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Cytochrome P450 monooxygenases (P450s) play important roles in herbicide resistance. In this study, there are four amino acid mutations (F39Y, H163Y, S203A, and V361E) between CYP96A146-Sand CYP96A146-R, which were cloned, respectively, from susceptible (S) and tribenuron-methyl-resistant (TR) Descurainia sophia. The Arabidopsis expressing CYP96A146-Sor CYP96A146-Rshowed resistance to tribenuron-methyl, carfentrazone-ethyl, and oxyfluorfen, while Arabidopsis transformed with CYP96A146-R or CYP96A146 with any two or three mutations of H163Y, S203A, or V361E exhibited significantly higher resistance to tribenuron-methyl than Arabidopsis expressing CYP96A146-S. The metabolic rates of tribenuron-methyl were significantly faster in Arabidopsis expressing CYP96A146-Rthan that with CYP96A146-S. The molecular dynamics simulation demonstrated that amino acid mutations did not affect the domain of the HEM ring, which could significantly enhance the volume of the catalytic pocket in P450 (CYP96A146), thereby increasing the collision rate between the catalytic pocket and tribenuron-methyl. Hence, the amino acid mutations may be one of the mechanisms underlying P450-mediated herbicide resistance.

Periodontitis is characterized by dysbiotic biofilms, gingival inflammation, and bone resorption, highlighting the urgent need for a comprehensive approach to drug combination therapy. In this study, we introduce dynamic covalent nanonetworks (dcNNWs) synthesized through a one-pot, four-component reaction-induced self-assembly method using polyamines, 2-formylphenylboronic acid, epigallocatechin gallate, and alendronate. The formation of iminoboronate bonds drives the creation of dcNNWs, allowing controlled release in the periodontitis microenvironment. The inclusion of catechol and bisphosphonate imparts exceptional bioadhesive properties to the dcNNWs, enhancing their efficacy in preventing pathogenic bacterial biofilm formation and eliminating mature biofilms. Moreover, the dcNNWs efficiently absorb pathogen-associated molecular patterns and scavenge excess reactive oxygen species, regulating the local immune response and demonstrating anti-inflammatory effects. Additionally, the released polyphenol and alendronate from the dcNNWs alleviated inflammation and enhanced osteogenesis significantly. The detailed synergistic effects of dcNNWs in biofilm eradication, anti-inflammation, and bone remodeling, with minimal impact on healthy tissues, are confirmed in a rat model of periodontitis. With a facile synthesis process, excellent synergistic effects in periodontitis treatment, and biocompatibility, our dcNNWs present a promising and translational solution for the effective management of periodontitis.

By utilizing the principle of optical logic signal processing of periodically poled lithium niobate (PPLN) waveguide, this paper proposes schemes of all-optical general set-reset (RS) flip-flop and clocked RS flip-flop based on cascaded second-order nonlinearities of sum-frequency generation (SFG) and difference-frequency generation (DFG), and the principle is theoretically investigated. The waveforms, eye diagrams, extinction ratio (ER) and full width at half maximum (FWHM) of the light waves are calculated and simulated numerically. The results of static simulation demonstrate that the logic of general and clocked RS flip-flops are achieved well by these schemes; the timing sequential simulation demonstrate that the logic properties of flip-flops with a feedback loop can also be achieved well for timing sequential optical signals.

Psoriasis is a common, chronic, recurrent, and inflammatory skin disease, which causes physical and psychological problems in patients and lacks effective and economic therapeutics. Herein, we designed Janus kinase (JAK) and histone deacetylase (HDAC) dual inhibitors as a new strategy for the treatment of psoriasis. In particular, compound 11iwas identified with excellent inhibitory activity toward JAKs (JAK2 IC50= 0.49 nM) and HDACs (HDAC6 IC50= 12 nM). Moreover, it exhibited potent activities in inhibiting the proliferation of TNF-α-induced HaCAT cells and the production of nitric oxide. Importantly, compound 11isignificantly ameliorated psoriasis-like skin lesions in an imiquimod-induced murine model with low toxicity, which was superior to JAK inhibitor momelotinib, HDAC inhibitor vorinostat, and their combination. This work provided a proof-of-concept for JAK/HDAC dual inhibitors as a promising strategy for the treatment of psoriasis.

Environmental inequality is a prevalent issue in developing countries undergoing urban expansion. Urban expansion induces the formation and evolution of environmental inequality by creating environmental and structural conditions that lead to the spatial relocation of environmental hazards and the socio-spatial segregation of different groups in developing countries. This study investigated the spatial patterns and temporal trends of environmental inequality under urban expansion in Guangzhou, a megacity in China. It considered how environmental disparities and socio-demographic attributes interact in terms of industrial pollution exposure using additive semiparametric quantile regression, combined with spatial visualisation, on the basis of the economic and population census data from 1990 to 2020. This study revealed that urban expansion sparked the spatial displacement of environmental risks and the social-spatial differentiation, exposing the peripheral regions and disadvantaged groups to higher environmental risks. A reciprocal transformation occurred between central and peripheral regions, as well as a process of redistributing environmental risks across social space. In the context of urban expansion in developing countries, the causes of environmental inequality shifted from individual socio-economic differences to structural factors, such as industrial layout and social division of labour in cities, leading to the spatial displacement and concealment of environmental inequality. This study provides insights and guidance for policymakers to address the issue of environmental inequality in the context of urban expansion.

Tuning magnetic anisotropy via perturbing the coordination environment of metal ions is of great importance for developing high-performance single-ion magnets (SIMs). We herein reported the syntheses and characterization of four one-dimensional cobalt(II) coordination polymers featuring distorted tetrahedral metal center, namely {[Co(pdms)(bpy)]·bpy}n (Cobpy), {[Co(pdms)(bpen)]}n (Cobpen), {[Co(pdms)(bpdoz)]·H2O}n (Cobpdoz), and {[Co(pdms)(bimp)]·2DMF·3H2O}n (Cobimp) (bpy = 4,4′-bipyridine, bpen = 1,2-di(4-pyridyl)ethylene, bpdoz = 2,5- di(pyridin-4-yl)-1,3,4-oxadiazole, bimp = 1,4-bis[(1H-imidazol-1-yl)methyl]benzene). By the assembly of [Co(pdms)2]2+anions and different organic bridging ligands, the chains with highly anisotropic four-coordinate Co(II) ions exhibit a significant modification of the structures, especially the tetrahedral coordination sphere. Notably, the two ∠N–Co–N bite angles, which mainly determine the magnetic anisotropy of tetrahedral mononuclear cobalt complexes, were significantly changed due to the use of different organic linkers. Magnetic measurements reveal that the four complexes possess uniaxial magnetic anisotropy with the zero-field splitting (ZFS) parameters Dbeing −39.7, −32.1, −23.8, and −43.4 cm–1for Cobpy, Cobpen, Cobpdoz, and Cobimp, respectively. This observation and their electronic structures were further unveiled by theoretical calculations. Dynamic alternative current magnetic susceptibility measurements indicate that both the chains exhibit slow magnetic relaxation under an external field, indicating field-induced slow magnetic relaxation of the coordination polymers (1D SIM-CPs). Notably, the relaxation behaviors are also modified due to the structural differences induced by distinct linkers. The foregoing results not only enrich the family of 1D SIM-CPs showing low-coordinated metal centers but also offer a coordination chain platform for tuning magnetic anisotropy of four-coordinate Co(II) ions in 1D chains.

Barium titanate was successfully synthesized through both the solid-state method and the oxalate thermal decomposition method. The differences in tetragonality and particle size between the two methods were discussed using X-ray diffraction, scanning electron microscopy, and the laser diffraction method. The elemental content of the impurities ws characterized by an inductively coupled plasma optical emission spectrometer. Meanwhile, the influence of process parameters such as sintering temperature, aging time, and ball milling treatment on the morphology and size of powders was investigated. The results revealed that the oxalate thermal decomposition method could fabricate the BaTiO3with a narrow particle size distribution and high tetragonality. Additionally, ball milling treatment offered a significant advantage in reducing particle agglomeration caused by high sintering temperatures and in producing homogeneous BaTiO3, which was suitable for industrial production.

Diabetic foot ulcers (DFUs) are one of the most serious complications of diabetes, often leading to necrosis and amputation. DFU is caused by the intricate diabetic microenvironment, including ischemia, hypoxia, hyperinflammation, reduced angiogenesis, and persistent infection. Traditional wound dressings made of single or mixed materials often struggle to meet all the requirements for effective diabetic wound healing. In contrast, multilayer dressings comprising more than single layers have the potential to address these challenges by combining their diverse chemical and physical properties. In this study, we developed a bilayer hydrogel comprising a GelMA-ALG-nano-ZnO protective film and a COL1-PRP regenerative hydrogel for facilitating diabetic wound healing. We demonstrated the protective properties against bacterial infection of the protective film, while highlighting the regenerative potential of the COL1-PRP hydrogel in promoting fibroblast and MUVEC migration, extracellular matrix secretion and deposition, and angiogenesis. Importantly, the bilayer hydrogel exhibited superior efficacy in promoting full-thickness wound healing in a diabetic rat model compared to its single-layer hydrogel counterparts. This multi-layer approach offers a promising strategy for addressing the complexities of diabetic foot treatment and improving clinical outcomes.

We investigate the inverse scattering transform for the focusing nonlinear Schrödinger (NLS) equation with a particular class of nonvanishing boundary conditions (NVBCs), especially in the case of reflectionless potentials that give rise to a transmission coefficient with an arbitrary finite number Npairs of higher-order poles. The inverse problem is characterized in terms of a 2×2matrix Riemann-Hilbert (RH) problem equipped with several residue conditions at Npairs of higher-order poles. In the reflectionless case, we point out that the N-multipole soliton solutions including higher-order Kuznetsov-Ma breathers and Akhmediev breathers can be reconstructed by a linear algebraic system. Furthermore, we verify these special solutions by numerical simulations and display their density structures, also derive some Peregrine solitons by choosing appropriate parameters and taking limits.

RNA modification, especially N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine methylation, participates in the occurrence and progression of cancer through multiple pathways. The function and expression of these epigenetic regulators have gradually become a hot topic in cancer research. Mutation and regulation of noncoding RNA, especially lncRNA, play a major role in cancer. Generally, lncRNAs exert tumor-suppressive or oncogenic functions and its dysregulation can promote tumor occurrence and metastasis. In this review, we summarize N6-methyladenosine, 5-methylcytosine, and N7-methylguanosine modifications in lncRNAs. Furthermore, we discuss the relationship between epigenetic RNA modification and lncRNA interaction and cancer progression in various cancers. Therefore, this review gives a comprehensive understanding of the mechanisms by which RNA modification affects the progression of various cancers by regulating lncRNAs, which may shed new light on cancer research and provide new insights into cancer therapy.

The Clemmensen reduction is a common example of a reaction demonstrating the deoxygenation of carbonyl groups, which is a topic that has been widely studied in the field of organic chemistry. The use of trimethylchlorosilane, as a substitute for concentrated hydrochloric acid, allows for the reduction of carbonyl groups. The Clemmensen reduction experiment is performed by undergraduates for project-based learning. As a part of this program, students evaluate the influence of active functional groups, electron-donating and electron-withdrawing groups, steric hindrance, and other factors on the modified Clemmensen reduction using different reaction substrates. This lab activity aims to show the effectiveness of teaching organic chemistry laboratory methodologies to undergraduate students and serves as a tool for the final evaluation of practical knowledge using experiments. Project-based learning not only effectively improves the experimental ability of organic chemistry students but also has great importance in the development of interpersonal skills, including teamwork and innovative thinking. This helps to achieve the integration of applied-project-based learning and organic chemistry experimental teaching objectives.

The receptor tyrosine kinase AXL is an emerging driver of cancer recurrence, while its molecular mechanism remains unclear. In this study we investigated how AXL regulated the disease progression and poor prognosis in non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We performed AXL transcriptome analysis from TCGA datasets, and found that AXL expression was significantly elevated in NSCLC and TNBC correlating with poor prognosis, epithelial-mesenchymal transition (EMT) and immune-tolerant tumor microenvironment (TME). Knockdown of AXL or treatment with two independent AXL antibodies (named anti-AXL and AXL02) all diminished cell migration and EMT in AXL-high expressing NSCLC and TNBC cell lines. In a mouse model of 4T1 TNBC, administration of anti-AXL antibody substantially inhibited lung metastases formation and growth, accompanied by reduced downstream signaling activation, EMT and proliferation index, as well as an increased apoptosis and activated anti-tumor immunity. We found that AXL was abundantly activated in tumor nodule-infiltrated M2-macrophages. A specific anti-AXL antibody blocked bone marrow-derived macrophage (BMDM) M2-polarization in vitro. Targeting of AXL in M2-macrophage in addition to tumor cell substantially suppressed CSF-1 production and eliminated M2-macrophage in TME, leading to a coordinated enhancement in both the innate and adaptive immunity reflecting M1-like macrophages, mature dendritic cells, cytotoxic T cells and B cells. We generated a novel and humanized AXL-ADC (AXL02-MMAE) employing a site-specific conjugation platform. AXL02-MMAE exerted potent cytotoxicity against a panel of AXL-high expressing tumor cell lines (IC50< 0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors (a minimum efficacy dose<1 mg/kg). Compared to chemotherapy, AXL02-MMAE achieved a superior efficacy in regressing large sized tumors, eliminated AXL-H tumor cell-dependent M2-macrophage infiltration with a robust accumulation of inflammatory macrophages and mature dendritic cells. Our results support AXL-targeted therapy for treatment of advanced NSCLC and TNBC.

Ulcerative colitis (UC) is one of types of inflammatory bowel disease with high recurrence. Recent studies have highlighted that microbial dysbiosis as well as abnormal gut immunity are crucial factors that initiate a series of inflammatory responses in the UC. Modulating the gut microbiota-intestinal immunity loop has been suggested as one of key strategies for relieving UC. Many Chinese herbal medicines including some of single herb, herbal formulas and the derived constituents have been reported with protective effect against UC through modulating gut microbiome and intestinal immunity. Some clinical trials have shown promising results. This review thus focused on the current knowledge on using Chinese herbal medicines for treating UC from the mechanism aspects of regulating intestinal homeostasis involving microbiota and gut immunity. The existing clinical trials are also summarized.

Reported are the synthesis, material characterization, and electrocatalytic hydrogen evolution reaction (HER) in acid and alkaline electrolytes for the Brewer intermetallic phase, Nb6Co7and Mo6Co7. It was realized that the overpotential at a current density of 10 mA/cm2(η10) for Nb6Co7(η10= 62 mV) and Mo6Co7(η10= 143 mV) are both much lower than that of using a single Co metal (η10= 253 mV) in alkaline electrolytes. The enhancement of electrocatalytic HER activity of Nb6Co7and Mo6Co7can be attributed to the hypo-hyper-d-electronic interaction between Nb/Mo and Co elements. Based on the result of density functional theory calculation, alloying between Nb/Mo and Co elements will increase the antibonding state population of the Co–Co bond near the Fermi level (EF), which induces the synergistic effect to influence the adsorption energy of the H atom (ΔGH) on the surface of Nb6Co7and Mo6Co7. Moreover, the role of the Nb element is not only a simple electron donor but is also an anchor position for the OH molecule (i.e., dual function) due to the bonding character of the Nb–Co bond near EF. It can reduce the OH position effect as well as the activation energy for water dissociation, which rationalizes the high and robust HER performance of Nb6Co7to that of commercial Pt/C (η10= 67 mV) in alkaline electrolytes.

Oral squamous cell carcinoma (OSCC) represents the predominant form of malignancy within the head and neck region, accounting for more than 90 ​% of all oral cavity tumors. OSC cells commonly overexpress epidermal growth factor receptor (EGFR), which is closely associated with the development, progression, and differentiation of tumors. Despite surgery and chemotherapy being the primary therapeutic interventions for OSCC, their efficacy is suboptimal compared with that of other oral malignancies. We engineered a polypeptide molecule (HCPT-GDFDFDpYERGD, designated HP), which features the chemotherapeutic agent 10-hydroxycamptothecin (HCPT) at its N-terminus and the tumor-homing ligand Arginine-Glycine-Aspartic acid (RGD) at its C-terminus. The RGD moiety confers upon the polypeptide the ability to co-target cancer cells synergistically. The EGFR inhibitor cetuximab was co-assembled with HP via an enzymatic catalysis co-assembly technique to create a nanofibrillar structure, resulting in antibody‒polypeptide coassembly. In vitro assays have demonstrated that the co-assembled nanomedicine exhibits high affinity for OSCC cells, is efficiently internalized, and elicits potent inhibitory effects. Furthermore, bioinformatics analysis suggested that the co-assembled nanomedicine downregulated genes enriched in the PI3K-Akt signaling cascade. The co-assembled nanomedicine dramatically reduces cancer while sparing negative effects, as shown by in vivo animal models. This research endeavors to develop a new nanomedicine delivery platform that integrates molecular targeting with efficient intracellular drug delivery. This system not only markedly augments the therapeutic efficacy of the chemotherapeutic agent HCPT but also substantially mitigates patient adverse effects, thus offering a more secure and efficacious therapeutic strategy for the management of OSCC.

VV116 (JT001) is an oral drug candidate of nucleoside analog against SARS-CoV-2. The purpose of the three phase I studies was to evaluate the safety, tolerability, and pharmacokinetics of single and multiple ascending oral doses of VV116 in healthy subjects, as well as the effect of food on the pharmacokinetics and safety of VV116. Three studies were launched sequentially: Study 1 (single ascending-dose study, SAD), Study 2 (multiple ascending-dose study, MAD), and Study 3 (food-effect study, FE). A total of 86 healthy subjects were enrolled in the studies. VV116 tablets or placebo were administered per protocol requirements. Blood samples were collected at the scheduled time points for pharmacokinetic analysis. 116-N1, the metabolite of VV116, was detected in plasma and calculated for the PK parameters. In SAD, AUC and Cmaxincreased in an approximately dose-proportional manner in the dose range of 25–800 mg. T1/2was within 4.80–6.95 h. In MAD, the accumulation ratio for Cmaxand AUC indicated a slight accumulation upon repeated dosing of VV116. In FE, the standard meal had no effect on Cmaxand AUC of VV116. No serious adverse event occurred in the studies, and no subject withdrew from the studies due to adverse events. Thus, VV116 exhibited satisfactory safety and tolerability in healthy subjects, which supports the continued investigation of VV116 in patients with COVID-19.

It is well known that the “iron” impurity will influence the oxygen evolution reaction (OER) in an alkaline electrolyte, especially for the Ni-based electrocatalyst. Many research studies have investigated the function of Fe in the OER active phase, such as M(OH)2/MOOH (M= Ni and/or Fe), while, surprisingly, very few studies have examined the function of Fe in the “precatalyst” system. Accordingly, in this work, the Ni3–xFexP (x= 0, 0.5, 1) series as an Ni-based precatalyst was employed to inspect the function of internal and external Fe in the Ni-based precatalyst system. It was realized that the sample with internal Fe (i.e., Ni2.5Fe0.5P and Ni2FeP) exhibits efficient OER activity compared to that of the Fe-free one (i.e., Ni3P) owing to the large amount of active M(OH)2/MOOH formed on the surface. This indicates that the internal Fe in the present system may have the ability to facilitate the phase transformation; it was later rationalized from electronic structural calculations that the d band center of the internal Fe (middle transition metal) and Ni (late transition metal) holds the key for this observation. Adding excessive ferrous chloride tetrahydrate (FeCl2·4H2O) as the external Fe in the electrolyte will greatly improve the OER performances for Ni3P; nevertheless, that the OER activity of Ni2FeP is still much superior than that of Ni3P corroborates the fact that the Fe impurity is not the only reason for the elevated OER activity of Ni2FeP and that internal Fe is also critical to the phase transformation as well as OER performance.