Epigenetic mutagen-like environmental chemicals alter neural differentiation of human induced pluripotent stem cells.

Various chemicals, including pesticides, heavy metals, and metabolites of tobacco, have been detected in fetal environment. Fetuses are exposed to these chemicals at relatively low concentrations; however, their risk of developing neurological and behavioral disorders increases after birth. We aimed to evaluate the effects of five chemicals (diethylphosphate, cotinine, octachlorodipropyl ether, mercury, and selenium) detected in the serum of pregnant mothers on neural development using human neurospheres (NSphs) differentiated from induced pluripotent stem cells.

Internal Trapping of a Growing Ruptured Dissecting Aneurysm of the A1 Segment: A Case Report and Literature Review.

A 47-year-old man presented with sudden-onset headache and Fisher group 3 subarachnoid hemorrhage. The World Federation of Neurological Surgeons grade was II. Digital subtraction angiography (DSA) only showed a vessel wall irregularity in the A1 segment of the right anterior cerebral artery (ACA), but an obvious bleeding source was not detected.

Factors affecting reasonable duration of continuous electrocardiographic monitoring to detect atrial fibrillation in acute ischemic stroke.

Background: To examine the reasonable duration of continuous electrocardiographic monitoring (CEM) to detect AF at acute ischemic stroke.

Materials And Method: 811 consecutive patients admitted to Tsuruga Municipal Hospital by acute ischemic stroke between April 2013 and December 2021 were enrolled in this study. Excluding 78 patients, 733 patients were analyzed by cluster analysis with SurvCART algorithm, followed by Kaplan-Meier analysis.

Variation of DNA methylation on the genes is responsible for the neural differentiation propensity in human induced pluripotent stem cells.

Introduction: Human induced pluripotent stem cells (hiPSCs) are useful tools for reproducing neural development . However, each hiPSC line has a different ability to differentiate into specific lineages, known as differentiation propensity, resulting in reduced reproducibility and increased time and funding requirements for research. To overcome this issue, we searched for predictive signatures of neural differentiation propensity of hiPSCs focusing on DNA methylation, which is the main modulator of cellular properties.

Lead optimization of pyrido[2,3-d][1]benzazepin-6-one derivatives leading to the discovery of a potent, selective, and orally available human parathyroid hormone receptor 1 (hPTHR1) antagonist (DS69910557).

We report the discovery of a series of novel zwitterionic hPTHR1 antagonists. Optimization of lead compound 2 led to 4-[[1-[4-(2,9-dichloro-5,5-dimethyl-6-oxo-pyrido[2,3-d][1]benzazepin-7-yl)phenyl]-3-fluoro-azetidin-3-yl]methylamino]cyclohexanecarboxylic acid (19e, DS69910557), a compound with excellent potency and selectivity over activity at the human ether-a-go-go-related-gene (hERG) channel. Compound 19e demonstrated in vivo potency to decrease the plasma calcium concentration in rats upon oral administration.

Identification of an epigenetic signature in human induced pluripotent stem cells using a linear machine learning model.

The use of human induced pluripotent stem cells (iPSCs), used as an alternative to human embryonic stem cells (ESCs), is a potential solution to challenges, such as immune rejection, and does not involve the ethical issues concerning the use of ESCs in regenerative medicine, thereby enabling developments in biological research. However, comparative analyses from previous studies have not indicated any specific feature that distinguishes iPSCs from ESCs. Therefore, in this study, we established a linear classification-based learning model to distinguish among ESCs, iPSCs, embryonal carcinoma cells (ECCs), and somatic cells on the basis of their DNA methylation profiles.

Discovery of novel, potent, and orally bioavailable pyrido[2,3-d][1]benzazepin-6-one antagonists for parathyroid hormone receptor 1.

Structural modification of a 1,4-benzodiazepin-2-one-based PTHR1 antagonist 5, a novel type of PTHR1 antagonist previously synthesized in our laboratories, yielded compound 10, which had better chemical stability than compound 5. Successive optimization of the lead 10 improved aqueous solubility, metabolic stability, and animal pharmacokinetics, culminating in the identification of DS37571084 (12). Our study paves the way for the discovery of novel and orally bioavailable PTHR1 antagonists.

Dog Steroidogenic Factor-1: Molecular cloning and analysis of epigenetic regulation.

Steroidogenic factor 1 (SF-1) is a nuclear receptor that is important in steroid hormone production, and adrenal and gonad development. The SF-1 gene is highly conserved among most vertebrates. However, dog SF-1 registered in public databases, such as CanFam3.

DNA methylation ambiguity in the Fibrillin-1 (FBN1) CpG island shore possibly involved in Marfan syndrome.

Fibrillin-1 (FBN1) is responsible for haploinsufficient and autosomal dominant Marfan syndrome. Even in the same Marfan pedigree, penetrance and expressivity in heterozygous individuals can differ and result in variable disease onset and severity. Thus, other factors in addition to mutations in FBN1 are likely to contribute to the disease.

Discovery and structure-activity relationships of spiroindolines as novel inducers of oligodendrocyte progenitor cell differentiation.

A novel series of spiroindoline derivatives was discovered for use as inducers of oligodendrocyte progenitor cell (OPC) differentiation, resulting from optimization of screening hit 1. Exploration of structure-activity relationships led to compound 18, which showed improved potency (rOPC EC = 0.0032 μM).

Discovery of novel PTHR1 antagonists: Design, synthesis, and structure activity relationships.

The discovery and optimization of a novel series of PTHR1 antagonists are described. Starting from known PTHR1 antagonists, we identified more potent 1,4-benzodiazepin-2-one derivatives by means of a scaffold-hopping approach. The representative compound 23 (DS08210767) exhibited nanomolar-level PTHR1 antagonist activity and potential oral bioavailability in a pharmacokinetic study.

Effectiveness of bioengineered islet cell sheets for the treatment of diabetes mellitus.

Background: The present study aimed to evaluate whether bioengineered mouse islet cell sheets can be used for the treatment of diabetes mellitus.

Methods: Isolated mouse pancreatic islets were dispersed, and cells were plated on temperature-responsive culture plates coated with iMatrix-551. On day 3 of culture, the sheets were detached from the plates and used for further analysis or transplantation.

[Significance of Thoraco-laparoscopic Observation in Repairing Diaphragmatic Injury by the Penetrating Trauma].

A 53-year-old man with a penetrating trauma was admitted to our hospital. Thoracoabdominal computed tomography (CT) on admission showed left diaphragmatic injury and peritoneal fat in the left thoracic cavity. Under a diagnosis of the traumatic diaphragmatic injury, an emergency operation was performed, and the left diaphragm was repaired.

Evidence of exposure to chemicals and heavy metals during pregnancy in Japanese women.

Purpose: Prenatal exposure to environmental chemicals is a growing concern, because such exposures have been shown to be associated with various diseases. The levels of chemicals and heavy metals in maternal blood, cord blood, maternal urine and amniotic fluid in Japanese pregnant women were investigated.

Methods: A total of 145 women, including 14 fetal growth restriction cases, were included in the present study.

DNA hypermethylation enhanced telomerase reverse transcriptase expression in human-induced pluripotent stem cells.

During reprogramming into human induced pluripotent stem cells (iPSCs), several stem cell marker genes are induced, such as OCT-4, NANOG, SALL4, and TERT. OCT-4, NANOG, and SALL4 gene expression can be regulated by DNA methylation. Their promoters become hypomethylated in iPSCs during reprogramming, leading to their induced expression.

Evaluation of obliteration of arteriovenous malformations after stereotactic radiosurgery with arterial spin labeling MR imaging.

Purpose: Complete obliteration of treated arteriovenous malformations (AVMs) can be diagnosed only by confirming the disappearance of arterio-venous (A-V) shunts with invasive catheter angiography. The authors evaluated whether non-invasive arterial spin labeling (ASL) magnetic resonance (MR) imaging can be used to diagnose the obliteration of AVMs facilitate the diagnosis of AVM obliteration after treatment with stereotactic radiosurgery (SRS).

Material And Methods: Seven patients with a cerebral AVM treated by SRS were followed up with ASL images taken with a 3T-MR unit, and received digital subtraction angiography (DSA) after the AVM had disappeared on ASL images.

Deflation of a Rathke cleft cyst triggered rupture of a superior hypophyseal artery aneurysm: a case report.

A 57-year-old woman was diagnosed as a Rathke cleft cyst (RCC). Endoscopic transsphenoidal surgery (TSS) was performed uneventfully. She developed subarachnoid haemorrhage on postoperative day 3.

Establishment of DNA methylation patterns of the Fibrillin1 (FBN1) gene in porcine embryos and tissues.

DNA methylation in transcriptional regulatory regions is crucial for gene expression. The DNA methylation status of the edges of CpG islands, called CpG island shore, is involved in tissue/cell-type-specific gene expression. Haploinsufficiency diseases are caused by inheritance of one mutated null allele and are classified as autosomal dominant.

Cerebral hyperperfusion syndrome resulting in subarachnoid hemorrhage after carotid artery stenting.

A 64-year-old, right-handed man underwent endovascular treatment for internal carotid artery stenosis after experiencing a left-hemispheric transient ischemic attack. O-gas and H O positron emission tomography revealed slightly reduced cerebral blood flow (CBF), elevated cerebral blood volume, and severely reduced cerebral vasoreactivity in the ipsilateral hemisphere as determined by an acetazolamide challenge test. The patient underwent left carotid artery stenting (CAS) via a prefemoral approach under local anesthesia without any complications.

A transgenic-cloned pig model expressing non-fluorescent modified Plum.

Genetically modified pigs that express fluorescent proteins such as green and red fluorescent proteins have become indispensable biomedical research tools in recent years. Cell or tissue transplantation studies using fluorescent markers should be conducted, wherein the xeno-antigenicity of the fluorescent proteins does not affect engraftment or graft survival. Thus, we aimed to create a transgenic (Tg)-cloned pig that was immunologically tolerant to fluorescent protein antigens.

Ultra-Deep Bisulfite Sequencing to Detect Specific DNA Methylation Patterns of Minor Cell Types in Heterogeneous Cell Populations: An Example of the Pituitary Tissue.

DNA methylation is an epigenetic modification important for cell fate determination and cell type-specific gene expression. Transcriptional regulatory regions of the mammalian genome contain a large number of tissue/cell type-dependent differentially methylated regions (T-DMRs) with DNA methylation patterns crucial for transcription of the corresponding genes. In general, tissues consist of multiple cell types in various proportions, making it difficult to detect T-DMRs of minor cell types in tissues.

Putative Epimutagens in Maternal Peripheral and Cord Blood Samples Identified Using Human Induced Pluripotent Stem Cells.

The regulation of transcription and genome stability by epigenetic systems are crucial for the proper development of mammalian embryos. Chemicals that disturb epigenetic systems are termed epimutagens. We previously performed chemical screening that focused on heterochromatin formation and DNA methylation status in mouse embryonic stem cells and identified five epimutagens: diethyl phosphate (DEP), mercury (Hg), cotinine, selenium (Se), and octachlorodipropyl ether (S-421).

[A long-term follow up of right ophthalmoplegia and severe right middle cerebral artery stenosis with right herpes zoster ophthalmics: a case report].

Here we report a case of a 68-year-old man with severe stenosis of the right middle cerebral artery (MCA) following herpes zoster ophthalmicus. He presented with right-sided ptosis and ophthalmoplegia 2 months after herpes zoster ophthalmicus. Cerebrospinal fluid (CSF) analysis revealed monocytosis, increased protein levels, and positivity for herpes zoster virus immunoglobulin M (IgM).

A new system to evaluate the influence of immunosuppressive drugs on pancreatic islets using epigenetic analysis in a 3-dimensional culture.

Objective: The present study aimed to establish a new method to evaluate the influence of immunosuppressive drugs on pancreatic islets in short-term in vitro cultures using epigenetic analysis in a 3-dimensional culture.

Methods: For this purpose, we selected (a) a 3-dimensional culture system utilizing thermoreversible gelation polymer, (b) pancreatic duodenal homeobox-1 (pdx-1)-Venus transgenic pigs expressing the green fluorescent protein, (c) FK506 as an immunosuppressive drug of the evaluation, and (d) the bisulfite sequencing technique to evaluate the methylation levels of pdx-1 and insulin genes. Each isolated pancreatic islet was cultured with several doses of FK506.