Micromechanisms of failure in short-fiber-reinforced high-impact polystyrene under tensile loading

Injection-molded, short-glass-fiber-reinforced high-impact polystyrene was investigated under uniaxial tension with special attention to the effects of fiber and rubber concentration on fracture behavior. According to a fracture morphology study performed by polarized optical and scanning electron microscopy, crazes were consecutively initiated from rubber-styrene composite particles and from fiber ends. The rubber particles exhibited an intra-particle failure mode which resulted from the failure manner of the matrix becoming of a more brittle character with increasing fiber fraction. Fibers were surrounded by neigh boring growing crazes. Failure at the fiber-matrix interfaces proceeded with an increase in the number of crazes. With increasing concentration of the fibers, crazing at rubber particles appeared to be suppressed and crazing occurred more preferentially at the fiber ends, which accelerated a macroscopic fracture.Dedicated to Prof. H. H. Kausch on the occasion of his 60th birthday.     

Enhancing the enantioselectivity of lipase in transesterification by substrate matching: an enzyme memory based approach

The substrate matching strategy is described as a new approach for effectively enhancing the lipase enantioselectivity in organic solvent. In the lipase-catalyzed transesterifications of 3a-c, higher enantioselectivities have been achieved using 1a-c, respectively, as the structurally matched acyl donors.     

Intramitochondrial co-assembly between ATP and nucleopeptides induces cancer cell apoptosis

Mitochondria are essential intracellular organelles involved in many cellular processes, especially adenosine triphosphate (ATP) production. Since cancer cells require high ATP levels for proliferation, ATP elimination can be a unique target for cancer growth inhibition. We describe a newly developed mitochondria-targeting nucleopeptide (MNP) that sequesters ATP by self-assembling with ATP inside mitochondria. MNP interacts strongly with ATP through electrostatic and hydrogen bonding interactions. MNP exhibits higher binding affinity for ATP (−637.5 kJ mol⁻¹) than for adenosine diphosphate (ADP) (−578.2 kJ mol⁻¹). To improve anticancer efficacy, the small-sized MNP/ADP complex formed large assemblies with ATP inside cancer cell mitochondria. ATP sequestration and formation of large assemblies of the MNP/ADP–ATP complex inside mitochondria caused physical stress by large structures and metabolic disorders in cancer cells, leading to apoptosis. This work illustrates a facile approach to developing cancer therapeutics that relies on molecular assemblies.

Mitochondria-targeting nucleopeptide (MNP) can sequester ATP by self-assembling with ATP. A small nanosized MNP/ADP complex forms a large assembly with ATP. Thus, intramitochondrial co-assembly causes stress by large structures and apoptosis.     

The Extracts of Polygonum cuspidatum Root and Rhizome Block the Entry of SARS-CoV-2 Wild-Type and Omicron Pseudotyped Viruses via Inhibition of the S-Protein and 3CL Protease

COVID-19, resulting from infection by the SARS-CoV-2 virus, caused a contagious pandemic. Even with the current vaccines, there is still an urgent need to develop effective pharmacological treatments against this deadly disease. Here, we show that the water and ethanol extracts of the root and rhizome of Polygonum cuspidatum (Polygoni Cuspidati Rhizoma et Radix), a common Chinese herbal medicine, blocked the entry of wild-type and the omicron variant of the SARS-CoV-2 pseudotyped virus into fibroblasts or zebrafish larvae, with IC₅₀ values ranging from 0.015 to 0.04 mg/mL. The extracts were shown to inhibit various aspects of the pseudovirus entry, including the interaction between the spike protein (S-protein) and the angiotensin-converting enzyme II (ACE2) receptor, and the 3CL protease activity. Out of the chemical compounds tested in this report, gallic acid, a phytochemical in P. cuspidatum, was shown to have a significant anti-viral effect. Therefore, this might be responsible, at least in part, for the anti-viral efficacy of the herbal extract. Together, our data suggest that the extracts of P. cuspidatum inhibit the entry of wild-type and the omicron variant of SARS-CoV-2, and so they could be considered as potent treatments against COVID-19.     

Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease

Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identifying new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC₅₀ value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mammals and decreased in vivo fat accumulation.     

Reaction dynamics studied via femtosecond X-ray liquidography at X-ray free-electron lasers

X-ray free-electron lasers (XFELs) provide femtosecond X-ray pulses suitable for pump–probe time-resolved studies with a femtosecond time resolution. Since the advent of the first XFEL in 2009, recent years have witnessed a great number of applications with various pump–probe techniques at XFELs. Among these, time-resolved X-ray liquidography (TRXL) is a powerful method for visualizing structural dynamics in the liquid solution phase. Here, we classify various chemical and biological molecular systems studied via femtosecond TRXL (fs-TRXL) at XFELs, depending on the focus of the studied process, into (i) bond cleavage and formation, (ii) charge distribution and electron transfer, (iii) orientational dynamics, (iv) solvation dynamics, (v) coherent nuclear wavepacket dynamics, and (vi) protein structural dynamics, and provide a brief review on each category. We also lay out a plausible roadmap for future fs-TRXL studies for areas that have not been explored yet.

Femtosecond X-ray liquidography using X-ray free-electron lasers (XFELs) visualizes various aspects of reaction dynamics.     

Tomatidine-stimulated maturation of human embryonic stem cell-derived cardiomyocytes for modeling mitochondrial dysfunction

Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) have been reported to exhibit immature embryonic or fetal cardiomyocyte-like phenotypes. To enhance the maturation of hESC-CMs, we identified a natural steroidal alkaloid, tomatidine, as a new substance that stimulates the maturation of hESC-CMs. Treatment of human embryonic stem cells with tomatidine during cardiomyocyte differentiation stimulated the expression of several cardiomyocyte-specific markers and increased the density of T-tubules. Furthermore, tomatidine treatment augmented the number and size of mitochondria and enhanced the formation of mitochondrial lamellar cristae. Tomatidine treatment stimulated mitochondrial functions, including mitochondrial membrane potential, oxidative phosphorylation, and ATP production, in hESC-CMs. Tomatidine-treated hESC-CMs were more sensitive to doxorubicin-induced cardiotoxicity than the control cells. In conclusion, the present study suggests that tomatidine promotes the differentiation of stem cells to adult cardiomyocytes by accelerating mitochondrial biogenesis and maturation and that tomatidine-treated mature hESC-CMs can be used for cardiotoxicity screening and cardiac disease modeling.Subject terms: Heart failure, Embryonic stem cells, Stem-cell differentiation     

Dioscin-Mediated Autophagy Alleviates MPP+-Induced Neuronal Degeneration: An In Vitro Parkinson’s Disease Model

Autophagy is a cellular homeostatic process by which cells degrade and recycle their malfunctioned contents, and impairment in this process could lead to Parkinson’s disease (PD) pathogenesis. Dioscin, a steroidal saponin, has induced autophagy in several cell lines and animal models. The role of dioscin-mediated autophagy in PD remains to be investigated. Therefore, this study aims to investigate the hypothesis that dioscin-regulated autophagy and autophagy-related (ATG) proteins could protect neuronal cells in PD via reducing apoptosis and enhancing neurogenesis. In this study, the 1-methyl-4-phenylpyridinium ion (MPP⁺) was used to induce neurotoxicity and impair autophagic flux in a human neuroblastoma cell line (SH-SY5Y). The result showed that dioscin pre-treatment counters MPP⁺-mediated autophagic flux impairment and alleviates MPP⁺-induced apoptosis by downregulating activated caspase-3 and BCL2 associated X, apoptosis regulator (Bax) expression while increasing B-cell lymphoma 2 (Bcl-2) expression. In addition, dioscin pre-treatment was found to increase neurotrophic factors and tyrosine hydroxylase expression, suggesting that dioscin could ameliorate MPP⁺-induced degeneration in dopaminergic neurons and benefit the PD model. To conclude, we showed dioscin’s neuroprotective activity in neuronal SH-SY5Y cells might be partly related to its autophagy induction and suppression of the mitochondrial apoptosis pathway.     

Improvement of Biological Effects of Root-Filling Materials for Primary Teeth by Incorporating Sodium Iodide

Therapeutic iodoform (CHI₃) is commonly used as a root-filling material for primary teeth; however, the side effects of iodoform-containing materials, including early root resorption, have been reported. To overcome this problem, a water-soluble iodide (NaI)-incorporated root-filling material was developed. Calcium hydroxide, silicone oil, and NaI were incorporated in different weight proportions (30:30:X), and the resulting material was denoted DX (D5~D30), indicating the NaI content. As a control, iodoform instead of NaI was incorporated at a ratio of 30:30:30, and the material was denoted I30. The physicochemical (flow, film thickness, radiopacity, viscosity, water absorption, solubility, and ion releases) and biological (cytotoxicity, TRAP, ARS, and analysis of osteoclastic markers) properties were determined. The amount of iodine, sodium, and calcium ion releases and the pH were higher in D30 than I30, and the highest level of unknown extracted molecules was detected in I30. In the cell viability test, all groups except 100% D30 showed no cytotoxicity. In the 50% nontoxic extract, D30 showed decreased osteoclast formation compared with I30. In summary, NaI-incorporated materials showed adequate physicochemical properties and low osteoclast formation compared to their iodoform-counterpart. Thus, NaI-incorporated materials may be used as a substitute for iodoform-counterparts in root-filling materials after further (pre)clinical investigation.     

First observation of the P-wave spin-singlet bottomonium states hb(1P) and hb(2P)

We report the first observations of the spin-singlet bottomonium states h(b)(1P) and h(b)(2P). The states are produced in the reaction e(+)e(-)→h(b)(nP)π(+)π(-) using a 121.4 fb(-1) data sample collected at energies near the Υ(5S) resonance with the Belle detector at the KEKB asymmetric-energy e(+)e(-) collider. We determine M[h(b)(1P)]=(9898.2(-1.0-1.1)(+1.1+1.0)) MeV/c(2) and M[h(b)(2P)]=(10,259.8±0.6(-1.0)(+1.4)) MeV/c(2), which correspond to P-wave hyperfine splittings ΔM(HF)=(+1.7±1.5) and (+0.5(-1.2)(+1.6)) MeV/c(2), respectively. The significances of the h(b)(1P) and h(b)(2P) are 5.5σ and 11.2σ, respectively. We find that the production of the h(b)(1P) and h(b)(2P) is not suppressed relative to the production of the Υ(1S), Υ(2S), and Υ(3S).