Rational Design of Novel Anticancer Small-Molecule RNA m6A Demethylase ALKBH5 Inhibitors

The RNA 6-N-methyladenosine (m6A) demethylase ALKBH5 has been shown to be oncogenic in several cancer types, including leukemia and glioblastoma. We present here the target-tailored development and first evaluation of the antiproliferative effects of new ALKBH5 inhibitors. Two compounds, 2-[(1-hydroxy-2-oxo-2-phenylethyl)sulfanyl]acetic acid (3) and 4-{[(furan-2-yl)methyl]amino}-1,2-diazinane-3,6-dione (6), with IC50 values of 0.84 mu M and 1.79 mu M, respectively, were identified in high-throughput virtual screening of the library of 144 000 preselected compounds and subsequent verification of hits in an m6A antibody-based enzyme-linked immunosorbent assay (ELISA) enzyme inhibition assay. The effect of these compounds on the proliferation of selected target cancer cell lines was then measured. In the case of three leukemia cell lines (HL-60, CCRF-CEM, and K562) the cell proliferation was suppressed at low micromolar concentrations of inhibitors, with IC50 ranging from 1.38 to 16.5 mu M. However, the effect was low or negligible in the case of another leukemia cell line, Jurkat, and the glioblastoma cell line A-172. These results demonstrate the potential of ALKBH5 inhibition as a cancer-cell-type-selective antiproliferative strategy.Peer reviewe

Penggunaan Bahasa Figuratif dalam Kumpulan Puisi Deru Campur Debu Karya Chairil Anwar

This study aims to delineate the use of figurative language, the meaning of figurative language, and implementation plans in the figurative language of poetry DCD works Anwar. Method of research is descriptive method qualitative terms with the semiotic approach. Based on the results of data analysts, then the resulting conclusions as follows: 1) The use of figurative language in poetry collection DCD, the metaphor contained in the poem "Sia-sia", the comparison contained in the poem "Penerimaan", the parable epos contained in poem "Kabar dari Laut", the personification contained in the poem "Cintaku Jauh di Pulau”, "Hampa", "Selamat Tinggal", "Sajak Putih", and "Penerimaan", metonymy contained in the poem "Kabar dari Laut" and "Tuti Artic "sinekdoki contained in the poem "Kabar dari Laut", and “Senja di Pelabuhan Kecil", and not in the allegorical poetry collection. 2) The meaning of figurative language in poetry DCD collection consists of icons, indices, and symbols. 3) Plan for implementation in this study contained on Unit Level Curriculum with the SK 5.Listening: understand poetry delivered directly and indirectly and KD to identify the elements of poetry forms submitted directly or through recording

Penggunaan Bahasa Figuratif dalam Kumpulan Puisi Deru Campur Debu Karya Chairil Anwar

This study aims to delineate the use of figurative language, the meaning of figurative language, and implementation plans in the figurative language of poetry DCD works Anwar. Method of research is descriptive method qualitative terms with the semiotic approach. Based on the results of data analysts, then the resulting conclusions as follows: 1) The use of figurative language in poetry collection DCD, the metaphor contained in the poem "Sia-sia", the comparison contained in the poem "Penerimaan", the parable epos contained in poem "Kabar dari Laut", the personification contained in the poem "Cintaku Jauh di Pulau”, "Hampa", "Selamat Tinggal", "Sajak Putih", and "Penerimaan", metonymy contained in the poem "Kabar dari Laut" and "Tuti Artic "sinekdoki contained in the poem "Kabar dari Laut", and “Senja di Pelabuhan Kecil", and not in the allegorical poetry collection. 2) The meaning of figurative language in poetry DCD collection consists of icons, indices, and symbols. 3) Plan for implementation in this study contained on Unit Level Curriculum with the SK 5.Listening: understand poetry delivered directly and indirectly and KD to identify the elements of poetry forms submitted directly or through recording

Probe-caught spontaneous and deliberate mind wandering in relation to self-reported inattentive, hyperactive and impulsive traits in adults.

Research has revealed a positive relationship between types of mind wandering and ADHD at clinical and subclinical levels. However, this work did not consider the relationship between mind wandering and the core symptoms of ADHD: inattention, hyperactivity and impulsivity. Given that the DMS-V attributes mind wandering to inattention only, and that only inattention is thought to result from impairment to the executive function linked to mind wandering, the present research sought to examine this relationship in 80 undiagnosed adults. Using both standard and easy versions of the Sustained Attention to Response Task (SART) we measured both spontaneous and deliberate mind wandering. We found that spontaneous mind wandering was related to self-reported inattentive traits when the task was cognitively more challenging (standard SART). However, hyperactive and impulsive traits were related to spontaneous mind wandering independent of task difficulty. The results suggest inattentive traits are not uniquely related to mind wandering; indeed, adults with hyperactive/impulsive traits were more likely to experience mind wandering, suggesting that mind wandering might not be useful diagnostic criteria for inattention

Metabolomics and its application for non-invasive embryo assessment in IVF

Morphology and cleavage rate remain the mainstay of embryo assessment. However, a number of additional technologies for this application are under investigation. These include the measurement of glucose, lactate, pyruvate or amino acid levels in the embryo culture media, assessment of oxygen consumption by the embryo, genomic and proteomic profiling, and most recently, analytical examination of the embryonic metabolome. As the number of assisted reproduction cycles increases worldwide, improvements in the ability to quickly and non-invasively identify the best embryos for transfer remain a critical goal for reproductive medicine. Recent studies suggest that metabolomic profiling of embryo culture media using optical and non-optical spectroscopies may provide a useful adjunct to the current embryo assessment strategies and provide insight into the phenotype of embryos with increasing reproductive potential

Spontaneous and deliberate future thinking: A dual process account

© 2019 Springer Nature.This is the final published version of an article published in Psychological Research, licensed under a Creative Commons Attri-bution 4.0 International License. Available online at: https://doi.org/10.1007/s00426-019-01262-7.In this article, we address an apparent paradox in the literature on mental time travel and mind-wandering: How is it possible that future thinking is both constructive, yet often experienced as occurring spontaneously? We identify and describe two ‘routes’ whereby episodic future thoughts are brought to consciousness, with each of the ‘routes’ being associated with separable cognitive processes and functions. Voluntary future thinking relies on controlled, deliberate and slow cognitive processing. The other, termed involuntary or spontaneous future thinking, relies on automatic processes that allows ‘fully-fledged’ episodic future thoughts to freely come to mind, often triggered by internal or external cues. To unravel the paradox, we propose that the majority of spontaneous future thoughts are ‘pre-made’ (i.e., each spontaneous future thought is a re-iteration of a previously constructed future event), and therefore based on simple, well-understood, memory processes. We also propose that the pre-made hypothesis explains why spontaneous future thoughts occur rapidly, are similar to involuntary memories, and predominantly about upcoming tasks and goals. We also raise the possibility that spontaneous future thinking is the default mode of imagining the future. This dual process approach complements and extends standard theoretical approaches that emphasise constructive simulation, and outlines novel opportunities for researchers examining voluntary and spontaneous forms of future thinking.Peer reviewe

Alternative splicing of the mouse embryonic poly(A) binding protein (Epab) mRNA is regulated by an exonic splicing enhancer: a model for post-transcriptional control of gene expression in the oocyte

Embryonic poly(A) binding protein (EPAB), expressed in oocytes and early embryos, binds and stabilizes maternal mRNAs, and mediates initiation of their translation. We identified an alternatively spliced form of Epab lacking exon 10 (c.Ex10del) and investigated the regulation of Epab mRNA alternative splicing as a model for alternative splicing in oocytes and early preimplantation embryos. Specifically, we evaluated the following mechanisms: imprinting; RNA editing and exonic splicing enhancers (ESEs). Sequence analysis led to the identification of two single nucleotide polymorphisms (SNPs): one was detected in exon 9 (rs55858A/G), and served as a marker for the parental origin of the alternatively spliced form, and the other was found in exon 10 (rs56574G/C), and co-segregated with the exon 9 SNP. We found that the presence of rs56574G in exon 10 led to the formation of an ESE, leading to efficient exclusion of exon 10. Real-time RT–PCR results revealed a 5-fold increase in the expression of the c.Ex10del alternative splicing variant in animals carrying rs56574G/G in exon 10 compared with rs56574C/C at the same locus. Our findings suggest that SNPs may alter the ratio between alternative splicing variants of oocyte-specific proteins. The role that these subtle differences play in determining individual reproductive outcome remains to be determined

Electrochemical lactate biosensor based upon chitosan/carbon nanotubes modified screen-printed graphite electrodes for the determination of lactate in embryonic cell cultures.

l-lactate is an essential metabolite present in embryonic cell culture. Changes of this important metabolite during the growth of human embryo reflect the quality and viability of the embryo. In this study, we report a sensitive, stable, and easily manufactured electrochemical biosensor for the detection of lactate within embryonic cell cultures media. Screen-printed disposable electrodes are used as electrochemical sensing platforms for the miniaturization of the lactate biosensor. Chitosan/multi walled carbon nanotubes composite have been employed for the enzymatic immobilization of the lactate oxidase enzyme. This novel electrochemical lactate biosensor analytical efficacy is explored towards the sensing of lactate in model (buffer) solutions and is found to exhibit a linear response towards lactate over the concentration range of 30.4 and 243.9µM in phosphate buffer solution, with a corresponding limit of detection (based on 3-sigma) of 22.6µM and exhibits a sensitivity of 3417±131µAM(-1) according to the reproducibility study. These novel electrochemical lactate biosensors exhibit a high reproducibility, with a relative standard deviation of less than 3.8% and an enzymatic response over 82% after 5 months stored at 4°C. Furthermore, high performance liquid chromatography technique has been utilized to independently validate the electrochemical lactate biosensor for the determination of lactate in a commercial embryonic cell culture medium providing excellent agreement between the two analytical protocols