Combined therapy of CAR-IL-15/IL-15Rα-T cells and GLIPR1 knockdown in cancer cells enhanced anti-tumor effect against gastric cancer.

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has shown remarkable responses in hematological malignancies with several approved products, but not in solid tumors. Patients suffer from limited response and tumor relapse due to low efficacy of CAR-T cells in the complicated and immunosuppressive tumor microenvironment. This clinical challenge has called for better CAR designs and combined strategies to improve CAR-T cell therapy against tumor changes. METHODS: In this study, IL-15/IL-15Rα was inserted into the extracellular region of CAR targeting mesothelin. In-vitro cytotoxicity and cytokine production were detected by bioluminescence-based killing and ELISA respectively. In-vivo xenograft mice model was used to evaluate the anti-tumor effect of CAR-T cells. RNA-sequencing and online database analysis were used to identify new targets in residual gastric cancer cells after cytotoxicity assay. CAR-T cell functions were detected in vitro and in vivo after GLI Pathogenesis Related 1 (GLIPR1) knockdown in gastric cancer cells. Cell proliferation and migration of gastric cancer cells were detected by CCK-8 and scratch assay respectively after GLIPR1 were overexpressed or down-regulated. RESULTS: CAR-T cells constructed with IL-15/IL-15Rα (CAR-ss-T) showed significantly improved CAR-T cell expansion, cytokine production and cytotoxicity, and resulted in superior tumor control compared to conventional CAR-T cells in gastric cancer. GLIPR1 was up-regulated after CAR-T treatment and survival was decreased in gastric cancer patients with high GLIPR1 expression. Overexpression of GLIPR1 inhibited cytotoxicity of conventional CAR-T but not CAR-ss-T cells. CAR-T treatment combined with GLIPR1 knockdown increased anti-tumor efficacy in vitro and in vivo. CONCLUSIONS: Our data demonstrated for the first time that this CAR structure design combined with GLIPR1 knockdown in gastric cancer improved CAR-T cell-mediated anti-tumor response.

Electrochemical Benzylic C-H Amination via N-Aminopyridinium.

An electrochemical protocol for benzylic C(sp3)-H aminopyridylation via direct C-H/N-H cross-coupling of alkylarenes with N-aminopyridinium triflate has been developed. This method features excellent site-selectivity, broad substrate scope, redox reagent-free and facile scalability. The generated benzylaminopyridiniums can be readily converted to benzylamines via electroreductive N-N bond cleavage.

A Simple-Structured Perovskite Wavelength Sensor for Full-Color Imaging Application.

In this study, simple-structured wavelength sensors were developed by depositing two back-to-back Au/MAPbI3/Au photodetectors on an MAPbI3 single crystal. This sensor could quantitatively distinguish wavelengths. Further device analysis showed that both photodetectors possess entirely disparate optoelectronic properties. Consequently, the as-developed wavelength sensor could accurately distinguish incident-light wavelengths ranging from 265 to 860 nm with a resolution of less than 1.5 nm based on the relation between the photocurrent ratios of both photodetectors and the incident light wavelengths. Notably, a high resolution and wide detection range are among the optimum reported values for such sensors and enable full-color imaging. Furthermore, technology computer-aided design (TCAD) simulations showed that a mechanism involved in distinguishing wavelengths is attributed to the wavelength-dependent photon generation rate in MAPbI3 single crystals. The high-performance MAPbI3 wavelength sensor can potentially drive the research progress of perovskites in wavelength recognition and full-color imaging.

Asynchronous photonic time-delay reservoir computing.

Time-delay reservoir computing uses a nonlinear node associated with a feedback loop to construct a large number of virtual neurons in the neural network. The clock cycle of the computing network is usually synchronous with the delay time of the feedback loop, which substantially constrains the flexibility of hardware implementations. This work shows an asynchronous reservoir computing network based on a semiconductor laser with an optical feedback loop, where the clock cycle (20 ns) is considerably different to the delay time (77 ns). The performance of this asynchronous network is experimentally investigated under various operation conditions. It is proved that the asynchronous reservoir computing shows highly competitive performance on the prediction task of Santa Fe chaotic time series, in comparison with the synchronous counterparts.

Electrochemical chemoselective hydrogenation of 1,4-enediones with HFIP as the hydrogen donor: scalable access to 1,4-diketones.

A straightforward electrochemical protocol for efficient hydrogenation of unsaturated CC bonds has been reported in an undivided cell. A series of versatile 1,4-diketones are smoothly generated under metal-free and external-reductant-free electrolytic conditions. Moreover, the tolerance of various functional groups and decagram-scale experiments have shown the practicability and potential applications of this methodology. Moreover, a range of heterocyclic compounds were easily prepared through follow-up procedures of 1,4-diketones.

Non-Ultrawide Bandgap Semiconductor GaSe Nanobelts for Sensitive Deep Ultraviolet Light Photodetector Application.

In this paper, the authors report the fabrication of a sensitive deep ultraviolet (DUV) photodetector by using an individual GaSe nanobelt with a thickness of 52.1 nm, which presents the highest photoresponse at 265 nm illumination with a responsivity and photoconductive gain of about 663 A W-1 and 3103 at a 3 V bias, respectively, comparable to or even better than other reported devices based on conventional wide bandgap semiconductors. According to the simulation, this photoelectric property is associated with the wavelength-dependent absorption coefficient of the GaSe crystal, for which incident light with shorter wavelengths will be absorbed near the surface, while light with longer wavelengths will have a larger penetration depth, leading to a blueshift of the absorption edge with decreasing thickness. Further finite element method (FEM) simulation reveals that the relatively thin GaSe nanobelt exhibits an enhanced transversal standing wave pattern compared to its thicker counterpart at a wavelength of 265 nm, leading to an enhanced light-matter interaction and thereby more efficient photocurrent generation. The device can also function as an effective image sensor with acceptable spatial resolution. This work will shed light on the facile fabrication of a high-performance DUV photodetector from non-ultrawide bandgap semiconductors.

Clinical efficacy of gouty tea on chronic gouty arthritis and its effects on serum vascular endothelial function and inflammatory cytokines.

To observe the efficacy of Gouty Tea on chronic gouty arthritis and its effect on vascular endothelial function and inflammatory factor levels. Totally 120 patients with chronic gouty arthritis were divided into control group (allopurinol orally, 100 mg/time, tid, for 12 weeks) and observation group (Gouty Tea, 1 bag/time, tid, for 12 weeks) randomly (n=60 per group). Compared with those before treatment, the TCM symptom scores, visual analogue score (VAS) and the levels of UA and XOD of the two groups were reduced, while the levels of NO, ET-1, VEGF, vWF, CRP, IL-1ß, TNF- α and NALP3 of the two groups improved, 6 and 12 weeks after treatment (P< 0.05). Nevertheless, after 6 weeks of treatment, there were no significantly difference of the level of VAS between the two groups. After 12 weeks of treatment, in the observation group, VAS was significantly lower compared to the control group. The TCM symptom scores and the levels of UA and XOD were significantly lower, while the levels of NO, ET-1, VEGF, vWF, CRP, IL-1ß TNF- α and NALP3 were significantly better in the observation group than those of the control group 12 weeks after treatment (P< 0.05). The total effective rate was significantly higher and the incidence of adverse reactions was significantly lower in the observation group compared to the control group (P< 0.05). Gouty Tea can effectively reduce the UA, XOD levels and VAS, effectively improve the vascular endothelial function and inhibit the inflammation of patients.

Highly Sensitive Ultraviolet and Visible Wavelength Sensor Composed of Two Identical Perovskite Nanofilm Photodetectors.

This work reports the design of a wavelength sensor composed of two identical perovskite (FA0.85 Cs0.15 PbI3 ) photodetectors (PDs) that are capable of discriminating incident wavelength in a quantitative way. Due to strong wavelength-dependent absorption coefficient, the penetration depth of the photons in the FA0.85 Cs0.15 PbI3 nanofilms increases with the increasing wavelength, leading to a gradual decrease of photo-generated current for PD1, but an increase of photocurrent in PD2, according to the theoretical simulation of Technology Computer Aided Design. This special evolution of photo-generated current as a function of wavelength facilitates the quantitative determination of the wavelength since the current ratio of both PDs monotonously decreases with the increase of wavelength from 265 to 810 nm. The average absolute error and the average relative error are estimated to be 7.6 nm and 1.68%, respectively, which are much better than other semiconductors materials-based wavelength sensors previously reported. It is believed that the present perovskite film-based wavelength sensor will have potential application in the future color/spectrum optoelectronic devices.

Nickel-promoted oxidative domino Csp3-H/N-H bond double-isocyanide insertion reaction to construct pyrrolin-2-ones.

The first nickel-catalyzed oxidative domino Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional groups are compatible with this reaction system by utilizing Ni(acac)2 as a catalyst. In this transformation, isocyanide could serve as a C1 connector and insert into the inactive Csp3-H bond, representing an effective way to construct heterocycles.

Ultrathin Polymer Nanofibrils for Solar-Blind Deep Ultraviolet Light Photodetectors Application.

Solar-blind deep ultraviolet photodetectors (DUVPDs) based on conventional inorganic ultrawide bandgap semiconductors (UWBS) have shown promising application in various civil and military fields and yet they can hardly be used in wearable optoelectronic devices and systems for lack of mechanical flexibility. In this study, we report a non-UWBS solar-blind DUVPD by designing ultrathin polymer nanofibrils with a virtual ultrawide bandgap, which was obtained by grafting P3HT with PHA via a polymerization process. Optoelectronic analysis reveals that the P3HT-b-PHA nanofibrils are sensitive to DUV light with a wavelength of 254 nm but are virtually blind to both 365 nm and other visible light illuminations. The responsivity is 120 A/W with an external quantum efficiency of up to 49700%, implying a large photoconductive gain in the photoresponse process. The observed solar-blind DUV photoresponse is associated with the resonant mode due to the leakage mode of the ultrathin polymer nanofibrils. Moreover, a flexible image sensor composed of 10 × 10 pixels can also be fabricated to illustrate their capability for image sensing application. These results signify that the present ultrathin P3HT-b-PHA nanofibrils are promising building blocks for assembly of low-cost, flexible, and high-performance solar-blind DUVPDs.

Aqueous Extract of Whitmania Pigra Whitman Alleviates Thrombus Burden Via Sirtuin 1/NF-κB Pathway.

BACKGROUND: Whitmania pigra Whitman (W pigra), a traditional Chinese medicine, has functions of breaking stagnant and eliminating blood stasis. The aim of this study was to investigate the underlying mechanism of W pigra against deep vein thrombosis (DVT). METHODS: A rat model of DVT induced by inferior vena cava stenosis was successfully established. Rats were administered vehicle (saline solution, p.o.), three doses of W pigra aqueous extract (34.7, 104.2, or 312.5 mg crude W pigra/kg, p.o.), heparin (200 U/kg, i.v.), or clopidogrel (25 mg/kg, p.o.) once daily for 2 d. Thrombus weight and histopathological changes were examined. Blood samples were collected to determine blood cell counts, blood viscosity, blood coagulation, blood fibrinolysis, serum levels of interleukin-1ß, and tumor necrosis factor-α. Protein expressions of Sirtuin1 (SIRT1), acetylated p65 (Ace-p65), and phosphorylated p65 (p-p65) were determined by Western blot. Furthermore, SIRT1-specific inhibitor EX527 was applied to confirm the role of SIRT1 in the antithrombotic effect of W pigra. RESULTS: W pigra significantly decreased thrombus weight. W pigra had no effects on blood cell counts, whole blood viscosity, blood coagulation, blood fibrinolysis. However, it reduced tissue factor protein expression in the vein wall and thrombus. Moreover, it sharply increased SIRT1 protein expression and decreased leukocytes recruitment in the thrombus and vein wall, serum levels of interleukin-1ß and tumor necrosis factor-α, and protein expressions of Ace-p65 and p-p65. Furthermore, the antithrombotic effect of W pigra was significantly abolished by EX527. CONCLUSIONS: Aqueous extract of W pigra effectively reduced DVT burden by inhibiting inflammation via SIRT1/nuclear factor-kappa B signaling pathway.

Fast construction of isoquinolin-1(2H)-ones by direct intramolecular C-H/N-H functionalization under metal-free conditions.

The general protocol for the synthesis of isoxazolidine-fused isoquinolin-1(2H)-ones was established with the help of bench stable hypervalent iodine reagent PIDA. Polycyclic six-, seven- and eight-membered N-heterocycles can be rapidly synthesized from available amides under metal-free conditions within 1 min at room temperature through C-H/N-H functionalization. Moreover, the protocol has the merits of broad substrate scope, atom economy and operational simplicity.

The ruthenium(ii)-catalyzed C-H olefination of indoles with alkynes: the facile construction of tetrasubstituted alkenes under aqueous conditions.

An environmentally-friendly and facile protocol for the construction of tetrasubstituted alkenes has been established with Ru(ii)-catalyzed C-H bond functionalizations under mild conditions. The method features the usage of readily available substrates, without external oxidants and additives, 100% atom economy, and excellent regioselectivity, thus enhancing the practicability of this protocol. Moreover, this transformation proceeded smoothly under aqueous conditions and could be extended to the gram scale. N-Methoxyamide, as a directing group (DG), played a vital role in the transformation.

Identification of FerLCH, isolation of ferritin and functional analysis related to interaction with pathogens in Eri-silkworm, Samia cynthia ricini.

Ferritin is a ubiquitous and conserved iron storage protein that plays a significant role in host detoxification, iron storage, and immune response. Although ferritin has been studied in many species, little is known about its role in the Eri-silkworm (Samia cynthia ricini). In this study, the ferritin light-chain subunit gene, named ScFerLCH, was identified from S. c. ricini. The full-length gene, ScFerLCH, was 1,155 bp and encoded a protein consisting of 231 amino acids with a deduced molecular weight of 26.38 kDa. Higher ScFerLCH expression levels were found in the midgut, silk gland, and fat body by quantitative reverse-transcription polymerase chain reaction and western blot analysis. Injection of Staphylococcus aureus and Pseudomonas aeruginosa could induce upregulation of ScFerLCH in the hemolymph, fat body, and midgut, indicating that ScFerLCH may contribute to the host defense against invading pathogens. In addition, the native ferritin protein was isolated from S. c. ricini by native polyacrylamide gel electrophoresis and its two subunits, ferritin heavy-chain subunit (ScFerHCH) and ferritin light-chain subunit (ScFerLCH), were identified by mass spectrometry. Specifically, we found that recombinant ferritin subunits could self-assemble into a protein complex in vitro; moreover, both recombinant subunits and the protein complex were found to bind different bacteria, including Escherichia coli, P. aeruginosa, S. aureus, and Bacillus subtilis. However, bactericidal tests showed that the protein complex could not inhibit the growth of bacteria directly. Taken together, our results suggest that ScFerritin might play an important role in mediating molecular interaction with pathogens.

Purification and antioxidant capacity analysis of anthocyanin glucoside cinnamic ester isomers from Solanum nigrum fruits.

In a recent study, anthocyanins, which have a strong free radical-scavenging activity, were examined for their potential to effectively prevent cancer. However, clinical trials are limited by the purity of the anthocyanin. Multiple methods are used to extract and purify anthocyanins. Based on previous work on Solanum nigrum, which is a widely distributed plant, in this study, DM130 macroporous resin, Sephadex LH20, and a C18 column were used to separate cis-trans anthocyanin isomers. These anthocyanins constitute the majority of total S. nigrum anthocyanins. The results showed that this "DM130-LH20-C18 system" can be used to obtain a cinnamic acid-derived cis-trans anthocyanin, petunidin-3-(p-coumaroyl)-rutinoside-5-glucoside, with a purity of 98.5%, for effective quantitation. In order to determine the antioxidant ability of the petunidin-3-(p-coumaroyl)-rutinoside-5-glucoside cis-trans isomers, three ordinary methods were adopted. The maximum antioxidant ability of the cis-trans anthocyanin was dozens of times higher than that of vitamin C.

DNA Methylation Is Correlated with Gene Expression during Diapause Termination of Early Embryonic Development in the Silkworm (Bombyx mori).

DNA modification is a naturally occurring DNA modification in prokaryotic and eukaryotic organisms and is involved in several biological processes. Although genome-wide methylation has been studied in many insects, the understanding of global and genomic DNA methylation during insect early embryonic development, is lacking especially for insect diapause. In this study, we analyzed the relationship between DNA methylomes and transcriptomes in diapause-destined eggs compared to diapause-terminated eggs in the silkworm, Bombyx mori (B. mori). The results revealed that methylation was sparse in this species, as previously reported. Moreover, methylation levels in diapause-terminated eggs (HCl-treated) were 0.05% higher than in non-treated eggs, mainly due to the contribution of CG methylation sites. Methylation tends to occur in the coding sequences and promoter regions, especially at transcription initiation sites and short interspersed elements. Additionally, 364 methylome- and transcriptome-associated genes were identified, which showed significant differences in methylation and expression levels in diapause-destined eggs when compared with diapause-terminated eggs, and 74% of methylome and transcriptome associated genes showed both hypermethylation and elevated expression. Most importantly, Kyoto Encyclopaedia of Genes and Genomes (KEGG) analyses showed that methylation may be positively associated with Bombyx mori embryonic development, by regulating cell differentiation, metabolism, apoptosis pathways and phosphorylation. Through analyzing the G2/M phase-specific E3 ubiquitin-protein ligase (G2E3), we speculate that methylation may affect embryo diapause by regulating the cell cycle in Bombyx mori. These findings will help unravel potential linkages between DNA methylation and gene expression during early insect embryonic development and insect diapause.

Interpenetrating Liquid-Crystal Polyurethane/Polyacrylate Elastomer with Ultrastrong Mechanical Property.

Liquid-crystal elastomer (LCE) materials, which have been developed and investigated for 4 decades, still lack real industrial applications. The fundamental obstacle is the modest force of LCEs generated in the LC-to-isotropic phase transition process, which is the most important actuation moment. Here, we report an interpenetrating liquid-crystal polyurethane/polyacrylate elastomer material, consisting of one main-chain polyurethane LCE and another liquid-crystal polyacrylate thermoset network, which are simultaneously polymerized. This two-way shape memory material can reversibly shrink/expand under thermal stimulus and show ultrastrong actuation-mechanics properties. With a maximum shrinkage ratio of 86% at 140 °C, which is beyond the LC-to-isotropic phase transition, its actuation blocking stress, actuation work capacity, breaking strength, and elastic modulus reach 2.53 MPa, 1267.7 kJ/m3, 7.9 MPa, and 10.4 MPa, respectively. Such LCE material can lift up a load 30 000 times heavier than its own weight. We hope the outstanding mechanical properties of this interpenetrating polymer network-LCE material would pave the way for real industrial utilizations of LCE-based soft actuators.

Graphene-Assisted Growth of Patterned Perovskite Films for Sensitive Light Detector and Optical Image Sensor Application.

Controlled growth of high-quality patterned perovskite films on a large scale is essentially required for the application of this class of materials in functional integrated devices and systems. Herein, graphene-assisted hydrophilic-hydrophobic surface-induced growth of Cs-doped FAPbI3 perovskite films with well-patterned shapes by a one-step spin-coating process is developed. Such a facile fabrication technique is compatible with a range of spin-coated perovskite materials, perovskite manufacturing processes, and substrates. By employing this growing method, controllable perovskite photodetector arrays are realized, which have not only prominent photoresponse properties with a responsivity and specific detectivity of 4.8 AW-1 and 4.2 × 1012 Jones, respectively, but also relatively small pixel-to-pixel variation. Moreover, the photodetectors array can function as an effective visible light image sensor with a decent spatial resolution. Holding the above merits, the proposed technique provides a convenient and effective pathway for large-scale preparation of patterned perovskite films for multifunctional application purposes.

Light Confinement Effect Induced Highly Sensitive, Self-Driven Near-Infrared Photodetector and Image Sensor Based on Multilayer PdSe2 /Pyramid Si Heterojunction.

In this study, a highly sensitive and self-driven near-infrared (NIR) light photodetector based on PdSe2 /pyramid Si heterojunction arrays, which are fabricated through simple selenization of predeposited Pd nanofilm on black Si, is demonstrated. The as-fabricated hybrid device exhibits excellent photoresponse performance in terms of a large on/off ratio of 1.6 × 105 , a responsivity of 456 mA W-1 , and a high specific detectivity of up to 9.97 × 1013 Jones under 980 nm illumination at zero bias. Such a relatively high sensitivity can be ascribed to the light trapping effect of the pyramid microstructure, which is confirmed by numerical modeling based on finite-difference time domain. On the other hand, thanks to the broad optical absorption properties of PdSe2 , the as-fabricated device also exhibits obvious sensitivity to other NIR illuminations with wavelengths of 1300, 1550, and 1650 nm, which is beyond the photoresponse range of Si-based devices. It is also found that the PdSe2 /pyramid Si heterojunction device can also function as an NIR light sensor, which can readily record both "tree" and "house" images produced by 980 and 1300 nm illumination, respectively.

N-Phenoxyamides as Multitasking Reagents: Base-Controlled Selective Construction of Benzofurans or Dihydrobenzofuro[2,3- d]oxazoles.

An efficient method to selectively construct benzofuran and dihydrobenzofuro[2,3- d]oxazole derivatives has been successfully established by means of base-controlled cyclization of N-phenoxyamides with 1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1 H)-one (TIPS-EBX). N-phenoxyamides as multitasking reagents have triggered two different cascade reaction sequences. This is the first example of using TIPS-EBX for the transformation of C(sp) to either C(sp2) or C(sp3) under metal-free conditions.