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Abstract Acoustic gravimetric biosensors attract attention due to their simplicity, robustness, and low cost. However, a prevailing challenge in these sensors is dissipation which manifests in a low quality factor (Q-factor), which limits their sensitivity and accuracy. To mitigate dissipation of acoustic sensors in liquid environments we introduce an innovative approach in which we combine microfluidic channels with gravimetric sensors. To implement this novel paradigm we chose the quartz crystal microbalance (QCM) as our model system, owing to its wide applicability in biosensing and the relevance of its operating principles to other types of acoustic sensors. We postulate that the crucial determinant for enhancing performance lies in the ratio between the width of the microfluidic channels and the wavelength of the pressure wave generated by the oscillating channel side walls driven by the QCM. Our hypothesis is supported by finite element analysis (FEA) and dimensional studies, which revealed two key factors that affect device performance: (1) the ratio of the channel width to the pressure wavelength ( $$W/{\lambda }_{{\rm {p}}}$$ W / λ p ) and (2) the ratio of the channel height to the shear evanescent wavelength ( $$H/{\lambda }_{{\rm {s}}}$$ H / λ s ). To validate our hypothesis, we fabricated a microfluidic QCM (µ-QCM) and demonstrated a remarkable 10-fold improvement in its dissipation when compared to conventional QCM. The novel microfluidic approach offers several additional advantages, such as direct data interpretation, reduced volume requirement for sample liquids, and simplified temperature control, augmenting the sensor’s overall performance. By fostering increased sensitivity, accuracy, and ease of operation, our novel paradigm unlocks new possibilities for advancing gravimetric technologies, potentially for biosensing applications.

Abstract Pancreatic cancer, predominantly pancreatic ductal adenocarcinoma (PDAC), remains a highly lethal malignancy with limited therapeutic options and a dismal prognosis. By targeting the underlying molecular abnormalities responsible for PDAC development and progression, gene therapy offers a promising strategy to overcome the challenges posed by conventional radiotherapy and chemotherapy. This study sought to explore the therapeutic potential of small activating RNAs (saRNAs) specifically targeting the CCAAT/enhancer-binding protein alpha (CEBPA) gene in PDAC. To overcome the challenges associated with saRNA delivery, tetrahedral framework nucleic acids (tFNAs) were rationally engineered as nanocarriers. These tFNAs were further functionalized with a truncated transferrin receptor aptamer (tTR14) to enhance targeting specificity for PDAC cells. The constructed tFNA-based saRNA formulation demonstrated exceptional stability, efficient saRNA release ability, substantial cellular uptake, biocompatibility, and nontoxicity. In vitro experiments revealed successful intracellular delivery of CEBPA-saRNA utilizing tTR14-decorated tFNA nanocarriers, resulting in significant activation of tumor suppressor genes, namely, CEBPA and its downstream effector P21, leading to notable inhibition of PDAC cell proliferation. Moreover, in a mouse model of PDAC, the tTR14-decorated tFNA-mediated delivery of CEBPA-saRNA effectively upregulated the expression of the CEBPA and P21 genes, consequently suppressing tumor growth. These compelling findings highlight the potential utility of saRNA delivered via a designed tFNA nanocarrier to induce the activation of tumor suppressor genes as an innovative therapeutic approach for PDAC.

ObjectiveTo measure the palatal soft tissue thickness and cortical bone density to determine safe regions for the placement of orthodontic mini-implants and to examine the influence of sex and age on soft tissue thickness and cortical bone density.Materials and methodsCone-beam computed tomography images of 42 patients (22 males and 20 females), including 21 adults and 21 adolescents, were examined in this study. The palatal soft tissue thickness and cortical bone density were measured at the coronal planes between the premolars (P4–5), between the second premolars and first molars (P5–6), and between the first molars and second molars (P6–7).ResultsThe thickness of the soft tissue revealed similar coronal planes, but the bone density varied. The mean thickness was 3.8 mm at 0°–60° and 1.5 mm at 60°–90°. P4–5 had the highest bone density (>600 HU), decreasing toward P6–7 (

Abstract The development of a robust quasi-ohmic contact with minimal resistance, good stability and cost-effectiveness is crucial for perovskite solar cells. We introduce a generic approach featuring a Lewis-acid layer sandwiched between dopant-free semicrystalline polymer and metal electrode in perovskite solar cells, resulting in an ideal quasi-ohmic contact even at elevated temperature up to 85 °C. The solubility of Lewis acid in alcohol facilitates nondestructive solution processing on top of polymer, which boosts hole injection from polymer into metal by two orders of magnitude. By integrating the polymer-acid-metal structure into solar cells, devices exhibit remarkable resilience, retaining 96% ± 3%, 96% ± 2% and 75% ± 7% of their initial efficiencies after continuous operation in nitrogen at 35 °C for 2212 h, 55 °C for 1650 h and 85 °C for 937 h, respectively. Leveraging the Arrhenius relation, we project an impressive T 80 lifetime of 26,126 h at 30 °C.

Abstract Limitations in the clinical treatment of Staphylococcus aureus (S. aureus) infections have arisen due to the advent of antibiotic-resistant strains. Given the immense potential of therapeutic strategies targeting bacterial virulence, the role of MgrA as a pivotal virulence determinant in S. aureus-orchestrating resistance, adherence, and hundreds of virulence targets—becomes indispensable. In this investigation, leveraging advanced virtual screening and fluorescence anisotropy assays, we discerned methylophiopogonanone A (Mo-A), a flavonoid derivative, as a potent disruptor of the MgrA-DNA interaction nexus. Subsequent analysis revealed that Mo-A effectively inhibits the expression of virulence factors such as Hla and Pvl in S. aureus and markedly reduces its adhesion capability to fibrinogen. On a cellular landscape, Mo-A exerts a mitigating influence on the deleterious effects inflicted by S. aureus USA300 on A549 cells. Furthermore, our data indicate that Mo-A downregulates the transcription of genes associated with immune evasion, such as nucleases (nuc), Staphylococcal Chemotaxis Inhibitory Protein (chips), and Staphylococcal Complement Inhibitor (scin), thereby undermining immune escape and amplifying neutrophil chemotaxis. Upon application in an in vivo setting, Mo-A assumes a protective persona in a murine model of S. aureus USA300-induced pneumonia and demonstrates efficacy in the Galleria mellonella infection model. Of note, S. aureus displayed no swift acquisition of resistance to Mo-A, and the effect was synergistically enhanced when used in combination with vancomycin. Our findings add substantive weight to the expanding field of virulence-targeted therapeutic strategies and set the stage for more comprehensive exploration of Mo-A potential in combating antibiotic-resistant S. aureus.

Men who have sex with men (MSM) are at a high risk of HIV infection and should be offered effective preventive measures, such as pre-exposure prophylaxis (PrEP). However, PrEP uptake among eligible MSM was not as high as desired. Diverse research findings on how risky sexual behaviors affect PrEP uptake highlight the necessity for a comprehensive investigation. Understanding the interconnectedness of different sexual behaviors is crucial for evaluating their impact on PrEP uptake among eligible MSM.Using a proportional sampling method, we recruited 5877 MSM aged 16 years and above in mainland China according to PrEP eligibility criteria. Through latent class analysis (LCA), three distinct sexual behavior patterns were identified among eligible MSM. Demographic variances and PrEP uptake among the three distinct sexual behavior patterns were examined using chi-squared tests and multinomial logistic regression.LCA revealed three patterns: low-risk (4,815 MSM), medium-risk (516 MSM), and high-risk (546 MSM). MSM aged 25 years or older with a monthly income of ≥¥8,000 were more likely to be in the medium-risk group. Those from areas with high HIV prevalence and engaging as ''top'' in anal sex were more likely to be in the medium- and high-risk groups. The medium- and high-risk groups had a higher willingness, uptake, and adherence rates for PrEP than the low-risk group.LCA is effective in identifying diverse sexual behavior patterns among MSM, aiding targeted interventions to enhance PrEP uptake. Addressing demographic variations and tailoring interventions for specific risk groups are crucial for promoting PrEP dissemination and reducing HIV infection risk in eligible MSM.

Abstract Light-induced halide segregation constrains the photovoltaic performance and stability of wide-bandgap perovskite solar cells and tandem cells. The implementation of an intermixed two-dimensional/three-dimensional heterostructure via solution post-treatment is a typical strategy to improve the efficiency and stability of perovskite solar cells. However, owing to the composition-dependent sensitivity of surface reconstruction, the conventional solution post-treatment is suboptimal for methylammonium-free and cesium/bromide-enriched wide-bandgap PSCs. To address this, we develop a generic three-dimensional to two-dimensional perovskite conversion approach to realize a preferential growth of wider dimensionality (n ≥ 2) atop wide-bandgap perovskite layers (1.78 eV). This technique involves depositing a well-defined MAPbI3 thin layer through a vapor-assisted two-step process, followed by its conversion into a two-dimensional structure. Such a two-dimensional/three-dimensional heterostructure enables suppressed light-induced halide segregation, reduced non-radiative interfacial recombination, and facilitated charge extraction. The wide-bandgap perovskite solar cells demonstrate a champion power conversion efficiency of 19.6% and an open-circuit voltage of 1.32 V. By integrating with the thermal-stable FAPb0.5Sn0.5I3 narrow-bandgap perovskites, our all-perovskite tandem solar cells exhibit a stabilized PCE of 28.1% and retain 90% of the initial performance after 855 hours of continuous 1-sun illumination.

Purpose: The purpose of this study was to examine the pharmacokinetics (PK), bioequivalence and safety of generic sunitinib and its original product Sutent® in healthy Chinese subjects through a phase-I clinical trial.Methods: The study selected two groups of 24 healthy Chinese subjects in a 1:1 ratio through random allocation. Each participant received either 12.5 mg of sunitinib or Sutent® per cycle. A total of 15 different time points were employed for blood sample collection during each cycle. Furthermore, a comprehensive assessment of the drugs’ safety was consistently maintained throughout the trial.Results: The average adjusted geometric mean ratios (GMR) (90% CI) for the primary PK parameters Cmax, AUC0-t and AUC0-∞ were 97.04% (93.06%–101.19%), 98.45% (93.27%–103.91%) and 98.22% (93.15%–103.56%), respectively. The adjusted GMRs for essential pharmacokinetic (PK) parameters all met the requirements for bioequivalence, with values within the acceptable range of 80%–125%. In addition, the two drugs showed comparable results for the other PK parameters. These results indicate that the two drugs were bioequivalent. Furthermore, both drugs showed well safety.Conclusion: The research results proved that the PK and safety profiles of sunitinib in healthy Chinese subjects were comparable to those of Sutent®. These results advocate the clinical application of generic sunitinib as a potential alternative to original product Sutent® in the treatment of certain medical conditions.

Oncolytic viruses are able to target tumours and thought to induce apoptosis while remodelling the tumour immune microenvironment. Here authors show in an oncolytic parapoxvirus ovis model that pyroptosis, a highly immunogenic Gasdermin-E-dependent cell death mechanism, is the dominant cell death pathway during virotherapy.

Abstract Background Vector-borne flaviviruses, including tick-borne encephalitis virus (TBEV), Zika virus (ZIKV), West Nile virus (WNV), yellow fever virus (YFV), dengue virus (DENV), and Japanese encephalitis virus (JEV), pose a growing threat to public health worldwide, and have evolved complex mechanisms to overcome host antiviral innate immunity. However, the underlying mechanisms of flavivirus structural proteins to evade host immune response remain elusive. Results We showed that TBEV structural protein, pre-membrane (prM) protein, could inhibit type I interferon (IFN-I) production. Mechanically, TBEV prM interacted with both MDA5 and MAVS and interfered with the formation of MDA5-MAVS complex, thereby impeding the nuclear translocation and dimerization of IRF3 to inhibit RLR antiviral signaling. ZIKV and WNV prM was also demonstrated to interact with both MDA5 and MAVS, while dengue virus serotype 2 (DENV2) and YFV prM associated only with MDA5 or MAVS to suppress IFN-I production. In contrast, JEV prM could not suppress IFN-I production. Overexpression of TBEV and ZIKV prM significantly promoted the replication of TBEV and Sendai virus. Conclusion Our findings reveal the immune evasion mechanisms of flavivirus prM, which may contribute to understanding flavivirus pathogenicity, therapeutic intervention and vaccine development.

The resistance of Staphylococcus aureus (S. aureus) to various antibiotics has increased dramatically due to the misuse of antibiotics, and thus the development of new anti-infective drugs with new targets is urgently needed to combat resistance. Caseinolytic peptidase P is a case in hydrolase that regulates the virulence level of S. aureus. Here, we found that nepetin, a small-molecule compound from traditional Chinese herbal flavonoids, effectively inhibits ClpP activity. Nepetin suppressed the virulence of S. aureus and effectively combated the lethal pneumonia caused by MRSA. The results of cellular thermal shift assay showed that nepetin could bind to ClpP and reduce the thermal stability of ClpP, and the KD value of 602 nM between them was determined using localized surface plasmon resonance. The binding mode of nepetin and ClpP was further investigated by molecular docking, and it was found that Ser-22 and Gln-47 of ClpP residues were found to be involved in the binding of nepetin to ClpP. In conclusion, we determined that nepetin is a ClpP inhibitor and an effective lead compound for the development of a virulence factor-based treatment for MRSA infection.

Methicillin-resistant Staphylococcus aureus (MRSA) has been developing rapidly in recent years. It poses a severe peril to global health care, and the new strategies to against the MRSA is urgently needed. Sortase A (SrtA) regulates the anchoring of many surface proteins. Compounds repress Staphylococcus aureus (S. aureus) cysteine transpeptidase SrtA are considered adequate potent virulence inhibitors. Then, we describe the identification of an effective SrtA inhibitor, cyanidin chloride, a bioflavonoid compound isolated from various plants. It has a reversible inhibitory effect on SrtA activity at an IC50 of 21.91 μg/mL. As a SrtA inhibitor, cyanidin chloride antagonizes SrtA-related virulence phenotypes due to its breadth and specificity, including fibrinogen adhesion, A549 cell invasion, biofilm formation, and surface protein (SpA) anchoring. Subsequently, molecular docking and fluorescence quenching revealed that SrtA and cyanidin chloride had robust mutual affinity. Further mechanistic studies revealed that Arg-197, Gly-167, and Sep-116 were the key-binding sites mediating the interaction between SrtA and cyanidin chloride. Notably, a significant therapeutic effect of cyanidin chloride in vivo was also observed on the mouse pneumonia model induced by MRSA. In conclusion, our study indicates that cyanidin chloride potentially represents a new candidate SrtA inhibitor for S. aureus and potentially be developed as a new antivirulence agent.

Background: Exploring the correspondences across multi-view images is the basis of many computer vision tasks. However, most existing methods are limited on accuracy under challenging conditions. In order to learn more robust and accurate correspondences, we propose the DSD-MatchingNet for local feature matching in this paper. First, we develop a deformable feature extraction module to obtain multi-level feature maps, which harvests contextual information from dynamic receptive fields. The dynamic receptive fields provided by deformable convolution network ensures our method to obtain dense and robust correspondences. Second, we utilize the sparse-to-dense matching with the symmetry of correspondence to implement accurate pixel-level matching, which enables our method to produce more accurate correspondences. Experiments have shown that our proposed DSD-MatchingNet achieves a better performance on image matching benchmark, as well as on visual localization benchmark. Specifically, our method achieves 91.3% mean matching accuracy on HPatches dataset and 99.3% visual localization recalls on Aachen Day-Night dataset.

Antimicrobial resistance (AMR) is a global, multifaceted crisis that poses significant challenges to the successful eradication of devastating pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), a persistent superbug that causes devastating infections. The scarcity of new antibacterial drugs is obvious, and antivirulence strategies that reduce the pathogenicity of bacteria by weakening their virulence have become the subject of intense investigation. Alpha-hemolysin (Hla), a cytolytic pore-forming toxin, has a pivotal role in S. aureus pathogenesis. Here, we demonstrated that echinatin, a natural compound isolated from licorice, effectively inhibited the hemolytic activity of MRSA at 32 μg/mL. In addition, echinatin did not interfere with bacterial growth and had no significant cytotoxicity at the inhibitory concentration of S. aureus hemolysis. Heptamer formation tightly correlated with Hla-mediated cell invasion, whereas echinatin did not affect deoxycholic acid-induced oligomerization of Hla. Echinatin affected hemolytic activity through indirect binding to Hla as confirmed by the neutralization assay and cellular thermal shift assay (CETSA). Furthermore, qRT–PCR and western blot analyses revealed that echinatin suppressed Hla expression at both the mRNA and protein levels as well as the transcript levels of Agr quorum-sensing system-related genes. Additionally, when echinatin was added to a coculture system of A549 cells and S. aureus, it significantly reduced cell damage. Importantly, echinatin exhibited a significant therapeutic effect in an MRSA-induced mouse pneumonia model. In conclusion, the present findings demonstrated that echinatin significantly inhibits the hemolysin effect and may be a potential candidate compound for combating drug-resistant MRSA infections.

The mountain area is faced with complex conditions such as vertical and horizontal valleys, complex geological topography, many earthquake fault zones, high seismic intensity, fragile ecology, and changeable climate. The traditional concrete bridges have a heavy weight, high consumption of sand and gravel materials, large structural dimensions of steel box composite bridges, high steel consumption, and poor overall horizontal performance of steel plate composite beams, which are not suitable for mountain construction conditions. Therefore, based on the construction environment and application requirements of highway bridges in mountainous areas, the structural scheme of steel box-steel plate composite beam is put forward in this paper, and the design of a 25 m–50 m standard-span steel box-steel plate composite beam is studied. The results show that the steel box-steel plate composite beam structure scheme is adopted, which has excellent mechanical characteristics of steel box girder and simple structure of steel plate girder. It has the mechanical characteristics of “balanced transverse force and excellent longitudinal force”, so it is a reasonable choice for small radius curved beam bridge in a mountainous area, so it is a reasonable choice for small radius curved beam bridge in a mountainous area. The steel box-steel plate composite beam adopts the integrated technology of manufacture, transportation and installation, which can better meet the road transport conditions in the mountain area. The longitudinal assembly of the manufacturing unit as the installation unit can ensure the rapid and high-precision installation of the construction site, and the assembly construction of the bridge in the mountain area has been realized. The technical and economic comparison shows that the mechanical performance of steel box-steel plate composite beam is similar to that of steel box beam and obviously better than that of steel plate girder. The steel consumption and construction period of steel box-steel plate composite beam are similar to that of steel plate girder, and are significantly less than that of the steel box girder. Therefore, the steel box-steel plate composite beam is a good choice for mountain bridge construction.

Abstract Background Calcium ions (Ca2+) participates in various intracellular signal cascades and especially plays a key role in pathways relevant to cancer cells. Mitochondrial metabolism stimulated by calcium overload can trigger the opening of the mitochondrial permeability transition pore (MPTP), which leads to cancer cell death. Methods Herein, a mitochondrial pathway for tumour growth inhibition was built via the double-activation of MPTP channel. Fe2+ doped covalent organic frameworks (COF) was synthesised and applied as template to grow CaCO3 shell. Then O2 was storaged into Fe2+ doped COF, forming O2-FeCOF@CaCO3 nanocomposite. After modification with folic acid (FA), O2-FeCOF@CaCO3@FA (OFCCF) can target breast cancer cells and realize PDT/Ca2+ overload synergistic treatment. Results COF can induce the production of 1O2 under 650 nm irradiation for photodynamic therapy (PDT). Low pH and hypoxia in tumour microenvironment (TME) can activate the nanocomposite to release oxygen and Ca2+. The released O2 can alleviate hypoxia in TME, thus enhancing the efficiency of COF-mediated PDT. Abundant Ca2+ were released and accumulated in cancer cells, resulting in Ca2+ overload. Notably, the reactive oxygen species (ROS) and Ca2+ overload ensure the sustained opening of MPTP, which leads to the change of mitochondria transmembrane potential, the release of cytochrome c (Cyt c) and the activation of caspases 3 for cancer cell apoptosis. Conclusion This multifunctional nanosystem with TME responded abilities provided a novel strategy for innovative clinical cancer therapy. Graphical Abstract

In the fields of optics and photonics, phase-only spatial light modulators (SLMs) play an increasingly important role in wave-front engineering. However, the SLMs are subject to wavefront distortion arising from the imperfection in the birefringence effect and physical structure of modulators. This paper presents a simple self-interference phase calibration method applicable to liquid-crystal SLM. We build an interferometric imaging system based on the Pancharatnam phase-shifting to measure the phase distribution of a light beam coming from SLMs. Two types of phase modulation errors of SLMs can be characterized in the measurement process: the erroneous gamma curve and shape aberration. The former belongs to dynamic phase distortion and is measured through a four-step Pancharatnam phase-shifting interference, which allows a one-shot recording of interference pattern via a polarization camera; the latter represents static phase distortion and is extracted from the interference between light waves coming from different regions of the SLM panel by using Zernike polynomial fitting. Our method has the advantages of high-precision pixel-wise phase correction and robustness against environmental disturbance and thus can facilitate the applications of SLM in optical field manipulation.

Phagocytic ability of macrophage is responsible for tuberculosis infection. Nicotine has been shown to attenuate the phagocytic ability of macrophage; however, the underlying mechanism remains unclear. Here, we demonstrated that nicotine increased the message RNA (mRNA) and protein expression of signal regulatory protein alpha (SIRPα) and enhanced the stability of SIRPα mRNA in macrophage. Nicotine decreased the expression of microRNA (miR)-296-3p, which directly targeted the 3′-untranslated region (3′-UTR) of SIRPα mRNA in macrophage. Furthermore, nicotine inhibited the phagocytic ability of macrophage by regulating the miR-296-3p–SIRPα axis. Moreover, nicotine decreased miR-296-3p expression via increasing c-Myc expression in macrophage. Together, we found that nicotine attenuate the phagocytic ability of macrophage by regulating the c-Myc-miR-296-3p–SIRPα signal.

Utilizing brake pad waste (BPW) in asphalt mixture can not only reduce the consumption of natural mineral material, but also alleviate the environmental pollution problem caused by such solid waste. This paper concentrates on the feasibility and strategy of using BPW as aggregate in asphalt mixture. Firstly, BPW aggregate within five different particle sizes were separately used to replace the limestone aggregate or filler with different proportions (25%, 50%, 75% and 100%) in asphalt mixture by the volume control method. The corresponding optimum asphalt contents of 21 kinds of asphalt mixtures were determined by the Marshall design procedure. Due to its high asphalt-absorption, BPW aggregate would increase the optimum asphalt content of asphalt mixture, which depends on the particle size of BPW aggregate. To meet the Chinese Standard Specification for asphalt mixture, the maximum substitution proportions for the BPW aggregates of 0–0.075 mm, 0.075–2.36 mm, 2.36–4.75 mm, 4.75–9.5 mm, 9.5–16 mm were 75%, 50%, 25%, 100%, and 100%, respectively. On this basis, BPW mixture simultaneously using the BPW aggregate with different sizes and the corresponding maximum substitution proportions were prepared and evaluated by a series of laboratory tests as well. Results implied that BPW mixture (BPW-M) outperformed the limestone asphalt mixture (Control-M) in term of the moisture stability, the high-temperature performance, the low-temperature property, and the fatigue life. Furthermore, dynamic modulus test results indicated that BPW-M mixture was more stiffness at relative low frequency (high temperature) and more flexible at relative high frequency (low temperature). Overall, this study verifies the feasibility and provides a reference datum of using BPW materials as aggregate in asphalt mixture.

We conducted a phase I bioequivalence trial in healthy Chinese subjects in the fasting and postprandial states. The goal of this trial was to compare the pharmacokinetics and safety of the test preparation Cefaclor granule (Disha Pharmaceutical Group Co., Ltd.) and the reference preparation Cefaclor suspension (Ceclor®, Eli Lilly and Company). In this trial, 24 subjects were selected in the fasting and postprandial states, respectively. Enrolled subjects randomly accepted a single dose of 0.125 g Cefaclor granule or Cefaclor suspension. The washout period was set as 2 days. Blood samples were collected within 8 h after administration in the fasting state and within 10 h after administration in the postprandial state. Plasma concentrations were determined by Liquid chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters (AUC, Cmax) were used to evaluate bioequivalence of the two drugs. In the fasting trial, the geometric mean ratios (90% confidence intervals CIs) for Cmax, AUC0-t, and AUC0-∞ were 93.01% (85.96%–100.63%), 97.92% (96.49%–99.38%) and 97.95% (96.52%–99.41%), respectively. The GMR (90% CIs) for Cmax, AUC0-t, and AUC0-∞ in postprandial state were 89.27% (81.97%–97.22%), 97.31% (95.98%–98.65%) and 97.31% (95.93%–98.71%), respectively. The 90% CIs of AUC and Cmax in the fasting and postprandial states were within the 80–125% bioequivalence range. Therefore, Cefaclor granule and Cefaclor suspension were bioequivalent and displayed similar safety profiles. Furthermore, food intake affected the pharmacokinetic parameters of both drugs.

Hypopharyngeal squamous cell carcinoma (HSCC) is one of the high mortality cancers with a poor prognosis, which is driving the development of new chemotherapeutic agents. We identified the anticancer effects of a natural compound, solamargine (SM), on FaDU cells and explored its mechanism in terms of non-coding RNA. It was observed that SM inhibited the proliferation of FaDU cells with an IC50 of 5.17 μM. High-throughput sequencing data revealed that lncRNA HOXA11-AS was significantly downregulated in cells co-incubated with SM. Further assays demonstrated that SM-induced downregulation of lncRNA HOXA11-AS showed important implications for apoptosis. Given the properties of HOXA11-AS as a miR-155 sponge, we further confirmed that SM upregulated the expression of miR-155 in FaDU cells. C-Myc is a transcription factor that regulates cell differentiation and apoptosis, whose mRNA is considered to be targeted by miR-155. We showed that c-Myc expression was downregulated by SM and accompanied by increased apoptosis, which was consistent with the findings of transcriptome sequencing. Furthermore, SM administration suppressed xenograft tumor growth in a xenograft mouse model in vivo. In the light of the aforementioned findings, our results suggested that SM downregulated the expression of HOXA11-AS, which in turn induces apoptosis by downregulating c-Myc in FaDU, providing evidence for the anticancer effect of SM on HSCC and uncovering the effect of SM on non-coding RNAs as, at least partly, a mechanism of action.

Arginine has a positive effect on pre-implantation development in pigs. However, the exact mechanism by which arginine promotes embryonic development is undefined. Here, single-cell RNA sequencing technology was applied to porcine in vivo pre-implantation embryos from the zygote to morula stage, it was found that that the expression of arginine metabolism-related genes clearly changed from the 2-cell stage to the 4-cell stage, when zygotic genome activation (ZGA) occurs in porcine embryos. Further analysis showed that arginine metabolism-related genes are significantly correlated with key ZGA genes. To determine the function of arginine in porcine embryos during ZGA, the in vitro fertilization embryos were cultured in PZM-3 medium (0.12 mM arginine, Control group), a modified PZM-3 medium (0 mM arginine, Block group) and a modified PZM-3 medium supplemented with arginine (0.12 mM arginine, Block + Arg group). The results showed that the 4-cell arrest rate was significantly increased in the Block group compared to the Control group (P < 0.05). The 4-cell arrest rate in the Block + Arg group was significantly decreased than that in the Block group (P < 0.05). Meanwhile, the expression of ZGA marker genes and SIRT1 protein in 4-cell embryos was significantly decreased in the Block group compared to the Control group, and their expression was significantly increased in the Block + Arg group. In addition, we observed that the glutathione (GSH), ATP levels, and lipid droplet contents were significantly increased, and the reactive oxygen species (ROS) level was decreased in the Block + Arg group compared to the Block group. Compared with Control group, spermine content in culture medium and the mRNA expression of ornithine decarboxylase1 (ODC1) of embryos in the Block group were significantly decreased (P < 0.05), and those in the Block + Arg group were significantly increased compared with the Block group (P < 0.05). Moreover, when difluoromethylornithine (an inhibitor of ODC1) was added to the modified PZM-3 medium supplemented with arginine, the effect of arginine on ZGA was inhibited. In summary, our findings demonstrated that arginine may regulate ZGA under nutrition restriction in porcine embryos by promoting polyamine synthesis.

Current view of the impact of A-site cation on the stability of perovskite materials and devices is derived from accelerated ageing tests at high temperature, which is beyond normal operation range. Here, the authors reveal the great impact of ageing condition on assessing the photothermal stability of mixed-cation perovskites using high-throughput robot system coupled with machine learning.

Mixed-halide perovskites are of interest for photovoltaic devices, but light-induced halide segregation obstructs bandgap tuning and is not fully understood. Here the authors study the effects of strain and iodide/bromide ratio on light-induced halide segregation in mixed-halide perovskites.

ABSTRACT The dramatic increase of methicillin-resistant Staphylococcus aureus (MRSA) poses a great challenge to the treatment of Staphylococcus aureus (S. aureus) infections. Therefore, there is an urgent need to identify novel anti-infective agents to attack new targets to overcome antibiotic resistance. Casein hydrolase P (ClpP) is a key virulence factor in S. aureus to maintain cellular homeostasis. We screened from flavonoids and finally determined that quercetin could effectively attenuate the virulence of MRSA. The results of the thermal shift assay showed that quercetin could bind to ClpP and reduce the thermal stability of ClpP, and the KD value between quercetin and ClpP was 197 nM as determined by localized surface plasmon resonance. We found that quercetin exhibited a protective role of a mouse model of MRSA-induced lethal infection in a murine model. Based on the above facts, quercetin, as a ClpP inhibitor, could be further developed as a potential candidate for antivirulence agents to combat S. aureus infections. IMPORTANCE The resistance of Staphylococcus aureus (S. aureus) to various antibiotics has increased dramatically, and thus the development of new anti-infective drugs with new targets is urgently needed to combat resistance. Caseinolytic peptidase P (ClpP) is a casein hydrolase that has been shown to regulate a variety of important virulence factors in S. aureus. Here, we found that quercetin, a small-molecule compound from traditional Chinese herbal flavonoids, effectively inhibits ClpP activity. Quercetin attenuates the expression of multiple virulence factors in S. aureus and effectively protects mice from lethal pneumonia caused by MRSA. In conclusion, we determined that quercetin is a ClpP inhibitor and an effective lead compound for the development of a virulence factor-based treatment for S. aureus infection.

Herpesviruses, known as large DNA viruses, have a wide host range. In addition to human beings, cattle, and horses, even carp can be hosts for herpesvirus infection. Herpesviruses are pathogens possessing elaborate mechanisms that regulate host cell components for its replication, assembly and generating mature virus particles that can infect humans and most animals, usually causing multiple and lifelong infections. In addition, several human diseases, such as genital or mouth herpes, mononucleosis, and Burkitt lymphoma, are usually associated with herpesvirus infection. Blocking the steps of viral infection, such as entry, replication and assembly, may be an effective way for many different herpes viruses and their related diseases. Therefore, we aim to describe antiviral agents that are able to prevent herpesvirus entry, replication and assembly in host cells. We summarize antiviral strategies, including certain small molecular drugs, RNA interference and CRISPR/Cas9 system-based antiviral approaches, which represent promising approaches.

Objectives: Pertuzumab is a monoclonal antibody for the treatment of breast cancer. The aim of this study was to compare the pharmacokinetics, immunogenicity and safety of the test preparation SHR-1309 injecta and the reference preparation Perjeta® in healthy Chinese male subjects.Methods: In this randomized, double-blind, single dose, two-way, parallel bioequivalence trial, a total of 80 qualified Chinese male subjects were selected and randomly divided into two groups. Each subject was intravenously injected with SHR-1309 or Perjeta®. Blood samples were collected at 21 different time points for pharmacokinetic analysis. In addition, immunogenicity was assessed at five different time points. The safety of the medication was monitored throughout the whole trial.Results: Cmax and AUC0-t were the primary pharmacokinetic parameters. Under a 90% confidence interval, their geometric mean ratios were 98.30 and 88.41% for SHR-1309 injection and Perjeta®, respectively. The geometric mean ratio of secondary pharmacokinetic parameters AUC0-∞ was 88.58%. These evaluation indexes are in the standard range of 80–125%, so SHR-1309 can be considered bioequivalent to Perjeta®. After 1,680 h (day 70) of administration, the two groups had 12 and 13 subjects who produced antidrug antibody (ADA), respectively. The occurrence time and proportion of ADA in SHR-1309 and Perjeta® were similar between subjects, and they had similar immunogenicity. During the entire trial period, there were 71 drug-related adverse reactions in 29 subjects who received SHR-1309 and 61 drug-related adverse reactions in 32 subjects who received Perjeta®. The incidence of adverse reactions between the two drugs was similar.Conclusion: The pharmacokinetic parameters, immunogenicity and safety of the biosimilar SHR-1309 injection produced by Shanghai Hengrui Pharmaceutical Co. Ltd. were similar to the original drug Perjeta® produced by Roche Pharma AG. The two drugs met the bioequivalence evaluation criteria. Therefore, SHR-1309 is bioequivalent to Perjeta®. Clinical trial registration: CTR20200,738.

Non-small cell lung cancer (NSCLC) has the highest morbidity and mortality among all carcinomas. However, it is difficult to diagnose in the early stage, and current therapeutic efficacy is not ideal. Although numerous studies have revealed that Ailanthone (Aila), a natural product, can inhibit multiple cancers by reducing cell proliferation and invasion and inducing apoptosis, the mechanism by which Aila represses NSCLC progression in a time-dependent manner remains unclear. In this study, we observed that most long noncoding RNAs (lncRNAs) were either notably up- or downregulated in NSCLC cells after treatment with Aila. Moreover, alterations in lncRNA expression induced by Aila were crucial for the initiation and metastasis of NSCLC. Furthermore, in our research, expression of DUXAP8 was significantly downregulated in NSCLC cells after treatment with Aila and regulated expression levels of EGR1. In conclusion, our findings demonstrate that Aila is a potent natural suppressor of NSCLC by modulating expression of DUXAP8 and EGR1.

Alumina aerogels are considered to have good application prospects in the high-temperature field. In this study, monolithic mullite fiber-reinforced alumina aerogels with excellent mechanical and thermal properties were synthesized via a facile method without the use of any chelating agents. This method successfully avoids the introduction of impurities during the use of catalysts and chelating agents while greatly reducing gelation time, and thus helps mullite fibers to uniformly disperse in the sol. The compressive stress at 80% strain of the obtained mullite fiber-reinforced alumina aerogels was as high as 16.04 MPa—426% higher than that of the alumina aerogel without the addition of mullite fibers. Regarding thermal properties, the shrinkage of the mullite fiber-reinforced alumina aerogels (AM) samples was less than 1% after heat treatment at 1300 °C for 2 h. Furthermore, the rear-surface temperature of the AM samples burned by a butane blow torch was only 68 °C. These outstanding properties make AM samples promising for application in thermal insulation materials in high-temperature fields such as aerospace and industrial thermal protection in the future.

The corrosion resistance of zirconium alloys is closely related to the size of precipitates. β-phase quenching is the key process for controlling the precipitate size of zirconium alloy. In this study, the microstructure and the precipitates size of nuclear graded Zircaloy-4 (hereinafter called as Zr-4) alloy treated by the quenching in different cooling mediums were studied, and the critical quenching diameter of the Zr-4 alloy rod was determined by finite element method. The results showed that, the cooling rate of the β-phase quenching had small effect on the grain size of the alloy, however the size of the needle α grains increased with a decrease of cooling rate. The thickness of α grains quenched in water, quenched in oil, quenched at room temperature and quenched at 440 °C were about 1 μm, 5 μm, 9 μm, and 15 μm, respectively. When the cooling rate was high (water-quenching and oil-quenching), the precipitates formed only along the grain boundary, and with the length of less than 100 nm. When the cooling rate was low (air quenching), precipitates formed not only at the grain boundaries but also inside the grains, and the precipitates length was about 150–200 nm. When the Zr-4 alloy rod was quenched in water or oil, the maximum diameter of the specimen with suitable precipitate size (about 100–200 nm) was 140 and 97 mm, respectively. Keywords: Zr-4 alloy, βphase quenching, Cooling rate, Microstructure, Critical quenching diameter

Pancreatic cancer is a common malignant tumor with a high incidence and mortality rate. The prognosis of patients with pancreatic cancer is considerably poor due to the lack of effective treatment in clinically. Despite numerous studies have revealed that baicalein, a natural product, is responsible for suppressing multiple cancer cells proliferation, motility and invasion. The mechanism by which baicalein restraining pancreatic cancer progression remains unclear. In this study, we firstly verified that baicalein plays a critical role in inhibiting pancreatic tumorigenesis in vitro and in vivo. Then we analyzed the alteration of microRNAs (miRNAs) expression levels in Panc-1 cells incubated with DMSO, 50 and 100 μM baicalein by High-Throughput sequencing. Intriguingly, we observed that 20 and 39 miRNAs were accordingly up- and down-regulated through comparing Panc-1 cells exposed to 100 μM baicalein with the control group. Quantitative PCR analysis confirmed that miR-139-3p was the most up-regulated miRNA after baicalein treatment, while miR-196b-5p was the most down-regulated miRNA. Further studies showed that miR-139-3p induced, miR-196b-5p inhibited the apoptosis of Panc-1 cells via targeting NOB1 and ING5 respectively. In conclusion, we demonstrated that baicalein is a potent inhibitor against pancreatic cancer by modulating the expression of miR-139-3p or miR-196b-5p.

As an important regulatory mechanism at the posttranscriptional level in metazoans, adenosine deaminase acting on RNA (ADAR)-induced A-to-I RNA editing modification of double-stranded RNA has been widely detected and reported. Editing may lead to non-synonymous amino acid mutations, RNA secondary structure alterations, pre-mRNA processing changes, and microRNA-mRNA redirection, thereby affecting multiple cellular processes and functions. In recent years, researchers have successfully developed several bioinformatics software tools and pipelines to identify RNA editing sites. However, there are still no widely accepted editing site standards due to the variety of parallel optimization and RNA high-seq protocols and programs. It is also challenging to identify RNA editing by normal protocols in tumor samples due to the high DNA mutation rate. Numerous RNA editing sites have been reported to be located in non-coding regions and can affect the biosynthesis of ncRNAs, including miRNAs and circular RNAs. Predicting the function of RNA editing sites located in non-coding regions and ncRNAs is significantly difficult. In this review, we aim to provide a better understanding of bioinformatics strategies for human cancer A-to-I RNA editing identification and briefly discuss recent advances in related areas, such as the oncogenic and tumor suppressive effects of RNA editing.

Abstract Thin‐film solar cells based on hybrid lead halide perovskites have achieved certified power conversion efficiencies exceeding 24%, approaching those of crystalline silicon. This motivates deeper studies of the mechanisms that determine their performance. Twin defect sites have been proposed as a source of traps in perovskites, yet their origin and influence on photovoltaic performance remain unclear. It is found that twin defects—observed herein via both transmission electron microscopy and X‐ray diffraction—are correlated with the amount of antisolvent added to the perovskite and that twin defects in the highest‐performing perovskite photovoltaics are suppressed. Heterogeneous supersaturation nucleation is discussed as a contributor to efficient perovskite‐based optoelectronic devices.

As a common therapy for prostate cancer, androgen deprivation therapy (ADT) is effective for the majority of patients. However, prolonged ADT promotes drug resistance and progression to an aggressive variant with reduced androgen receptor signaling, so called neuroendocrine prostate cancer (NEPC). Until present, NEPC is still poorly understood, and lethal with no effective treatments. Elevated expression of neuroendocrine related markers and increased angiogenesis are two prominent phenotypes of NEPC, and both of them are positively associated with cancers progression. However, direct molecular links between the two phenotypes in NEPC and their mechanisms remain largely unclear. Their elucidation should substantially expand our knowledge in NEPC. This knowledge, in turn, would facilitate the development of effective NEPC treatments. We recently showed that a single critical pathway regulates both ADT-enhanced angiogenesis and elevated expression of neuroendocrine markers. This pathway consists of CREB1, EZH2, and TSP1. Here, we seek new insights to identify molecules common to pathways promoting angiogenesis and neuroendocrine phenotypes in prostate cancer. To this end, our focus is to summarize the literature on proteins reported to regulate both neuroendocrine marker expression and angiogenesis as potential molecular links. These proteins, often described in separate biological contexts or diseases, include AURKA and AURKB, CHGA, CREB1, EZH2, FOXA2, GRK3, HIF1, IL-6, MYCN, ONECUT2, p53, RET, and RB1. We also present the current efforts in prostate cancer or other diseases to target some of these proteins, which warrants testing for NEPC, given the urgent unmet need in treating this aggressive variant of prostate cancer.

The performance of wide-bandgap perovskite photovoltaics is limited by the undesired phase transition and high density of deep level traps. Here, Tan et al. incorporate dipolar methylammonium cation to make the material defect-tolerant and achieve a high power conversion efficiency of 20.7%.

Formamidinium-lead-iodide-based perovskites have a preferred bandgap below 1.55 eV for solar cell applications but suffer from operational instability. Here, Zhao et al. improve the film quality using cesium-containing seeded growth to show high stabilized efficiency and more than 100 h lifetime under simulated sunlight.

Perovskite solar cells exhibit large conversion efficiencies, but their stability still represents a bottleneck. Here, the authors integrate a hygroscopic polymer scaffold to the perovskite active layer and fabricate efficient and stable devices that recover after being exposed to a humid environment.

The genus Alnus (Betulaceae) is comprised of more than 40 species. Many species of this genus have a long history of use in folk medicines. Phytochemical investigations have revealed the presence of diarylheptanoids, polyphenols, flavonoids, terpenoids, steroids and other compounds. Diarylheptanoids, natural products with a 1,7-diphenylheptane structural skeleton, are the dominant constituents in the genus, whose anticancer effect has been brought into focus. Pure compounds and crude extracts from the genus exhibit a wide spectrum of pharmacological activities both in vitro and in vivo. This paper compiles 273 naturally occurring compounds from the genus Alnus along with their structures and pharmacological activities, as reported in 138 references.

Cinnamic acid sugar ester derivatives (CASEDs) are a class of natural product with one or several phenylacrylic moieties linked with the non-anomeric carbon of a glycosyl skeleton part through ester bonds. Their notable anti-depressant and brains protective activities have made them a topic of great interest over the past several decades. In particular the compound 3′,6-disinapoylsucrose, the index component of Yuanzhi (a well-known Traditional Chinese Medicine or TCM), presents antidepressant effects at a molecular level, and has become a hotspot of research on new lead drug compounds. Several other similar cinnamic acid sugar ester derivatives are reported in traditional medicine as compounds to calm the nerves and display anti-depression and neuroprotective activity. Interestingly, more than one third of CASEDs are distributed in the family Polygalaceae. This overview discusses the isolation of cinnamic acid sugar ester derivatives from plants, together with a systematic discussion of their distribution, chemical structures and properties and pharmacological activities, with the hope of providing references for natural product researchers and draw attention to these interesting compounds.