The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response.

The induction of type I interferons by the bacterial secondary messengers cyclic di-GMP (c-di-GMP) or cyclic di-AMP (c-di-AMP) is dependent on a signaling axis that involves the adaptor STING, the kinase TBK1 and the transcription factor IRF3. Here we identified the heliase DDX41 as a pattern-recognition receptor (PRR) that sensed both c-di-GMP and c-di-AMP. DDX41 specifically and directly interacted with c-di-GMP. Knockdown of DDX41 via short hairpin RNA in mouse or human cells inhibited the induction of genes encoding molecules involved in the innate immune response and resulted in defective activation of STING, TBK1 and IRF3 in response to c-di-GMP or c-di-AMP. Our results suggest a mechanism whereby c-di-GMP and c-di-AMP are detected by DDX41, which forms a complex with STING to signal to TBK1-IRF3 and activate the interferon response.

A novel quinoline-based fluorescent probe for real-time monitoring of Cys in glioma.

Cysteine (Cys), a small-molecule biothiol, has recently been identified as a novel Glioblastoma (GBM) biomarker. The highly selective real-time monitoring and fluorescence imaging of Cys levels in vivo is of great significance for the early diagnosis and treatment of GBM. In this work, we reported a highly selective Cys fluorescent probe ZS-C1, based on quinoline according to the mechanism of the conjugate addition cyclization reaction. The Limit of Detection (LOD) of probe ZS-C1 was 1.97 µM, λex = 380 nm; λem = 531 nm. In vitro experiments showed that ZS-C1 could be distinguished from Hcy and GSH significantly, and the fluorescence quantum yield was reduced by 30 times. Further, biological imaging and 3D tumor sphere penetration assay showed that the ZS-C1 could monitor both exogenous and endogenous Cys in the living U87MG cells, and the fluorescence of probe ZS-C1 diffusely distributed inside the U87MG three-dimensional solid cell spheroid (up to 60 µM deep into the solid tumors). This work provided a potential tool for further investigations of Cys in biological samples and critical information for early diagnosis of glioma and guidance for clinical surgery.

Exploring optical resonances of nanoparticles excited by optical Skyrmion lattices.

Recently, optical Skyrmion lattices (OSLs) have been realized in evanescent electromagnetic fields. OSLs possess topologically stable field configurations, which promise many optics and photonics applications. Here, we demonstrate that OSLs can serve as versatile structured optical near-fields to assist with studies of a variety of photonic modes in nanoparticles. We firstly show that OSL is capable of selectively exciting electric and magnetic multipole modes by placing a nanoparticle at different positions in the lattice. We then disclose that OSLs can efficiently excite some intriguing resonant modes, including toroidal and plasmonic dark modes, in dielectric or metal nanoparticles. Our results may enhance understanding of the interaction between OSLs and nanoparticles and find applications associated with precise control over resonant modes in nanostructures.

[Study on regularity of Tibetan medicine in treatment of gZav-Grib disease (apoplexy sequelae) based on HIS clinical medical records].

This research is launched to look for the medication rules and characteristics of Tibetan medicine in the treatment of gZav-Grib( apoplexy sequelae). HIS records of gZav-Grib patients were selected from the Tibetan Hospital of Tibet Autonomous Region and Tibetan Hospital of the city of Naqu. SPSS Modeler,Gephi and other data mining and visualization software were used to study the actual law of drug use in the treatment of gZav-Grib in Tibetan medicine. Finally,479 cases of gZav-Grib patients in Tibetan medicine were included. Their average age is 63 and average hospital stay was 32 days. In total,82 Tibetan medicine prescriptions were used for treating gZav-Grib. The frequency in the front is Twenty-flavor Chenxiang Pills( 338 times),Ruyi Zhenbao Pills( 322 times),and Seventy-flavor Zhenzhu Pills( 315 times). According to the regularity of Tebitan medicine,they were applied in different time periods including the early morning,morning,noon,and evening,for example,in the early morning: Seventy-flavor Zhenzhu Pills,morning: Ruyi Zhenbao Pills,noon: Eighteen-flavor Dujuan Pills,evening: Twenty-flavor Chenxiang Pills. In the clinical joint,18 groups were found in the 10% support and 70% confidence. There are two prescriptions confidence more than 80% which nature focus on Gan,Ruan,Xi,Liang,Dun,Han,Wen. gZav-Grib of Tibetan medicine can be divided into two types: r Lung-Grib type and k Hrag-Grib type,in which the medicine of r Lung-Grib type takes Seventy-flavor Zhenzhu Pills as the core prescription,while the medicine of k Hrag-Grib type takes Ruyi Zhenbao Pills as the core prescription. It is found that the treatment of gZav-Grib by Tibetan medicine is mainly dominated by the treatment idea about " Therapeutic r Lung and blood,Consideration of venous diseases". Treatment functions is promoting the circulation of Qi,clearing blood heat and getting rid of bad blood,achieving the purpose of treating both principal secondary aspect of gZav-Grib. The research methods based on the HIS can't only optimize the Tibetan treating gZav-Grib sequela treatment plan and rule of medication,but also provide the scientific basis for Tibetan medicine treat gZav-Grib.

Dual-band unidirectional forward scattering with all-dielectric hollow nanodisk in the visible.

High-index dielectric nanoantennas have become an emerging branch of optical nanoantennas, essentially due to their low loss. These types of nanoantennas can achieve both forward and backward unidirectional scattering, enabled by electric dipole and magnetic dipole interaction. Here, we show that the scattering directionality can be further enhanced if higher-order moments are properly balanced and reach the generalized Kerker condition at two different wavelengths in an all-dielectric hollow nanodisk. Moreover, putting the nanodisks in an array of transverse configuration can enhance the unidirectionality to be needle-like, with the main lobe angular beam width α<15°. Finally, we show that such unidirectional radiation properties can be maintained for a local electric dipole source.

Unidirectional excitation of plasmonic waves via a multilayered metal-dielectric-metal Huygens' nanoantenna.

Huygens' nanoantennas maintain orthogonal electric and magnetic dipole resonances satisfying the Kerker condition and can generate directional radiation in both the near-field and far-field regimes. Here we study a multilayered metal-dielectric-metal (MDM) Huygens' type nanoantenna which is capable of launching surface plasmon polaritons (SPPs) unidirectionally when excited by a dipole source. We show that the radiative decay rates of the dipole source are strongly enhanced by the antenna, and the generated SPP waves propagate in opposite directions at two different wavelengths. The directionality of the excited SPPs can be switched by changing the geometry and the material composition. We further demonstrated that the beam width of the SPP waves can be narrowed by arranging the MDM antennas in a chain.

[Analysis on medication regularity and action mechanism of Tibetan medicine in treatment of spleen and stomach diseases based on data mining and integrated pharmacology].

To explore the medication regularity of Tibetan medicine in the treatment of spleen and stomach diseases, analyze the potential drug targets and interactions of the prescriptions, and reveal the mechanism of Tibetan medicine in the treatment of spleen and stomach diseases. The prescriptions in Tibetan medicine for treatment of spleen and stomach diseases were collected, and Traditional Chinese Medicine Inheritance Support System (TCMISS) was used to analyze the association rules between the herbs and discover the core herbs and new prescriptions. The integrated pharmacology platform V1.0 software was used to construct "herb-compound-target" network and investigate the interactions between various herbs and related pathways of Tibetan medicine Wuwei Shiliu powder in the treatment of spleen and stomach diseases. Among the 216 prescriptions of Tibetan medicine in the treatment of spleen and stomach diseases, pomegranate seed was used at a highest frequency (118 times), followed by white cardamom (107 times) and comatose (107 times). 12 new prescriptions were evolved by using the association rules (support>=34%, confidence>=0.85). 5 242 related drug targets and 20 related pathways were obtained from classic formula Wuwei Shiliu Powder (FDR<0.01). It was proposed that Tibetan medicine treatment for spleen and stomach diseases was mainly based on proliferation of "stomach fire" and the main drugs were for regulating Qi-flowing for strengthening spleen. The mechanism may be associated with regulation of digestive juice secretion, proton pump, mitochondria, regulation of intestinal digestion and immunity, the body's immunity to microorganisms function and other multiple targets and pathways to achieve the joint intervention.

Protein binding for detection of small changes on a nanoparticle surface.

Protein adsorption on nanoparticles is closely associated with the physicochemical properties of particles, in particular, their surface properties. We synthesized two batches of polyacrylic acid-coated nanoparticles under almost identical conditions except for the heating duration and found differences in the head-group structure of the polyacrylic acid. The structure change was confirmed by NMR and MS. The two batches of particles had varied binding affinities to a selected group of proteins. Computational work confirmed that the head group of the polymer on the surface of a nanoparticle could directly interact with a protein, and small structural changes in the head group were sufficient to result in a significant difference in the free energy of binding. Our results demonstrate that protein adsorption is so sensitive to the surface properties of particles that it can reveal even small variations in the structure of a nanoparticle surface ligand, and should be useful for quick assessment of nanoparticle properties.

Conventional and novel [18F]FDG PET/CT features as predictors of CAR-T cell therapy outcome in large B-cell lymphoma.

Relapse and toxicity limit the effectiveness of chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL), yet biomarkers that predict outcomes and toxicity are lacking. We examined radiomic features extracted from pre-CAR-T 18F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scans (n = 341) of 180 patients (121 male; median age, 66 years). Three conventional (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG]) and 116 novel radiomic features were assessed, along with inflammatory markers, toxicities, and outcomes. At both pre-apheresis and pre-infusion time points, conventional PET features of disease correlated with elevated inflammatory markers. At pre-infusion, MTV was associated with grade ≥ 2 cytokine release syndrome (odds ratio [OR] for 100 mL increase: 1.08 [95% confidence interval (CI), 1.01-1.20], P = 0.031), and SUVmax was associated with failure to achieve complete response (CR) (OR 1.72 [95% CI, 1.24-2.43], P < 0.001). Higher pre-apheresis and pre-infusion MTV values were associated with shorter progression-free survival (PFS) (HR for 10-unit increase: 1.11 [95% CI, 1.05-1.17], P < 0.001; 1.04 [95% CI, 1.02-1.07], P < 0.001) and shorter overall survival (HR for 100-unit increase: 1.14 [95% CI, 1.07-1.21], P < 0.001; 1.04 [95% CI, 1.02-1.06], P < 0.001). A combined MTV and LDH measure stratified patients into high and low PFS risk groups. Multiple pre-infusion novel radiomic features were associated with CR. These quantitative conventional [18F]FDG PET/CT features obtained before CAR-T cell infusion, which were correlated with inflammation markers, may provide prognostic biomarkers for CAR-T therapy efficacy and toxicity. The use of conventional and novel radiomic features may thus help identify high-risk patients for earlier interventions.

Processing methods and the underlying detoxification mechanisms for toxic medicinal materials used by ethnic minorities in China: A review.

ETHNOPHARMACOLOGICAL RELEVANCE: Various toxic medicinal materials have been used by different ethnic minorities in China for thousands of years because of their extraordinary pharmacological activities. However, the improper use and complex toxicity-efficacy relationship could cause poisoning and even death. Therefore, the study of toxicity-attenuating methods and mechanisms is necessary. AIM OF THE STUDY: This review aims to summarize commonly used toxic ethnomedicines and their processing methods as well as the underlying mechanisms to potentially reduce toxicity and even enhance or preserve efficacy. Prospective for possible future investigations is also discussed. MATERIALS AND METHODS: Processing methods and mechanisms are investigated mainly through literature review. RESULTS: Processing methods with heating (boiling, stir frying, and steaming, etc.) and without heating (soaking) are usually used by Chinese ethnic minorities to attenuate the toxicity of ethnomedicines. Wheat bran, vinegar, wine, and herbal decoction are commonly used processing excipients. The mechanisms of detoxification by processing can be briefly summarized into three major categories: (1) direct elimination of impurities or reduction of toxic constituents' contents of ethnomedicines by cutting, washing, soaking or frosting; (2) chemical structure transformation of toxic constituents, such as alkaloids, glycosides, toxic proteins, animal toxicants, and mineral components, during heating and/or soaking; and (3) biological synergism or antagonism effects between the chemical constituents of processing excipients and ethnomedicines in vivo, to reduce toxicity and protect target organs. CONCLUSION: Toxic ethnomedicines have long been used in China, and detoxification by processing is the prerequisite for their safe clinical application. However, understanding on the special processing methods and detoxification mechanisms of ethnomedicines in China remains insufficient. Investigations on quality control of toxic ethnomedicines, as well as evaluation of processing methods and studies of the corresponding mechanisms should be further strengthened for safe and effective clinical application.

Detection of femtomolar proteins by nonfluorescent ZnS nanocrystal clusters.

Cation exchange (CX) in the nonfluorescent ZnS nanocrystal clusters (NCCs) was employed to detect trace biomolecules with immunoassays. The NCCs were porous and allowed fast cation exchange reaction to release an ultralarge number of Zn(2+) from each cluster that turned on the Zn-responsive dyes for fluorescence detection. The ZnS NCCs were highly stable in biological buffers and more biocompatible than quantum dots. Zn(2+) release efficiency and target binding by NCCs with average diameters of 44 nm, 86 nm, and 144 nm were investigated. The smallest NCCs exhibited the highest CX efficiency because of its larger surface area and bigger pores inside the cluster structure, and 71.0% of the enclosed Zn(2+) were freed by CX with 2-min microwave irradiation. They also experienced the least space hindrance and the fastest rate when binding to target molecules immobilized on surface. When the 44-nm NCCs were used to detect IgE in a sandwich assay, the limit of detection (LOD) was 5 pg/mL (33 fM), 1,000 times better than that of ELISA. Our results well demonstrate that CX in the ZnS NCCs is superior to the conventional signaling strategies in its high amplification efficiency, robustness, and biocompatibility.

Exploration of possible binding sites of nanoparticles on protein by cross-linking chemistry coupled with mass spectrometry.

For the first time, the possible binding site of nanoparticles on protein was revealed by cross-linking chemistry coupled with mass spectrometry. The peptides located very close to the poly(acrylic acid) (PAA)-coated Fe(3)O(4) nanoparticles (NPs) during interaction with human serum albumin (HSA) were cross-linked to the surface of NPs. Following protease digestion, the attached peptides were cleaved off the particle surface and identified by matrix-assisted laser desorption/ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS). The peptides were found to be part of the so-called drug binding site 2 of HSA; and the competitive binding to HSA between the corresponding drug, ibuprofen, and the NPs was observed. Our results demonstrated that cross-linking chemistry coupled with MS was a quick and simple method for locating the possible binding sites of NPs on protein. Information on NP-protein binding interface will benefit the study of how the interactions are governed by the physicochemical properties of NPs, for guiding the design of functional bionano constructs. It can also help to predict the biological consequence of protein adsorption on NPs, for obtaining more knowledge on nanotoxicity.

A new fluorescently labeled bisphosphonate for theranostics in tumor bone metastasis.

Bone metastasis of malignant solid tumors has become one of the most serious complications, especially in breast cancer, which was particularly challenging for early detection and treatment in clinical practice. In this work, we reported a new fluorescently labeled bisphosphonate for bone metastasis detection of breast cancer. The designed probes were based on Rhodamine B and bisphosphonate as recognition group, which can specifically target hydroxyapatite (HA) existed in bone tissue. After the osteoclasts were adsorbed on the bone surface, the surrounding microenvironment was acidified, causing the HA to locally dissolve. The probe bound to the HA was then released, and realized the fluorescence turn on under acidic conditions. In vitro experiments showed that G0 was more excellent than G2 owing to shorter connecting arm. Subsequently, we proved that G0 could combine with HA rapidly and exhibit excellent response in solid state. More importantly, we established a model of bone metastasis with MDA-MB-231 cells which was similar to the clinical cases and evaluated the theranostics value of G0 prospectively, which provide the potential application prospect in clinical.

Glutathione-responsive prodrug conjugates for image-guided combination in cancer therapy.

Theranostic prodrug was highly desirable for precise diagnosis and anti-cancer therapy to decrease side effects. However, it is difficult to conjugate chemo-drug and molecular probe for combined therapy due to the complex pharmacokinetics of different molecules. Here, a novel anticancer theranostic prodrug (BTMP-SS-PTX) had been designed and synthesized by conjugating paclitaxel (PTX) with 2-(benzo[d]thiazol-2-yl)-4-methoxyphenol (BTMP) through a disulphide (-S-S-) linkage, which was redox-sensitive to the high concentration of glutathione in tumors. Upon activation with glutathione in weakly acid media, the BTMP-SS-PTX can be dissociated to release free PTX and visible BTMP, which realized the visual tracking of free drug. The cytotoxicity study demonstrated that soluble prodrug BTMP-SS-PTX displayed more outstanding anticancer activity in HepG2, MCF-7 and HeLa cells, lower toxicity to non-cancer cells (293 T) than free drugs. Furthermore, BTMP-SS-PTX was still able to induce apoptosis of HeLa cells and significantly inhibited tumor growth in HeLa-xenograft mouse model. On the basis of these findings, BTMP-SS-PTX could play a potential role in cancer diagnosis and therapy.

Probing nanoparticle--protein interaction by capillary electrophoresis.

Understanding nanoparticle-protein interaction could help in promoting applications of nanoparticles in the biomedical fields and reducing/preventing possible adverse effects to the biological systems caused by nanoparticles. Quantitative measurement of the biophysical parameters of nanoparticle-protein interaction will improve such understanding, which could be conveniently performed by capillary electrophoresis (CE) as demonstrated in the present study. Two interaction situations were identified. Stable nanoparticle-protein complexes were resolved from the free nanoparticles and the proteins by capillary zone electrophoresis (CZE). Transient complexes with fast association/dissociation rates showed distinct mobility change from the free nanoparticles in affinity capillary electrophoresis (ACE). Interactions of bovine serum albumin (BSA) with the Fe(3)O(4) nanoparticles (average diameters of 8 and 10 nm) and with the Au nanoparticles (average diameters of 5 and 10 nm) displayed slow and fast binding kinetics, respectively. Using the Hill equation, we could calculate the dissociation constants (K(D)) and cooperativity coefficients (n). Impacts on nanoparticle-protein interaction from the physicochemical properties of nanoparticles and the incubation buffer were evaluated on the basis of the K(D) and n values to interpret the interaction driving forces. Our study demonstrated the high simplicity and flexibility of CE in probing the interaction of proteins with diverse particles. The separation power of CE should also facilitate studies of the multicomponent interaction systems for investigating how adsorption onto nanoparticles could affect the protein-protein or protein-small molecule interactions.

Norovirus gastroenteritis in young children receiving human rotavirus vaccine.

We explored whether human rotavirus vaccine had any efficacy against norovirus (NV)-associated gastroenteritis in young children. In an efficacy trial of rotavirus vaccine, 405 infants were immunized with a human rotavirus vaccine or placebo at a ratio of 2:1, and prospectively followed for acute gastroenteritis (AGE) from approximately 2 months to 2 y of age. Multiplex real-time reverse transcription polymerase chain reaction (Mrt RT-PCR) assays were used for detection and quantitation of NVs of genogroup I (GI) and genogroup II (GII) in stool specimens. NVs were detected in 155 (32%) of 485 episodes of AGE. Of these, NV was the only gastroenteritis virus detected in the stools in 142 (29%) episodes. GI and GII NVs were found in 12% and 88% of the cases, respectively. NV as the only gastroenteritis virus was detected in 36% of the infants in the rotavirus vaccine group and 27% in the placebo group. The clinical severity of NV-associated AGE in the vaccine and placebo recipients was not different. NVs were the most common etiologic agents of AGE in children under 2 y of age. Human rotavirus vaccine did not protect against NV gastroenteritis.

[Corrigendum] Hypoxia­induced internalization of connexin 26 and connexin 43 in pulmonary epithelial cells is involved in the occurrence of non­small cell lung cancer via the P53/MDM2 signaling pathway.

Following the publication of this article, the authors have realized that the corrsesponding author's name was printed incorrectly in the journal: This was mispelled as "Jin Zhou". The corrected name (Jing Zhou) is printed above. The authors regret any inconvenience this has caused, and thank the Editor for allowing them the opportunity to publish a Corrigendum.[the original article was published in International Journal of Oncology 55: 845­859, 2019; DOI: 10.3892/ijo.2019.4867].

Hypoxia­induced internalization of connexin 26 and connexin 43 in pulmonary epithelial cells is involved in the occurrence of non­small cell lung cancer via the P53/MDM2 signaling pathway.

Reports have highlighted an association between connexins (CXs) or gap junction proteins and non­small cell lung cancer (NSCLC). In the present study, it was aimed to elucidate the regulatory mechanism of CX26 and CX43 under hypoxic conditions in NSCLC. Clinical samples were collected for analysis of CX26 and CX43 expression and clinical cancerization followed by quantification of CX26 and CX43 expression. Following the establishment of an in vitro hypoxia model, P53/murine double minute­2 (MDM2) signaling pathway­, proliferation­ and epithelial­mesenchymal transition (EMT)­related genes were quantified to evaluate the influence of CX26 and CX43 on the biological functions of pulmonary epithelial cells in NSCLC. In addition, the proliferation and tumorigenicity of cancer cells were assessed by EdU staining and xenograft tumors, respectively. Decreased expression of CX26 and CX43 was found in cancer tissues compared with surrounding normal tissue. Hypoxia was shown to activate the P53/MDM2 axis and stimulate the downregulation, ubiquitination and degradation of CX26 and CX43, which were translocated from the membrane to the cytoplasm. Low levels of CX26 and CX43 were demonstrated to further promote EMT and the induction of the proliferation and tumorigenicity of cancer cells. These results were reflected by decreased E­cadherin expression and increased N­cadherin expression, along with increased cell migration, promoted cell proliferation ability and elevated relative protein expression of Oct4 and Nanog, and accelerated tumor growth, accompanied by a higher number of metastatic nodes. Taken together, the key observations of the present study demonstrate that the internalization of CX26 and CX43 promoted proliferation, EMT and migration and thus induced NSCLC via aberrant activation of the P53/MDM2 signaling pathway under hypoxic conditions.

MicroRNA-497-5p negatively regulates the proliferation and cisplatin resistance of non-small cell lung cancer cells by targeting YAP1 and TEAD1.

BACKGROUND: MicroRNAs (miRNAs) are crucial regulators in the pathological processes and drug resistance of lung cancer. In this study, we investigated the role of miR-497-5p in modulating the function of non-small cell lung cancer (NSCLC). METHODS: MiR-497-5p expression in lung cancer tissues and cells was evaluated by qRT-PCR. Cell proliferation was evaluated by CCK-8 assay and colony-formation assay. Cell cycle and cell apoptosis were detected by flow cytometry. The effect of miR-497-5p on the expression of Yes-associated protein 1 (YAP1) and TEA domain family member 1 (TEAD1) was analyzed by qRT-PCR, Western blot and luciferase activity assay. RESULTS: The expression of miR-497-5p was significantly downregulated in lung cancer tissues and cells compared with paired normal tissues and cells. Overexpression of miR-497-5p induced growth retardation and apoptosis of A549 lung cancer cells. Mechanistically, YAP1 and TEAD1 were targeted and downregulated by miR-497-5p. Finally, we found that miR-497-5p increased cisplatin chemosensitivity in A549 cells. CONCLUSIONS: MiR-497-5p suppresses cell proliferation and resistance to cisplatin in NSCLC by downregulating the expression of YAP1 and TEAD1.

Estrogen Receptor α (ERα)-targeting Compounds and Derivatives: Recent Advances in Structural Modification and Bioactivity.

Breast cancer is the most common cancer suffered by female, and the second highest cause of cancer-related death among women worldwide. At present, hormone therapy is still the main treatment route and can be divided into three main categories: selective estrogen receptor modulators (SERMs), selective estrogen receptor downregulators (SERDs), and aromatase inhibitors (AIs). However, breast cancer is difficult to cure even after several rounds of anti-estrogen therapy and most drugs have serious side-effects. Here, we review the literature published over the past five years regarding the isolation and synthesis of analogs and their derivatives.