Enantioselective Construction of C-SCF3 Stereocenters via Nickel Catalyzed Asymmetric Negishi Coupling Reaction.

The construction of the SCF3-containing 1,1-diaryl tertiary carbon stereocenters with high enantioselectivities is reported via a nickel-catalyzed asymmetric C-C coupling strategy. This method demonstrates simple operations, mild conditions and excellent functional group tolerance, with newly designed SCF3-containing synthon, which can be easily obtained from commercially available benzyl bromide and trifluoromethylthio anion in a two-step manner. Further substrate exploration indicated that the reaction system could be extended to diverse perfluoroalkyl sulfide (SC2F5, SC3F7, SC4F9, SCF2CO2Et)-substituted 1,1-diaryl compounds with excellent enantioselectivities. The synthetic utility of this transformation was further demonstrated by convenient derivatization to optical SCF3-containing analogues of bioactive compounds without an apparent decrease in enantioselectivity.

A bivalent inhibitor against TDRD3 to suppress phase separation of methylated G3BP1.

The formation of membrane-less organelles is driven by multivalent weak interactions while mediation of such interactions by small molecules remains an unparalleled challenge. Here, we uncovered a bivalent inhibitor that blocked the recruitment of TDRD3 by the two methylated arginines of G3BP1. Relative to the monovalent inhibitor, this bivalent inhibitor demonstrated an enhanced binding affinity to TDRD3 and capability to suppress the phase separation of methylated G3BP1, TDRD3, and RNAs, and in turn inhibit the stress granule growth in cells. Our result paves a new path to mediate multivalent interactions involved in SG assembly for potential combinational chemotherapy by bivalent inhibitors.

Photoinduced Copper-Catalyzed Monofluoroalkylation of Terminal Alkynes to Propargylic Fluorides.

A photoinduced copper-catalyzed strategy for the monofluoroalkylation of alkynes with readily available monofluoroalkyl triflates was developed. It provides a new protocol to access valuable propargyl fluoride compounds via C-C bond formation by avoiding the use of highly toxic fluorination reagents. This reaction proceeded under mild conditions to afford propargyl monofluorides in moderate to high yields. Preliminary mechanistic studies reveal that a ligand-matched alkynyl copper complex might be the key photoactive substance.

DAP10 integration in CAR-T cells enhances the killing of heterogeneous tumors by harnessing endogenous NKG2D.

Although chimeric antigen receptor T (CAR-T) cells have achieved remarkable successes in hematological malignancies, the efficacies of CAR-T cells against solid tumors remains unsatisfactory. Heterogeneous antigen expression is one of the obstacles on its effective elimination of solid cancer cells. DNAX-activating protein 10 (DAP10) interacts with natural killer group 2D (NKG2D), acting as an adaptor that targets various malignant cells for surveillance. Here, we designed a DAP10 chimeric receptor that utilized native NKG2D on T cells to target NKG2D ligand-expressing cancer cells. We then tandemly incorporated it with anti-glypican 3 (GPC3) single-chain variable fragment (scFv) to construct a dual-antigen-targeting system. T cells expressing DAP10 chimeric receptor (DAP10-T cells) displayed with an enhancement on both cytotoxicity and cytokine secretion against solid cancer cell lines, and its tandem connection with anti-GPC3 scFv (CAR GPC3-DAP10-T cells) exhibited a dual-antigen-targeting capacity on eliminating heterogeneous cancer cells in vitro and suppressing the growth of heterogeneous cancer in vivo. Thus, this novel dual-targeting system enabled a high efficacy on killing cancer cells and extended the recognition profile of CAR-T cells toward tumors, which providing a potential strategy on treatment of solid cancer clinically.

A Novel Parallel Processing Model for Noise Reduction and Temperature Compensation of MEMS Gyroscope.

To eliminate the noise and temperature drift in an Micro-Electro-Mechanical Systems (MEMS) gyroscope's output signal for improving measurement accuracy, a parallel processing model based on Multi-objective particle swarm optimization based on variational modal decomposition-time-frequency peak filter (MOVMD-TFPF) and Beetle antennae search algorithm- Elman neural network (BAS-Elman NN) is established. Firstly, variational mode decomposition (VMD) is optimized by multi-objective particle swarm optimization (MOPSO); then, the best decomposition parameters [kbest,abest] can be obtained. Secondly, the gyroscope output signals are decomposed by VMD optimized by MOPSO (MOVMD); then, the intrinsic mode functions (IMFs) obtained after decomposition are classified into a noise segment, mixed segment, and drift segment by sample entropy (SE). According to the idea of a parallel model, the noise segment can be discarded directly, the mixed segment is denoised by time-frequency peak filtering (TFPF), and the drift segment is compensated at the same time. In the compensation part, the beetle antennae search algorithm (BAS) is adopted to optimize the network parameters of the Elman neural network (Elman NN). Subsequently, the double-input/single-output temperature compensation model based on the BAS-Elman NN is established to compensate the drift segment, and these processed segments are reconstructed to form the final gyroscope output signal. Experimental results demonstrate the superiority of this parallel processing model; the angle random walk of the compensated gyroscope output is decreased from 0.531076 to 5.22502 × 10-3°/h/√Hz, and its bias stability is decreased from 32.7364°/h to 0.140403°/h, respectively.

Nickel-catalyzed reductive monofluoroakylation of alkyl tosylate with bromofluoromethane to primary alkyl fluoride.

A nickel-catalysed direct terminal monofluoromethlyation between alkyl tosylates and a low-cost, industrial raw material bromofluoromethane has been developed. This transformation has demonstrated high efficiency, mild conditions, and good functional-group compatibility. The key to success of this transformation lies in the ligand and mild base selection, ensuring the generation of various terminal monofluormethylation products.

Copper-Catalyzed Enantioselective Arylation via Radical-Mediated C-C Bond Cleavage: Synthesis of Chiral ω,ω-Diaryl Alkyl Nitriles.

The first example of copper-catalyzed ring-opening, enantioselective arylation of cyclic ketoxime esters to access ω,ω-diaryl alkyl nitriles has been developed in high yield (up to 92% yield) with excellent enantioselectivity (up to 91% ee). Side-arm bis(oxazoline) ligand plays a significant role in this asymmetric catalytic transformation, which provides an efficient route to construct diverse chiral ω,ω-diaryl alkyl nitriles. Synthetic utility has also been demonstrated in the further derivatization of the ω,ω-diaryl alkyl nitrile to the corresponding amide.

Facile synthesis of axially chiral styrene-type carboxylic acids via palladium-catalyzed asymmetric C-H activation.

A novel method by a one-step introduction of axial chirality and sterically hindered group has been developed for facile synthesis of axially chiral styrene-type carboxylic acids. With the palladium-catalyzed C-H arylation and olefination of readily available cinnamic acid established, this transformation demonstrated excellent yield, excellent stereocontrol (up to 99% yield and 99% ee), and broad substrate scope under mild conditions. The axially chiral styrene-type carboxylic acids produced have been successfully applied to Cp*CoIII-catalyzed asymmetric C-H activation reactions, indicating their potential as chiral ligands or catalysts in asymmetric synthesis.

Stress-relaxing double-network hydrogel for chondrogenic differentiation of stem cells.

The mechanical environment of extracellular matrix (ECM) plays an important role in adjusting the behaviors of cells. Natural ECM are highly viscoelastic materials with stress-relaxion behavior. Hydrogel is considered as a promising and attractive material for cell carrier, but they are typically elastic serving as synthetic ECM. Double-network (DN) hydrogel has an interpenetrating network of special structure combining the advantages of both rigid and ductile components, due to which the mechanical properties of the system can be very different from that of the single-network ones, and some special biological properties can be obtained. In this study, GG/PEGDA DN hydrogel was prepared by combining gellan gum (GG) with polyethylene glycol diacrylate (PEGDA), and then the influence of the two individual networks on the viscoelasticity of the system were investigated. Furthermore, the effects of viscoelasticity of GG/PEGDA DN hydrogel on the biological behavior of bone mesenchymal stem cells (BMSCs) were explored in vitro and in vivo. The results indicate that the spreading of BMSCs was closely related to the relaxation behavior of the hydrogels. GG/PEGDA DN hydrogel shows excellent mechanical and relaxation properties which provide a favorable physical environment for cell proliferation and spreading, and induce chondrogenic differentiation. Our study demonstrates that this DN hydrogel has bright prospects in the fields of cell carrier and cartilage tissue engineering.

Role of Epstein-Barr virus encoded latent membrane protein 1 in the carcinogenesis of nasopharyngeal carcinoma.

Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) has been known to have oncogenic properties during latent infection in nasopharyngeal carcinoma (NPC). Our studies focused on the role of LMP1 in NPC, and showed that LMP1 triggers the NF-kappaB, AP-1 and STAT signaling pathways. Strikingly, LMP1 was found to mediate the formation of a new heterodimer between c-Jun and JunB. Also, we have identified JAK/STAT and PI-PLC-PKC activation triggered by LMP1 through upregulating the expression of JAK3 and enhancing the phosphorylation of STAT. The constitutive activation of these signaling cascades explains LMP1's ability to induce such a diverse array of morphological and phenotypic effects in cells and provides insight into how LMP1 may induce cell transformation, in which multihit targeted genes in the downstream play an essential role. All signaling cascades triggered by LMP1 ultimately lead to the disruption of the cell cycle: the acceleration of G1/S phase and the arrest of G2/M phase. We also found that LMP1 induced the expression of hTERT and promoted cell immortalization. Importantly, by intervening physical intracellular signal transduction pathways and disturbing the progression of the cell cycle, LMP1, an important oncoprotein encoded by EBV, is thought to be a key modulator in the pathogenesis of NPC. Interfering LMP1 signaling could be a promising strategy to target the malignant phenotype of NPC.

Upregulated expression of kappa light chain by Epstein-Barr virus encoded latent membrane protein 1 in nasopharyngeal carcinoma cells via NF-kappaB and AP-1 pathways.

B lymphocytes are generally considered to be the only source of immunoglobulins. However, increasing evidence revealed that some human epithelial cancer cell lines, including nasopharyngeal carcinoma (NPC) cell lines, expressed immunoglobulins. Moreover, we previously found that expression of kappa light chain in NPC cells could be upregulated by EBV-encoded latent membrane protein 1 (LMP1). Here, Western blot and flow cytometric analysis of intracellular kappa staining indicated that upregulation of the expression of kappa was inhibited by using LMP1-targeted DNAzyme and that Bay11-7082 and SP600125, inhibitors of JNK and NF-kappaB, respectively, inhibited LMP1-augmented kappa light chain expression in NPC cells. LMP1-positive NPC cells expressing the dominant-negative mutant of IkappaBalpha (DNMIkappaBalpha) or of c-Jun (TAM67) exhibited significantly decreasing kappa production compared with their parental cells. These results suggest that LMP1 elevated kappa light chain through activation of the NF-kappaB and AP-1 signaling pathways. The present study provided some hints of possible mechanisms by which human cancer cells of epithelial origin produced immunoglobulins.

Immunoglobulin alpha heavy chain derived from human epithelial cancer cells promotes the access of S phase and growth of cancer cells.

It is generally believed that under normal conditions only B lymphocytes express immunoglobulin. Interestingly, our previous work demonstrated that epithelial cancer tissues and cancer cell lines also express Ig alpha heavy chain. So we further analyzed the potential function of cancer-derived Ig alpha heavy chain. Here we show that blockade of cancer-derived Ig alpha suppressed the growth and viability of cancer cells. And cancer-derived Ig alpha promotes the malignant proliferation ability of cancer cells. Furthermore, we demonstrated that Ig alpha protein increases the access percentage of S phase from the early mitosis of synchronized cancer cells. Our findings support the important role of cancer-derived Ig alpha as a growth promoter of cancer cells, and reveal a novel molecular mechanism for growth and proliferation of cancer cells.