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The tail of imidazole regulated the assembly of fascinating 2D sql topology and 3D 2-fold interpenetrated lvt structure polyoxotungstate-based open frameworks with efficient visible-white-light-driven aerobic catalytic oxidation of sulfides.

One-pot synthesis of 4-(imidazol-1-yl)indole derivatives through sequential dearomatization and Ag-catalyzed cyclization/Cs2CO3-mediated addition/aromatization reaction.

Reservoir pressure relief is a practical method to enhance permeability for coalbed methane (CBM) extraction in tectonically deformed coal (TDC) reservoirs. To explore the coal permeability response to stress changes, the primary undeformed coal (PUC) and TDC from the same coal seam were sampled for the pore-fissure structure analysis, mechanical property test, and permeability experiments under different stress loading-unloading methods in this study. The experimental results demonstrated that the coal permeability is more sensitive to the changes in confining pressure (perpendicular to airflow) than axial stress (parallel to airflow). Coal permeability decreases negatively exponentially as the confining pressure increases, and its change process with increased axial pressure can be divided into five stages in this study. The pore structures and mechanical properties of coal samples affected their permeability response to stress changes. Under the stress loading condition, the coal matrix and fractures of PUC samples were compressed simultaneously, and the permeability was regulated by the pore-fissure structures in the coal matrix. Due to the deformation and displacement of coal particles, the permeability of the TDC sample is predominantly dependent on changes in intergranular pores. At the initial stress unloading stage, the fissure recovery and expansion lead to a rapid increase in permeability, but the permeability cannot rereach the original value when the stress is fully released. Furthermore, the influencing factors of coal permeability in response to stress loading-unloading also include confining pressure conditions and coal matrix adsorption swelling. Research on the permeability response characteristics of the stress loading-unloading process can provide some clarifications for the reservoir depressurization and permeability enhancement of CBM extraction in the TDC reservoir.

Yanrui Liang,1,* Weihong Guo,1,* Chuangji Li,1,* Guodong Shen,1,* Haoxian Tan,2 Peiwen Sun,2 Zhian Chen,1 Huilin Huang,1 Zhenhao Li,1 Zhenyuan Li,1 Yingxin Ren,1 Guoxin Li,1 Yanfeng Hu1 1Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, Guangzhou, People’s Republic of China; 2The First School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Guoxin Li; Yanfeng Hu, Department of General Surgery & Guangdong Provincial Key Laboratory of Precision Medicine for Gastrointestinal Tumor, Nanfang Hospital, Southern Medical University, No. 1838 North Guangzhou Ave, Baiyun District, Guangzhou, 510515, People’s Republic of China, Tel +86-20-6164-1681 ; +86-20-6164-1682, Fax +86-20-6164-1681, Email yfenghu@qq.com; gzliguoxin@163.comPurpose: Lymphadenectomy with lymph node (LN) mapping is essential for surgical removal of solid tumors. Existing agents do not provide accurate multimodal mapping and antitumor therapy for metastatic LNs; therefore, we fabricated a polydopamine (PDA) nanoparticle (NP)-based tumor-targeted LN mapping agent capable of multimodal mapping and guided photothermal therapy (PTT) for metastatic LNs.Materials and Methods: PDA NPs modified with polyethylene glycol (PEG) were obtained by polymerization under alkaline conditions. The PEG-PDA NPs were loaded with the circular tripeptide Arg-Gly-Asp (cRGD) to achieve tumor-targeting capacity and with the fluorescent dye IR820 and magnetic resonance imaging (MRI) contrast Gd(NH2)2 for in situ detection. The resulting cRGD-PEG-PDA@IR820/Gd(NH2)2 (cRGD-PPIG) NPs were tested for their biosafety and metastatic LN mapping ability. They were drained specifically into LNs and selectively taken up by gastric MKN45 cells via αvβ 3 integrin-mediated endocytosis.Results: This phenomenon enabled MR/optical/near-infrared fluorescence multimodal metastatic LN mapping, guiding the creation of accurate and highly efficient PTT for gastric cancer metastatic LNs in mice.Conclusion: In summary, we fabricated tumor-targeted cRGD-PPIG NPs with MR/optical/near-infrared fluorescence multimodal metastatic LN mapping capacity for surgery and efficient PTT guidance post-surgery.Keywords: multimodal imaging, lymph node mapping, metastatic lymph node, photothermal therapy

Background Resistance to immune checkpoint inhibitor (ICI) therapy narrows the efficacy of cancer immunotherapy. Although 4-1BB is a promising drug target as a costimulatory molecule of immune cells, no 4-1BB agonist has been given clinical approval because of severe liver toxicity or limited efficacy. Therefore, a safe and efficient immunostimulatory molecule is urgently needed for cancer immunotherapy. Methods HK010 was generated by antibody engineering, and the Fab/antigen complex structure was analyzed using crystallography. The affinity and activity of HK010 were detected by multiple in vitro bioassays, including enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), flow cytometry, and luciferase-reporter assays. Humanized mice bearing human PD-L1-expressing MC38 (MC38/hPDL1) or CT26 (CT26/hPDL1) tumor transplants were established to assess the in vivo antitumor activity of HK010. The pharmacokinetics (PK) and toxicity of HK010 were evaluated in cynomolgus monkeys. Results HK010 was generated as an Fc-muted immunoglobulin (Ig)G4 PD-L1x4-1BB bispecific antibody (BsAb) with a distinguished Fab/antigen complex structure, and maintained a high affinity for human PD-L1 (KD: 2.27 nM) and low affinity for human 4-1BB (KD: 493 nM) to achieve potent PD-1/PD-L1 blockade and appropriate 4-1BB agonism. HK010 exhibited synergistic antitumor activity by blocking the PD-1/PD-L1 signaling pathway and stimulating the 4-1BB signaling pathway simultaneously, and being strictly dependent on the PD-L1 receptor in vitro and in vivo. In particular, when the dose was decreased to 0.3 mg/kg, HK010 still showed a strong antitumor effect in a humanized mouse model bearing MC38/hPDL1 tumors. Strikingly, HK010 treatment enhanced antitumor immunity and induced durable antigen-specific immune memory to prevent rechallenged tumor growth by recruiting CD8+ T cells and other lymphocytes into tumor tissue and activating tumor-infiltrating lymphocytes. Moreover, HK010 not only did not induce nonspecific production of proinflammatory cytokines but was also observed to be well tolerated in cynomolgus monkeys in 5 week repeated-dose (5, 15, or 50 mg/kg) and single-dose (75 or 150 mg/kg) toxicity studies. Conclusion We generated an Fc-muted anti-PD-L1x4-1BB BsAb, HK010, with a distinguished structural interaction with PD-L1 and 4-1BB that exhibits a synergistic antitumor effect by blocking the PD-1/PD-L1 signaling pathway and stimulating the 4-1BB signaling pathway simultaneously. It is strictly dependent on the PD-L1 receptor with no systemic toxicity, which may offer a new option for cancer immunotherapy.

Purpose Choosing a suitable surgical approach is crucial and challenging for type C pilon fractures. This article aims to explore the clinical efficacy of the medial malleolar window approach for varus-type tibial pilon fractures. Methods A retrospective analysis was conducted on 38 patients with type C varus-type pilon fractures treated between May 2018 and June 2021. In total, 16 cases underwent surgical treatment through the medial malleolar window approach and 22 cases were treated with the traditional anteromedial approach combined with a posterior approach. The operation time, hospitalization time, fracture healing time, the American Orthopedic Foot and Ankle score, Visual Analogue Scale, and complications were recorded to comprehensively evaluate the clinical efficacy of the technique. Fracture reduction quality was evaluated using the criteria proposed by Burwell and Charnley. Results All patients were followed up. No patients presented delayed union or nonunion. Compared with the conventional approach, the medial malleolar window approach had the advantage of better clinical effect recovery and better fracture reduction (P Conclusion The medial malleolar window approach provides excellent exposure to type C pilon fractures, allowing for satisfactory fracture reduction and functional rehabilitation. The medial window approach is recommended for varus-type pilon fractures, which can effectively avoid a posterior incision and reduce the operation time.

Leftover food consumption is very prevalent among the Chinese older adults, however, the potential effects of leftover eating consumption on depression have not yet been investigated.The study aims to determine the association between leftover consumption on depression among older adults.Data of leftover consumption frequency was collected in a cross-sectional study with a provincial representative sample of 5992 older adults (aged 60 or older) in 2019. Depression symptoms were assessed by the 9-item screener Patient Health Questionnaire (PHQ-9). Multiple logistic regression models were applied to analyze the association of the frequency of leftover eating consumption and the presence and the severity of depression.After controlling for all the covariates, the participants who consume leftover food everyday had higher risk of having depression symptom comparing to those who had the lowest frequency of leftover eating (OR: 1.675, 95% CI: 1.435-1.956, p 0.001). The participants who consume leftover food every day was also associated with more severe depression symptoms (OR: 1.621, 95% CI: 1.397-1.881, p 0.001), when comparing to the reference group. The associations seemed stronger in men than women.The causal relationship between leftover consumption behavior and depression could not be determined due to the cross-sectional design. Moreover, the variety or handling method of the leftover food was not specified.Leftovers eating frequency was associated with the presence and severity of depression symptoms among older adults.

Three imidazole-modified Ag-polyoxovanadates frameworks (APFs) with a controllable molar ratio of Ag+ to polyoxovanadates (POVs) [Ag(IM)2]2V4O12∙2Ag(IM)2 (APF-1), [Ag2(1-eIM)4]2[Ag(1-eIM)2]3∙2Ag(1-eIM)2∙3(1-HeIM)[V10O28]2 (APF-2) and [Ag(1-pIM)2]3[HV10O28]∙2Ag(1-pIM)2∙2H2O (APF-3) (IM = imidazole; 1-eIM = 1-ethylimidazole and 1-pIM = 1-propylimidazole) have been successfully achieved by self-assembly of POVs, Ag+ cations, and three different imidazole derivatives. Interestingly, the molar ratios of Ag+ to POVs vary from 4:1, 4.5:1 to 5:1 by changing the vanadium resources and imidazole derivatives. Notably, the coordination environment of Ag+ cations and the structure of POVs in the APFs are also different. Specifically, for APF-1, the four Ag atoms adopt three-coordinated and four-coordinated geometries, respectively, and Ag-imidazole complexes and [V4O12]4− cluster form the one-dimensional polymeric chains. While Ag atoms in APF-2 and APF-3 exhibit two-, four- and five-coordinated geometries for APF-2, four-, five- and six-coordinated geometries for APF-3, respectively. These Ag+ cations and decavanadate clusters are assembled into the 2D supramolecular structure through the Ag-O bonds and Ag…Ag argentophilic interaction. Remarkably, thus-obtained APF-2 can serve as powerful efficient heterogeneous catalyst for construction of C-N bond and detoxification of simulant sulfur mustard (yields up to 99%), which enable successful recycling for three cycles with remained catalytic activities and structure stability.

The ankle biomechanics is easily changed due to the acute injury of the tissue around the ankle joint and the damage of the ankle joint structure, such as ankle instability and joint surface imbalance. When the mechanical load of the ankle changes, it can cause ankle regeneration and remodeling processes such as cartilage loss, bone remodeling, and degenerative changes. The aim of this study was to investigate the effect and mechanism of ginsenoside Rg1 against interleukin-1β (IL-1β)-induced apoptosis in human articular chondrocytes (HACs). The apoptosis model of HAC cells was established by IL-1β induction, and then the HAC cells were cultured with different concentrations of Rg1. The protective effect of Rg1 on HAC cell apoptosis was investigated by detecting the changes of apoptosis and activity of PI3K/Akt/mitochondrial signaling pathway. The results showed that a specific concentration of Rg1 could promote the proliferation of IL-1β-induced HAC cells and inhibit apoptosis. At the same time, Rg1 treatment with specific concentration can reduce the content of reactive oxygen species (ROS) and malondialdehyde (MDA) in HACs and improve the related expression of mitochondrial membrane potential (MMP). Furthermore, qRT-PCR and western blot results showed that Rg1 could improve the low expression of Bcl-2 and inhibit the high expression of Bax, caspase-3, caspase-8, caspase-9, FasL, AIF, and Cyto c in IL-1β-induced cells. In summary, Rg1 can inhibit IL-1β-induced apoptosis of HAC cells by decreasing the activity of PI3K/Akt/mitochondrial signaling pathway, and Rg1 has a protective effect on apoptosis of HAC cells.

Pyroptosis, a kind of programmed cell death involving inflammation, might be a powerful way to fight against tumors, for example, using immunotherapy. However, how to trigger pyroptosis in cancer cells is an important issue. Photothermal (PTT)/photodynamic (PDT) therapy is a crucial strategy for inducing cancer cell pyroptosis with noninvasiveness. In this work, a sericin derivative modified with poly(γ-benzyl-l-glutamate) (PBLG) could self-assemble and was stable in an aqueous environment. Furthermore, the sericin derivative was conjugated with the tumor-targeting agent VB12 and loaded with IR780. Finally, we successfully synthesized VB12-sericin-PBLG-IR780 nanomicelles. The as-designed nanomicelles showed appropriate particle sizes, spherical morphology, improved photothermal stability, and high photothermal conversion efficiency (∼40%), which generated reactive oxygen species (ROS) simultaneously. Through enhanced cellular uptake, VB12-sericin-PBLG-IR780 could deliver more IR780 into cancer cells. With near-infrared (NIR), the VB12-sericin-PBLG-IR780 could significantly inhibit the expression of ATP synthase, called ATP5MC3, followed by mitochondrial damage. The presence of mitochondrial reactive oxygen species (mitoROS) led to oxidative damage of mitochondrial DNA (mitoDNA), which further activates NLRP3/Caspase-1/gasdermin D (GSDMD)-dependent pyroptosis and could promote dendritic cell (DC) maturation by pyroptosis. Furthermore, our data showed that VB12-sericin-PBLG-IR780 could achieve a brilliant antitumor effect and could activate DC maturation, initiate T-cell recruiting, and prime adaptive antitumor efficiency. Overall, our well-prepared nanomicelles might offer a tumor-targeted approach for programmed cell pyroptosis and inducing antitumor immunity via photothermal PTT/PDT effect-induced mitoDNA oxidative damage.

Supplemental Figure 1. Th17 cells are not induced in the lung after the tumor cell challenge. Supplemental Figure 2. No significant difference in the production of IFN-gamma by NK cells in the Abt mice compared with the control.

Background There is no gold standard for the operative treatment of patients with Müller-Weiss disease (MWD). This study reports the mid-term follow-up results for at least 5 years following talonavicular-cuneiform (TNC) arthrodesis for Müller-Weiss disease. Methods A total of 15 patients undergoing TNC arthrodesis for MWD were retrospectively reviewed between January 2015 and August 2017. Two senior doctors assessed the radiographic results twice at each visit (preoperative, three months after the operation, and final follow-up). The clinical results and complications from preoperative and final follow-up were recorded. Results The mean follow up period was 74.0 (range 64 to 90) months. The calcaneal pitch angle, lateral Meary's angle, anteroposterior (AP) Meary's angle, AP talocalcaneal angle, and talonavicular coverage were significantly different before and three months after the operation (p p > 0.05). The radiological measurements of the two senior doctors were calculated and found to be moderate to strong (ICC:0.899–0.995). The AOFAS, VAS, and SF-12 scores significantly improved at the last follow-up compared to those before the operation (p Conclusion This research confirms that using TNC arthrodesis for the treatment of MWD can substantially improve the clinical and radiographic results. These results were maintained until mid-term follow-up.

Objectives: To evaluate the expression of ubiquitin-like containing PHD and RING finger domain 1 (UHRF1) in early oral squamous cell carcinoma (OSCC) and explore its clinical significance. Methods: In total, 104 patients with early OSCC who had undergone surgery in the First Affiliated Hospital of the University of Science and Technology of China from 2008 to 2016 were retrospectively analyzed. The correlation between UHRF1 and vimentin was assessed by evaluating their expression levels in OSCC tissue using immunofluorescence staining. The patients were divided into UHRF1/vimentin high and low expression groups on the basis of an immunoreactivity intensity distribution index value of 4. The relationships between the UHRF1 and vimentin expression levels and the clinic opathological characteristics of patients were analyzed. The influence of relevant risk factors on the patient survival rate was analyzed with the Kaplan– Meier method, whereas the relevant risk factors affecting the survival rate of patients with oral cancer were analyzed using the Cox proportional hazards model. Results: High UHRF1 expression was observed in OSCC tissue. Likewise, vimentin was highly expressed in mesenchymal tumor tissue, and its expression level was positively correlated with that of UHRF1 (R2 = 0.2626, P < 0.001). UHRF1 expression was correlated with the patient gender; N stage; T, N stages of the 8th edition of TNM classification; tumor differentiation; occult lymph node metastasis; neck recurrence; and postoperative local recurrence (P < 0.05). Moreover, it was positively correlated with the depth of invasion (R2 = 0.2105, P < 0.001). The vimentin expression level was related to the patient gender, T stage, 8th edition T stage, occult lymph node metastasis, neck recurrence, and local recurrence (P < 0.05). According to the Cox regression model, the UHRF1 expression level of UHRF1 was an influencing factor affecting the survival rate of patients (HR: 2.64; 95 CI%: 1.35–5.15; P = 0.004). Conclusion: UHRF1 is highly expressed in early OSCC and is closely related to epithelial–mesenchymal transition and the prognosis of patients.

A facile one-step ball-milling strategy to prepare gram-scale Mg3Al-LDH-Nb6 has been demonstrated and the thus-obtained catalyst exhibited efficient selective catalytic activities in the synthesis of biologically active organic molecules in water.

The selective oxidation of amines into imines is a priority research topic in organic synthesis and has attracted much attention over the past few decades. However, the oxidation of amines generally suffers from the drawback of transition-metal, even noble-metal catalysts. Thus, the strategy of metal- and oxidant-free selective synthesis of imines is highly desirable yet largely unmet. This paper unravels a metal-free and external oxidant-free electrochemical strategy for the oxidative coupling methodology of amines. This general transformation is compatible with various functional amines and led to functionalized imines in moderate to satisfactory yields.

A condition-controlled strategy for selectively synthesis of 2-acylbenzothiazoles and bibenzo[b][1,4]thiazines from aryl methyl ketones and disulfanediyldianilines was realized using I2/DMSO or I2/MeCN systems, respectively. The desired products were synthesized in only 15 min with moderate to excellent yields (50%-90%) under microwave-assisted, metal-free conditions. The strategy provides a great advantage for selective synthetic applications in the efficient synthesis of benzothiazoles and bibenzothiazines heterocycle compounds.

Supplemental material, sj-docx-2-inq-10.1177_00469580231155295 for The Value of Handgrip Strength and Self-Rated Squat Ability in Predicting Mild Cognitive Impairment: Development and Validation of a Prediction Model by Han Xiao, Hou Fangfang, Wang Qiong, Zhou Shuai, Zhang Jingya, Lou Xu, Shen Guodong and Zhang Yan in INQUIRY: The Journal of Health Care Organization, Provision, and Financing

Supplemental material, sj-docx-1-inq-10.1177_00469580231155295 for The Value of Handgrip Strength and Self-Rated Squat Ability in Predicting Mild Cognitive Impairment: Development and Validation of a Prediction Model by Han Xiao, Hou Fangfang, Wang Qiong, Zhou Shuai, Zhang Jingya, Lou Xu, Shen Guodong and Zhang Yan in INQUIRY: The Journal of Health Care Organization, Provision, and Financing

Four transition-metal lacunary polyoxometalates (TM-LPOMs, TM = Cu, Co, Ni, and Mn) are prepared and fabricated into ultralow density LPOM-based foams (LPOMs@CMC) for the efficient flowing catalytic production of sulfenamide additives.

Supplemental material, sj-docx-2-inq-10.1177_00469580231155295 for The Value of Handgrip Strength and Self-Rated Squat Ability in Predicting Mild Cognitive Impairment: Development and Validation of a Prediction Model by Han Xiao, Hou Fangfang, Wang Qiong, Zhou Shuai, Zhang Jingya, Lou Xu, Shen Guodong and Zhang Yan in INQUIRY: The Journal of Health Care Organization, Provision, and Financing

in presented paper the transient characteristics of an asynchronous electric drive of a pump unit with PID-similar fuzzy controller are investigated. A comparative analysis of control quality in a system with traditional and fuzzy controllers is performed. The use of fuzzy controller in the asynchronous electric drive of the pump unit for water supply system is substantiated and it is proved that the use of fuzzy logic leads to the improvement of the quality of the transient process of the system. The simulation was performed using the Scilab mathematical application package.

The efficient "One-pot" CuCl

A microwave sintering procedure has been developed to achieve high quality multiferroic composites of (1

Two concise strategies to synthesize oxazolidin-2-imines by cascade nucleophilic attack/addition cyclization reactions of (

Simple reaction conditions and recyclable reagents are crucial for environmentally friendly industrial applications. An environment-friendly, recyclable and economic strategy was developed to synthesize diaryl chalcogenides by the CuCl2-catalyzed C–S bond-formation reaction via iodobenzenes and benzenethiols/1,2-diphenyldisulfanes using N,N′-dimethylethane-1,2-diamine (DMEDA) as ligand, base, and solvent. For these reactions, especially the reactions of diiodobenzenes and aminobenzenethiols/disulfanediyldianilines, a range of substrates are compatible and give the corresponding products in good to excellent yields. Both of the reagents in the catalytic system (CuCl2/DMEDA) are inexpensive, conveniently separable, and recyclable for more than five cycles.

A novel percutaneous distractor with the advantage of axial and direct distraction was designed for the minimally invasive treatment of calcaneal fractures. The purpose of this study was to investigate the clinical results and complications of a novel distractor combined with sinus tarsi approach (STA) in treatment of the joint depression-type of calcaneal fractures.Fifty-four patients with the depression-type of calcaneal fractures (30 Sanders type II, 22 Sanders type III, 2 Sanders type IV) who were subjected to the novel distractor combined with STA were retrospectively assessed. Calcaneal height, width, and length; Bohler's angle; and the Gissane angle were evaluated pre-operatively and post-operatively. Clinical outcomes were assessed using the American Orthopedic Foot and Ankle Society (AOFAS) and visual analog scale (VAS) pain scores from the last follow-up. Complications were also recorded.Fifty-two patients achieved an average follow-up of 24.3 months (range 18 to 34 months), and two patients were lost to follow-up six months post-operatively. There was significant difference between pre-operative and post-operative calcaneal height, width, and length; Bohler's angle; and Gissane angle (p 0.01), but no significant difference was detected between the post-operative and normal side Bohler's angle (p 0.05). The AOFAS ankle and hind foot score was 88.4 ± 6.6, and the VAS score was 1.9 ± 0.7 at the last follow-up. Nine (17.3%) patients developed complications: One experienced skin necrosis and two had screws loosening; three patients developed early degenerative changes of the subtalar joint; two had no symptoms; one had light pain around the subtalar joint without medical treatment; complex regional pain syndrome (CRPS) developed in one patient after seven months post-operatively; and two developed transient ankle stiffness.The novel distractor combined with the STA effectively reconstructs the facet depression-type of calcaneal fractures (sanders type II and III) with minimal complications.

PIGK gene, encoding a key component of glycosylphosphatidylinositol (GPI) transamidase, was recently reported to be associated with inherited GPI deficiency disorders (IGDs). However, little is known about the specific downstream effects of PIGK on neurodevelopment due to the rarity of the disease and the lack of in vivo study. Here, we described 2 patients in a Chinese family presented with profound global developmental delay, severe hypotonia, seizures, and postnatal progressive global brain atrophy including hemisphere, cerebellar and corpus callosum atrophy. Two novel compound heterozygous variants in PIGK were identified via genetic analysis, which was proved to cause significant decrease of PIGK protein and reduced cell surface presence of GPI-APs in the patients. To explore the role of Pigk on embryonic and neuronal development, we constructed Pigk knock-down zebrafish and knock-in mouse models. Zebrafish injected with a small dose of morpholino oligonucleotides displayed severe developmental defects including small eyes, deformed head, curly spinal cord, and unconsumed yolk sac. Primary motor neuronal dysplasia and extensive neural cell apoptosis were further observed. Meanwhile, the mouse models, carrying the two variants respectively homologous with the patients, both resulted in complete embryonic lethality of the homozygotes, which suggested the intolerable effect caused by amino acid substitution of Asp204 as well as the truncated mutation. Our findings provide the in vivo evidence for the essential role of PIGK during the embryonic and neuronal development. Based on these data, we propose a basis for further study of pathological and molecular mechanisms of PIGK-related neurodevelopmental defects.

BiOBr sheets of controllable shape and size were synthesized via an ultrasound-assisted co-precipitation method at room temperature by varying the bromine source and reactant concentration. The BiOBr sheets synthesized from KBr and NaBr were rounded rectangles and round, respectively. The size of BiOBr sheets increased with increasing reactant concentration. As the reactant concentration increased from 10 mmol L−1 to 15 mmol L−1 until 20 mmol L−1, the size of as-prepared BiOBr sheets increased from 100–300 nm to 300–500 nm until 700–1000 nm, respectively. Moreover, the size difference in BiOBr sheets did not significantly affect the photocatalytic performance in degrading organic dyes. Such a simple and rapid method of controlling the shape and size of BiOBr sheets could provide more abundant matrix materials for the synthesis and modification of BiOBr.

A method for the synthesis of fused chromeno quinolines by the palladium/copper cocatalyzed C-H bond activation and C-C bond cleavage reaction has been developed. A variety of fused chromeno quinoline derivatives could be synthesized by coumarin derivatives and anilines through the C-C bond cleavage/C-H functionalization/C-C bond formation process. The MTT assay was used to evaluate the chromeno quinolines against the human cervix tumor cells (HeLa), 3c and 9c without coordination metals showed good inhibition effect.

A palladium-catalyzed cascade reaction of β′-allenoate adducts with aryl/heteroaryl carboxamides through a vinylogous elimination/C–H functionalization/intramolecular allylation reaction sequence h...

A novel and efficient approach to the synthesis of benzimidazo[2,1-b]thiazoline derivatives has been developed through an addition/cyclization/intramolecular oxidative C–H functionalization process...

Pipeline leakages have plagued pipeline transportation for long time. Therefore, accurately extracting the features of leak signal in the presence of noise, and prompt identification of leak states and leak sizes is essential when leakage occurs. A novel leakage detection method based on the improved adaptive filter, whose parameters were optimized by the particle swarm optimization (PSO), was formulated and applied. The PSO-adaptive filter proved to be an effective signal processing method in contrast with variational mode decomposition (VMD). Its efficiency stems from the fact that the adaptive filter employs the noise collected from the detection environment. Therefore, the filter can adjust its parameters according to the changing situation. What is more, the application of PSO is conducive to automatically set suitable parameters for adaptive filter. After signal denoising, principal component analysis (PCA) was used for feature dimension reduction and selecting optimal features. The features after PCA proved to be more helpful in pattern recognition than the features without PCA. Furthermore, the relationship between the recognition results of leakage sizes and the measurement distance of the sensor was studied. Experimental results show that the method used in this paper can identify the leakage states with the accuracy of 100%. The identification result of leakage size reaches an accuracy of 86.75% under the influence of the measurement distance.

Background: CD137 (TNFRSF9, 4-1BB) is a member of the tumor necrosis factor receptor superfamily that functions as a costimulatory molecule of immunocytes and is mainly expressed on the surface of immune cells including activated T and natural killer (NK) cells. Agonists against CD137 have shown promising therapeutic activity in mouse tumor models but have suffered setback in the clinic due to notably hepatotoxicity, or suboptimal agonistic potency. Here, we developed a fully human agonistic anti-CD137 monoclonal IgG4 antibody, ZG033, with an exclusive epitope, to achieve a better efficacy and safety profile for immunotherapy. Methods: The antigen binding specificity and affinity of ZG033 were determined by ELISA, surface plasmon resonance (SPR). X-ray crystallography was conducted to resolve the binding epitopes of the respective binding arms. The activities were determined using cell-based and reporter gene assays. In vivo antitumor activities were evaluated in human 4-1BB transgenic mice bearing with syngeneic tumors, and possible toxicity was evaluated in humanized mice and cynomolgus monkeys. Cytokine release assay was conducted by incubating ZG033 with PBMCs from healthy donors. The pharmacokinetic (PK) behavior of ZG033 were characterized in cynomolgus monkeys. A phase 1 study was initiated to evaluate the safety and preliminary clinical activities of ZG033, as well as the immunogenicity and pharmacokinetics. Results: ZG033 showed high specificity for human CD137 without cross-species reactivity across mouse, rat and exhibited potent CD137 agonist activity dependent on FcγR crosslinking. The binding affinity of ZG033 determined by surface plasmon resonance (SPR) was moderate (KD=10 nM). X-ray crystallography revealed that the Fab of ZG033 binds CD137 at an epitope overlap with the ligand binding interface. ZG033 increased CD137-driven NFκB reporter gene activation and the production of IFN-γ by human T cells in a FcγR-dependent manner. In human CD137 transgenic mice, ZG033 showed robust antitumor activity and induced durable antigen-specific immunological memory that prevented the tumor formation in the rechallenged mice. There were no signs of toxicity in human cytokine release assay which confirmed that ZG033 did not induce pro-inflammatory cytokines in the absence of TCR stimulation. Toxicology data in mice showed that ZG033 was well-tolerated with normal ALT and AST levels. ZG033 was further confirmed to well tolerated up to 180 mg/kg (MTD≥180mg/kg) dose without systemic toxicity in cynomolgus monkeys. Patients with advanced tumors, who are refractory after exhausting available therapies, were enrolled for ZG033 treatment. We will report the results from early dose escalation part of the study. Conclusion: These data demonstrate that ZG033 is an FcγR crosslinking-dependent CD137 agonist that displays a favorable safety profile and has potential in either mono- or combinational immunotherapies. Citation Format: Yang Huang, Liangwei Li, Wenting Liu, Dayan Zhang, Pengfei Zhou, Qing Fang, Weiming Zhou, Fengrong Wang, Guodong Shen, Liansheng Cheng. A novel CD137 agonist exhibits potent antitumor efficacy with a good safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1880.

Background: Checkpoint inhibitors targeting the PD-1/PD-L1 have changed the treatment and prognosis for patients with advanced solid tumors. There remains a unmet need for additional therapies due to treatment resistance. Tumor-necrosis superfamily members, such as CD137 and CD40, have been shown to synergize with the checkpoint inhibitors in preclinical studies. However, agonists antibodies have exhibited limited clinical activity for severe liver toxicity. Here we have developed a Fc-silenced bispecific antibody targeting PD-L1 and CD137, HK010, which could overcome these limitations by tumor-directed T-cell activation and checkpoint blockade. Methods: The antigen binding specificity and affinity of HK010 were determined by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR) and flow cytometry. The functional activity of HK010 was determined using in vitro cell-based assays and reporter gene assay. Transgenic mice expressing human PD-L1 and 4-1BB were transplanted with human PD-L1-expressing murine MC38 cells to assess in vivo antitumor activity. Cytokine release assay was conducted by incubating HK010 with peripheral blood mononuclear cells (PBMCs) from healthy donors (n=6). The pharmacokinetic (PK) behavior and safety profiles of HK010 were characterized in cynomolgus monkeys. Results: HK010 is a IgG4 PD-L1 × 4-1BB bsAb, which was designed to maintain a high affinity for human PD-L1 and a low affinity for human 4-1BB (KD PD-L1: 2.27 nM; KD 4-1BB: 493 nM) to achieve strong blocking of PD-1/PD-L1 and appropriate agonism of 4-1BB. HK010 retained full blockade activity on PD-1/PD-L1 signaling and enhances T-cell proliferation and IFN-γ production in vitro primary cell assays and Mixed lymphoid reaction (MLR). In addition, it led to a dose-dependent increase in the CD137-driven NFκB reporter gene activation through the bridging of PD-L1 on target cells and CD137 on effector cells. In humanized PD-L1/4-1BB transgenic mice bearing with MC38/hPDL1 tumor, HK010 showed robust single agent anti-tumor activity and induced durable antigen-specific immunological memory that prevents the growth of the same tumor cells in the mice re-challenged. There were no signs of toxicity in human cytokine release assay for HK010. Toxicology data in cynomolgus monkeys showed that HK010 was well-tolerated up to 150 mg/kg (MTD≥150mg/kg) dose without systemic toxicity. Furthermore, HK010 was confirmed to be highly safe in the 5-week repeated-dose toxicity study with no observed treatment-related mortality, abnormality in hematological indexes, important organs. Conclusion: These data demonstrate that HK010, an anti-PD-L1 × CD137 bispecific antibody, may exert a strong localized anti-tumor therapeutic efficacy with a low risk of liver toxicity through tumor-directed T-cell activation and checkpoint blockade in tumors. Citation Format: Liangwei Li, Wenting Liu, Guodong Shen, Dayan Zhang, Weiming Zhou, Fengrong Wang, Xiaoli Zeng, Yang Huang, Liansheng Cheng. HK010, a novel anti-PDL1 × CD137 bispecific antibody, exhibits potent anti-tumor immunity and low toxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5657.