Structure-activity relationship study of new carbazole sulfonamide derivatives as anticancer agents with dual-target mechanism.

A series of novel carbazole sulfonamide derivatives were synthesized and evaluated for antiproliferative activity. Among them, compounds 7 and 15 showed strong potency (IC50 values of 0.81-31.19 nM) against five different cancer cells including multidrug-resistant MCF7/ADR cells. Compound 15 displayed a high cancer cell selectivity (IC50(L02)/average IC50: SI = 7.7). The l-valine prodrug 7a and the phosphate prodrug 15a exerted rohust in vivo antitumor efficacies and accepted safety prolifes. Further mechanism studies revealed that 7 and 15 directly bind to the colchicine site in tubulin to block tubulin polymerization, promote microtubule fragmentation at the cellular level, and induce apoptosis with G2/M cell cycle arrest. These compounds also inhibit HEMC-1 cells migration and vascular tube formation. Additionally, compound 7 displayed a selective inhibition of Topo I. Collectively, these studies suggest that 7 and 15 represents a promising new generation of tubulin inhibitors for cancer treatment.

Erratum: Author correction to 'Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects' [Acta Pharmaceutica Sinica B 13 (2023) 2138-2151].

[This corrects the article DOI: 10.1016/j.apsb.2022.12.009.].

Pre-Treatment, Extraction Solvent, and Color Stability of Anthocyanins from Purple Sweetpotato.

Purple sweetpotato anthocyanins (PSPA) exhibit significant potential as food colorants with associated health benefits. However, challenges related to browning and instability have hindered the application of PSPA. In this study, various pre-treatments and solvents for PSPA extraction were evaluated based on color, anthocyanin yields, antioxidant capabilities, and brown index. Browning markedly influenced the color and reduced the antioxidant capacity. Optimal results were obtained with the pre-treatment of "steaming of unpeeled whole sweetpotato" and the solvent "1% citric acid-ddH2O". Furthermore, the color stability of purified PSPA solutions was evaluated under pH levels from 1 to 13 at 25 °C and 65 °C. The PSPA solutions showed a color spectrum from magenta, blue/green, and then to yellow across the pH range. The blue/green hues at pH 10-12 rapidly degraded, while the magenta hue at lower pH showed higher color stability. Elevated temperatures significantly accelerated the PSPA degradation. However, PSPA solutions at pH 1-2 exhibited remarkable color stability, with no spectral decay at either 65 °C for 12 h or 25 °C for 32 days. These results provide valid guidance for the extraction, preservation, and application of PSPA in the food industry.

Isolation, characterization, and circulation sphere of a filovirus in fruit bats.

Bats are associated with the circulation of most mammalian filoviruses (FiVs), with pathogenic ones frequently causing deadly hemorrhagic fevers in Africa. Divergent FiVs have been uncovered in Chinese bats, raising concerns about their threat to public health. Here, we describe a long-term surveillance to track bat FiVs at orchards, eventually resulting in the identification and isolation of a FiV, Dehong virus (DEHV), from Rousettus leschenaultii bats. DEHV has a typical filovirus-like morphology with a wide spectrum of cell tropism. Its entry into cells depends on the engagement of Niemann-Pick C1, and its replication is inhibited by remdesivir. DEHV has the largest genome size of filoviruses, with phylogenetic analysis placing it between the genera Dianlovirus and Orthomarburgvirus, suggesting its classification as the prototype of a new genus within the family Filoviridae. The continuous detection of viral RNA in the serological survey, together with the wide host distribution, has revealed that the region covering southern Yunnan, China, and bordering areas is a natural circulation sphere for bat FiVs. These emphasize the need for a better understanding of the pathogenicity and potential risk of FiVs in the region.

Differential flatness-based adaptive robust tracking control for wheeled mobile robots with slippage disturbances.

Wheeled mobile robots (WMRs) have a wide range of applications in logistics transportation and industrial productions, among which the motion control has always been one of the hot spots in the current WMR researches. However, most of previous designed controllers assumed that the WMR motion had no slippage. Ignoring the slippage factors usually results in a decrease in control performance and even leads to unstable motion. To address such a challenge, a kinematic model with differential flatness is established through dynamic feedback-linearization, which comprehensively considers the multidirectional slippage of mobile robot, including longitudinal and steering slippage. Subsequently, benefited from the one-to-one mapping of states and inputs to flat outputs in differential flat system, an adaptive robust control (ARC) method is proposed to stabilize the system. Different from previous robust control studies, even if the knowledge of the upper bound of system uncertainties is unknown in advance, the proposed adaptive robust controller can still achieve satisfying performance by adaptive estimation of the upper bound of system uncertainties. The effectiveness and feasibility of the proposed method are confirmed by comparative experiments on WMR with slippage disturbance.

Design, synthesis and biological evaluation of biaryl amide derivatives against SARS-CoV-2 with dual-target mechanism.

The COVID-19 pandemic highlights the urgent need to develop effective small-molecule antivirals. Thirty-three novel biaryl amide derivatives were synthesized and evaluated for anti-coronaviral activity. Some significant SARs were uncovered and the intensive structure modifications led to the most active compounds 8b and 8h. The broad-spectrum anti-coronaviral effects of 8h were validated at RNA and protein levels. 8h inhibits coronavirus replication at multiple stages, from virus entry to virus dsRNA synthesis. The mechanism of action showed that 8h may simultaneously act on 3CLpro and TMPRSS2 to display anti-coronaviral effects. 8h combined with RdRp inhibitor showed synergistic inhibitory activity against coronavirus. This study confirmed that biaryl amide derivatives may be a new class of potential therapeutic agents against coronavirus with multiple target effect, worthy of further investigation.

Application of remote electrocardiogram monitoring systems in chest pain centers for patients with high-risk chest pain.

BACKGROUND: Chinese chest pain centers (CPCs) have been expanding and maturing for the past decade, but patient wait times for pre-hospital care remain long. OBJECTIVE: To demonstrate that the remote electrocardiogram (ECG) monitoring system can ensure more efficient treatment for patients with ST-elevation myocardial infarction (STEMI) in CPCs, we compared patients with high-risk chest pain who used remote ECG monitoring systems to those who used conventional ECGs in retrospective cohort study. METHODS: Based on the inclusion and exclusion criteria, 290 patients who visited our CPC between June 2019 and March 2022 with acute chest pain and a diagnosis of STEMI as well as patients who had undergone an emergency primary percutaneous coronary intervention were selected. Among them, 73 patients with STEMI had employed remote real-time dynamic 12-lead ECG monitoring devices, while 217 patients with STEMI (i.e., the controls) had used conventional ECG monitoring. The effectiveness of treatment procedures for the two groups was investigated. As statistical measures, the symptom onset-to-wire times, first medical contact (FMC)-to-wire times, door-to-wire times, major adverse cardiac events in hospital, and the troponin T levels were analyzed. RESULTS: Compared with the control group, the patients with remote real-time dynamic 12-lead ECG monitoring devices showed shorter times for both symptom onset-to-wire (234.8 ± 95.8 min vs. 317.6 ± 129.6 min, P= 0.0321) and from symptom onset-to-FMC (170.5 ± 86.3 min vs. 245.3 ± 115.6 min, P= 0.0287); this group also had a lower 30-day mortality rate (2.73% vs. 4.14%, P= 0.003). The differences between the two groups were statistically significant (P< 0.05). CONCLUSION: With remote real-time dynamic 12-lead ECG monitoring equipment, myocardial ischemia can be treated more quickly, leading to fewer possible cardiac events and a better prognosis.

Steering competitive N2 and CO adsorption toward efficient urea production with a confined dual site.

Electrocatalytic urea synthesis under mild conditions via the nitrogen (N2) and carbon monoxide (CO) coupling represents an ideal and green alternative to the energy-intensive traditional synthetic protocol. However, this process is challenging due to the more favorable CO adsorption than N2 at the catalytic site, making the formation of the key urea precursor (*NCON) extremely difficult. Herein, we theoretically construct a spatially isolated dual-site (DS) catalyst with the confinement effect to manipulate the competitive CO and N2 adsorption, which successfully guarantees the dominant horizontal N2 adsorption and subsequent efficient *NCON formation via C-N coupling and achieves efficient urea synthesis. Among all the computationally evaluated candidates, the catalyst with dual V sites anchored on 4N-doped graphene (DS-VN4) stands out and shows a moderate energy barrier for C-N coupling and a low theoretical limiting potential of -0.50 V for urea production, which simultaneously suppresses the ammonia production and hydrogen evolution. The confined dual-site introduced in this computational work has the potential to not only properly address part of the challenges toward efficient urea electrosynthesis from CO and N2 but also provide an elegant theoretical strategy for fine-tuning the strength of chemical bonds to achieve a rational catalyst design.

Annihilation of Non-small Cell Lung Cancer by NKG2D CAR-T Cells Produced from T Cells from Peripheral Blood of Healthy Donors.

Some progress has been made in immunotherapy with chimeric antigen receptor (CAR)-T cells targeting NKG2D-NKG2DL with the purpose of eradicating solid tumors. Non-small cell lung cancer (NSCLC) has been shown to express NKG2DL. This study hence evaluated the therapeutic effect of NKG2D CAR-T cells on NSCLC. Accordingly, NKG2D CAR-T cells were obtained from diverse human autologous T cell sources. T cells from peripheral blood T lymphocytes of healthy volunteers (without NKG2D CAR insertion) were used as NT-T cells. Coculture of effector cells (CAR-T cells or NT-T cells) with target cells (NSCLC cells such as PC-9 or NCL-H460 cells) was performed at different ratios. The cytotoxicity of CAR-T cells was examined using lactate dehydrogenase assay kits. Murine xenograft assay was conducted to investigate the in vivo antitumor effect of CAR-T cells. Cytokines secreted from CAR-T cells were assessed by enzyme-linked immunosorbent assay. CAR-T cell infiltration into xenografts was observed through immunochemical assay. Based on the results, NKG2DL was highly expressed in NSCLC cells. Compared with NT-T cells, NKG2D CAR-T cells from different sources of T cells delivered stronger toxicity, and secreted more effector and memory function-related cytokines to NSCLC cells, and those from the peripheral blood of healthy donors (H-T cells) exhibited the strongest effect. Furthermore, compared with NT-T cells, H-T cells and NKG2D CAR-T cells from NSCLC patients' peripheral blood diminished tumor, improved survival, increased body weight and tumor-infiltrating capacity, and upregulated serum IFN-γ level in NOG mice. Collectively speaking, NKG2D CAR-T cells exhibit a robust effect on eradicating NSCLC in a NKG2DL-dependent manner, thus making themselves a promising therapeutic candidate for NSCLC patients.

Influence of Planting Density on Sweet Potato Storage Root Formation by Regulating Carbohydrate and Lignin Metabolism.

An appropriate planting density could realize the maximum yield potential of crops, but the mechanism of sweet potato storage root formation in response to planting density is still rarely investigated. Four planting densities, namely D15, D20, D25, and D30, were set for 2-year and two-site field experiments to investigate the carbohydrate and lignin metabolism in potential storage roots and its relationship with the storage root number, yield, and commercial characteristics at the harvest period. The results showed that an appropriate planting density (D20 treatment) stimulated cambium cell differentiation, which increased carbohydrate accumulation and inhibited lignin biosynthesis in potential storage roots. At canopy closure, the D20 treatment produced more storage roots, particularly developing ones. It increased the yield by 10.18-19.73% compared with the control D25 treatment and improved the commercial features by decreasing the storage root length/diameter ratio and increasing the storage root weight uniformity. This study provides a theoretical basis for the high-value production of sweet potato.

Evolution and development of potent monobactam sulfonate candidate IMBZ18g as a dual inhibitor against MDR Gram-negative bacteria producing ESBLs.

A series of new monobactam sulfonates is continuously synthesized and evaluated for their antimicrobial efficacies against Gram-negative bacteria. Compound 33a (IMBZ18G) is highly effective in vitro and in vivo against clinically intractable multi-drug-resistant (MDR) Gram-negative strains, with a highly druglike nature. The checkerboard assay reveals its significant synergistic effect with ß-lactamase inhibitor avibactam, and the MIC values against MDR enterobacteria were reduced up to 4-512 folds. X-ray co-crystal and chemoproteomic assays indicate that the anti-MDR bacteria effect of 33a results from the dual inhibition of the common PBP3 and some class A and C ß-lactamases. Accordingly, preclinical studies of 33a alone and 33a‒avibactam combination as potential innovative candidates are actively going on, in the treatment of ß-lactamase-producing MDR Gram-negative bacterial infections.

Discovery and identification of EIF2AK2 as a direct key target of berberine for anti-inflammatory effects.

Using chemoproteomic techniques, we first identified EIF2AK2, eEF1A1, PRDX3 and VPS4B as direct targets of berberine (BBR) for its synergistically anti-inflammatory effects. Of them, BBR has the strongest affinity with EIF2AK2 via two ionic bonds, and regulates several key inflammatory pathways through EIF2AK2, indicating the dominant role of EIF2AK2. Also, BBR could subtly inhibit the dimerization of EIF2AK2, rather than its enzyme activity, to selectively modulate its downstream pathways including JNK, NF-κB, AKT and NLRP3, with an advantage of good safety profile. In EIF2AK2 gene knockdown mice, the inhibitory IL-1ß, IL-6, IL-18 and TNF-α secretion of BBR was obviously attenuated, confirming an EIF2AK2-dependent anti-inflammatory efficacy. The results highlight the BBR's network mechanism on anti-inflammatory effects in which EIF2AK2 is a key target, and inhibition of EIF2AK2 dimerization has a potential to be a therapeutic strategy against inflammation-related disorders.

The interaction effects of biodegradable microplastics and Cd on Folsomia candida soil collembolan.

In real-field soil conditions, multiple chemicals exposure may be the real scenario for soil biota. The co-occurrence of microplastics (MPs) and cadmium (Cd) is common in soils, which may pose a potential risk to soil ecosystems. Degradable microplastics are producing more MPs, and the potential effects on soil ecosystems are unknown. Therefore, a standard soil animal collembolan Folsomia candida was used to evaluate the single and interaction effects of biodegradable MPs (PLA) and Cd. The results showed that single and co-biodegradable PLA and Cd all had negative influences on the survival, reproduction, and growth of F. candida, and the effects intensified with PLA concentrations. The survival rate, reproduction rate, adult body length, and juvenile body length decreased by 20.0%, 24.2%, 22.9%, and 32.2% at MPs-100 treatment. But combined PLA and Cd alleviated the toxicity of single Cd on F. candida at lower PLA concentrations. The number of juveniles increased by 29.3%, the survival rate increased by 7.52%, the adult body length increased by 11.7%, and the juvenile body length increased by 19.0% at MPs-1 + Cd than single Cd treatment. Biochemical assays on antioxidant enzymes had the same results. Antioxidant enzymes CAT and POD were more sensitive than SOD. CAT and POD activities were induced quickly at shorter exposure periods, and MP treatment thus may be promising biomarkers on soil collembolan for soil MP exposure. PLA is degraded with time in soils; therefore, the long-term effects of co-MPs and Cd in soils are suggested to be further studied.

Bounded synchronization for uncertain master-slave neural networks: An adaptive impulsive control approach.

This paper investigates the bounded synchronization of the discrete-time master-slave neural networks (MSNNs) with uncertainty. To deal with the unknown parameter in the MSNNs, a parameter adaptive law combined with the impulsive mechanism is proposed to improve the estimation efficiency. Meanwhile, the impulsive method also is applied to the controller design for saving the energy. In addition, a novel time-varying Lyapunov functional candidate is employed to depict the impulsive dynamical characteristic of the MSNNs, wherein a convex function related to the impulsive interval is used to obtain a sufficient condition for bounded synchronization of the MSNNs. Based on the above condition, the controller gain is calculated utilizing an unitary matrix. An algorithm is proposed to reduce the boundary of the synchronization error by optimizing its parameters. Finally, a numerical example is provided to illustrate the correctness and the superiority of the developed results.

Energy scheduling for DoS attack over multi-hop networks: Deep reinforcement learning approach.

This paper studies the energy scheduling for Denial-of-Service (DoS) attack against remote state estimation over multi-hop networks. A smart sensor observes a dynamic system, and transmits its local state estimate to a remote estimator. Due to the limited communication range of the sensor, some relay nodes are employed to deliver data packets from the sensor to the remote estimator, which constitutes a multi-hop network. To maximize the estimation error covariance with energy constraint, a DoS attacker needs to determine the energy level implemented on each channel. This problem is formulated as an associated Markov decision process (MDP), and the existence of an optimal deterministic and stationary policy (DSP) is proved for the attacker. Besides, a simple threshold structure of the optimal policy is obtained, which significantly reduces the computational complexity. Furthermore, an up-to-date deep reinforcement learning (DRL) algorithm, dueling double Q-network (D3QN), is introduced to approximate the optimal policy. Finally, a simulation example illustrates the developed results and verifies the effectiveness of D3QN for optimal DoS attack energy scheduling.

Denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women: A randomized, double-blind, placebo-controlled, multicenter phase III study.

Objectives: This study assessed the efficacy, safety, pharmacokinetics (PK), and immunogenicity profiles of a denosumab biosimilar (LY06006) in Chinese postmenopausal osteoporotic women with a high risk of fracture. Methods: In this multicenter, randomized, double-blind, placebo-controlled, phase 3 trial, 448 postmenopausal women aged 50-85 years with osteoporosis were enrolled at 49 centers in China and were randomly assigned (3:1) to receive 60 â€‹mg of the denosumab biosimilar (LY06006) or placebo subcutaneously every 6 months for 1 year. Lumbar spine bone mineral density (BMD) change was the primary endpoint. Results: Of the 448 randomized patients, 409 (LY06006, n â€‹= â€‹311; placebo, n â€‹= â€‹98) completed the study. All 448 (100.0%) subjects were included in the intent-to-treat (ITT) trial, 427 (95.3%) were included in the full analysis set (FAS), 408 (91.1%) were included in the per protocol set (PPS), 446 (99.6%) were included in the safety set (SS), and 336 (75.0%) were included in the pharmacokinetics concentration set (PKCs). For the primary endpoint, a 4.71% (95% CI, 3.81%, 5.60%) treatment difference in percent change in lumbar spine BMD from baseline to month 12 was observed in the LY06006 group compared with the placebo group (P â€‹< â€‹0.0001). For the secondary endpoints, LY06006 was associated with increased lumbar spine BMD levels measured at month 6, BMD levels at the femoral neck, total hip, and trochanter measured at months 6 and 12 and reduced serum C-terminal telopeptide of type 1 collagen (CTX) and procollagen type 1 â€‹N-peptide (P1NP) levels at months 1, 6, and 12. Safety analysis was based on the safety analysis set (SS), and 264 (78.6%) subjects in the LY06006 group and 83 (75.5%) in the placebo group experienced adverse events (AEs). Most events were mild or moderate and not related to the study drugs. Conclusion: In postmenopausal women with a high risk of fracture, LY06006 increased the BMD and decreased bone resorption; thus, LY06006 might be an effective treatment for osteoporosis. LY06006 was generally safe and well tolerated without unexpected adverse reactions, similar to the reference drug Prolia®. The characteristics of effectiveness and safety were similar to those reported in previous studies. The translational potential of this article: In this multi-center, randomized, double-blind, placebo-controlled phase 3 study, LY06006 showed substantially efficacy to increase BMD and well tolerance without unexpected adverse reactions, which is comparable to the reference drug Prolia ®. The presented results are encouraging and can offer some valuable evidence for the clinical practice.

Discovery and development of palmatine analogues as anti-NASH agents by activating farnesoid X receptor (FXR).

Sixty-one palmatine (PMT) derivatives, of which twenty-eight were new, were synthesized and evaluated for their anti-fibrogenic activities via collagen type I α 1 (COL1A1)-promoter based luciferase model in LX-2 cells, taking 2,3,10-trimethoxy-9-p-isopropyloxyprotopalmatine bromide (1) as the lead. Among them, compound 3a exerted the highest potency with the IC50 value of 8.19 µmol/L and SI value of 8.59, and reduced the expressions of multiple fibrogenic biomarkers, including COL1A1, TGF-ß1, α-SMA and TIMP1 in a dose-dependent manner. In addition, it significantly reduced liver steatosis and inflammation, and especially attenuated the degree of liver fibrosis in choline-deficient, l-amino acid-defined, high-fat diet (CDAHFD)-induced NASH mice model in vivo. Mechanism study indicated that it significantly ameliorated liver injury by activating farnesoid X receptor (FXR). BDL-induced fibrosis rats model further verified its liver-protective and anti-fibrosis activities. Therefore, PMT derivatives constituted a new family of non-steroidal FXR agonists as anti-NASH candidates, with the advantage of good safety profile, and are worthy for further investigation.

Guaranteeing Global Stability for Neuro-Adaptive Control of Unknown Pure-Feedback Nonaffine Systems via Barrier Functions.

Most existing approximation-based adaptive control (AAC) approaches for unknown pure-feedback nonaffine systems retain a dilemma that all closed-loop signals are semiglobally uniformly bounded (SGUB) rather than globally uniformly bounded (GUB). To achieve the GUB stability result, this article presents a neuro-adaptive backstepping control approach by blending the mean value theorem (MVT), the barrier Lyapunov functions (BLFs), and the technique of neural approximation. Specifically, we first resort the MVT to acquire the intermediate and actual control inputs from the nonaffine structures directly. Then, neural networks (NNs) are adopted to approximate the unknown nonlinear functions, in which the compact sets for maintaining the approximation capabilities of NNs are predetermined actively through the BLFs. It is shown that, with the developed neuro-adaptive control scheme, global stability of the resulting closed-loop system is ensured. Simulations are conducted to verify and clarify the developed approach.