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Based on the structure of caerulomycin A, 90 novel bipyridine derivatives were designed and synthesized. Among these, compound B19exerted strong antitumor effects in vivo and in vitro. Importantly, NOP2/Sun RNA methyltransferase 3 (NSUN3) protein was identified as the target specific binding to B19, which inhibits oxidative phosphorylation of mitochondrial energy metabolism and enhances glycolytic activity by binding to NSUN3. Knockdown of NSUN3inhibited both proliferation and migration of colorectal cancer (CRC) cells by activating AMPK-related signaling and inhibiting downstream STAT3 signaling to exert antiproliferative and pro-apoptotic effects. Our findings support the use of NSUN3 inhibitors as promising therapeutic strategies against CRC.

To enable rapid characterization of the complex permittivity of unknown solutions, we propose a low-cost, compact, and highly integrated microwave microfluidic sensor. This sensor, fabricated on an FR4 substrate, employs a substrate-integrated waveguide (SIW) structure combined with a complementary split-ring resonator (CSRR). The structure includes a ring of closely spaced metal vias surrounding the hexagonal CSRR, enhancing the electric field’s concentration. We optimized the sensor’s parameters and developed its equivalent circuit model using ADS software. Interaction with the sample occurs when a polydimethylsiloxane (PDMS) microfluidic channel, positioned above the sensing structure, contains the liquid sample. This setup alters the sensor’s no-load frequency, initially set at 2.46 GHz, impacting the resonant frequency and Q-factor. We introduced a first-order characteristic matrix model to analyze and confirm the sample’s properties based on these changes. Our results, with a measurement error of approximately 5%, affirm the accuracy in determining the complex permittivity. The sensor’s dimensions are $44\times 30\times 0.8$ mm3, requiring a minimal sample volume of $2.32~\mu $ L and offering a high sensitivity of 0.448%. Its ease of fabrication, capability for rapid noninvasive measurements, and high sensitivity make it an ideal tool for noninvasive liquid characterization in biological and chemical fields.

The current challenges faced by microwave planar sensors include their low sensitivity, limited detection range, and difficulties in operating small devices. This study proposes a metamaterial microwave sensor based on complementary split ring resonator (CSRR) for determining the dielectric constants of liquid and solid materials. The novelty of the proposed sensor lies in the use of curved slots in the CSRR structure to achieve higher electric field concentration and to store a large amount of energy, the determination of the measurement area based on its electric field distribution, and the design of microfluidic channels to further improve the sensitivity to the resonance frequency change. The sensor operates at 2.45 GHz and has dimensions of $40\times 30\times 0.6\,\,\text {mm}^{3}$ . Since the dielectric constant of the contacting object affects the microwave sensor’s resonant frequency, the displacement of the sensor’s resonant frequency is measured using various items. The resonant frequency of the sensor adjusts when materials with varying dielectric constants are introduced into the measurement region. By measuring the frequency point of the measured material at the maximum return loss of the resonator, empirical equations with different coefficients are established to derive the dielectric constants of solids and liquids. The sensitivity and resolution were 4.12% and 102 MHz in solid and 0.78% and 8.4 MHz in liquid. The sensors were tested using five substrate materials commonly used in microwave circuits and different concentrations of ethanol solutions as samples. These findings validate the potential application of the sensor as a cost-effective alternative to expensive commercial sensors for dielectric characterization. The results demonstrate that the sensor possesses high sensitivity, high measurement accuracy, low cost, and ease of fabrication, making it an excellent alternative to expensive commercial sensors for dielectric characterization. This confirms the promising application of the sensor in the field of dielectric constant measurement.

Psoriasis, a prevalent chronic skin disorder, remains a significant therapeutic obstacle. This study centers on rho-associated coiled-coil-containing kinase2 (ROCK2) as an advantageous target for treating psoriasis and identifies five potent and selective ROCK2 inhibitors (A31–35). Notably, A32–35outperform KD025 in ROCK2/ROCK1 selectivity by up to 216-fold. Among these candidates, A31emerged as an exceedingly promising molecule, showcasing remarkable inhibitory potency (IC50= 3.7 ± 0.8 nM), 19-fold ROCK2/ROCK1 selectivity, and favorable pharmacokinetics. Insights from the binding mode study further underscored the pivotal role of interactions with Phe103 on the P-loop in determining the selectivity between ROCK1 and ROCK2. In an imiquimod-induced psoriasis-like mouse model, oral administration of A31notably ameliorated symptoms by targeting the IL-23/Th17 axis. Based on these compelling findings, A31was selected as a highly promising compound for further investigation as a potential treatment for psoriasis.

Container port congestion threatens the effectiveness and sustainability of the global supply chain because it stagnates cargo flows and triggers ripple effects across connected, multimodal freight transport networks. This study aims to develop a novel and tangible method to measure port congestion by investigating ship behaviors between different zones in port waters. Different port zones have varying ship densities because ships moor in the anchorage area randomly but dock at berths in an orderly and close fashion. This observation leads us to apply the density-based clustering method for port zone identification and differentiation. In order to ensure the method is globally applicable and accurate, we develop a new clustering algorithm, an iterative, multi-attribute DBSCAN (IMA-DBSCAN), which incorporates an iterative process, together with both spatial information and domain knowledge. The necessary input data for the algorithm is extracted from the Automatic Identification System (AIS), a satellite-based tracking system with real-time ship positioning and sailing data. An illustrative case suggests that our algorithm can rapidly and precisely identify anchorage areas and individual berths (even in a port with complicated geographic features), while other methods cannot. The algorithm is applied to measure congestion at 20 major container ports in the world. The results show a significant increase in congestion at the Port of Los Angeles from August to December 2020, which matches the realistic statistics and proves the efficiency and practical applicability of the proposed algorithm.

The consensus tracking problem means that a group of followers tracks the desired trajectory with local communication. In this article, partial components of cluster consensus have been considered. In this scenario, the $p$ components of the followers in different clusters track the leader at different lag times, while $p$ components of each agent in the same cluster reach a consensus, which is called $p$ components of cluster-lag (PCCL) consensus. By using a seminorm $\|x_{i}\|_{2,p}$ and a Lyapunov–Krasovskii functional, PCCL consensus for second-order multiagent systems with homogeneous nonlinear systems on cooperative–competitive networks has been considered. For the case that the communication network graph is undirected, a decentralized adaptive controller, which is based on the exchanged neighbors’ information from the same cluster, is designed such that all the agents reach PCCL consensus. For the directed graph case, an adaptive protocol based on the intracoupling strength is constructed for each cluster to achieve PCCL consensus. Finally, two simulation examples are illustrated to show the effectiveness of the proposed control protocols.

Microwave fracturing of rocks before mechanical breakage could improve the performance of mechanical excavators and reduce environmental impacts. Previous research focused on the microwave fracturing of intact rock blocks. By using an open‐ended antenna, this paper investigates the effect of pre‐existing joints on the microwave fracturing of the Singapore Bukit Timah granite blocks. The results show that the specimens are weakened in the manners of cracking, spalling, melting, or a combination of them. The crack number and the total crack length produced by microwave treatment of jointed rock blocks are slightly smaller than those in the intact rock blocks. The interaction between joints and microwave‐induced cracks can be summarized into the following four patterns: (1) microwave‐induced cracks become arrested so that the crack propagation is terminated; (2) microwave‐induced cracks penetrate the joints and continue to propagate; (3) microwave‐induced cracks become deflected along the joints; and (4) microwave‐induced cracks propagate forward following the joints. The smaller the approach angle between the microwave‐induced crack and the pre‐existing joint is, the more microwave‐induced cracks tend to be arrested at the joint. Increasing the approach angle between the microwave‐induced crack and the joint can increase the chance of microwave‐induced crack penetrating the joint. The results also show that the smaller the distance is between the microwave radiation point and the joint, the easier it is for microwave‐induced cracks to penetrate the joints; otherwise, the microwave‐induced crack is more likely to be arrested at the pre‐existing joint. This study used an open‐ended microwave antenna to fracture the Bukit Timah granite at different dimensions. The effect of joints on microwave fracturing of the granite and the pattern of crack–joint interactions were systematically investigated.

Health-related quality of life (HRQoL) is an important consideration in managing patients. Spleen aminopeptide oral lyophilized powder (SAOLP) has been used to enhance cellular immunity in a patient. This multicenter, randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the safety and efficacy of SAOLP for improving HRQoL in patients with breast cancer. Patients diagnosed with advanced breast cancer were included, and were administered SAOLP or placebo 4 mg qd for two cycles. The primary endpoint was improvement in HRQoL on day 42 measured by the EORTC QLQ-C30 and EORTC QLQ-BR23. Secondary endpoints included immunologic function, improvement in HRQoL on day 21 and 84, objective response rate, disease control rate, BMI and adverse events. On day 42, on the EORTC QLQ-C30 or EORTC QLQ-BR23, scores on the functional scales and QoL scale were significantly higher and scores on symptom scales were significantly lower in patients who received SAOLP compared to placebo (P< 0.05). On day 84, the number of CD3, CD4 and CD8 cells were significantly higher in patients who received SAOLP. There were no significant differences in objective response rate, disease control rate or BMI. SAOLP may improve HRQoL and the immune response in patients with advanced breast cancer, represents a convenient and safe adjuvant therapy.

HDAC8 is a therapeutic target with great promise for breast cancer. Here, we reported a novel compound corallorazine D from Nocardiopsissp. XZB108, selectively inhibited HDAC8 (IC50= 0.90 ± 0.014 μM), suggesting that it may be a promising nonhydroxamate HDAC8 inhibitor. Upon additional modifications of corallorazine D, a candidate compound 5k, demonstrated remarkable inhibitory potency against HDAC8 (IC50= 0.12 ± 0.01 nM), 89-fold superior to PCI-34051. The selectivity of 5kwas at least 439-fold, superior to corallorazine D, confirming the efficacy of our modifications. In an orthotopic mouse model of breast cancer, 5kdisplayed nearly 4-fold superior antitumor activity than SAHA. Furthermore, 5ktriggered antitumor immunity by activating T cells. Treatment with 5ksignificantly increased the proportion of M1 macrophages and decreased the proportion of M2 macrophages (M1/M2 ratio = 2.67 ± 0.25). 5krepresents a promising compound for further investigation as a potential treatment for breast cancer.

Protein kinases C (PKCs) are a family of serine/threonine kinases involved in various cellular processes, including proliferation, differentiation, cell survival, and apoptosis. Here, we report the identification, structure–activity relationship (SAR), and 3D-QSAR studies of 69 natural indolocarbazoles, including 15 new compounds, from marine streptomyces strains. Interestingly, we found that the chair conformational isomer of 7-oxo-staurosporine (compound 15) inhibited PKCθ more potently than the corresponding boat isomer. An evaluation of kinase selectivity and antitumor efficacy revealed that 15was a potent dual PKCθ/δ inhibitor and that it could efficiently inhibit tumor growth in pancreatic cancer (PC) by inducing cellular apoptosis and suppressing the NF-κB/p-P65 pathway. In addition, we demonstrated that overexpression of p-PKCδ and p-P65 was associated with poor survival rates in patients with PC, and p-PKCθ expression also showed significant positive correlations with p-PKCδ and p-P65 levels. Finally, the PC patient-derived xenograft model further confirmed the potential anti-PC efficacy of 15.

•A Ni and N-doped porous interconnected carbon (NiNPIC) was prepared by a rapid and facile ultrasonic assisted method.•A high current density of 10.2 mA cm−2, an FE of 95.1%, a TOF of 1886 h-1for CO2-to-CO at a low over-potential of -0.54 V.•The interconnected structure, high surface area and rich Ni-N-C moisture leads to better electron transfer and lower interface resistance.•The hierarchical porous structure greatly enhanced the mass transport in the electrode.

The antiviral metabolites from bacterial stress response to bacteriophage infection can maintain homeostasis of host cells, while metabolism disorder is a remarkable characteristic of tumorigenesis. In the aspect of metabolic homeostasis, therefore, the antiviral homeostasis-maintaining metabolites of bacteria may possess anti-tumor activity. However, this issue has not been addressed. Here we show that the homeostasis-challenged maintaining metabolites from deep-sea bacteriophage-challenged thermophile can suppress tumor metastasis. The results indicated that the metabolic profiles of the bacteriophage GVE2-infected and virus-free thermophile Geobacillus sp. E263 from a deep-sea hydrothermal vent were remarkably different. Thirteen metabolites were significantly elevated and two metabolites were downregulated in thermophile stress response to GVE2 infection. As an example, the upregulated L-norleucine was characterized. The data showed that L-norleucine had antiviral activity in thermophile. Furthermore, the in vitro and in vivo assays revealed that L-norleucine, as well as its derivative, significantly suppressed metastasis of gastric and breast cancer cells. L-norleucine interacted with hnRNPA2/B1 protein to inhibit the expressions of Twist1 and Snail, two inhibitors of E-cadherin, and promote the E-cadherin expression, leading to the inhibition of tumor metastasis. Therefore, our study presented that antiviral homeostasis-maintaining metabolites of microbes might be a promising source for anti-tumor drugs.

In order to avoid congestion in the second-order nonlinear leader-following multiagent systems over capacity-limited paths, an approach called cluster lag consensus is proposed, which means that the agents in different clusters will pass through the same positions with the same velocities but lag behind the leader at different times. Lyapunov functionals and matrix theory are applied to analyze such cluster lag consensus. It is shown that when the graphic roots of clusters are influenced by the leader and the intracoupling of cluster agents is larger than a threshold, the cluster lag consensus can be achieved. Furthermore, the cluster lag consensus with a time-varying communication topology is investigated. Finally, an illustrative example is presented to demonstrate the effectiveness of the theoretical results. In particular, when the physical sizes of the agents are taken into consideration, it is shown that with a rearrangement and a position transformation, the multiagent system will reach cluster lag consensus in the new coordinate system. This means that all agents in the same cluster will reach consensus on the velocity, but their positions may be different and yet their relative positions converge to a constant asymptotically.

Thirteen new compounds, including suncheonosides E–M (1–9), four benzothioate derivatives (10–13), and one known compound (14), were identified from the marine-derived Streptomycessp. ZSN77. Suncheonosides E–M incorporate β-d-glucose, while the reported suncheonosides (A–D) incorporate only l-rhamnose. All of the structures were determined by extensive analysis of NMR spectroscopic and HRESIMS data. Bioactivity evaluation of these compounds showed that 6had significant activity against PC3 cells with an IC50value of 4.1 ± 0.1 μM, while compounds 12and 14exhibited cytotoxicity against HCT116 cells with IC50values of 7.3 ± 0.4 and 3.9 ± 0.3 μM, respectively. In addition, compounds 1, 2, 6, 10, and 14displayed potent in vivoanti-inflammatory efficacy with inhibition of NO production in a dose-dependent manner.

Single atom catalysts (SACs) have received considerable attention due to their high-atomic-utilization efficiency and tunable activity and selectivity. Here, in combination of experiments and calculations, we demonstrated that the electronic structures and the oxygen evolution reaction (OER) activity of the confined Ni SAC in a nitrogen-doped carbon nanotube are modulated by the encapsulated Ni nanoparticle (Ni@NiNCNT). The synergistic interaction between Ni SAC and Ni nanoparticle endows the Ni@NiNCNT with a satisfactory OER performance of 358 mV to achieve 10 mA cm–2current density and a Tafel slope of 89 mV dec–1, superior to the control samples and commercial RuO2. In addition, when employed as an air-cathode catalyst for rechargeable zinc–air batteries (ZABs), a Ni@NiNCNT modified battery outperformed a Pt/C+RuO2modified battery, with a higher power density and superior constant current charge–discharge cycle stability for 40 h. Theoretical simulations further revealed that the Ni nanoparticle can remarkably optimize the adsorption strength of oxygen atom on Ni SAC, leading to a small overpotential of 0.22 V for the rate-limiting step of *O formation. Furthermore, the charge transfer from Ni nanoparticle to Ni SAC, which handles Ni-d orbital characters of Ni SAC and accordingly the adsorption strength toward oxygenates, is responsible for the origin of the OER activity. Our results provide a new way to tune electronic structures of the SAC and thus to tune its catalytic activity and should be insightful for designing new type electrocatalysts based on SAC.

Aromatase (CYP19), which can catalyze the conversion of androgens to estrogens, has been one of the main inducers of hormone-related cancers. As a result, it is very important and necessary to find an aromatase inhibitor quickly and effectively. In this article, we screened for compounds that can bind to aromatase in the extract of Broussonetia papyrifera. The screening method HPLC/ESI-MS was employed in this presentation. Structures of twelve compounds were studied on the basis of LC-MS data. Six compounds were characterized as aromatase ligands through HPLC. Three of the ligands were identified as the glucosides of scopoletin, kaempferol and apigenin, whilst the others were vitexin, luteolin-7-O-β-D-glucopyranosid and dihydrochalcone. The bioassay indicated these compounds had aromatase inhibitory activity. We concluded that HPLC/ESI-MS was an effective means to reveal aromatase ligands. Moreover, five of the ligands found in this study were flavonoids. The C2, C3 double bond and the 7-OH were essential for the binding activity, which may be the binding sites for flavonoids.

In the present study, a simple fluorescein isothiocyanate (FITC)-based screening method was established for the rapid discovery of electrophilic compounds from natural products. The test sample is firstly allowed to alkylate a certain proportion of glutathione (GSH) under basic conditions (pH 8.0), then FITC is added to conjugate with the remaining GSH from the first step. By analyzing the fluorescence intensity of the reaction solution under acidic conditions (pH 3.0), it could be determined whether the test sample contained electrophilic compounds. A botanical sample, the ethyl acetate extract of Radix Salvia miltiorrhiza, was tested using this screening assay and we successfully discovered four electrophilic compounds from it, which were miltirone and its three derivatives (1-oxomiltirone, 4-methylenemiltirone, and 1,2-didehydromiltirone). The findings indicate that the screening method is effective and suitable for high-throughput screening (HTS) assays in the future.

A new thiophene, echinothiophenegenol (1), together with seven known thiophenes was isolated from the crude ethanol extract of roots of Echinops grijisii Hance. The structure of 1 was elucidated on the basis of spectroscopic data. Compounds 2 and 5, isolated from the plant for the first time, and compounds 1 - 7 were tested for their cytotoxicity against two human cancer cell lines, HL60 and K562. The thiophenes showed better activity than the bithiophenes

The cytotoxicity of three cycloartane triterpenoids, 9, 19-cycloart-7β, 24R, 25- triol-1-en-3-one (1), 9, 19-cycloart-7β, 24R, 25-triol-1-en-3-one 25-O-β-D-glucopynanoside (2), and 25-O-β-D-arabinopyranosyl-(1→4)- β-D-glucopyranosyl-9, 19-cycloart-7β, 24R, 25-triol-1-en-3-one (3), isolated from Sphaerophysa salsulawas investigated on SF188, U87wt, MCF-7, and H460 cancer cell lines. Compound 1 showed the strongest activity. Cell cycle analysis was employed to elucidate the cytotoxicity on the tested U87wt cells, which led to G2/M arrest. In addition, from the Western blotting experiments, the expression of P21 is increased.

Two new cycloartane glycosides were isolated from the whole herbs of Camptosorus sibiricusRupr.. By means of chemical and spectroscopic methods (IR, 1D- and 2D- NMR, HRMS, ESI-MS), the structures were established as (24R)-3β,7β,24,25,30-pentahydroxycycloartane 3-O-β-D-glucopyranosyl-24-O-β-D-glucopyranosyl-30-O-β-D-glucopyranoside (1), and (24R)-3β,7β,24,25,30-pentahydroxycycloartane 3-O-β-D-glucopyranosyl-(1→2)-β-D-glucopyranosyl-24-O-β-D-xylopyranosyl-(1→2)-β-D-glucopyranoside (2). The two new compounds were tested for their cytotoxicity in vitroagainst human tumor cell lines (A375-S2, Hela) using the MTT method, but both compounds were inactive.

Bioassay-directed separation of the light petroleum and methylene chloride extracts of the root tuber of Curcuma wenyujinY. H. Chen et C. Ling against five cell lines led to the isolation of one hexane derivative, crotepoxide (1), four sesquiterpenes, 4-epi-curcumenol (2), curcumenol (3), curcumadiol (4), and gweicurculactone (5), and three curcuminoids, curcumin (6), demethoxy-curcumin (7), and bisdemethoxycurcumin (8). Compounds 1–5have not been found previously in C. wenyujin; compounds 2and 3were obtained as an epimeric mixture. The structures of the compounds were established on the basis of NMR spectroscopic data. When tested for cytotoxity against cell lines HL-60, HepG2, K562, KB and MCF-7, compounds 5–8showed better antitumor activity than the others.

The crude ethanol extract of Pulsatilla chinensis(Bunge) Regel roots was extracted successively with light petroleum, dichloromethane and n-butanol. The light petroleum fraction (PEF) exhibited potent anti-proliferation activity on HL60 cells with an IC50value of 14 μg/mL. As a result, ICR mice transplanted with tumor strain S180 were employed for testing the effectiveness of drug administration of PEF. The tumor inhibitory rate was 36.7% at a dose of 20 mg/kg/d, which was higher than the positive control, which produced 31.5% inhibition. However, an unusual phenomenon was observed in that the tumor inhibitory response was reverse dose-dependent since tumor inhibition was only 19.5% at a dose of 180 mg/kg/d. GC-MS revealed that the main components of the PEF were C-19 and C-22 polyunsaturated fatty acids. Previous studies had revealed that polyunsaturated fatty acids exhibit either anti-tumor or tumor promoting activities, and so it is proposed that the effects of PEF on tumor growth is dependent on dosage.