Total Synthesis of (±)-Simonsol C.

Total synthesis of simonsol C has been achieved, focusing on the postdearomatization transformations. Our methodology integrates an efficient combination of dearomatization and Zn/AcOH reduction to introduce an allyl group, followed by oxo-Michael addition, to construct the 6/5/6 benzofuran skeleton. It offers a novel method for synthesizing allyl-containing quaternary carbon atoms in a straightforward manner.

CircFNTA promotes tumorigenesis and progression of gastric cancer via miR-604/miR-647/SCN8A axis.

Gastric cancer (GC) is a major contributor to cancer-related deaths and is characterized by high heterogeneity in epidemiology and histopathology worldwide. Increasing evidence indicates that circular RNAs (circRNAs) play multifaceted roles in cellular processes in human cancers. Here, we demonstrated that circFNTA high expression increases the proliferation, metastasis, and epithelial-mesenchymal transition process and tumorigenicity of GC cells. First, we found that circFNTA was upregulated in GC cells and tissues, and the high circFNTA levels were positively associated with the poor prognosis in GC patients. Using luciferase reporter and RNA-pull down assays, we elucidated that circFNTA sponged two microRNAs, miR-604 and miR-647. In addition, the proliferation and metastatic ability of GC cell reduction caused by silencing circFNTA was hindered by inhibitors of miR-604 and miR-647. Moreover, SCN8A was predicted by miRDB as a common target gene of miR-604 and miR-647, which was then verified by the luciferase reporter assay. Knockdown of circFNTA causes messenger RNA and protein levels in SCN8A to be downregulated in GC cells. However, this effect was overturned by cotransfection miR-604 and miR-647. Also, we identified that SCN8A was downregulated in GC tissues, which was positively correlated with circFNTA expression. In rescue experiments, the attenuated cell proliferation and metastatic ability caused by circFNTA knockdown was reversed by miR-604 and miR-647 inhibitors and SCN8A overexpression. Collectively, our findings suggest an oncogenic role of circFNTA in GC progression and elucidate that circFNTA exerts its function by modulating the miR-604/miR-647/SCN8A axis.

Computational design of ultrashort peptide inhibitors of the receptor-binding domain of the SARS-CoV-2 S protein.

Targeting the interaction between severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2)-receptor-binding domain (RBD) and angiotensin-converting enzyme 2 (ACE2) is believed to be an effective strategy for drug design to inhibit the infection of SARS-CoV-2. Herein, several ultrashort peptidase inhibitors against the RBD-ACE2 interaction were obtained by a computer-aided approach based on the RBD-binding residues on the protease domain (PD) of ACE2. The designed peptides were tested on a model coronavirus GX_P2V, which has 92.2 and 86% amino acid identity to the SARS-CoV-2 spike protein and RBD, respectively. Molecular dynamics simulations and binding free energy analysis predicted a potential binding pocket on the RBD of the spike protein, and this was confirmed by the specifically designed peptides SI5α and SI5α-b. They have only seven residues, showing potent antiviral activity and low cytotoxicity. Enzyme-linked immunosorbent assay result also confirmed their inhibitory ability against the RBD-ACE2 interaction. The ultrashort peptides are promising precursor molecules for the drug development of Corona Virus Disease 2019, and the novel binding pocket on the RBD may be helpful for the design of RBD inhibitors or antibodies against SARS-CoV-2.

Bovine lactoferrin inhibits SARS-CoV-2 and SARS-CoV-1 by targeting the RdRp complex and alleviates viral infection in the hamster model.

Breast milk has been found to inhibit coronavirus infection, while the key components and mechanisms are unknown. We aimed to determine the components that contribute to the antiviral effects of breastmilk and explore their potential mechanism. Lactoferrin (Lf) and milk fat globule membrane inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related coronavirus GX_P2V and transcription- and replication-competent SARS-CoV-2 virus-like particles in vitro and block viral entry into cells. We confirmed that bovine Lf (bLf) blocked the binding between human angiotensin-converting enzyme 2 and SARS-CoV-2 spike protein by combining receptor-binding domain (RBD). Importantly, bLf inhibited RNA-dependent RNA polymerase (RdRp) activity of both SARS-CoV-2 and SARS-CoV in vitro in the nanomolar range. So far, no biological macromolecules have been reported to inhibit coronavirus RdRp. Our result indicated that bLf plays a major role in inhibiting viral replication. bLf treatment reduced viral load in lungs and tracheae and alleviated pathological damage. Our study provides evidence that bLf prevents SARS-CoV-2 infection by combining SARS-CoV-2 spike protein RBD and inhibiting coronaviruses' RdRp activity, and may be a promising candidate for the treatment of coronavirus disease 2019.

Neuroprotective schinortriterpenoids from Schisandra neglecta collected in Medog County, Tibet, China.

Schisdilactones K-U (1-11), a series of previously unreported 16,17-secopreschisanartane-type schinortriterpenoids (SNTs), were isolated from the leaves and stems of Schisandra neglecta A. C. Smith. Their structures were mainly established through analysis of their spectroscopic data. Besides, schisdilactones K (1), O (5) and R (8) were confirmed by single-crystal X-ray crystallographic analysis, and the configurations of schisdilactones T and U (10 and 11) were elucidated via quantum chemical calculation of their NMR chemical shifts and electronic circular dichroism (ECD) spectra. Schisdilactones L-S (2-8) and U (11) were found to exhibit moderate protective activities against corticosterone-induced apoptosis of PC12 cells at 20 µM, with cell viability in the range of 62.95-66.97%.

Metabolic Activation of Elemicin Leads to the Inhibition of Stearoyl-CoA Desaturase 1.

Elemicin is a constituent of natural aromatic phenylpropanoids present in many herbs and spices. However, its potential to cause toxicity remains unclear. To examine the potential toxicity and associated mechanism, elemicin was administered to mice for 3 weeks and serum metabolites were examined. Enlarged livers were observed in elemicin-treated mice, which were accompanied by lower ratios of unsaturated- and saturated-lysophosphatidylcholines in plasma, and inhibition of stearoyl-CoA desaturase 1 (Scd1) mRNA expression in liver. Administration of the unsaturated fatty acid oleic acid reduced the toxicity of 1'-hydroxylelemicin, the primary oxidative metabolite of elemicin, while treatment with the SCD1 inhibitor A939572 potentiated its toxicity. Furthermore, the in vitro use of recombinant human CYPs and chemical inhibition of CYPs in human liver microsomes revealed that CYP1A1 and CYP1A2 were the primary CYPs responsible for elemicin bioactivation. Notably, the CYP1A2 inhibitor α-naphthoflavone could attenuate the susceptibility of mice to elemicin-induced hepatomegaly. This study revealed that metabolic activation of elemicin leads to SCD1 inhibition in liver, suggesting that upregulation of SCD1 may serve as potential intervention strategy for elemicin-induced toxicity.

Synthesis of trisaccharide repeating unit of fucosylated chondroitin sulfate.

We described the chemical synthesis of a sulfated trisaccharide repeating unit of fucosylated chondroitin sulfate (FCS), which has significant anticoagulant activity. Well-functionalized monosaccharides were readily prepared, and highly efficient glycosylations using a common activator (NIS/TfOH) were also presented. The synthesized trisaccharide 4 could be used to extend oligosaccharide sequences.

A Theoretical Review on Interfacial Thermal Transport at the Nanoscale.

With the development of energy science and electronic technology, interfacial thermal transport has become a key issue for nanoelectronics, nanocomposites, energy transmission, and conservation, etc. The application of thermal interfacial materials and other physical methods can reliably improve the contact between joined surfaces and enhance interfacial thermal transport at the macroscale. With the growing importance of thermal management in micro/nanoscale devices, controlling and tuning the interfacial thermal resistance (ITR) at the nanoscale is an urgent task. This Review examines nanoscale interfacial thermal transport mainly from a theoretical perspective. Traditional theoretical models, multiscale models, and atomistic methodologies for predicting ITR are introduced. Based on the analysis and summary of the factors that influence ITR, new methods to control and reduce ITR at the nanoscale are described in detail. Furthermore, the challenges facing interfacial thermal management and the further progress required in this field are discussed.

Discovery of an intrinsic tenase complex inhibitor: Pure nonasaccharide from fucosylated glycosaminoglycan.

Selective inhibition of the intrinsic coagulation pathway is a promising strategy for developing safer anticoagulants that do not cause serious bleeding. Intrinsic tenase, the final and rate-limiting enzyme complex in the intrinsic coagulation pathway, is an attractive but less explored target for anticoagulants due to the lack of a pure selective inhibitor. Fucosylated glycosaminoglycan (FG), which has a distinct but complicated and ill-defined structure, is a potent natural anticoagulant with nonselective and adverse activities. Herein we present a range of oligosaccharides prepared via the deacetylation-deaminative cleavage of FG. Analysis of these purified oligosaccharides reveals the precise structure of FG. Among these fragments, nonasaccharide is the minimum fragment that retains the potent selective inhibition of the intrinsic tenase while avoiding the adverse effects of native FG. In vivo, the nonasaccharide shows 97% inhibition of venous thrombus at a dose of 10 mg/kg in rats and has no obvious bleeding risk. This nonasaccharide may therefore serve as a novel promising anticoagulant.

Flexible, Stretchable Sensors for Wearable Health Monitoring: Sensing Mechanisms, Materials, Fabrication Strategies and Features.

Wearable health monitoring systems have gained considerable interest in recent years owing to their tremendous promise for personal portable health watching and remote medical practices. The sensors with excellent flexibility and stretchability are crucial components that can provide health monitoring systems with the capability of continuously tracking physiological signals of human body without conspicuous uncomfortableness and invasiveness. The signals acquired by these sensors, such as body motion, heart rate, breath, skin temperature and metabolism parameter, are closely associated with personal health conditions. This review attempts to summarize the recent progress in flexible and stretchable sensors, concerning the detected health indicators, sensing mechanisms, functional materials, fabrication strategies, basic and desired features. The potential challenges and future perspectives of wearable health monitoring system are also briefly discussed.

Thermal-Performance Instability in Piezoresistive Sensors: Inducement and Improvement.

The field of piezoresistive sensors has been undergoing a significant revolution in terms of design methodology, material technology and micromachining process. However, the temperature dependence of sensor characteristics remains a hurdle to cross. This review focuses on the issues in thermal-performance instability of piezoresistive sensors. Based on the operation fundamental, inducements to the instability are investigated in detail and correspondingly available ameliorative methods are presented. Pros and cons of each improvement approach are also summarized. Though several schemes have been proposed and put into reality with favorable achievements, the schemes featuring simple implementation and excellent compatibility with existing techniques are still emergently demanded to construct a piezoresistive sensor with excellent comprehensive performance.

Polycyclic Polyprenylated Acylphloroglucinol Congeners Possessing Diverse Structures from Hypericum henryi.

Polycyclic polyprenylated acylphloroglucinols (PPAPs) are a class of hybrid natural products sharing the mevalonate/methylerythritol phosphate and polyketide biosynthetic pathways and showing considerable structural and bioactive diversity. In a systematic phytochemical investigation of Hypericum henryi, 40 PPAP-type derivatives, including the new compounds hyphenrones G-Q, were obtained. These compounds represent 12 different structural types, including four unusual skeletons exemplified by 5, 8, 10, and 17. The 12 different core structures found are explicable in terms of their biosynthetic origin. The structure of a known PPAP, perforatumone, was revised to hyphenrone A (5) by NMR spectroscopic and biomimetic synthesis methods. Several compounds exhibited inhibitory activities against acetylcholinesterase and human tumor cell lines. This study deals with the structural diversity, function, and biogenesis of natural PPAPs.

GWAS identifies novel susceptibility loci on 6p21.32 and 21q21.3 for hepatocellular carcinoma in chronic hepatitis B virus carriers.

Genome-wide association studies (GWAS) have recently identified KIF1B as susceptibility locus for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). To further identify novel susceptibility loci associated with HBV-related HCC and replicate the previously reported association, we performed a large three-stage GWAS in the Han Chinese population. 523,663 autosomal SNPs in 1,538 HBV-positive HCC patients and 1,465 chronic HBV carriers were genotyped for the discovery stage. Top candidate SNPs were genotyped in the initial validation samples of 2,112 HBV-positive HCC cases and 2,208 HBV carriers and then in the second validation samples of 1,021 cases and 1,491 HBV carriers. We discovered two novel associations at rs9272105 (HLA-DQA1/DRB1) on 6p21.32 (OR = 1.30, P = 1.13×10⁻¹9) and rs455804 (GRIK1) on 21q21.3 (OR = 0.84, P = 1.86×10⁻8), which were further replicated in the fourth independent sample of 1,298 cases and 1,026 controls (rs9272105: OR = 1.25, P = 1.71×10⁻4; rs455804: OR = 0.84, P = 6.92×10⁻³). We also revealed the associations of HLA-DRB1*0405 and 0901*0602, which could partially account for the association at rs9272105. The association at rs455804 implicates GRIK1 as a novel susceptibility gene for HBV-related HCC, suggesting the involvement of glutamate signaling in the development of HBV-related HCC.

Cold atmospheric plasma can effectively disinfect SARS-CoV-2 in the wastewater.

COVID-19 is currently pandemic and the detection of SARS-CoV-2 variants in wastewater is causing widespread concern. Herein, cold atmospheric plasma (CAP) is proposed as a novel wastewater disinfection technology that effectively inactivates SARS-CoV-2 transcription- and replication-competent virus-like particles, coronavirus GX_P2V, pseudotyped SARS-CoV-2 variants, and porcine epidemic diarrhoea virus in a large volume of water within 180 s (inhibition rate > 99%). Further, CAP disinfection did not adversely affect the viability of various human cell lines. It is identified that CAP produced peroxynitrite (ONOO-), ozone (O3), superoxide anion radicals (O2 -), and hydrogen peroxide (H2O2) as the major active substances for coronavirus disinfection. Investigation of the mechanism showed that active substances not only reacted with the coronavirus spike protein and affected its infectivity, but also destroyed the nucleocapsid protein and genome, thus affecting virus replication. This method provides an efficient and environmentally friendly strategy for the elimination of SARS-CoV-2 and other coronaviruses from wastewater.

Structural Engineering in Piezoresistive Micropressure Sensors: A Focused Review.

The longstanding demands for micropressure detection in commercial and industrial applications have led to the rapid development of relevant sensors. As a type of long-term favored device based on microelectromechanical system technology, the piezoresistive micropressure sensor has become a powerful measuring platform owing to its simple operational principle, favorable sensitivity and accuracy, mature fabrication, and low cost. Structural engineering in the sensing diaphragm and piezoresistor serves as a core issue in the construction of the micropressure sensor and undertakes the task of promoting the overall performance for the device. This paper focuses on the representative structural engineering in the development of the piezoresistive micropressure sensor, largely concerning the trade-off between measurement sensitivity and nonlinearity. Functional elements on the top and bottom layers of the diaphragm are summarized, and the influences of the shapes and arrangements of the piezoresistors are also discussed. The addition of new materials endows the research with possible solutions for applications in harsh environments. A prediction for future tends is presented, including emerging advances in materials science and micromachining techniques that will help the sensor become a stronger participant for the upcoming sensor epoch.

Decreased KLF3 Expression via miR-660-5p Targeting Suppresses Gastric Cancer Cell Progression.

OBJECTIVE: Gastric cancer (GC) is one of the most frequent cancers in the world. Recent studies have suggested that microRNAs (miRNAs/miRs) may act as novel therapeutic regimens for GC. This study revealed that miR-660-5p regulated the proliferation, migration, invasion, and apoptosis of GC cells via controlling the level of Krüppel-like factor 3 (KLF3). METHODS: The level of miR-660-5p was measured in clinical GC tissues. Then, the miRNA targeting relationship between miR-660-5p and KLF3 was explored in vitro. GC cell lines, including HGC-27, SNU-1, HS-746T, NCI-N87, and human gastric epithelial GES-1 cells, were used. The impact of miR-660-5p on cell proliferation, colony formation, invasion, migration, and apoptosis were determined by knocking down KLF3. RESULTS: It was demonstrated that the KLF3 expressions were significantly increased in GC tissues and cell lines compared to normal tissues or cells, and GC cell development was suppressed following KLF3 knockdown. Moreover, it was also revealed that miR-660-5p expression was significantly decreased in GC cells, and miR-660-5p acted as the direct regulator of KLF3. CONCLUSIONS: This study firstly reported the miR-660-5p/KLF3 interaction in GC, and the results provided a potential promising therapeutic target for GC.

Multidirectional Piezoelectric Vibration Energy Harvester Based on Cam Rotor Mechanism.

The techniques that harvest mechanical energy from low-frequency, multidirectional environmental vibrations have been considered a promising strategy to implement a sustainable power source for wireless sensor networks and the Internet of Things. However, the obvious inconsistency in the output voltage and operating frequency among different directions may bring a hindrance to energy management. To address this issue, this paper reports a cam-rotor-based approach for a multidirectional piezoelectric vibration energy harvester. The cam rotor can transform vertical excitation into a reciprocating circular motion, producing a dynamic centrifugal acceleration to excite the piezoelectric beam. The same beam group is utilized when harvesting vertical and horizontal vibrations. Therefore, the proposed harvester reveals similar characterization in its resonant frequency and output voltage at different working directions. The structure design and modeling, device prototyping and experimental validation are conducted. The results show that the proposed harvester can produce a peak voltage of up to 42.4 V under a 0.2 g acceleration with a favorable power of 0.52 mW, and the resonant frequency for each operating direction is stable at around 3.7 Hz. Practical applications in lighting up LEDs and powering a WSN system demonstrate the promising potential of the proposed approach in capturing energy from ambient vibrations to construct self-powered engineering systems for structural health monitoring, environmental measuring, etc.

Anti-Coronaviral Nanocluster Restrain Infections of SARS-CoV-2 and Associated Mutants through Virucidal Inhibition and 3CL Protease Inactivation.

Antivirals that can combat coronaviruses, including SARS-CoV-2 and associated mutants, are urgently needed but lacking. Simultaneously targeting the viral physical structure and replication cycle can endow antivirals with sustainable and broad-spectrum anti-coronavirus efficacy, which is difficult to achieve using a single small-molecule antiviral. Thus, a library of nanomaterials on GX_P2V, a SARS-CoV-2-like coronavirus of pangolin origin, is screened and a surface-functionalized gold nanocluster (TMA-GNC) is identified as the top hit. TMA-GNC inhibits transcription- and replication-competent SARS-CoV-2 virus-like particles and all tested pseudoviruses of SARS-CoV-2 variants. TMA-GNC prevents viral dissemination through destroying membrane integrity physically to enable a virucidal effect, interfering with viral replication by inactivating 3CL protease and priming the innate immune system against coronavirus infection. TMA-GNC exhibits biocompatibility and significantly reduces viral titers, inflammation, and pathological injury in lungs and tracheas of GX_P2V-infected hamsters. TMA-GNC may have a role in controlling the COVID-19 pandemic and inhibiting future emerging coronaviruses or variants.

A natural biological adhesive from snail mucus for wound repair.

The discovery of natural adhesion phenomena and mechanisms has advanced the development of a new generation of tissue adhesives in recent decades. In this study, we develop a natural biological adhesive from snail mucus gel, which consists a network of positively charged protein and polyanionic glycosaminoglycan. The malleable bulk adhesive matrix can adhere to wet tissue through multiple interactions. The biomaterial exhibits excellent haemostatic activity, biocompatibility and biodegradability, and it is effective in accelerating the healing of full-thickness skin wounds in both normal and diabetic male rats. Further mechanistic study shows it effectively promotes the polarization of macrophages towards the anti-inflammatory phenotype, alleviates inflammation in chronic wounds, and significantly improves epithelial regeneration and angiogenesis. Its abundant heparin-like glycosaminoglycan component is the main active ingredient. These findings provide theoretical and material insights into bio-inspired tissue adhesives and bioengineered scaffold designs.