A novel inhibitory mechanism of MRTF-A/B on the ICAM-1 gene expression in vascular endothelial cells

The roles of myocardin-related transcription factor A (MRTF-A) and MRTF-B in vascular endothelial cells are not completely understood. Here, we found a novel regulatory mechanism for MRTF-A/B function. MRTF-A/B tend to accumulate in the nucleus in arterial endothelial cells in vivo and human aortic endothelial cells (HAoECs) in vitro. In HAoECs, nuclear localization of MRTF-A/B was not significantly affected by Y27632 or latrunculin B, primarily due to the reduced binding of MRTF-A/B to G-actin and in part, to the low level of MRTF-A phosphorylation by ERK. MRTF-A/B downregulation by serum depletion or transfection of siRNA against MRTF-A and/or MRTF-B induced ICAM-1 expression in HAoECs. It is known that nuclear import of nuclear factor-kappa B (NF-kappa B) plays a key role in ICAM-1 gene transcription. However, nuclear accumulation of NF-kappa B p65 was not observed in MRTF-A/B-depleted HAoECs. Our present findings suggest that MRTF-A/B inhibit ICAM-1 mRNA expression by forming a complex with NF-kappa B p65 in the nucleus. Conversely, downregulation of MRTF-A/B alleviates this negative regulation without further translocation of NF-kappa B p65 into the nucleus. These results reveal the novel roles of MRTF-A/B in the homeostasis of vascular endothelium

Serum growth differentiation factor 15 is a novel biomarker with high predictive capability for liver cancer occurrence in patients with MASLD regardless of liver fibrosis

Kumazaki S., Hikita H., Tahata Y., et al. Serum growth differentiation factor 15 is a novel biomarker with high predictive capability for liver cancer occurrence in patients with MASLD regardless of liver fibrosis. Alimentary Pharmacology and Therapeutics , (2024); https://doi.org/10.1111/apt.18063.Background and Aims: Although metabolic dysfunction-associated steatotic liver disease (MASLD) patients with a Fib-4 index >1.3 are recommended for fibrosis evaluation via elastography or biopsy, a more convenient method identifying high-risk populations requiring follow-up is needed. We explored the utility of serum levels of growth differentiation factor-15 (GDF15), a cell stress-responsive cytokine related to metabolic syndrome, for stratifying the risk of clinical events in MASLD patients. Methods: Serum GDF15 levels were measured in 518 biopsy-performed MASLD patients, 216 MASLD patients for validation, and 361 health checkup recipients with MASLD. Results: In the biopsy-MASLD cohort, multivariate analysis indicated that the serum GDF15 level was a risk factor for liver cancer, independent of the fibrosis stage or Fib-4 index. Using a GDF15 cutoff of 1.75 ng/mL based on the Youden index, high-GDF15 patients, regardless of fibrosis status, had a higher liver cancer incidence rate. While patients with a Fib-4 index 1.3 developed liver cancer and decompensated liver events at significantly higher rates and had poorer prognoses. In the validation cohort, high-GDF15 patients had significantly higher incidences of liver cancer and decompensated liver events and poorer prognoses than low-GDF15 patients, whether limited to high-Fib-4 patients. Among health checkup recipients with MASLD, 23.0% had a Fib-4 index >1.3, 2.7% had a Fib-4 index >1.3 and >1.75 ng/mL GDF15. Conclusions: Serum GDF15 is a biomarker for liver cancer with high predictive capability and is useful for identifying MASLD patients requiring regular surveillance

Ephrin-A5 and EphA5 Interaction Induces Synaptogenesis during Early Hippocampal Development

Synaptogenesis is a fundamental step in neuronal development. For spiny glutamatergic synapses in hippocampus and cortex, synaptogenesis involves adhesion of pre and postsynaptic membranes, delivery and anchorage of pre and postsynaptic structures including scaffolds such as PSD-95 and NMDA and AMPA receptors, which are glutamate-gated ion channels, as well as the morphological maturation of spines. Although electrical activity-dependent mechanisms are established regulators of these processes, the mechanisms that function during early development, prior to the onset of electrical activity, are unclear. The Eph receptors and ephrins provide cell contact-dependent pathways that regulate axonal and dendritic development. Members of the ephrin-A family are glycosyl-phosphatidylinositol-anchored to the cell surface and activate EphA receptors, which are receptor tyrosine kinases.Here we show that ephrin-A5 interaction with the EphA5 receptor following neuron-neuron contact during early development of hippocampus induces a complex program of synaptogenic events, including expression of functional synaptic NMDA receptor-PSD-95 complexes plus morphological spine maturation and the emergence of electrical activity. The program depends upon voltage-sensitive calcium channel Ca2+ fluxes that activate PKA, CaMKII and PI3 kinase, leading to CREB phosphorylation and a synaptogenic program of gene expression. AMPA receptor subunits, their scaffolds and electrical activity are not induced. Strikingly, in contrast to wild type, stimulation of hippocampal slices from P6 EphA5 receptor functional knockout mice yielded no NMDA receptor currents.These studies suggest that ephrin-A5 and EphA5 signals play a necessary, activity-independent role in the initiation of the early phases of synaptogenesis. The coordinated expression of the NMDAR and PSD-95 induced by eprhin-A5 interaction with EphA5 receptors may be the developmental switch that induces expression of AMPAR and their interacting proteins and the transition to activity-dependent synaptic regulation

CNVs in Three Psychiatric Disorders

BACKGROUND: We aimed to determine the similarities and differences in the roles of genic and regulatory copy number variations (CNVs) in bipolar disorder (BD), schizophrenia (SCZ), and autism spectrum disorder (ASD). METHODS: Based on high-resolution CNV data from 8708 Japanese samples, we performed to our knowledge the largest cross-disorder analysis of genic and regulatory CNVs in BD, SCZ, and ASD. RESULTS: In genic CNVs, we found an increased burden of smaller (500 kb) exonic CNVs in SCZ/ASD. Pathogenic CNVs linked to neurodevelopmental disorders were significantly associated with the risk for each disorder, but BD and SCZ/ASD differed in terms of the effect size (smaller in BD) and subtype distribution of CNVs linked to neurodevelopmental disorders. We identified 3 synaptic genes (DLG2, PCDH15, and ASTN2) as risk factors for BD. Whereas gene set analysis showed that BD-associated pathways were restricted to chromatin biology, SCZ and ASD involved more extensive and similar pathways. Nevertheless, a correlation analysis of gene set results indicated weak but significant pathway similarities between BD and SCZ or ASD (r = 0.25–0.31). In SCZ and ASD, but not BD, CNVs were significantly enriched in enhancers and promoters in brain tissue. CONCLUSIONS: BD and SCZ/ASD differ in terms of CNV burden, characteristics of CNVs linked to neurodevelopmental disorders, and regulatory CNVs. On the other hand, they have shared molecular mechanisms, including chromatin biology. The BD risk genes identified here could provide insight into the pathogenesis of BD

シンキョウジュホウ ト ニホンゴ キョウイク : ドイツ ヤポニクム ニオケル ジッセン ト オウヨウ

ドイツ・ノルトライン・ウェストファーレン州立日本語研修所「ヤポニクム」では 、伝統的教授法の中に新教授法を取り入れ、新しい語学教育を目指している。従来の 知識中心の左脳偏重教育から、頭だけでなく全身を使用する全脳教育を目指す。 新教授法においては、まず全身を使う学習として、教師が口頭で与える命令に対し、学習者が全身で反応するＴＰＲがある。発声練習では、身体の緊張と弛緩を利用した音の生成を「身体リズム運動」で機能的に発音指導できるものとしてＶＴ法がある。「リラックス練習」は、人間の脳と音楽を聴くことによって生じるアルファ波の関係を外国語学習に応用したものである。また、サジェストペディアコースは人間のもつ潜在能力の開発・活用を目指したものであり、その教授法には未知の可能性が潜ん でいる。アンケートの回答から得た学習者のこれら新教授法についての反応は、肯定的な意見とともに否定的意見があるが、否定的なものに関してはその教授法のもつ意義が正 しく理解されていないことから出てきたものが多い。新教授法を用いる際には、教師・学習者間のこれら新教授法に対する相互の理解が前提とされる。At the Japonicum, the Japanese-language institute of Nordrhein-Westfalen in Germany, we try to achieve an alternative language education, while we integrate alternative teaching methods into the framework of a traditionally oriented curriculum. Our aim is the education of the whole brain, in which we use the whole body, in contrast to the previous "left-brain only "education methods, which consider only the mind as most important part. As a learning method, which uses the whole body as an alternative method, there is "TPR. " In this method, the learner responds through the whole body to the orders, which the teacher gives in the form of imperative sentences. For the pronunciation exercise, there is the VT-method, in which the phonetic signals are produced by using the tension and looseness of a body. "Relaxation exercises "use the positive relation between the brain and alpha-waves for the learning of foreign languages. The Suggestopedia course aims of the development and utilization of reserve capacities of learners. This method has unknown abilities. From the answers on the questionnaires about these alternative methods, we got not only positive, but also negative opinions. But what the latter ones concern, are that the learners often did not understand the meanings, which the alternative methods contain. By using the alternative methods, it is important as a presupposition that both learners and teachers complete the course with the understanding of the meanings of these methods

Gold-catalysed cycloisomerisation reactions of 2-(2-propynyl)pyridine N-oxides leading to indolizinones.

Gold(I)-catalysed tandem oxygen-transfer/cycloisomerisation reaction of 2-(2-propynyl)pyridine N-oxides provides an atom-economical route to indolizinone frameworks

Rhodium-Catalyzed Carbene-Transfer Reactions via Thienylcarbene Complexes Generated from Thiocarbamoyl-ene-yne Compounds

Catalytic thienylcarbene-transfer reactions have been developed. The rhodium-catalyzed reaction of alkenes, furans, and thiophenes with a thiocarbamoyl-ene-yne compound as a carbene source gave the cyclopropanation products or ring-opened products of heterocycles. These processes provide efficient synthetic methods for thiophene-containing complex molecules

Copper-Catalyzed C–H Cyanation of Terminal Alkynes with Cyanogen Iodide

A copper-catalyzed reaction of terminal alkynes with cyanogen iodide (ICN) that produces alkynyl cyanides has been developed. The use of tetramethylpiperidine as a sterically congested base was successful in this reaction. Some control experiments revealed that the reaction involves the noncatalyzed formation of alkynyl iodides followed by copper-catalyzed cyanation of the iodides without the formation of copper(I) acetylide. This observation contrasts with what is normally observed in various copper-mediated reactions using terminal alkynes