Tumor-targeted delivery of a STING agonist improvescancer immunotherapy.

The cGAS-STING pathway is essential for immune defense against microbial pathogens and malignant cells; as such, STING is an attractive target for cancer immunotherapy. However, systemic administration of STING agonists poses safety issues while intratumoral injection is limited by tumor accessibility. Here, we generated antibody-drug conjugates (ADCs) by conjugating a STING agonist through a cleavable linker to antibodies targeting tumor cells. Systemic administration of these ADCs was well tolerated and exhibited potent antitumor efficacy in syngeneic mouse tumor models. The STING ADC further synergized with an anti-PD-L1 antibody to achieve superior antitumor efficacy. The STING ADC promoted multiple aspects of innate and adaptive antitumor immune responses, including activation of dendritic cells, T cells, natural killer cells and natural killer T cells, as well as promotion of M2 to M1 polarization of tumor-associated macrophages. These results provided the proof of concept for clinical development of the STING ADCs.

Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING.

The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5'-phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation.

Design and Development of Highly Efficient Light-Emitting Layers in OLEDs with Dimesitylboranes: An Updated Review.

With excellent luminescent properties and transport properties, triarylborane compounds containing two mesitylenes (Mes) have gained much attention for their application in OLEDs as light-emitting layers. This study serves as an updated review summarizing recent developments in the design of fluorescent chromophores and phosphorescent host materials for OLEDs comprising small molecular compounds of dimesitylborane (BMes2 ) as luminescent layers, with attention to the performance of different light-emitting devices. Problems that need to be solved in the research and application of BMes2 in OLEDs are presented and the application prospects of such materials are suggested.

cGAS is essential for the antitumor effect of immune checkpoint blockade.

cGMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses. cGAS catalyzes the synthesis of cGAMP, which functions as a second messenger that binds and activates the adaptor protein STING to induce type I interferons (IFNs) and other immune modulatory molecules. Here we show that cGAS is indispensable for the antitumor effect of immune checkpoint blockade in mice. Wild-type, but not cGAS-deficient, mice exhibited slower growth of B16 melanomas in response to a PD-L1 antibody treatment. Consistently, intramuscular delivery of cGAMP inhibited melanoma growth and prolonged the survival of the tumor-bearing mice. The combination of cGAMP and PD-L1 antibody exerted stronger antitumor effects than did either treatment alone. cGAMP treatment activated dendritic cells and enhanced cross-presentation of tumor-associated antigens to CD8 T cells. These results indicate that activation of the cGAS pathway is important for intrinsic antitumor immunity and that cGAMP may be used directly for cancer immunotherapy.

Vital Sign Detection during Large-Scale and Fast Body Movements Based on an Adaptive Noise Cancellation Algorithm Using a Single Doppler Radar Sensor.

The non-contact detection of human vital signs (i.e., respiration rate (RR) and heartbeat rate (HR)) using a continuous-wave (CW) Doppler radar sensor has great potential for intensive care monitoring, home healthcare, etc. However, large-scale and fast random body movement (RBM) has been a bottleneck for vital sign detection using a single CW Doppler radar. To break this dilemma, this study proposed a scheme combining adaptive noise cancellation (ANC) with polynomial fitting, which could retrieve the weak components of both respiration and heartbeat signals that were submerged under serious RBM interference. In addition, the new-type discrete cosine transform (N-DCT) was introduced to improve the detection accuracy. This scheme was first verified using a numerical simulation. Then, experiments utilizing a 10-GHz Doppler radar sensor that was built from general-purpose radio frequency (RF) and communication instruments were also carried out. No extra RF/microwave components and modules were needed, and neither was a printed circuit board nor an integrated-chip design required. The experimental results showed that both the RR and HR could still be extracted during large-scale and fast body movements using only a single Doppler radar sensor because the RBM noises could be greatly eliminated by utilizing the proposed ANC algorithm.

Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING.

Cyclic GMP-AMP containing a unique combination of mixed phosphodiester linkages (2'3'-cGAMP) is an endogenous second messenger molecule that activates the type-I IFN pathway upon binding to the homodimer of the adaptor protein STING on the surface of endoplasmic reticulum membrane. However, the preferential binding of the asymmetric ligand 2'3'-cGAMP to the symmetric dimer of STING represents a physicochemical enigma. Here we show that 2'3'-cGAMP, but not its linkage isomers, adopts an organized free-ligand conformation that resembles the STING-bound conformation and pays low entropy and enthalpy costs in converting into the active conformation. Our results demonstrate that analyses of free-ligand conformations can be as important as analyses of protein conformations in understanding protein-ligand interactions.

Two Novel Two-Stage Direction of Arrival Estimation Algorithms for Two-Dimensional Mixed Noncircular and Circular Sources.

This paper addresses the two-dimensional (2D) direction-of-arrival (DOA) estimation problem with two novel methods for mixed noncircular and circular signals. The first proposed method is named the two-stage direction-of-arrival matrix (TSDOAM) method, and the other is called the two-stage rank reduction (TSRARE) method. The proposed methods utilize both the circularity and the direction-of-arrival differences between the noncircular and circular sources to estimate the 2D directions-of-arrival (DOAs). The maximum detectable 2D angle parameters of the TSDOAM and TSRARE methods are twice those of the existing methods. Moreover, the TSRARE method can detect more incident signals than the TSDOAM method due to the array aperture of two parallel uniform linear arrays (ULAs) being fully utilized. Simulation results show that compared to the existing methods for the small angle separation of 2D directions-of-arrival, the two proposed methods perform well in terms of the signal-to-noise ratio (SNR) and snapshots.

SLPI knockdown induced pancreatic ductal adenocarcinoma cells proliferation and invasion.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease and still continues to have the worst prognosis of all gastrointestinal malignancies. Reports have demonstrated that secretory leukocyte protease inhibitor (SLPI) is overexpressed in various cancers and may be a potential therapeutic strategy for the treatment of different cancers. However, the possible role of SLPI in PDAC is still unknown. In the present study, we investigate the effects of SLPI gene knockdown on the biological behavior of human pancreatic cancer cells. The expressions of SLPI were detected, by qRT-PCR and Western blot, in human PDAC tissues as well as AsPC-1, BxPC-3 and PANC-1 cells. After transfection with siRNA targeting to SLPI, SLPI expression was detected by qRT-PCR and Western blot in cells. Cell proliferation and apoptosis were also evaluated by MTT assay and flow cytometry (FCM). The trans-well assays were also employed to explore the effects of SLPI knockdown on the migration and invasion of PDAC cells in vitro. RESULTS: The expressions of SLPI derived from human PDAC and PDAC cell lines were significant higher than those of control groups, respectively (P < 0.05). Regression analysis showed elevated SLPI level was positive correlated with development of PDAC. The siRNA target to SLPI significantly decreased the expressions of SLPI in these PDAC cell lines. Following SLPI-siRNA transduction, the proliferative capacity of the AsPC-1, BxPC-3 and PANC-1 cells was significantly inhibitions, compared to the blank (PDAC-wild type cells) and negative (non-targeting scrambled siRNA transduced PDAC cells) control ones, respectively (P < 0.05). Moreover, SLPI knockdown significantly increased the apoptosis fractions and reduced the migration and invasion of PDAC cells in vitro (P < 0.05). CONCLUSIONS: The present study demonstrated that: i) SLPI played an important role in PDAC progression; ii) SLPI might be an important characteristic of malignant PDAC associated with migration and invasion in vitro; and iii) siRNA targeting to SLPI might be a potential therapeutic strategy for the treatment of PCC.

A Luminescent Nitrogen-Containing Polycyclic Aromatic Hydrocarbon Synthesized by Photocyclodehydrogenation with Unprecedented Regioselectivity.

We present a nitrogen-containing polycyclic aromatic hydrocarbon (N-PAH), namely 12-methoxy-9-(4-methoxyphenyl)-5,8-diphenyl-4-(pyridin-4-yl)pyreno[1,10,9-h,i,j]isoquinoline (c-TPE-ON), which exhibits high quantum-yield emission both in solution (blue) and in the solid state (yellow). This molecule was unexpectedly obtained by a three-fold, highly regioselective photocyclodehydrogenation of a tetraphenylethylene-derived AIEgen. Based on manifold approaches involving UV/Vis, photoluminescence, and NMR spectroscopy as well as HRMS, we propose a reasonable mechanism for the formation of the disk-like N-PAH that is supported by density functional theory calculations. In contrast to most PAHs that are commonly used, our system does not suffer from entire fluorescence quenching in the solid state due to the peripheral aromatic rings preventing π-π stacking interactions, as evidenced by single-crystal X-ray analysis. Moreover, its rod-like microcrystals exhibit excellent optical waveguide properties. Hence, c-TPE-ON comprises a N-PAH with unprecedented luminescent properties and as such is a promising candidate for fabricating organic optoelectronic devices. Our design and synthetic strategy might lead to a more general approach to the preparation of solution- and solid-state luminescent PAHs.

Identification and characterization of ß-sitosterol target proteins.

ß-Sitosterol is the most abundant plant sterol in the human diet. It is also the major component of several traditional medicines, including saw palmetto and devil's claw. Although ß-sitosterol is effective against enlarged prostate in human clinical trials and has anti-cancer and anti-inflammatory activities, the mechanisms of action are poorly understood. Here, we report the identification of two new binding proteins for ß-sitosterol that may underlie its beneficial effects.

Construction of the 5,6,7-tricyclic skeleton of lancifodilactone F.

We report herein the synthesis of a fully functionalized B,C,D-ring system of lancifodilactone F. The key transformations involve an arene-olefin meta-photocycloaddition reaction and a palladium-catalyzed oxidative C-C cleavage reaction to establish its B,C-rings.

Molecular Engineering Towards Efficient Aggregation-Induced Delayed Fluorescence Luminogens as Emitters and Sensitizers for High-Performance Organic Light-Emitting Diodes.

Exploring efficient thermally-activated delayed fluorescence materials having maximum external quantum efficiencies (ηext,maxs) exceeding 30% for organic light-emitting diodes (OLEDs) still remains challenging because it generally requires efficient reverse intersystem crossing (RISC), high photoluminescence quantum yield (ΦPL), and large optical out-coupling efficiency (Φout) simultaneously. Herein, two green aggregation-induced delayed fluorescence (AIDF) luminogens, named XTCz-2 and XTCz-3, are designed and constructed by using xanthone (XT) as electron acceptor and phenylcarbazole-substituted carbazole as donors. XTCz-2 and XTCz-3 exhibit distinguished advantages of high thermal stability (439‒560 oC), excellent ΦPLs (84‒88%) and fast RISC rates (1.9 × 105‒4.2 × 105 s-1), and prefer horizontal dipole orientation and thus have high Φouts. Consequently, they can achieve the state-of-the-art electroluminescence (EL) performances with ηext,maxs of up to 35.0%. Moreover, XTCz-3 is selected as a sensitizer for sky-blue multi-resonance delayed fluorescence emitter in hyperfluorescence OLEDs, providing narrow EL spectra and excellent ηext,maxs of up to 33.8% with low efficiency roll-offs. The splendid comprehensive performances demonstrate the significant application potential of these AIDF luminogens as both light-emitting materials and sensitizers for OLEDs.

Diverse chemical scaffolds support direct inhibition of the membrane-bound O-acyltransferase porcupine.

Secreted Wnt proteins constitute one of the largest families of intercellular signaling molecules in vertebrates with essential roles in embryonic development and adult tissue homeostasis. The functional redundancy of Wnt genes and the many forms of cellular responses they elicit, including some utilizing the transcriptional co-activator ß-catenin, has limited the ability of classical genetic strategies to uncover their roles in vivo. We had previously identified a chemical compound class termed Inhibitor of Wnt Production (or IWP) that targets Porcupine (Porcn), an acyltransferase catalyzing the addition of fatty acid adducts onto Wnt proteins. Here we demonstrate that diverse chemical structures are able to inhibit Porcn by targeting its putative active site. When deployed in concert with small molecules that modulate the activity of Tankyrase enzymes and glycogen synthase kinase 3 ß (GSK3ß), additional transducers of Wnt/ß-catenin signaling, the IWP compounds reveal an essential role for Wnt protein fatty acylation in eliciting ß-catenin-dependent and -independent forms of Wnt signaling during zebrafish development. This collection of small molecules facilitates rapid dissection of Wnt gene function in vivo by limiting the influence of redundant Wnt gene functions on phenotypic outcomes and enables temporal manipulation of Wnt-mediated signaling in vertebrates.

A novel ratiometric emission probe for Ca2+ in living cells.

A ratiometric fluorescent probe for Ca(2+) based on 1,3,4-oxadiazole derivative has been designed and developed. The probe exhibits a large Stokes shift of 202 nm and a highly selective ratiometric emission response (490/582 nm) to Ca(2+) over other metal cations. Additionally, the probe can readily reveal the changes of intracellular Ca(2+) concentration in living human umbilical vein endothelial cells.

Synthesis, photoluminescence and electroluminescence properties of a new blue emitter with aggregation-induced emission and thermally activated delayed fluorescence characteristics.

The emitters with aggregation-induced emission (AIE) and thermally activated delayed fluorescence (TADF) characteristics are in high demand in organic light-emitting diodes (OLEDs) owing to their strong fluorescence and high exciton utilization under electrical excitation. Herein, a blue emitter, 10-(3-((3,5-di(9H-carbazol-9-yl)phenyl)sulfonyl)phenyl)-9,9-dimethyl-9,10-dihydroacridine (m-CZ-DPS-DMAC), was synthesized by incorporating carbazole as skeleton, acridine as electron donor, and diphenyl sulfone as electron acceptor. m-CZ-DPS-DMAC emits weak fluorescence in good solvent, while it is obviously enhanced in the aggregate state, which is typical of AIE molecules. Meanwhile, the energy levels of the singlet and triplet states (ΔEST) of the molecule is relatively small, and it also exhibits obvious temperature dependence and oxygen sensitivity, which directly proves its TADF properties. In view of the above properties, a series of non-doped and doped OLEDs were prepared using m-CZ-DPS-DMAC as light-emitting layers. Among them, non-doped OLED (device A) displays blue emission (488 nm) with the turn-on voltage (Von), the maximum luminance (Lmax), the maximum current efficiency (CEmax), the maximum power efficiency (PEmax) and the maximum external quantum efficiency (EQEmax) of 2.6 V, 3460 cd m-2, 26.09 cd A-1, 29.26 lm W-1 and 10.05%, respectively. Doped OLED (device C) constructed based on m-CZ-DPS-DMAC doped 30% in DPEPO shows the satisfactory performance with the maximum emission peak of 486 nm, the Von of 2.8 V, the Lmax of 4571 cd m-2, the CEmax of 21.37 cd A-1, the PEmax of 22.37 lm W-1, and the EQEmax of 9.44%, respectively. The outstanding performance of m-CZ-DPS-DMAC proves that it is a potential material for designing blue OLEDs with AIE-TADF properties.

Orthogonal Hydroxyl Functionalization of cGAMP Confers Metabolic Stability and Enables Antibody Conjugation.

cGAMP is a signaling molecule produced by the cGAS-DNA complex to establish antimicrobial and antitumor immunity through STING. Whereas STING activation holds potential as a new strategy to treat cancer, cGAMP is generally considered unsuitable for in vivo use because of the rapid cleavage of its phosphodiester linkages and the limited cellular uptake under physiological conditions. Consequently, phosphorothioation and fluorination are commonly used to improve the metabolic stability and permeability of cGAMP and its synthetic analogues. We now show that methylation of the 3'-hydroxyl group of cGAMP also confers metabolic stability and that acylation of the 2'-hydroxyl group can be achieved directly and selectively to enable receptor-mediated intracellular delivery. Unlike phosphorothioation and fluorination, these modifications do not create a new stereogenic center and do not require laborious building block synthesis. As such, orthogonal hydroxyl functionalization is a simple solution to issues associated with the in vivo use of cGAMP.

A boron-containing carbazole dimer: synthesis, photophysical properties and sensing properties.

A novel boron-containing π-conjugated compound has been synthesized by the introduction of electron-acceptors (dimesitylboron groups) at the 3,3'-positions of a carbazole dimer (electron-donor). The compound possesses excellent electrochemical properties and high fluorescence quantum yields. In addition, is a sensitive fluorescence sensor with remarkable colour changes and the results could be confirmed through theoretical calculations of the compounds and [(n)Bu(4)N](+)(2)[·(F)(2)](2-). Our studies indicate that could be used as an excellent optoelectronic material in OLED devices and a ratiometric fluorescent chemosensor.

One-Pot Preparation of HTPB/nNi and Its Catalyst for AP.

The liquid phase reduction method is a common method used for preparing nano-nickel powder (nNi). However, the nNi surface is easily oxidized to form nickel oxide film, which affects its performance. In this work, nNi was prepared using anhydrous ethanol as a solvent and hydrazine hydrate as a reducing agent. Furthermore, HTPB/nNi composites were prepared using hydroxyl-terminated polybutadiene (HTPB) as a coating agent. The structure and morphology of the samples are characterized by Fourier transform infrared spectroscopy (FT-IR), X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and energy dispersive spectroscopy (EDS). The catalytic behavior of HTPB/nNi on the thermal decomposition of ammonium perchlorate (AP) is studied by differential scanning calorimetry (DSC) and thermogravimetric analyzer (TG). The results show that HTPB/nNi has little effect on the low temperature thermal decomposition of AP, but the peak of high temperature thermal decomposition advances from 456 °C to 332 °C.

Ionic liquid-induced in situ deposition of perovskite quantum dot films with a photoluminescence quantum yield of over 85.

Metal halide perovskite quantum dots (QDs) hold great promise as building blocks for next-generation light emitting devices (LEDs). The preparation of perovskite QD films with high photoluminescence quantum yield (PLQY) is the key to realizing efficient LEDs. However, the conventional deposition method of spin-coating of pre-synthesized QD ink solutions results in perovskite QD films with low PLQY (typically <45%) due to non-radiative recombination centers induced in the deposition process. Here, by utilizing the ionic nature and steric hindrance effect of the ionic liquid, we demonstrate an in situ deposition method for perovskite QD films with high PLQY by directly spin-coating precursor solutions containing an ionic liquid. Furthermore, mechanistic study reveals that the ionic liquid not only induces the formation of QDs but also suppresses defect-related recombination through the interaction with uncoordinated metal atoms on the surface of the QDs. As a result, the in situ deposited CsPbBr3 QD film with a PLQY as high as 85.2% and long-term air stability is achieved. These findings demonstrate that the introduction of an ionic liquid provides an effective strategy to enhance the performance of in situ formed perovskite QD films, which could benefit the development of efficient LEDs and other optoelectronic devices.

Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9.

BACKGROUND: Chromosomal translocation-induced expression of the chromatin modifying oncofusion protein MLL-AF9 promotes acute myelocytic leukemia (AML). Whereas WNT/ß-catenin signaling has previously been shown to support MLL-AF9-driven leukemogenesis, the mechanism underlying this relationship remains unclear. METHODS: We used two novel small molecules targeting WNT signaling as well as a genetically modified mouse model that allow targeted deletion of the WNT protein chaperone Wntless (WLS) to evaluate the role of WNT signaling in AML progression. ATAC-seq and transcriptome profiling were deployed to understand the cellular consequences of disrupting a WNT signaling in leukemic initiating cells (LICs). FINDINGS: We identified Six1 to be a WNT-controlled target gene in MLL-AF9-transformed leukemic initiating cells (LICs). MLL-AF9 alters the accessibility of Six1 DNA to the transcriptional effector TCF7L2, a transducer of WNT/ß-catenin gene expression changes. Disruption of WNT/SIX1 signaling using inhibitors of the Wnt signaling delays the development of AML. INTERPRETATION: By rendering TCF/LEF-binding elements controlling Six1 accessible to TCF7L2, MLL-AF9 promotes WNT/ß-catenin-dependent growth of LICs. Small molecules disrupting WNT/ß-catenin signaling block Six1 expression thereby disrupting leukemia driven by MLL fusion proteins.