Superior Damage Tolerance of Fish Skins.

Skin is the largest organ of many animals. Its protective function against hostile environments and predatorial attack makes high mechanical strength a vital characteristic. Here, we measured the mechanical properties of bass fish skins and found that fish skins are highly ductile with a rupture strain of up to 30-40% and a rupture strength of 10-15 MPa. The fish skins exhibit a strain-stiffening behavior. Stretching can effectively eliminate the stress concentrations near the pre-existing holes and edge notches, suggesting that the skins are highly damage tolerant. Our measurement determined a flaw-insensitivity length that exceeds those of most engineering materials. The strain-stiffening and damage tolerance of fish skins are explained by an agent-based model of a collagen network in which the load-bearing collagen microfibers assembled from nanofibrils undergo straightening and reorientation upon stretching. Our study inspires the development of artificial skins that are thin, flexible, but highly fracture-resistant and widely applicable in soft robots.

Adaptive Estimation Distribution Distributed Differential Evolution for Multimodal Optimization Problems.

Multimodal optimization problems (MMOPs) require algorithms to locate multiple optima simultaneously. When using evolutionary algorithms (EAs) to deal with MMOPs, an intuitive idea is to divide the population into several small "niches," where different niches focus on locating different optima. These population partition strategies are called "niching" techniques, which have been frequently used for MMOPs. The algorithms for simultaneously locating multiple optima of MMOPs are called multimodal algorithms. However, many multimodal algorithms still face the difficulty of population partition since most of the niching techniques involve the sensitive niching parameters. Considering this issue, in this article, we propose a parameter-free niching method based on adaptive estimation distribution (AED) and develop a distributed differential evolution (DDE) algorithm, which is called AED-DDE, for solving MMOPs. In AED-DDE, each individual finds its own appropriate niche size to form a niche and acts as an independent unit to find a global optimum. Therefore, we can avoid the difficulty of population partition and the sensitivity of niching parameters. Different niches are co-evolved by using the master-slave multiniche distributed model. The multiniche co-evolution mechanism can improve the population diversity for fully exploring the search space and finding more global optima. Moreover, the AED-DDE algorithm is further enhanced by a probabilistic local search (PLS) to refine the solution accuracy. Compared with other multimodal algorithms, even the winner of CEC2015 multimodal competition, the comparison results fully demonstrate the superiority of AED-DDE.

Long-term stability and protection efficacy of the RBD-targeting COVID-19 mRNA vaccine in nonhuman primates.

Messenger RNA (mRNA) vaccine technology has shown its power in preventing the ongoing COVID-19 pandemic. Two mRNA vaccines targeting the full-length S protein of SARS-CoV-2 have been authorized for emergency use. Recently, we have developed a lipid nanoparticle-encapsulated mRNA (mRNA-LNP) encoding the receptor-binding domain (RBD) of SARS-CoV-2 (termed ARCoV), which confers complete protection in mouse model. Herein, we further characterized the protection efficacy of ARCoV in nonhuman primates and the long-term stability under normal refrigerator temperature. Intramuscular immunization of two doses of ARCoV elicited robust neutralizing antibodies as well as cellular response against SARS-CoV-2 in cynomolgus macaques. More importantly, ARCoV vaccination in macaques significantly protected animals from acute lung lesions caused by SARS-CoV-2, and viral replication in lungs and secretion in nasal swabs were completely cleared in all animals immunized with low or high doses of ARCoV. No evidence of antibody-dependent enhancement of infection was observed throughout the study. Finally, extensive stability assays showed that ARCoV can be stored at 2-8 °C for at least 6 months without decrease of immunogenicity. All these promising results strongly support the ongoing clinical trial.

Benzbromarone aggravates hepatic steatosis in obese individuals.

As a widely used anti-gout drug, benzbromarone has been found to induce hepatic toxicity in patients during clinical treatment. Previous studies have reported that benzbromarone is metabolized via cytochrome P450, thus causing mitochondrial toxicity in hepatocytes. In this study, we found that benzbromarone significantly aggravated hepatic steatosis in both obese db/db mice and high fat diet (HFD)-induced obese (DIO) mouse models. However, benzbromarone had less effect on the liver of lean mice. It was found that the expression of mRNAs encoding lipid metabolism and some liver-specific genes were obviously disturbed in benzbromarone-treated DIO mice compared to the control group. The inflammatory and oxidative stress factors were also activated in the liver of benzbromarone-treated DIO mice. In accordance with the in vivo results, an in vitro experiment using human hepatoma HepG2 cells also confirmed that benzbromarone promoted intracellular lipid accumulation under high free fatty acids (FFAs) conditions by regulating the expression of lipid metabolism genes. Importantly, prolonged treatment of benzbromarone significantly increased cell apoptosis in HepG2 cells in the presence of high FFAs. In addition, in benzbromarone-treated hyperuricemic patients, serum transaminase levels were positively correlated with patients' obesity level. CONCLUSION: This study demonstrated that benzbromarone aggravated hepatic steatosis in obese individuals, which could subsequently contribute to hepatic cell injury, suggesting a novel toxicological mechanism in benzbromarone-induced hepatotoxicity.

Amyloid beta: structure, biology and structure-based therapeutic development.

Amyloid beta peptide (Aß) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by ß- and γ-secretases. Aß accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aß are and by what mechanism Aß causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aß. We also discuss the potential receptors that interact with Aß and mediate Aß intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aß, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aß; inhibitors or modulators of ß- and γ-secretase; Aß-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

Large-area synthesis of high-quality monolayer 1T'-WTe2 flakes.

Large-area growth of monolayer films of the transition metal dichalcogenides is of the utmost importance in this rapidly advancing research area. The mechanical exfoliation method offers high quality monolayer material but it is a problematic approach when applied to materials that are not air stable. One important example is 1T'-WTe2, which in multilayer form is reported to possess a large non saturating magnetoresistance, pressure induced superconductivity, and a weak antilocalization effect, but electrical data for the monolayer is yet to be reported due to its rapid degradation in air. Here we report a reliable and reproducible large-area growth process for obtaining many monolayer 1T'-WTe2 flakes. We confirmed the composition and structure of monolayer 1T'-WTe2 flakes using x-ray photoelectron spectroscopy, energy-dispersive x-ray spectroscopy, atomic force microscopy, Raman spectroscopy and aberration corrected transmission electron microscopy. We studied the time dependent degradation of monolayer 1T'-WTe2 under ambient conditions, and we used first-principles calculations to identify reaction with oxygen as the degradation mechanism. Finally we investigated the electrical properties of monolayer 1T'-WTe2 and found metallic conduction at low temperature along with a weak antilocalization effect that is evidence for strong spin-orbit coupling.

Monolayer Single-Crystal 1T'-MoTe2 Grown by Chemical Vapor Deposition Exhibits Weak Antilocalization Effect.

Growth of transition metal dichalcogenide (TMD) monolayers is of interest due to their unique electrical and optical properties. Films in the 2H and 1T phases have been widely studied but monolayers of some 1T'-TMDs are predicted to be large-gap quantum spin Hall insulators, suitable for innovative transistor structures that can be switched via a topological phase transition rather than conventional carrier depletion [ Qian et al. Science 2014 , 346 , 1344 - 1347 ]. Here we detail a reproducible method for chemical vapor deposition of monolayer, single-crystal flakes of 1T'-MoTe2. Atomic force microscopy, Raman spectroscopy, X-ray photoelectron spectroscopy, and transmission electron microscopy confirm the composition and structure of MoTe2 flakes. Variable temperature magnetotransport shows weak antilocalization at low temperatures, an effect seen in topological insulators and evidence of strong spin-orbit coupling. Our approach provides a pathway to systematic investigation of monolayer, single-crystal 1T'-MoTe2 and implementation in next-generation nanoelectronic devices.

Ursolic acid derivatives as bone anabolic agents targeted to tryptophan hydroxylase 1 (Tph-1).

Tryptophan hydroxylase 1 (Tph-1) initiates the biosynthesis of peripheral serotonin. As peripheral serotonin suppresses bone formation, inhibitor of Tph-1 provides a useful tool to discover anabolic agents for osteoporosis. In the present study, series of ursolic acid (UA) derivatives were synthesized, and their inhibitory activity on serotonin biosynthesis and cytotoxicity were evaluated. Among the derivatives, 8d with potent inhibitory activity on serotonin was applied for further research. The data revealed that 8d significantly inhibited protein and mRNA expressions of Tph-1, and an SPR study indicated that 8d directly interacted to Tph-1 with a binding affinity of KD=15.09µM. Oral administration of 8d significantly prevented bone loss via suppressing serotonin biosynthesis without estrogenic side-effects in ovariectomized (OVX) rats.

SND-117, a sinomenine bivalent alleviates type II collagen-induced arthritis in mice.

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder that affects about 1% of the population worldwide. RA is mainly manifested by persistent synovitis and progressive joint destruction. The aim of the present study was to examine the anti-arthritis effects of SND-117, a sinomenine bivalent that is obtained from the structure modification of a clinically available anti-RA drug, sinomenine. The arthritis model (CIA) was established by immunizing DBA/1 mice with type II collagen, and the arthritis scores including inflammation, joint destruction and bone erosion were assessed after booster immunization for 3weeks. The levels of cytokines such as IL-1ß, IL-6 and TNF-α were analyzed by quantitative PCR and ELISA. The TNF-α induced NF-κB activation in fibroblast-like synovial cells (FLSCs) was analyzed by Western blot. SND-117 significantly relieved the inflammatory symptoms of collagen-induced arthritis, reduced bone erosion and joint destruction in CIA mice. The serum levels of IL-1ß, IL-6 and TNF-α of CIA mice were markedly decreased by SND-117. SND-117 also strongly inhibited the phosphorylation and nuclear translocation of NF-κB p65 in FLSCs upon TNF-α stimulation. These data demonstrated that SND-117 could effectively block the pathogenesis of collagen-induced arthritis in CIA mice via inhibition of NF-κB signaling, and might provide potential clinic benefits in rheumatoid arthritis management.

Tryptophan hydroxylase 1 (Tph-1)-targeted bone anabolic agents for osteoporosis.

Tryptophan hydroxylase 1 (Tph-1), the principal enzyme for peripheral serotonin biosynthesis, provides a novel target to design anabolic agents for osteoporosis. Here, we present a design, synthesis of a novel series of ursolic acid derivatives under the guidance of docking technique, and bioevaluation of the derivatives using RBL2H3 cells and ovariectomized (OVX) rats. Of the compounds, 9a showed a potent inhibitory activity on serotonin biosynthesis. Further investigations revealed that 9a, as an efficient Tph-1 binder identified by SPR (estimated KD: 6.82 µM), suppressed the protein and mRNA expressions of Tph-1 and lowered serotonin contents in serum and gut without influence on brain serotonin. Moreover, oral administration of 9a elevated serum level of N-terminal propeptide of procollagen type 1 (P1NP), a bone formation marker, and improved bone microarchitecture without estrogenic side effects in ovariectomized rats. Collectively, 9a may serve as a new candidate for bone anabolic drug discovery.

KOtBu-mediated stereoselective addition of quinazolines to alkynes under mild conditions.

A facile alkenylation of quinazolines with unactivated terminal alkynes has been achieved in the presence of KOtBu without the aid of any transition metal catalysts. The reaction is carried out under very mild conditions and shows a high stereoselectivity. A possible radical-based mechanism is also explored.