the other ticket. In the second task, we investigate the gambler’s fallacy, asking subjects what they believe the outcome of a fourth coin toss after a sequence of three identical outcomes will be. We find that most subjects prefer “random” sequences, and that approximately half believe in dependence between subsequent coin tosses. There is no correlation, though, between the initial choice of the lottery ticket and the prediction of the coin toss. Nonetheless, subjects who have a strong preference for certain number combinations (i.e., subjects who are willing to forgo the cash bonus and remain with their initial choice) also tend to predict a specific outcome (in particular a reversal, corresponding to the gambler’s fallacy) in the coin task.

Loss of tumor suppressor adenomatous polyposis coli (APC) activates β-catenin to initiate colorectal tumorigenesis. However, β-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.