Enhancing Triplet-Triplet Annihilation Upconversion of Pyrene Derivatives for Photoredox Catalysis via Molecular Engineering.

Triplet-triplet annihilation upconversion (TTA-UC) has the potential to enhance photoredox catalysis yield. It includes a sensitizer and an annihilator. Efficient and stable annihilators are essential for photoredox catalysis, yet only a few examples are reported. Herein, we designed four novel pyrene annihilators (1, 2, 3 and 4) via introducing aryl-alkynyl groups onto pyrene to systematically modulate their singlet and triplet energies. Coupled with platinum octaethylporphyrin (PtOEP), the TTA-UC efficiency is enhanced gradually as the number of aryl-alkynyl group increases. When combining 4 with palladium tetraphenyl-tetrabenzoporphyrin (PdTPTBP), we achieved the highest red-to-green upconversion efficiency (22.4±0.3 %) (out of a 50 % maximum) so far. Then, this pair was used to activate photooxidation of aryl boronic acid under red light (630 nm), which achieved a great improved reaction yield compared to that activated by green light directly. The results not only provide a design strategy for efficient annihilators, but also show the advantage of applying TTA-UC into improving the photoredox catalysis yield.

Förster Resonance Energy Transfer: Stimulus-Responsive Purely Organic Room Temperature Phosphorescence through Dynamic B-N bond.

Recently, stimulus-responsive organic materials with room-temperature phosphorescence (RTP) properties have attracted significant attention owing to their potential applications in chemical sensing, anticounterfeiting, and displays. However, molecular design currently lacks systematicity and effectiveness. Herein, we report a capture-release strategy for the construction of reversible RTP via B/N Lewis pairs. Specifically, the RTP of the Lewis acid of 7-bromo-5,9-dioxa-13b-boranaphtho[3,2,1-de]anthracene (BrBA) can be deactivated through capturing by the Lewis base, N,N-diphenyl-4-(pyridin-4-yl)aniline (TPAPy), and reactivated by dissociation of B-N bonds to release BrBA. Reversible RTP is attributed to the exceptional self-assembly capability of BrBA, whereas the tunable RTP colors are derived from distinct Förster resonance energy transfer (FRET) processes. The potential applications of RTP materials in information storage and anti-counterfeiting were also experimentally validated. The capture-release approach proposed in this study offers an effective strategy for designing stimulus-responsive materials.

JND4135, a New Type II TRK Inhibitor, Overcomes TRK xDFG and Other Mutation Resistance In Vitro and In Vivo.

The tropomyosin receptor kinases (TRKs) have been validated as effective targets in anticancer drug discovery. Two first-generation TRK inhibitors have been approved into market and displayed an encouraging therapeutic response in cancer patients harboring TRK fusion proteins. However, acquired resistance mediated by secondary TRK mutations especially in the xDFG motif remains an unsolved challenge in the clinic. Herein, we report the preclinical pharmacological results of JND4135, a new type II pan-TRK inhibitor, in overcoming TRK mutant resistance, including the xDFG mutations in vitro and in vivo. At a low nanomolar level, JND4135 displays a strong activity against wild-type TRKA/B/C and secondary mutations involving xDFG motif substitutions in kinase assays and cellular models; occupies the TRK proteins for an extended time; and has a slower dissociation rate than other TRK inhibitors. Moreover, by intraperitoneal injection, JND4135 exhibits tumor growth inhibition (TGI) of 81.0% at a dose of 40 mg/kg in BaF3-CD74-TRKA-G667C mice xenograft model. Therefore, JND4135 can be considered as a lead compound for drug discovery overcoming the resistance of TRK inhibitor drugs mediated by xDFG mutations.

Characterization of an aromatic trifluoromethyl ketone as a new warhead for covalently reversible kinase inhibitor design.

An aromatic trifluoromethyl ketone moiety was characterized as a new warhead for covalently reversible kinase inhibitor design to target the non-catalytic cysteine residue. Potent and selective covalently reversible inhibitors of FGFR4 kinase were successfully designed and synthesized by utilizing this new warhead. The binding mode of a representative inhibitor was fully characterized by using multiple technologies including MALDI-TOF mass spectrometry, dialysis assay and X-ray crystallographic studies etc. This functional group was also successfully applied to discovery of a new JAK3 inhibitor, suggesting its potential application in designing other kinase inhibitors.

The photophysical properties and imaging application of a new polarity-sensitive fluorescent probe.

A new excited-state intramolecular proton transfer (ESIPT) based and polarity-sensitive fluorescent probe M-HA was easily developed by conjugated connection of indole and 2'-hydroxyacetophenone through (E)-2-chloro-3-(hydroxymethylene)cyclohex-1-enecarbaldehyde. M-HA shows near-infrared fluorescence, high molar absorption coefficient and a large Stokes shift in various common solvents. In particular, M-HA exhibits red-shifted maximum emission wavelength, and extraordinarily high fluorescence intensity and quantum yield in high-polarity solvents. The theoretical calculation results indicate that the reduced electron-vibration coupling related to out-of-plane motions of benzene units in more polar solvents is mainly responsible for such unusual photophysical properties. For further application, M-HA was utilized to image live cells. The confocal fluorescence imaging results demonstrate that M-HA possesses excellent membrane permeability and can fluoresce brightly in the cytoplasm. Overall, M-HA, as a polarity-sensitive fluorescent probe, will serve as an excellent tool for quantitative determination of polarity in vitro and in-depth study of the polarity biology in physiopathology in future.

Using X-ray computed tomography and micro-Raman spectrometry to measure individual particle surface area, volume, and morphology towards investigating atmospheric heterogeneous reactions.

Heterogeneous reactions on the aerosol particle surface in the atmosphere play important roles in air pollution, climate change, and global biogeochemical cycles. However, the reported uptake coefficients of heterogeneous reactions usually have large variations and may not be relevant to real atmospheric conditions. One of the major reasons for this is the use of bulk samples in laboratory experiments, while particles in the atmosphere are suspended individually. A number of technologies have been developed recently to study heterogeneous reactions on the surfaces of individual particles. Precise measurements on the reactive surface area, volume, and morphology of individual particles are necessary for calculating the uptake coefficient, quantifying reactants and products, and understanding the reaction mechanism better. In this study, for the first time we used synchrotron radiation X-ray computed tomography (XCT) and micro-Raman spectrometry to measure individual CaCO3 particle morphology, with sizes ranging from 3.5-6.5µm. Particle surface area and volume were calculated using a reconstruction method based on software three-dimensional (3-D) rendering. The XCT was first validated with high-resolution field-emission scanning electron microscopy (FE-SEM) to acquire accurate CaCO3 particle surface area and volume estimates. Our results showed an average difference of only 6.1% in surface area and 3.2% in volume measured either by micro-Raman spectrometry or X-ray tomography. X-ray tomography and FE-SEM can provide more morphological details of individual CaCO3 particles than micro-Raman spectrometry. This study demonstrated that X-ray computed tomography and micro-Raman spectrometry can precisely measure the surface area, volume, and morphology of an individual particle.

Distribution, sources, and ecological risk assessment of SVOCs in surface sediments from Guan River Estuary, China.

The contamination of semi-volatile organic compounds (SVOCs) in the surface sediments of the Guan River Estuary, China was fully investigated. Total concentrations of 56 species of SVOCs ranged from 132 to 274 ng/g with an average of 186 ng/g (dry weight). Polycyclic aromatic hydrocarbon (PAH) concentrations were positively correlated with clay content and negatively correlated with sediment grain size. Source identification indicated that PAHs originated mainly from pyrolytic sources. However, intense ship traffic in the estuary may provide sources of petrogenic PAHs. Organochlorine pesticides (OCPs) mainly originated from direct input of dichlorodiphenyltrichloroethanes (DDTs) during some industrial processes. The SVOC concentrations were also compared with International Sediments Quality Guidelines and Sediments Quality Criteria, and the results indicated that negative biological impacts may originate from high concentrations of FLO, p,p'-DDE, and total DDTs.

Correlation between physicochemical properties, flavor characteristics and microbial community structure in Dushan shrimp sour paste.

Dushan shrimp sour paste (DSSP), a traditional Guizhou condiment, and its unique flavor is determined by the fermentation microbiota. However, the relationship between the microbiota structure and its flavor remains unclear. This study identified 116 volatile flavor compounds using electronic nose and headspace solid-phase microextraction-gas chromatography mass spectrometry (HS-SPME-GC-MS) techniques, of which 19 were considered as key flavor compounds, mainly consisting of 13 esters and 1 alcohol. High-throughput sequencing technique, the bacterial community structure of nine groups of DSSPs was determined. Further analysis revealed Vagococcus, Lactococcus, and Tepidimicrobium as key bacteria involved in flavor formation. This study contributes to our understanding of the relationship between bacterial communities and the flavor formation, and provides guidance for screening starter culture that enhance the flavor of DSSP in industrial production.

Solvent-Responsive Nonporous Adaptive Crystals Derived from Pyridinium Hydrochloride and the Application in Iodine Adsorption.

Nonporous adaptive crystals (NACs) are crystalline nonporous materials that can undergo a structural adaptive phase transformation to accommodate specific guest via porous cavity or lattice voids. Most of the NACs are based on pillararenes because of their flexible backbone and intrinsic porous structure. Here a readily prepared organic hydrochloride of 4-(4-(diphenylamino)phenyl)pyridin-1-ium chloride (TPAPyH), exhibiting the solvent dimension-dependent adaptive crystallinity is reported. Wherein it forms a nonporous α crystal in a solvent with larger dimensions, while forming two porous ß and γ crystals capable of accommodating solvent molecules in solvent with small size. Furthermore, the thermal-induced single-crystal-to-single-crystal (SCSC) transition from the ß to α phase can be initiated. Upon exposure to iodine vapor or immersion in aqueous solution, the nonporous α phase transforms to porous ß phase by adsorbing iodine molecules. Owing to the formation of trihalide anion I2Cl- within the crystal cavity, TPAPyH exhibits remarkable performance in iodine storage, with a high uptaking capacity of 1.27 g g-1 and elevated iodine desorption temperature of up to 110 and 82 °C following the first and second adsorption stage. The unexpected adaptivity of TPAPyH inspires the design of NACs for selective adsorption and separation of volatile compound from organic small molecules.

Design, synthesis and biological evaluation of 5-amino-1H-pyrazole-4-carboxamide derivatives as pan-FGFR covalent inhibitors.

The aberrant activation of FGFRs plays a critical role in various cancers, leading to the development of several FGFR inhibitors in clinic. However, the emergence of drug resistance, primarily due to gatekeeper mutations in FGFRs, has limited their clinical efficacy. To address the unmet medical need, a series of 5-amino-1H-pyrazole-4-carboxamide derivatives were designed and synthesized as novel pan-FGFR covalent inhibitors targeting both wild-type and the gatekeeper mutants. The representative compound 10h demonstrated nanomolar activities against FGFR1, FGFR2, FGFR3 and FGFR2 V564F gatekeeper mutant in biochemical assays (IC50 = 46, 41, 99, and 62 nM). Moreover, 10h also strongly suppressed the proliferation of NCI-H520 lung cancer cells, SNU-16 and KATO III gastric cancer cells with IC50 values of 19, 59, and 73 nM, respectively. Further X-ray co-crystal structure revealed that 10h irreversibly binds to FGFR1. The study provides a new promising point for anticancer drug development medicated by FGFRs.

Structure-Based Optimization of Pyrazinamide-Containing Macrocyclic Derivatives as Fms-like Tyrosine Kinase 3 (FLT3) Inhibitors to Overcome Clinical Mutations.

Secondary mutations in Fms-like tyrosine kinase 3-tyrosine kinase domain (FLT3-TKD) (e.g., D835Y and F691L) have become a major on-target resistance mechanism of FLT3 inhibitors, which present a significant clinical challenge. To date, no effective drugs have been approved to simultaneously overcome clinical resistance caused by these two mutants. Thus, a series of pyrazinamide macrocyclic compounds were first designed and evaluated to overcome the secondary mutations of FLT3. The representative 8v exhibited potent inhibitory activities against FLT3D835Y and FLT3D835Y/F691L with IC50 values of 1.5 and 9.7 nM, respectively. 8v also strongly suppressed the proliferation against Ba/F3 cells transfected with FLT3-ITD, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-D835Y-F691L, and MV4-11 acute myeloid leukemia (AML) cell lines with IC50 values of 12.2, 10.5, 24.6, 16.9, and 6.8 nM, respectively. Furthermore, 8v demonstrated ideal anticancer efficacy in a Ba/F3-FLT3-ITD-D835Y xenograft model. The results suggested that 8v can serve as a promising macrocycle-based FLT3 inhibitor for the treatment of AML.

Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity.

Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-b]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea 8z exhibited excellent potency against FGFR4WT, FGFR4V550L, and FGFR4V550M with IC50 values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4WT, FGFR4V550L, and FGFR4V550M, and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC50 values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, 8z displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.

Mixed fermentation with Lactobacillus plantarum, Bifidobacteriµm animalis subsp. lactis and Candida utilis improves the fermentation quality of Hong Suan Tang.

Lactobacillus plantarum NR1-7, Bifidobacteriµm animalis subsp. lactis BZ11 and Candida utilis RY were selected as specific starter cultures to ferment Hong Suan Tang (HST), a traditional hot and sour soup of southwest China made from tomatoes and red peppers. The fermentation conditions were optimized with response surface methodology (RSM). The changes in the physicochemical index, flavor quality, organic acids, and bioactive substances were evaluated. The results showed that the mixed starter fermented HST was quickly acidified, promoting product maturity and significantly reducing the nitrite content, which shortened the fermentation time and improved product safety. Moreover, lactic acid concentration was significantly increased, about 3 times higher than the control group. Sixteen compounds were confirmed to be the critical aroma-active compounds present in the HST. Furthermore, mixed inoculation improved the content of bioactive substances by lowering their degradation. This research sets the basis for the standardized production of HST products.

COVID-19 pandemic: impacts on air quality and economy before, during and after lockdown in China in 2020.

This paper comprehensively evaluates the dynamic effects on China's environment and economy during the COVID-19 pandemic. Results show that the COVID-19 lockdown resulted in a temporary improvement in air quality. Furthermore, nitrogen dioxide (NO2) levels in the atmosphere in China were 36% lower than in the week after last year's Lunar New Year holiday, but this also led to an economic downturn. Moreover, the aerosol optical depth (AOD) decreased significantly. During the back-to-work period, the economy recovered and there was an increase in energy consumption, and CO2, NO2 emissions sharply increased to pre-lockdown levels. In the post-lockdown period, the AOD was lower than that of the same period last year. This study can provide reference for environmental policy making, as it demonstrates to what extent the control of pollution sources can improve air quality. Precise emission reduction and regional joint prevention and control are important and effective means for the prevention and control of O3 pollution. The health and economic benefits of COVID-19 pandemic control measures are incalculable. And this can provide an effective scientific basis and theoretical support for the prevention and control of air pollution.

Cofacial porphyrin organic cages. Metals regulating excitation electron transfer and CO2 reduction electrocatalytic properties.

Herein, we introduce a comprehensive study of the photophysical behaviors and CO2 reduction electrocatalytic properties of a series of cofacial porphyrin organic cages (CPOC-M, M = H2, Co(ii), Ni(ii), Cu(ii), Zn(ii)), which are constructed by the covalent-bonded self-assembly of 5,10,15,20-tetrakis(4-formylphenyl)porphyrin (TFPP) and chiral (2-aminocyclohexyl)-1,4,5,8-naphthalenetetraformyl diimide (ANDI), followed by post-synthetic metalation. Electronic coupling between the TFPP donor and naphthalene-1,4 : 5,8-bis(dicarboximide) (NDI) acceptor in the metal-free cage is revealed to be very weak by UV-vis spectroscopic, electrochemical, and theoretical investigations. Photoexcitation of CPOC-H2, as well as its post-synthetic Zn and Co counterparts, leads to fast energy transfer from the triplet state porphyrin to the NDI unit according to the femtosecond transient absorption spectroscopic results. In addition, CPOC-Co enables much better electrocatalytic activity for CO2 reduction reaction than the other metallic CPOC-M (M = Ni(ii), Cu(ii), Zn(ii)) and monomeric porphyrin cobalt compartment, supplying a partial current density of 18.0 mA cm-2 at -0.90 V with 90% faradaic efficiency of CO.

Switch type I to type II TRK inhibitors for combating clinical resistance induced by xDFG mutation for cancer therapy.

TRK xDFG mutation-induced acquired resistance of 1st generation inhibitors larotrectinib and entrectinib remains an unmet clinical need. Here we report a series of 6-(pyrrolidin-1-yl)imidazo[1,2-b]pyridazine-based derivatives as selective type II TRK inhibitors by hybridization. A representative compound 12d potently inhibited TRKA/B/C and TRKAG667C with IC50 values of 3.3, 6.4, 4.3 and 9.4 nM, respectively. 12d potently suppressed proliferation of a panel of Ba/F3 cells stably transformed with wild type, xDFG as well as solvent-front (SF) mutant TRK fusion proteins. Compared with larotrectinib and selitrectinib, 12d displayed superior inhibitory activity towards Ba/F3 cells harboring CD74-TRKAG667C and ETV6-TRKCG696C with IC50 values of 2.6 and 6.1 nM, respectively. Moreover, 12d also exhibited potent antiproliferation activity against Ba/F3-ETV6-TRKCG623R and Ba/F3-ETV6-TRKCG623E mutants with IC50 values of 31.0 and 28.2 nM, respectively. This work provided a new potential type II TRK inhibitor-based lead compound for the treatment of TRK driven cancers.

Structure-Based Optimization of the Third Generation Type II Macrocycle TRK Inhibitors with Improved Activity against Solvent-Front, xDFG, and Gatekeeper Mutations.

The solvent-front (SF), gatekeeper, and xDFG motif mutations of tropomyosin receptor kinase (TRK) mediating acquired resistance of larotrectinib and entrectinib represent an unmet clinical need. To date, no effective drugs are being approved to overcome these mutants. Thus, a series of macrocycle compounds were designed and synthesized as new type II TRK inhibitors to combat clinically relevant mutations. The representative compound 10g exhibited excellent potency against wide type TRKA/C, TRKAG595R, TRKAG667C, and TRKAF589L with IC50 values of 5.21, 4.51, 6.77, 1.42, and 6.13 nM, respectively, and a good kinome selectivity against 378 kinases. 10g also strongly suppressed the proliferation of Ba/F3 cells transfected with SF, GK, xDFG, and others (Val to Met) single mutants with IC50 values of 1.43-47.56 nM. Moreover, 10g demonstrated ideal antitumor efficacy in both BaF3-CD74-NTRK1G595R and BaF3-CD74-NTRK1G667C xenograft models. The study provides a promising lead compound for pan-anticancer drug discovery.

Rational Design of Covalent Kinase Inhibitors by an Integrated Computational Workflow (Kin-Cov).

Covalent kinase inhibitors (CKIs) hold great promise for drug development. However, examples of computationally guided design of CKIs are still scarce. Here, we present an integrated computational workflow (Kin-Cov) for rational design of CKIs. The design of the first covalent leucine-zipper and sterile-α motif kinase (ZAK) inhibitor was presented as an example to showcase the power of computational workflow for CKI design. The two representative compounds, 7 and 8, inhibited ZAK kinase with half-maximal inhibitory concentration (IC50) values of 9.1 and 11.5 nM, respectively. Compound 8 displayed an excellent ZAK target specificity in Kinome profiling against 378 wild-type kinases. Structural biology and cell-based Western blot washout assays validated the irreversible binding characteristics of the compounds. Our study presents a rational approach for the design of CKIs based on the reactivity and accessibility of nucleophilic amino acid residues in a kinase. The workflow is generalizable and can be applied to facilitate CKI-based drug design.

Beauvericin suppresses the proliferation and pulmonary metastasis of osteosarcoma by selectively inhibiting TGFBR2 pathway.

Osteosarcoma (OS) patients, particularly those with distant metastasis, experience rapid progression and derive poor survival benefits from traditional therapies. Currently, effective drugs for treating patients with metastatic OS remain scarce. Here, we found that the cyclic hexadepsipeptide beauvericin (BEA) functioned as a new selective TGFBR2 inhibitor with potent antiproliferative and antimetastatic activities against OS cells. Functionally, BEA inhibited TGF-ß signaling-mediated proliferation, invasiveness, mesenchymal phenotype, and extracellular matrix remodeling of OS cells, and suppressed tumor growth and reduced pulmonary metastasis in vivo. Mechanistic investigation revealed that BEA selectively and directly bound to Asn 332 of TGFBR2 and inhibited its kinase activity, thereby suppressing the aggressive progression of OS cells. Together, our study identifies an innovative and natural selective TGFBR2 inhibitor with effective antineoplastic activity against metastatic OS and demonstrates that targeting TGFBR2 could be a potential therapeutic strategy for metastatic OS.

PCBP1 is associated with rheumatoid arthritis by affecting RNA products of genes involved in immune response in Th1 cells.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by persistent synovitis, in which T helper 1 (Th1) can promote the development of a pro-inflammatory microenvironment. Poly(rC)-binding protein 1 (PCBP1) has been identified as a promising biomarker of RA, while its molecular mechanisms in RA development are unknown. As a canonical RNA binding protein, we propose that PCBP1 could play roles in RA by affecting both expression and alternative splicing levels in Th1 cells. Here, microarray datasets (GSE15573 and GSE23561), including 102 peripheral blood mononuclear cell samples from 39 RA patients and 63 controls, were used to evaluate the PCBP1 expression changes in RA patients. High throughput sequencing data (GSE84702) of iron driven pathogenesis in Th1 cells were downloaded and reanalyzed, including two Pcbp1 deficiency samples and two control samples in Th1 cells. In addition, CLIP-seq data of PCBP1 in Jurkat T cells was also analyzed to investigate the regulatory mechanisms of PCBP1. We found PCBP1 were down-regulated in RA specimens compared with control. The result of differentially expressed genes (DEGs) showed that Pcbp1 silencing in Th1 cells affected the expression of genes involved in immune response pathway. Alternative splicing analysis also revealed that PCBP1-regulated alternative splicing genes (RASGs) were enriched in TNF-a/NF-κB signaling pathway, T cell activation, T cell differentiation and T cell differentiation associated immune response pathways, which were highly associated with RA. DEGs and RASGs by Pcbp1 deficiency in mice were validated in PBMCs specimens of RA patients by RT-qPCR. Investigation of the CLIP-seq data revealed PCBP1 preferred to bind to 3'UTR and intron regions. PCBP1-bound genes were also significantly associated with RASGs, identifying 102 overlapped genes of these two gene sets. These genes were significantly enriched in several immune response related pathways, including myeloid cell differentiation and positive regulation of NF-κB transcription factor activity. Two RA-related genes, PML and IRAK1, were screened from the above immune related pathways. These results together support our hypothesis that PCBP1 can regulate the expression of genes involved in immune response pathway, and can bind to and regulate the alternative splicing of immune response related genes in immune T cells, and ultimately participate in the molecular mechanism of RA, providing new research ideas and directions for clinical diagnosis and treatment.