The long noncoding RNA ANRIL has been found to be abnormally expressed and play important roles in different cancers. However, the expression and function of ANRIL in acute myeloid leukemia (AML) ...remain to be declared. In this study, we found that ANRIL is up-regulated in AML patients at diagnosis and down-regulated in patients after complete remission (CR). Functional studies showed that knockdown of ANRIL expression resulted in a decline in glucose uptake and inhibition of AML cell maintenance in vitro and in vivo. Mechanically, ANRIL was found to repress the expression of Adiponectin receptor (AdipoR1), a key regulator of glucose metabolism. Both ANRIL and AdipoR1 knockdown reduced the expression levels of phosphorylation of AMPK and SIRT1, implying a previously unappreciated ANRIL-AdipoR1-AMPK/SIRT1 signaling pathway in regulating cell glucose metabolism and survival in AML. The study is the first to demonstrate that ANRIL promotes malignant cell survival and cell glucose metabolism to accelerate AML progression and is a potential prognostic marker and therapeutic target in AML treatment.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The cereal endosperm is a major factor determining seed size and shape. However, the molecular mechanisms of endosperm development are not fully understood. Long noncoding RNAs (lncRNAs) function in ...various biological processes. Here we show a lncRNA, MISSEN, that plays an essential role in early endosperm development in rice (Oryza sativa). MISSEN is a parent-of-origin lncRNA expressed in endosperm, and negatively regulates endosperm development, leading to a prominent dent and bulge in the seed. Mechanistically, MISSEN functions through hijacking a helicase family protein (HeFP) to regulate tubulin function during endosperm nucleus division and endosperm cellularization, resulting in abnormal cytoskeletal polymerization. Finally, we revealed that the expression of MISSEN is inhibited by histone H3 lysine 27 trimethylation (H3K27me3) modification after pollination. Therefore, MISSEN is the first lncRNA identified as a regulator in endosperm development, highlighting the potential applications in rice breeding.
Photoplethysmography (PPG) is a noninvasive optical technique for detecting microvascular blood volume changes in tissues. Its ease of use, low cost and convenience make it an attractive area of ...research in the biomedical and clinical communities. Nevertheless, its single spot monitoring and the need to apply a PPG sensor directly to the skin limit its practicality in situations such as perfusion mapping and healing assessments or when free movement is required. The introduction of fast digital cameras into clinical imaging monitoring and diagnosis systems, the desire to reduce the physical restrictions, and the possible new insights that might come from perfusion imaging and mapping inspired the evolution of the conventional PPG technology to imaging PPG (IPPG). IPPG is a noncontact method that can detect heart-generated pulse waves by means of peripheral blood perfusion measurements. Since its inception, IPPG has attracted significant public interest and provided opportunities to improve personal healthcare. This study presents an overview of the wide range of IPPG systems currently being introduced along with examples of their application in various physiological assessments. We believe that the widespread acceptance of IPPG is happening, and it will dramatically accelerate the promotion of this healthcare model in the near future.
The regio‐ and enantioselective (3+3) cycloaddition of nitrones with 2‐indolylmethanols was accomplished by the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). ...Using this approach, a series of indole‐fused six‐membered heterocycles were synthesized in high yields (up to 98 %), with excellent enantioselectivities (up to 96 % ee) and exclusive regiospecificity. This approach enabled not only the first organocatalytic asymmetric (3+3) cycloaddition of nitrones but also the first C3‐nucleophilic asymmetric (3+3) cycloaddition of 2‐indolylmethanols. More importantly, theoretical calculations elucidated the role of the cocatalyst HFIP in helping CPA control the reactivity and enantioselectivity of the reaction, demonstrating a new mode of cooperative catalysis.
The regio‐ and enantioselective (3+3) cycloaddition of nitrones with 2‐indolylmethanols has been established under the cooperative catalysis of hexafluoroisopropanol (HFIP) and chiral phosphoric acid (CPA). This approach not only realized the first organocatalytic asymmetric (3+3) cycloaddition of nitrones and the first C3‐nucleophilic asymmetric (3+3) cycloaddition of 2‐indolylmethanols but also revealed a new mode of cooperative catalysis.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Human pluripotent and trophoblast stem cells have been essential alternatives to blastocysts for understanding early human development
. However, these simple culture systems lack the complexity to ...adequately model the spatiotemporal cellular and molecular dynamics that occur during early embryonic development. Here we describe the reprogramming of fibroblasts into in vitro three-dimensional models of the human blastocyst, termed iBlastoids. Characterization of iBlastoids shows that they model the overall architecture of blastocysts, presenting an inner cell mass-like structure, with epiblast- and primitive endoderm-like cells, a blastocoel-like cavity and a trophectoderm-like outer layer of cells. Single-cell transcriptomics further confirmed the presence of epiblast-, primitive endoderm-, and trophectoderm-like cells. Moreover, iBlastoids can give rise to pluripotent and trophoblast stem cells and are capable of modelling, in vitro, several aspects of the early stage of implantation. In summary, we have developed a scalable and tractable system to model human blastocyst biology; we envision that this will facilitate the study of early human development and the effects of gene mutations and toxins during early embryogenesis, as well as aiding in the development of new therapies associated with in vitro fertilization.
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GEOZS, IJS, IMTLJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZAGLJ
We formulate a version of the information paradox in de Sitter spacetime and show that it is solved by the emergence of entanglement islands in the context of the De Sitter/de Sitter correspondence; ...in particular, the entanglement entropy of a subregion obeys a time-dependent Page curve. Our construction works in general spacetime dimensions and keeps the graviton massless. We interpret the resulting behavior of the entanglement entropy using double holography. It suggests that the spatial distribution of microscopic degrees of freedom depends on descriptions, as in the case of a black hole. In the static (distant) description of de Sitter (black hole) spacetime, these degrees of freedom represent microstates associated with the Gibbons-Hawking (Bekenstein-Hawking) entropy and are localized toward the horizon. On the other hand, in a global (effective two-sided) description, which is obtained by the quantum analog of analytic extension and is intrinsically semiclassical, they are distributed uniformly and in a unique semiclassical de Sitter (black hole) vacuum state.
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CMK, CTK, FMFMET, IJS, NUK, PNG, UM
Zeolite Beta single crystals with intracrystalline hierarchical porosity at macro‐, meso‐, and micro‐length scales can effectively overcome the diffusion limitations in the conversion of bulky ...molecules. However, the construction of large zeolite Beta single crystals with such porosity is a challenge. We report herein the synthesis of hierarchically ordered macro‐mesoporous single‐crystalline zeolite Beta (OMMS‐Beta) with a rare micron‐scale crystal size by an in situ bottom‐up confined zeolite crystallization strategy. The fully interconnected intracrystalline macro‐meso‐microporous hierarchy and the micron‐sized single‐crystalline nature of OMMS‐Beta lead to improved accessibility to active sites and outstanding (hydro)thermal stability. Higher catalytic performances in gas‐phase and liquid‐phase acid‐catalyzed reactions involving bulky molecules are obtained compared to commercial Beta and nanosized Beta zeolites. The strategy has been extended to the synthesis of other zeolitic materials, including ZSM‐5, TS‐1, and SAPO‐34.
An in situ bottom‐up confined zeolite crystallization strategy is developed to construct micron‐sized hierarchically ordered macro‐mesoporous single‐crystalline zeolite Beta with improved accessibility to active sites and outstanding (hydro)thermal stability for both gas‐phase and liquid‐phase acid‐catalyzed reactions of bulky molecules.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Insulin resistance (IR) and the consequences of compensatory hyperinsulinemia are pathogenic factors for a set of metabolic abnormalities, which contribute to the development of diabetes mellitus and ...cardiovascular diseases. We compared traditional lipid levels and ratios and combined them with fasting plasma glucose (FPG) levels or adiposity status for determining their efficiency as independent risk factors for IR.
We enrolled 511 Taiwanese individuals for the analysis. The clinical usefulness of various parameters--such as traditional lipid levels and ratios; visceral adiposity indicators, visceral adiposity index (VAI), and lipid accumulation product (LAP); the product of triglyceride (TG) and FPG (the TyG index); TyG with adiposity status (TyG-body mass index BMI) and TyG-waist circumference index WC); and adipokine levels and ratios--was analyzed to identify IR.
For all lipid ratios, the TG/high-density lipoprotein cholesterol (HDL-C) ratio had the highest additional percentage of variation in the homeostasis model assessment of insulin resistance (HOMA-IR; 7.0% in total); for all variables of interest, TyG-BMI and leptin-adiponectin ratio (LAR) were strongly associated with HOMA-IR, with 16.6% and 23.2% of variability, respectively. A logistic regression analysis revealed similar patterns. A receiver operating characteristic (ROC) curve analysis indicated that TG/HDL-C was a more efficient IR discriminator than other lipid variables or ratios. The area under the ROC curve (AUC) for VAI (0.734) and TyG (0.708) was larger than that for TG/HDL-C (0.707). TyG-BMI and LAR had the largest AUC (0.801 and 0.801, respectively).
TyG-BMI is a simple, powerful, and clinically useful surrogate marker for early identification of IR.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Mixed-lineage leukemia (MLL) gene rearrangements trigger aberrant epigenetic modification and gene expression in hematopoietic stem and progenitor cells, which generates one of the most aggressive ...subtypes of leukemia with an apex self-renewal. It remains a challenge to directly inhibit rearranged MLL itself because of its multiple fusion partners and the poorly annotated downstream genes of MLL fusion proteins; therefore, novel therapeutic targets are urgently needed.
qRT-PCR, receiver operating characteristic (ROC), and leukemia-free survival analysis were used to validate LAMP5-AS1 (LAMP5 antisense 1) expression and evaluate its clinical value. We performed in vitro and in vivo experiments to investigate the functional relevance of LAMP5-AS1 in MLL leukemia progression and leukemia cell stemness. RNA electrophoretic mobility shift assays (EMSA), histone methyltransferase assay, RNA pull-down assay, and RNA fluorescence in situ hybridization (FISH) were used to validate the relationship between LAMP5-AS1 and the methyltransferase activity of DOT1L. The downstream ectopic target genes of LAMP5-AS1/DOT1L were validated by the chromatin immunoprecipitation (ChIP) and western blot.
We discovered that a long noncoding RNA (lncRNA) LAMP5-AS1 can promote higher degrees of H3K79 methylation, followed by upregulated expression of the self-renewal genes in the HOXA cluster, which are responsible for leukemia stemness in context of MLL rearrangements. We found that LAMP5-AS1 is specifically overexpressed in MLL leukemia patients (n = 58) than that in the MLL-wt leukemia (n = 163) (p < 0.001), and the patients with a higher expression level of LAMP5-AS1 exhibited a reduced 5-year leukemia-free survival (p < 0.01). LAMP5-AS1 suppression significantly reduced colony formation and increased differentiation of primary MLL leukemia CD34+ cells. Mechanistically, LAMP5-AS1 facilitated the methyltransferase activity of DOT1L by directly binding its Lys-rich region of catalytic domain, thus promoting the global patterns of H3K79 dimethylation and trimethylation in cells. These observations supported that LAMP5-AS1 upregulated H3K79me2/me3 and the transcription of DOT1L ectopic target genes.
This is the first study that a lncRNA regulates the self-renewal program and differentiation block in MLL leukemia cells by facilitating the methyltransferase activity of DOT1L and global H3K79 methylation, showing its potential as a therapeutic target for MLL leukemia.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Long noncoding enhancer RNAs (lnc-eRNAs) are a subset of stable eRNAs identified from annotated lncRNAs. They might act as enhancer activity-related therapeutic targets in cancer. However, the ...underlying mechanism of epigenetic activation and their function in cancer initiation and progression remain largely unknown.
We identify a set of lncRNAs as lnc-eRNAs according to the epigenetic signatures of enhancers. We show that these lnc-eRNAs are broadly activated in MLL-rearranged leukemia (MLL leukemia), an aggressive leukemia caused by a chromosomal translocation, through a mechanism by which the HOXA cluster initiates enhancer activity, and the epigenetic reader BRD4 cooperates with the coregulator MLL fusion oncoprotein to induce transcriptional activation. To demonstrate the functional roles of lnc-eRNAs, two newly identified lnc-eRNAs transcribed from the SEELA eRNA cluster (SEELA), SEELA1 and SEELA2, are chosen for further studies. The results show that SEELA mediated cis-activated transcription of the nearby oncogene Serine incorporate 2 (SERINC2) by directly binding to the K31 amino acid (aa) of histone H4. Chromatin-bound SEELA strengthens the interaction between chromatin and histone modifiers to promote histone recognition and oncogene transcription. Further studies show that the SEELA-SERINC2 axis regulated aspects of cancer metabolism, such as sphingolipid synthesis, to affect leukemia progression.
This study shows that lnc-eRNAs are epigenetically activated by cancer-initiating oncoproteins and uncovers a cis-activating mechanism of oncogene transcription control based on lnc-eRNA-mediated epigenetic regulation of enhancer activity, providing insights into the critical roles of lnc-eRNAs in cancer initiation and progression.
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