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• LAB core is utilized as a recognition unit for HClO based on a novel chromophore fragmentation sensing mechanism. • The colorimetric and ratiometric fluorescence "turn on" signals for naked eyes are shown. • The practical applications in real samples (water and vegetable) are demonstrated. • The fluorescence "turn on" imaging for detection of HClO in mung bean sprout is successfully achieved. The excess intake of hypochlorite (ClO−) in the human body and excessive emission in wastewater can pose serious health risks and environmental pollution. Therefore, it is vital to develop an efficient method for detecting ClO− in foodstuff and water. In this work, we reported a lactam-fused aza -BODIPY (LAB1) for ultrasensitive ClO− detection based on novel chromophore fragmentation strategy for the first time. It exhibited distinct advantages of good selectivity, high sensitivity, fast response (60 s) and low detection limit of 9.65 nM. The sensing mechanism revealed LAB1 core was fragmented by ClO−, leading to significantly colorimetric and ratiometric fluorescence changes. As a result, 320 nm blue-shift in absorption maximum (from green to colorless) and 340 nm blue-shift in emission maximum (from dark to bright blue) allowed for visual detection by the naked eyes. The potential applicability of LAB1 for ClO− detection with satisfactory recovery in the real samples (tap water and lake water) and vegetables (spinach, lettuce, Chinese cabbage, bean sprouts), and fluorescence "turn on" imaging in mung bean sprout were demonstrated. In addition, LAB1 -loaded test paper was suitable for semi-quantitative scanning ClO− analysis by using color recognition APP in a smartphone. Therefore, this work highlights a promising approach based on novel sensing mechanism for monitoring ClO− in food samples. [ABSTRACT FROM AUTHOR]

Our previous studies have demonstrated that BML284 is a colchicine-site tubulin degradation agent. To improve its antiproliferative properties, 45 derivatives or analogs of BML284 were designed and synthesized based on the cocrystal structure of BML284 and tubulin. Among them, 5i was the most potent derivative, with IC 50 values ranging from 0.02 to 0.05 μM against the five tested tumor cell lines. Structure–activity relationship studies verified that the N1 atom of the pyrimidine ring was the key functional group for its tubulin degradation ability. The 5i –tubulin cocrystal complex revealed that the binding pattern of 5i to tubulin is similar to that of BML284. However, replacing the benzodioxole ring with an indole ring strengthened the hydrogen bond formed by the 2-amino group with E198, which improved the antiproliferative activity of 5i. Compound 5i effectively suppressed tumor growth at an intravenous dose of 40 mg/kg (every 2 days) in paclitaxel sensitive A2780S and paclitaxel resistant A2780T ovarian xenograft models, with tumor growth inhibition values of 79.4% and 82.0%, respectively, without apparent side effects, showing its potential to overcome multidrug resistance. This study provided a successful example of crystal structure–guided discovery of 5i as a colchicine-targeted tubulin degradation agent, expanding the scope of targeted protein degradation. [Display omitted] • A series of colchicine-binding site tubulin degradation agents were synthesized. • Compound 5i showed improved antiproliferative activity compared with BML284. • Compound 5i exerted certain in vivo antitumor activity and can overcome MDR. • These new derivatives expanded the scope of targeted protein degradation. [ABSTRACT FROM AUTHOR]

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulatory factor in the necroptosis signaling pathway, and is considered an attractive therapeutic target for treating multiple inflammatory diseases. Herein, we describe the design, synthesis, and structure–activity relationships of 4-amino-1,6-dihydro-7 H -pyrrolo [2,3- d ]pyridazin-7-one derivatives as RIPK1 inhibitors. Among them, 13c showed favorable RIPK1 kinase inhibition activity with an IC 50 value of 59.8 nM, and high RIPK1 binding affinity compared with other regulatory kinases of necroptosis (RIPK1 K d = 3.5 nM, RIPK3 K d = 1700 nM, and MLKL K d > 30,000 nM). 13c efficiently blocked TNFα-induced necroptosis in both human and murine cells (EC 50 = 1.06–4.58 nM), and inhibited TSZ-induced phosphorylation of the RIPK1/RIPK3/MLKL pathway. In liver microsomal assay studies, the clearance rate and half-life of 13c were 18.40 mL/min/g and 75.33 min, respectively. 13c displayed acceptable pharmacokinetic characteristics, with oral bioavailability of 59.55%. In TNFα-induced systemic inflammatory response syndrome, pretreatment with 13c could effectively protect mice from loss of body temperature and death. Overall, these compounds are promising candidates for future optimization studies. [Display omitted] • Pyrrolo [2,3- d ] pyridazinone derivatives were synthesized as RIPK1 inhibitors. • 13c showed high RIPK1 binding affinity and anti-necrosis cell activity. • 13c could effectively protect mice from hypothermia and death in the SIRS model. [ABSTRACT FROM AUTHOR]

A novel chromophore reaction-based pyrrolopyrrole aza -BODIPY fluorescent probe for H 2 S detection was developed. [Display omitted] • A novel chromophore reaction-based sensing mechanism for H 2 S detection is developed. • The colorimetric and ratiometric fluorescence "turn on" signals are shown. • A new fluorescence approach for monitoring H 2 S in eggs is demonstrated. • An AIEE-active sensing material for H 2 S detection is developed. In this work, we developed an aggregation-induced emission enhancement (AIEE) active and NIR emissive pyrrolopyrrole aza -BODIPY (PPAB) polymer (P1) for H 2 S detection for the first time. P1 showed obvious colorimetric change from green to yellow-green and ratiometric fluorescence "turn on" phenomenon with 167 nm blue-shift (from dark red to bright green). The sensing mechanism revealed a novel chromophore reaction between imine in PPAB core and H 2 S was involved, leading to less conjugated product. It exhibited distinct advantages of good selectivity, high sensitivity, and low detection limit of 0.66 μM. The potential applicability of P1 for H 2 S detection in the real samples (tap water, lake water and milk) was demonstrated. In addition, the solid sensor prepared by loading P1 on the PMMA film was successfully realized the visual detection of gaseous H 2 S gas produced from egg spoilage. Therefore, this work provides a promising approach based on novel sensing mechanism for monitoring H 2 S in complicated biological systems and practical food samples. [ABSTRACT FROM AUTHOR]

Abstract A series of 7 H -pyrrolo[2,3- d ]pyrimidine derivatives were designed and synthesized as reversible BTK inhibitors, and evaluated their kinase selectivity, anti-proliferation against the B-cell lymphoma cell lines (Ramos, Jeko-1) and cell line BTK enhanced (Daudi) in vitro. Among them, compound 28a exhibited the most excellent potency (IC 50 = 3.0 nM against BTK enzyme, 8.52 μM, 11.10 μM and 7.04 μM against Ramos, Jeko-1, Daudi cells, respectively), good kinase selectivity and inhibited BTK Y223 auto-phosphorylation and PLCγ2 Tyr1217 phosphorylation. Importantly, 28a showed efficacy anti-arthritic effect on collagen-induced arthritis (CIA) model in vivo. 28a 60 mg/kg dose level once a day group displayed markedly reduced joint damage and cellular infiltration without any bone and cartilage morphology change. Graphical abstract Image 1 Highlights • 7 H -pyrrolo[2,3- d ]pyrimidine-4-amine derivatives were reversible BTK inhibitors. • The effect of different chiral structures on BTK activity can be confirmed. • Reversible BTK inhibitor showed efficacy anti-arthritic effect in vivo. [ABSTRACT FROM AUTHOR]

Mimicking the natural photosynthesis process, photocatalytic conversion of CO 2 has been an ongoing hotspot of scientific research and technology development. A key aspect is the discovery of high potency catalysts for facilitating the multi-electron participated reactions. Herein we successfully demonstrate exfoliated nanosheets from a conductive 2D-MOF Ni 3 (HITP) 2 as an efficient co-catalyst for CO 2 reduction in a hybrid photocatalytic system under visible light illumination. By taking advantage of the high conductivity for charge transportation and highly accessible active sites for redox reactions, an excellent selectivity of 97% for deoxygenative CO 2 reduction and a high CO yield rate of 3.45 × 10 4 μmol·g −1  h −1 were achieved with superior stability. This work provides essential insights into future design and development of more effective MOFs-based systems for catalytic CO 2 utilization. [ABSTRACT FROM AUTHOR]

Background: This study was designed to assess the clinical efficacy and toxicity of apatinib (YN968D1) as third or subsequent‐line treatment for stage III/IV non‐small cell lung cancer (NSCLC). Methods: A total of 100 patients with advanced NSCLC who were treated with apatinib at a daily dose of 250/425/500 mg at Shandong Cancer Hospital from January 2016 to June 2018 were enrolled in our study. The objective response, disease control, and median progression‐free survival rates were reviewed and evaluated. Univariate and multivariate analyses were performed to determine the prognostic factors. The main adverse events were evaluated per the Common Terminology Criteria for Adverse Events version 4.0. Results: All patients were assessable for response. No complete responses were observed, 11 patients achieved a partial response, and 56 showed stable disease. The objective response rate was 11.0%, the disease control rate was 67.0%, and the median progression‐free survival was 2.93 months (95% confidence interval 2.07–3.87). In Cox regression analysis, the Eastern Cooperative Oncology Group performance status score (hazard ratio 1.799; P < 0.05) and smoking history (hazard ratio 1.958; P < 0.05) were predictive indicators for apatinib treatment efficacy. Treatment‐related adverse events were tolerated, predictable, reversible, and controllable. Conclusion: Apatinib was found to be both effective and safe in advanced NSCLC patients without a genetic driver mutation who experienced progression after two or more lines of chemotherapy treatment. [ABSTRACT FROM AUTHOR]

The current study aimed to investigate the correlation between tumor-infiltrating lymphocytes (TILs) and immunotherapy efficacy in patients with advanced non-small cell lung cancer (NSCLC). Eighty-nine patients with advanced NSCLC who received immune checkpoint inhibitors (ICIs) monotherapy were retrospectively enrolled in this study. The density of TILs in paraffin-embedded pathological tissues taken before receiving ICIs was quantitatively analyzed by immunohistochemical staining. The density of TILs was treated as a dichotomous variable using the median as the cutoff value. The Kaplan–Meier analysis was used to assess survival differences between groups. Univariate and multivariate Cox analyses were applied to screen out independent prognostic factors and further construct a nomogram prediction model to predict survival. Survival analysis showed that CD8+ TILs, CD4+ TILs, and IFN-γ+ Th1 were significant positive indicators for predicting progression-free survival (PFS) and overall survival (OS) (p < 0.05), whereas Foxp3+ Treg were a significant negative predictor (p < 0.05). The predictive role of IL-4+ Th2 was not apparent in this study and requires further investigation and exploration (p > 0.05). The nomogram prediction model exhibited good discriminative ability, with C-index values of 0.723 (95% CI 0.682-0.764) and 0.793 (95% CI, 0.738-0.848) in the training cohort and validation cohort, respectively. The AUC values indicated that the nomogram prediction model had high predictive value and the calibration curve presented good prediction accuracy. TILs could predict the efficacy of immunotherapy and may become a promising predictor. [ABSTRACT FROM AUTHOR]

In patients with cancer, individualized treatment strategies are generally guided by an analysis of molecular biomarkers. However, genetic instability allows tumor cells to lose monoclonality and acquire genetic heterogeneity, an important characteristic of tumors, during disease progression. Researchers have found that there is tumor heterogeneity between the primary tumor and metastatic lesions, between different metastatic lesions, and even within a single tumor (either primary or metastatic). Tumor heterogeneity is associated with heterogeneous protein functions, which lowers diagnostic precision and consequently becomes an obstacle to determining the appropriate therapeutic strategies for individual cancer patients. With the development of novel testing technologies, an increasing number of studies have attempted to explore tumor heterogeneity by examining circulating tumor cells (CTCs), with the expectation that CTCs may comprehensively represent the full spectrum of mutations and/or protein expression alterations present in the cancer. In addition, this strategy represents a minimally invasive approach compared to traditional tissue biopsies that can be used to dynamically monitor tumor evolution. The present article reviews the potential efficacy of using CTCs to identify both spatial and temporal tumor heterogeneity. This review also highlights current issues in this field and provides an outlook toward future applications of CTCs. [ABSTRACT FROM AUTHOR]

Background: Non-small cell lung cancers (NSCLC) harboring Human Epidermal Growth Factor Receptor 2 (HER2) mutations represent a distinct subset with unique therapeutic challenges. Although immune checkpoint inhibitors (ICIs) have been transformative in lung cancer treatment, the efficacy of ICIs in HER2-mutated NSCLC remains to be established. Methods: We systematically searched for real-world studies investigating the use of ICIs in treating HER2-mutated NSCLC, sourced from the PubMed, Cochrane Library, and Embase databases. Outcomes including objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) were extracted for further analysis. Results: Twelve studies involving 260 patients were enrolled in this meta-analysis. Pooled data revealed an ORR of 0.26 (95% CI 0.17–0.34), a DCR of 0.68 (95% CI 0.55–0.81), and a median PFS (mPFS) of 5.36 months (95% CI 3.50–7.21). Notably, in the subgroup receiving combined immune and chemotherapy, the ORR increased to 0.37 (95% CI 0.26–0.49), the DCR to 0.79 (95% CI 0.70–0.87), and the mPFS to 7.10 months (95% CI 5.21–8.99). Conclusions: ICIs demonstrate promising anti-tumor activity and safety in patients with HER2-mutated NSCLC. Furthermore, the combined regimen of ICIs and chemotherapy may provide a significant therapeutic option for this patient population. [ABSTRACT FROM AUTHOR]

Reversible oxygen conversion is important for various green energy technologies. Herein we synthesize a series of bimetallic coordination polymers by varying the Ni/Co ratio and using HITP (HITP=2,3,6,7,10,11‐hexaiminotriphenylene) as the ligand, to interrogate the role of metal centres in modulating the activity of the oxygen reduction reaction (ORR). Co3HITP2 and Ni3HITP2 are compared. Unpaired 3d electrons in Co3HITP2 result in less coplanarity but more radical character. Thus, despite of a reduced crystallinity and conductivity, the best ORR activity, comparable to 20 % Pt/C, is obtained for Co3HITP2, showing the 3d orbital configuration of the metal centre promotes ORR. Experimental and DFT studies show a transition of ORR pathway from four‐electron for Co3HITP2 to two‐electron for Ni3HITP2. Rechargeable zinc–air batteries using Co3HITP2 as the air cathode catalyst demonstrate excellent energy efficiency and stability. [ABSTRACT FROM AUTHOR]

Reversible oxygen conversion is important for various green energy technologies. Herein we synthesize a series of bimetallic coordination polymers by varying the Ni/Co ratio and using HITP (HITP=2,3,6,7,10,11‐hexaiminotriphenylene) as the ligand, to interrogate the role of metal centres in modulating the activity of the oxygen reduction reaction (ORR). Co3HITP2 and Ni3HITP2 are compared. Unpaired 3d electrons in Co3HITP2 result in less coplanarity but more radical character. Thus, despite of a reduced crystallinity and conductivity, the best ORR activity, comparable to 20 % Pt/C, is obtained for Co3HITP2, showing the 3d orbital configuration of the metal centre promotes ORR. Experimental and DFT studies show a transition of ORR pathway from four‐electron for Co3HITP2 to two‐electron for Ni3HITP2. Rechargeable zinc–air batteries using Co3HITP2 as the air cathode catalyst demonstrate excellent energy efficiency and stability. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase (Btk) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) and Fcγ receptor (FcR) signaling pathways, which makes it a uniquely attractive target for the treatment of autoimmune diseases, such as rheumatoid arthritis (RA). We reported a series of compounds bearing 7 H -pyrrolo [2,3- d ]pyrimidin-4-amine scaffold that potently inhibited Btk in vitro . Analysis of the structure-activity relationships (SAR) and drug-like profiles led to the discovery of the optimal compound B16 . B16 preferentially inhibited Btk (IC 50  = 21.70 ± 0.82 nM) over closely related kinases with moderate selectivity. Cell-based tests also confirmed that B16 significantly inhibited Btk Y223 auto -phosphorylation and PLCγ2 Y1217 phosphorylation. MTT revealed that B16 displayed weak suppression against normal LO2, HEK293 and THP-1 cell lines with IC 50 values over 30 μM. Moreover, B16 showed very weak potential to block the hERG channel (IC 50  = 11.10 μM) in comparison to ibrutinib (IC 50  = 0.97 μM). Owing to its favorable physicochemical properties (ClogP = 2.53, aqueous solubility ≈ 0.1 mg/mL), pharmacokinetic profiles (F = 49.15%, t 1/2  = 7.02 h) and reasonable CYP450 profile, B16 exhibited potent anti-arthritis activity and similar efficacy to ibrutinib in reducing paw thickness in CIA mice. In conclusion, B16 is a potent, selective and durable inhibitor of Btk and has the potential to a safe and efficacious treatment for arthritis. [ABSTRACT FROM AUTHOR]

Described as a Btk inhibitor, ibrutinib also potently inhibits Bmx and EGFR, two good targets for lung cancer. Owing to its high CLogP (4.07) and low aqueous solubility (<0.01 mg/ml), resulting in unfavorable bioavailability, ibrutinib requires high dosages to achieve good clinical response in the treatment of non-small cell lung cancer (NSCLC). In our effort to improve the CLogP of ibrutinib by structural optimization led to the discovery of a potent anti-cancer agent B6 , with beneficial physicochemical parameters (CLogP = 2.56, solubility in water ≈ 0.1 mg/ml) meeting the principles of oral drugs. B6 exhibited anti-proliferation activities against EGFR-expressing cells, especially the mutant ones, such as H1975 (L858R/T790M, IC 50 = 0.92 ± 0.19 μM) and HCC827 (Del119 IC 50 = 0.014 ± 0.01 μM). Moreover, B6 significantly slowed down H1975 tumor growth with anti-tumor rate of 73.9% ( p < 0.01). Enzyme potencies assay demonstrated B6 moderately selectively inhibited Bmx (IC 50 = 35.7 ± 0.1 nM) over other kinases. So, as a potent Bmx inhibitor, B6 has the potential to be an efficacious treatment for NSCLC with acquired drug resistance. [ABSTRACT FROM AUTHOR]

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have transformed the treatment paradigm for patients with ALK-positive non-small cell lung cancer (NSCLC). Yet the differential efficacy between alectinib and crizotinib in treating patients with NSCLC and central nervous system (CNS) metastases has been insufficiently studied. A retrospective analysis was conducted of clinical outcomes of patients with ALK-positive NSCLC and CNS metastases treated at the Shandong Cancer Centre. Based on their initial ALK-TKI treatment, patients were categorised into either the crizotinib group or the alectinib group. Efficacy, progression-free survival (PFS), intracranial PFS and overall survival (OS) were evaluated. A total of 46 eligible patients were enrolled in the present study: 33 patients received crizotinib and 13 patients received alectinib. The median OS of the entire group was 66.8 months (95% CI: 48.5–85.1). Compared with the patients in the crizotinib group, the patients in the alectinib group showed a significant improvement in both median (m)PFS (27.5 vs. 9.5 months; P=0.003) and intracranial mPFS (36.0 vs. 10.8 months; P<0.001). However, there was no significant difference in OS between the alectinib and crizotinib groups (not reached vs. 58.7 months; P=0.149). Furthermore, there were no significant differences between patients receiving TKI combined with radiotherapy (RT) vs. TKI alone with respect to mPFS (11.0 vs. 11.7 months, P=0.863) as well as intracranial mPFS (12.5 vs. 16.9 months, P=0.721). In the present study, alectinib exhibited superior efficacy to crizotinib for treating patients with ALK-positive NSCLC and CNS metastases, especially in terms of delaying disease progression and preventing CNS recurrence. Moreover, the results demonstrated that it might be beneficial to delay local RT for patients with ALK-positive NSCL and CNS metastases. [ABSTRACT FROM AUTHOR]

Traf2-and Nck-interacting protein kinase (TNIK) plays an important role in regulating signal transduction of the Wnt/ β -catenin pathway and is considered an important target for the treatment of colorectal cancer. Inhibiting TNIK has potential to block abnormal Wnt/ β -catenin signal transduction caused by colorectal cancer mutations. We discovered a series of 6-(1-methyl-1 H -imidazole-5-yl) quinoline derivatives as TNIK inhibitors through Deep Fragment Growth and virtual screening. Among them, 35b exhibited excellent TNIK kinase and HCT116 cell inhibitory activity with IC 50 values of 6 nM and 2.11 μM, respectively. 35b also shown excellent kinase selectivity, PK profiles, and oral bioavailability (84.64%). At a p. o. dosage of 50 mg/kg twice daily 35b suppressed tumor growth on the HCT116 xenograft model. Taken together, 35b is a promising lead compound of TNIK inhibitors, which merits further investigation. [Display omitted] • TNIK inhibitors with novel skeleton had been discovered by Deep fragment growth method. • Compound 35b significantly inhibited TNIK kinase activity. • Compound 35b shown excellent kinase selectivity, PK profiles, and oral bioavailability. • Compound 35b suppressed tumor growth on the HCT116 xenograft model. [ABSTRACT FROM AUTHOR]

• The shadow problem harms the accuracy of vehicle detection. • Detecting vehicles using edge and grayscale information can simplify the algorithm. • The shadow location information can help improving the accuracy of shadow detection. Vehicle detection is one of the most fundamental aspects of traffic surveillance systems. However, the shadow problem often hinders the accuracy of vehicle detection. Shadows are often mistakenly understood as the parts of a vehicle, causing objects loss, or shape distortion. Collected data with these errors are unreliable, therefore shadow detection and elimination is a key step to promote the accuracy of vehicle detection. This paper proposes a robust vehicle detection method with shadow elimination. The method is divided into two steps: Firstly, we extract foreground regions using a background differential method based on edge information, then we detect and eliminate the shadows from the foreground regions combined with grayscale information, edge information, and prior knowledge. The experimental results show that the proposed method is superior to the faster R-CNN, and SSD methods in terms of real-time performance and vehicle detection accuracy. The proposed method has broad application prospects in the Intelligent Transportation Systems (ITS). [Display omitted] [ABSTRACT FROM AUTHOR]

Background: To study in vitro the effects of anlotinib combined with radiotherapy on the lung cancer H520 cell cycle and apoptosis. Methods: The log growth period H520 cells were divided into the control group, anlotinib group (A group), radiotherapy group (RT group) and combined group (A + RT group). Cell cycle and apoptosis were detected by flow cytometry and changes in H520 cell cycle and apoptosis were analyzed in each group. Results: Anlotinib was determined to significantly inhibit cell growth in all groups, both alone, or in combination with radiotherapy. After receiving corresponding treatments, the proportions of G2/M‐phase cells in the control group, A group, RT group and A + RT group were different, and statistically significant (F = 32.086, P < 0.001). The apoptotic cell statistics of H520 cells in the control group, A group, RT group and A + RT group were significantly different (F = 44.537, P < 0.01). The relative expression of CDK1 in each group of cells was 0.04 ± 0.02, 0.07 ± 0.12, 0.81 ± 0.11, and 0.56 ± 0.16, respectively. There were differences between the groups by analysis of variance which were statistically significant (F = 58.36, P < 0.0001). The relative expression of cycle B in each group of cells was 0.27 ± 0.05, 0.40 ± 0.16, 0.65 ± 0.14, and 0.57 ± 0.13, respectively. There were differences between the groups by analysis of variance which were statistically significant (F = 10.77, P = 0.0002). Conclusions: Anlotinib had an inhibitory effect on lung cancer H520 cell proliferation. A higher rate of apoptosis and G2/M phase block was observed in the anlotinib‐radiotherapy combined group. Anlotinib combined with radiotherapy was able to synergistically inhibit tumor cell growth. Key points: Anrotinib combined with radiotherapy can synergistically inhibit tumor cell growth. [ABSTRACT FROM AUTHOR]

[Display omitted] • Compound 9j showed potent JAK2 and BRD4(BD2) inhibitory potency with IC 50 values of 22 and 13 nM, respectively, and exhibited appropriate selectivity to other family proteins with high structural homology as well as the excellent human liver microsomal stability. • Compound 9j demonstrated a good therapeutic effect of acute ulcerative colitis and myeloproliferative disease in vivo. Based on the pharmacological synergy of JAK2 and BRD4 in the NF-κB pathway and positive therapeutic effect of combination of JAK2 and BRD4 inhibitors in treating MPN and inflammation. A series of unique 9 H -purine-2,6-diamine derivatives that selectively inhibited Janus kinase 2 (JAK2) and BRD4(BD2) were designed, prepared, and evaluated for their in vitro and in vivo potency. Among them, compound 9j exhibited acceptable inhibitory activity with IC 50 values of 13 and 22 nM for BD2 of BRD4 and JAK2, respectively. The western blot assay demonstrated that 9j performed good functional potency in the NF-κB pathway and the phosphorylation of p65, IκB-α, and IKKα/β signal intensities were suppressed on RAW264.7 cell lines. Furthermore, 9j significantly improved the disease symptoms in a Ba/F3- JAK2 V617F allograft model. Meanwhile, 9j was also effective in relieving symptoms in an acute ulcerative colitis model. Taken together, 9j was a potent JAK2/BRD4(BD2) dual target inhibitor and could be a potential lead compound in treating myeloproliferative neoplasms and inflammatory diseases. [ABSTRACT FROM AUTHOR]

A hierarchical structure of CuCoNC arrays constructed on copper foam that enriches multiple active species on the MOF-based scaffolds simultaneously delivers extraordinary HER, OER and ORR performance, resulting in highly efficient overall water splitting powered by Zn-air batteries using the same single catalyst. • MOF-templated hierarchical CuCoNC arrays are constructed on copper foam. • Remarkable trifunctionality of OER, HER and ORR are achieved using a single catalyst. • Overall water splitting can be powered by using a single dry cell of 1.50 V. • Zinc-air batteries demonstrate highly energy efficiency >58% for over 360 h. • ZAB-powered water splitting is capable of producing H 2 in 69 μL s−1. Multifunctional electrocatalysts based on earth-abundant elements are key for the development of Integrated Energy Systems (IES) such as electrolytic water splitting powered by metal-air batteries. Herein, hierarchical CuCoNC nanowire arrays are constructed on copper foam, enriching multiple active species on the catalytic scaffolds that lead to remarkable trifunctional activities of OER with η 10 = 245 mV, HER with η 10 = 59 mV and ORR comparable to Pt/C. While for overall water splitting a cell voltage of only 1.78 V is required to achieve a high current density of 500 mA cm−2, for Zn-air batteries (ZABs) a highly stabilized round-trip efficiency of >58% is achieved for over 360 h under 10 mA cm−2. Ultimately, a highly efficient IES of ZAB-powered water splitting employing a single catalyst is demonstrated with a hydrogen evolution rate of 69 μL s−1, showcasing a smart material design in simultaneously achieving multi-functionality and maximizing the energy efficiency. [ABSTRACT FROM AUTHOR]

• Composite thin films comprising 2D/2D MOF/rGO heterostructures for photocatalytic CO 2 reduction. • Modulated electronic structure of metal centers unveiled by XPS and XANES. • The activity and selectivity are among the best reported in literature. • The thin-film catalysts are highly stable and extremely easy to recycle. • High activity is well rationalized by the heterostructure configuration and electrostatic charge transfer. In this work, composite thin films comprising the 2D/2D MOF/rGO heterostructures assembled via Coulomb interaction are employed as the cocatalyst for photocatalytic CO 2 reduction for the first time. The electrostatic charge transfer and the strong π-π interaction induced in the heterostructure effectively modulate the electronic structure of the metal centers in the conductive 2D MOF (Ni 3 HITP 2), evidenced by Zeta Potentials, HR-TEM, XPS and XANES. The best thin-film catalyst with an optimal MOF/rGO ratio demonstrates a high CO evolution rate of 3.8 × 104 μmol h−1 g film −1 (0.46 min−1 in TOF) and a good selectivity of 91.74%, synergically contributed by the improved photoelectron harvesting on the rGO scaffold, the efficient charge transportation/transfer within the conductive and intimate 2D heterostructure, the coherent energy flow owing to aligned energy levels, and the enriched electron density at the isolated Ni-N 4 sites boosted by electrostatic charge transfer. [ABSTRACT FROM AUTHOR]