Multiple DNA damages induced by water radiolysis demonstrated using a dynamic Monte Carlo code.

Multiple DNA damage resulting from different nearby ionizations of water molecules is an important process of the initial step of radiobiological effects. Several important characteristics of the damaged DNA site such as the critical size and types of chemical lesions are not well-known. We investigated this long-term issue by developing a dynamic Monte Carlo code for the chemical process.

Moment analysis method for determination of rate constants of solute permeation across interface of spherical molecular aggregates by means of high-performance liquid chromatography.

A moment analysis method was developed for the study of solute permeation at the interface of spherical molecular aggregates. At first, new moment equations were developed for determining the partition equilibrium constant (K) and permeation rate constants (k and k) of solutes from the first absolute (μ) and second central (μ) moments of elution peaks measured by using high-performance liquid chromatography (HPLC). Then, the method was applied to the analysis of mass transfer phenomena of three solutes, i.

Osteoblastgenic and Osteogenic Effects of KY-273 with CDK8/19 Inhibitory Activity in Bone Marrow Mesenchymal Stem Cells and Female Rats.

Osteoporosis is caused by imbalance between osteogenesis and bone resorption, thus, osteogenic drugs and resorption inhibitors are used for treatment of osteoporosis. The present study examined the effects of (R)-4-(1-hydroxyethyl)-3-{4-[2-(tetrahydropyran-4-yloxy)ethoxy]phenoxy}benzamide (KY-273), a diphenyl ether derivative, on CDK8/19 activity, osteoblast differentiation and femoral bone using micro-computed tomography in female rats. KY-273 potently inhibited CDK8/19 activity, promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity, and gene expression of type I collagen, ALP and BMP-4 in mesenchymal stem cells (ST2 cells).

Discovery of Novel Chromenopyridine Derivatives as Readthrough-Inducing Drugs.

Hurler syndrome, a type of Mucopolysaccharidosis type I, is an inherited disorder caused by the accumulation of glycosaminoglycans (GAG) due to a deficiency in lysosomal α-L-iduronidase (IDUA), resulting in multiorgan dysfunction. In many patients with Hurler syndrome, IDUA proteins are not produced due to nonsense mutations in their genes; therefore, readthrough-inducing compounds, such as gentamycin, are expected to restore IDUA proteins by skipping the premature termination codon. In the present study, we synthesized a series of chromenopyridine derivatives to identify novel readthrough-inducing compounds.

Osteogenic Effects of KY-054, a Novel Coumarin Derivative on Femur Cortical Bone in Ovariectomized Female Rats.

Osteoporosis is treated with oral and parenteral bone resorption inhibitors such as bisphosphonates, and parenteral osteogenic drugs including parathyroid hormone (PTH) analogues and anti-sclerostin antibodies. In the present study, we synthesized KY-054, a 4,6-substituted coumarin derivative, and found that it potently promoted osteoblast differentiation with an increase in alkaline phosphatase (ALP) activity at 0.01-1 µM in mouse-derived mesenchymal stem cells (ST2 cells) and rat bone marrow-derived mesenchymal stem cells (BMSCs).

Synthesis and Evaluation of Novel Triaryl Derivatives with Readthrough-Inducing Activity.

The readthrough mechanism, which skips the premature termination codon and restores the biosynthesis of the defective enzyme, is an emerging therapeutic tactic for nonsense mutation-related diseases, such as Hurler syndrome, a type of mucopolysaccharidosis. In the present study, novel triaryl derivatives were synthesized and their readthrough-inducing activities were evaluated by a luciferase reporter assay with a partial α-L-iduronidase (IDUA) DNA sequence containing the Q70X nonsense mutation found in Hurler syndrome and by measuring the enzyme activity of IDUA knockout cells transfected with the mutant IDUA gene. KY-516, a representative compound in which the meta position carboxyl group of the left ring of the clinically used ataluren was converted to the para position sulfamoylamino group, the central ring to triazole, and the right ring to cyanobenzene, exhibited the most potent readthrough-inducing activity in the Q70X/luciferase reporter assay.

Rectal Carcinoma With a Sarcomatoid Component: A Case Report With Detailed Immunohistochemistry, Molecular Analysis, and Literature Review.

Carcinoma with sarcomatoid components is a highly malignant tumor exhibiting both epithelial and stromal malignant differentiation. Its tumorigenesis is associated with epithelial-mesenchymal transition (EMT), and phenotypic changes from carcinoma to sarcoma are associated with mutations. A 73-year-old female with bloody stool was diagnosed with rectal adenocarcinoma.

The relationship between evaluation of shared decision-making by pet owners and veterinarians and satisfaction with veterinary consultations.

Background: Communication skills are a necessary competency in veterinary medicine, and shared decision-making (SDM) between practitioners and patients is becoming increasingly important in veterinary practice as in human medicine. There are few studies that have quantitatively measured SDM in veterinary health care, and the relationship between SDM and consultation satisfaction is unknown. The purpose of this study was to investigate the status of SDM implementation in veterinary hospitals and the relationship between SDM implementation and consultation satisfaction among pet owners.

Identification of responsible amino acid residues in staphylococcal superantigen-like 12 for the activation of mast cells.

Staphylococcal superantigen-like 12 (SSL12) is reported to evoke the degranulation in murine mast cells. The allelic variant of SSL12 in the genome of reference strain NCTC8325 induced the degranulation of murine mast cells, that of MRSA252 strain did not, nevertheless relatively high sequence similarity (82%). To identify responsible amino acid residues of SSL12 for mast cell activation, we created a series of domain swap mutants and amino acid substitution mutants between the active and inactive variants.

Ribosomal protein L5 facilitates rDNA-bundled condensate and nucleolar assembly.

The nucleolus is the site of ribosome assembly and formed through liquid-liquid phase separation. Multiple ribosomal DNA (rDNA) arrays are bundled in the nucleolus, but the underlying mechanism and significance are unknown. In the present study, we performed high-content screening followed by image profiling with the wndchrm machine learning algorithm.

Genome-wide analysis of mRNA and microRNA expression in colorectal cancer and adjacent normal mucosa.

mRNA expression varies in human cancers. Such altered mRNA expression is negatively regulated by the expression of microRNAs (miRNAs), which play an important role in human tumorigenesis. According to this theory, inverse mRNA/miRNA expression may be a direct driver of cancer development, and certain genetic events may occur prior to the development of any discernible histological abnormalities.

Live imaging of transcription sites using an elongating RNA polymerase II-specific probe.

In eukaryotic nuclei, most genes are transcribed by RNA polymerase II (RNAP2), whose regulation is a key to understanding the genome and cell function. RNAP2 has a long heptapeptide repeat (Tyr1-Ser2-Pro3-Thr4-Ser5-Pro6-Ser7), and Ser2 is phosphorylated on an elongation form. To detect RNAP2 Ser2 phosphorylation (RNAP2 Ser2ph) in living cells, we developed a genetically encoded modification-specific intracellular antibody (mintbody) probe.

Visualizing looping of two endogenous genomic loci using synthetic zinc-finger proteins with anti-FLAG and anti-HA frankenbodies in living cells.

In eukaryotic nuclei, chromatin loops mediated through cohesin are critical structures that regulate gene expression and DNA replication. Here, we demonstrate a new method to see endogenous genomic loci using synthetic zinc-finger proteins harboring repeat epitope tags (ZF probes) for signal amplification via binding of tag-specific intracellular antibodies, or frankenbodies, fused with fluorescent proteins. We achieve this in two steps: First, we develop an anti-FLAG frankenbody that can bind FLAG-tagged proteins in diverse live-cell environments.

Effects of KY-903, a Novel Tetrazole-Based Peroxisome Proliferator-Activated Receptor γ Modulator, in Male Diabetic Mice and Female Ovariectomized Rats.

Peroxisome proliferator-activated receptor γ (PPARγ) modulators are expected to exert anti-diabetic effects without PPARγ-related adverse effects, such as fluid retention, weight gain, and bone loss. The present study showed that the novel tetrazole derivative KY-903 exerted similar selective PPARγ partial agonist properties to INT-131, a known PPARγ modulator, in transactivation assays, and decreased plasma glucose and triglyceride levels with increases in adiponectin levels in diabetic KK-Ay mice. These effects were similar to those of pioglitazone.

Synthesis and Evaluation of a Novel Series of 2,7-Substituted-6-tetrazolyl-1,2,3,4-tetrahydroisoquinoline Derivatives as Selective Peroxisome Proliferator-Activated Receptor γ Partial Agonists.

A novel series of 7-substituted-2-[3-(2-furyl)acryloyl]-6-tetrazolyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized to clarify structure-activity relationships for peroxisome proliferator-activated receptor γ (PPARγ) partial agonist activity and identify more efficacious PPARγ partial agonists with minor adverse effects. Among the derivatives synthesized, compound 26v with a 2-(2,5-dihydropyrrol-1-yl)-5-methyloxazol-4-ylmethoxy group at the 7-position of the tetrahydroisoquinoline structure exhibited stronger PPARγ agonist and antagonist activities (EC = 6 nM and IC = 101 nM) than previously reported values for compound 1 (EC = 13 nM and IC = 512 nM). Compound 26v had very weak protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and showed higher oral absorption (C = 11.

(S)-1,2,3,4-Tetrahydroisoquinoline Derivatives Substituted with an Acidic Group at the 6-Position as a Selective Peroxisome Proliferator-Activated Receptor γ Partial Agonist.

A novel series of 2,6,7-substituted 3-unsubstituted 1,2,3,4-tetrahydroisoquinoline derivatives were synthesized to find a peroxisome proliferator-activated receptor γ (PPARγ) partial agonist. Among the derivatives, (E)-7-[2-(cyclopent-3-eny)-5-methyloxazol-4-ylmethoxy]-2-[3-(2-furyl)acryloyl]-6-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydroisoquinoline (20g) exhibited potent partial agonist activity (EC = 13 nM, maximal response 30%) and very weak protein tyrosine phosphatase 1B (PTP1B) inhibition (IC = 1100 nM), indicating a selective PPARγ partial agonist. A computational docking calculation revealed that 20g bound to PPARγ in a similar manner to that of known partial agonists.

[A Novel Oral Anti-osteoporosis Drug with Osteogenesis-promoting Effects via Osteoblast Differentiation].

Osteoporosis increases the risk of bone fractures (e.g., the femur), reduces a person's activities of daily living (ADL) and increases the likelihood of being bedridden.

2-Acyl-3-carboxyl-tetrahydroisoquinoline Derivatives: Mixed-Type PTP1B Inhibitors without PPARγ Activation.

A novel series of 2-acyl-3-carboxyl-tetrahydroisoquinoline derivatives were synthesized and biologically evaluated. Among them, (S)-2-{(E)-3-furan-2-ylacryloyl}-7-[(2E,4E)-5-(2,4,6-trifluorophenyl)penta-2,4-dienyloxy]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (compound 17u) was identified as a potent protein tyrosine phosphatase 1B (PTP1B) inhibitor without peroxisome proliferator-activated receptor (PPAR) γ activation: PTP1B inhibition IC=0.19 µM and PPARγ ΕC>10 µM.

CLIP-170 is essential for MTOC repositioning during T cell activation by regulating dynein localisation on the cell surface.

The microtubule-organizing centre (MTOC) is repositioned to the centre of the contacted cell surface, the immunological synapse, during T cell activation. However, our understanding of its molecular mechanism remains limited. Here, we found that the microtubule plus-end tracking cytoplasmic linker protein 170 (CLIP-170) plays a novel role in MTOC repositioning using fluorescence imaging.