Textural Precursor Compositions Harvested for Independent Signal Generators: Scaling Micron-Sized Flower-Like Metal-Organic Frameworks as Amplifying Units for Dual-Mode Glycoprotein Assay.

In this work, a micron-sized flower-like metal-organic frameworks (MOFs)-based boronate-affinity sandwich-type immunoassay was fabricated for the dual-mode glycoprotein assay. For proof of concept, the flower-like MOFs were synthesized from transition Cu nodes and tetrakis (4-carboxyphenyl) porphyrin (TCPP) ligands by spontaneous standing assembly. In addition, the specificity toward glycoprotein involved the antigen recognition as well as covalent bonding via the boronate-glycan affinity, and the immediate signal responses were initiated by textural decomposition of the flower-like MOFs. Intriguingly, Cu nodes, of which the valence state is dominant by CuI species, can endow the Fenton-like catalytic reaction of the fluorogenic substrate for generating fluorescence signals. For benefits, TCPP ligands, in which each TCPP molecule has four guest donors, can provide multiple valences for the assembly of cyclodextrin-capped gold nanoparticles via host-guest interaction for colorimetry output. Albeit important, the scaling micrometer patterns for the flower-like MOFs carrying numerous Cu nodes and TCPP ligands can also function as amplifying units, signifying the output signal. The detection limit of the dual-mode glycoprotein assay can reach 10.5 nM for the fluorescence mode and 18.7 nM for the colorimetry mode, respectively. Furthermore, the merits of harvesting different signal generators toward the multimodal readout patterns can allow the mutual verification and make the analytical results more reliable. Collectively, our proposed assay may offer a new idea in combining the inherent textural merits from MOFs for dual signal generators, which can also emphasize accurate detection capability for glycoprotein assay.

A self-calibrating ratiometric fluorescence sensor with photonic crystal-based signal amplification for the detection of tetracycline in food.

A dual-color ratiometric fluorescence sensor based on photonic crystals (PCs) was developed to detect tetracycline (TC) in food. PC was fabricated via self-assembly of carbon dots (CDs)-loaded SiO2 nanoparticles. Gold nanoclusters (AuNCs) and copper ions (Cu2+) were then adsorbed onto the PC for sensor fabrication. The fluorescence of AuNCs was amplified by the PC with an enhancement ratio of 7.6, providing higher sensitivity. The fluorescence of AuNCs was quenched by Cu2+, whereas that of CDs remained unchanged as an internal reference. TC restored the fluorescence of AuNCs owing to its complexation with Cu2+, resulting in a change in the fluorescence intensity ratio. The sensor exhibited a good linear relationship with TC concentrations ranging from 0.1 to 10 µM, with a detection limit of 34 nM. Furthermore, the sensor was applied for TC detection in food with satisfactory recoveries and relative standard deviations, revealing great potential in practical application.

The allostery and modification of hGHRH molecules and specific dimer produced significant fertility effect by proliferating and activating in-situ ovarian mesenchymal stem cells.

The negative coordination of growth hormone secretagogue receptor (GHS-R) and growth hormone-releasing hormone receptor (GHRH-R) involves in the repair processes of cellular injury. The allosteric U- or H-like modified GHRH dimer Grinodin and 2Y were comparatively evaluated in normal Kunming mice and hamster infertility models induced by CPA treatment. 1-3-9 µg of Grinodin or 2Y per hamster stem-cell-exhaustion model was subcutaneously administered once a week, respectively inducing 75-69-46 or 45-13-50 % of birth rates. In comparison, the similar mole of human menopausal gonadotropin (hMG) or human growth hormone (hGH) was administered once a day but caused just 25 or 20 % of birth rates. Grinodin induced more big ovarian follicles and corpora lutea than 2Y, hMG, hGH. The hMG-treated group was observed many distorted interstitial cells and more connective tissues and the hGH-treated group had few ovarian follicles. 2Y had a plasma lifetime of 21 days and higher GH release in mice, inducing lower birth rate and stronger individual specificity in reproduction as well as only promoting the proliferation of mesenchymal-stem-cells (MSCs) in the models. In comparison, Grinodin had a plasma lifetime of 30 days and much lower GH release in mice. It significantly promoted the proliferation and activation of ovarian MSCs together with the development of follicles in the models by increasing Ki67 and GHS-R expressions, and decreasing GHRH-R expression in a dose-dependent manner. However, the high GH and excessive estrogen levels in the models showed a dose-dependent reduction in fertility. Therefore, unlike 2Y, the low dose of Grinodin specifically shows low GHS-R and high GHRH-R expressions thus evades GH and estrogen release and improves functions of organs, resulting in an increase of fertility.

Machine learning guided tuning charge distribution by composition in MOFs for oxygen evolution reaction.

Traditional design/optimization of metal-organic frameworks (MOFs) is time-consuming and labor-intensive. In this study, we utilize machine learning (ML) to accelerate the synthesis of MOFs. We have built a library of over 900 MOFs with different metal salts, solvent ratios, reaction durations and temperatures, and utilize zeta potentials as target variables for ML training. A total of four ML models have been used to train the collected dataset and assess their convergence performances, where Random Forest Regression (RFR) and Gradient Boosting Regression (GBR) models show strong correlation and accurate predictions. We then predicted two kinds of MOFs from RFR and GBR models. Remarkably, the experimentally data of the synthesized MOFs closely matched the predicted results, and these MOFs exhibited excellent electrocatalytic performances for oxygen evolution. This study would have general implications in the utilization of machine learning for accelerating the synthesis of MOFs for diverse applications.

Tandem-Parallel Electrochemical Cells to Produce Hydrogen Peroxide at Reduced Energy Consumption.

Large-scale industrialization of oxygen electroreduction requires producing hydrogen peroxide (H2O2) at large yield rates (current density >1 A cm-2, Faradic efficiency >95%). Under such vigorous reaction conditions, however, serious electric energy consumption (EEC) has been caused. According to the formula (EEC=Y×1000×R×F2172×FE2), a linear relationship can be identified between H2O2 yield rates (Y) and EEC, and therefore, achieving high yield rates (Y) while reducing EEC is very challenging in common electrochemical systems. In this work, we have designed a tandem-parallel oxygen electroreduction system composed of two oxygen electroreduction units. The tandem unit can effectively improve the Faradaic efficiency (FE) while the parallel section reduces total internal resistance (R). Consequently, the overall system can achieve a high H2O2 yield rate (592 mg h-1) with the lowest EEC (2.41 kWh kg-1) ever reported to the best of our knowledge. Further, the tandem-parallel system has shown promising stability by working for more than 10 cycles or 24 h. Besides oxygen electroreduction, other applications have been also demonstrated for the tandem-parallel system that can generate H2O2 for in situ degradation of rhodamine B pollutant.

An aptamer-functionalized photonic crystal sensor for ultrasensitive and label-free detection of aflatoxin B1.

As a novel optical responsive material, photonic crystal is a promising sensing material in the recognition and detection of small molecules. Herein, a label-free composite sensor for aflatoxin B1 (AFB1) based on aptamer-functionalized photonic crystal arrays was successfully developed. Three-dimensional photonic crystals (3D PhCs) with a controllable number of layers were produced by a layer-by-layer (LBL) approach, and the introduction of gold nanoparticles (AuNPs) facilitated the immobilization procedure of recognition element aptamers, thus creating the AFB1 sensing detection system (AFB1-Apt 3D PhCs). The sensing system AFB1-Apt 3D PhCs exhibited a good linearity in the wide range of 1 pg mL-1-100 ng mL-1 AFB1 with a limit of detection (LOD) of 0.28 pg mL-1. Furthermore AFB1-Apt 3D PhC was successfully applied in the determination of AFB1 in the millet and beer samples with good recovery. The sensing system performed ultrasensitive and label-free detection to the target, which could be further applied in the fields of food safety, clinical diagnosis or environmental monitoring, establishing an efficient and rapid universal detection platform.

Bioinspired inhibition of aggregation in metal-organic frameworks (MOFs).

Different from traditional procedures of using solid stabilizers like polymers and surfactants, here we demonstrate that water, as a very "soft" matter, could function as a "spacer" to prevent the aggregation of metal-organic frameworks (MOFs) in aqueous dispersions. Our theoretical calculations reveal in case of an excess of positively charged metal nodes of MOFs, where water molecules are ligated to metal nodes that greatly enhance MOFs' solution dispersibility through electrostatic stabilization. This discovery has motivated us to develop a facile experimental approach for producing a category of "clean" MOF dispersions without foreign additives. Potential application has been demonstrated for the size fractionation of MOFs, which results in small-size MOFs (50-80 nm) characteristic of superior electrocatalytic oxygen evolution activities (256 mV at 10 mA cm-2, Tafel slope of 49 mV dec-1 and durability >30 h). This work would provide new clues for aqueous processing of MOFs for many emerging applications.

Construction of magnetic covalent organic frameworks functionalized by benzoboroxole for efficient enrichment of glycoproteins in the physiological environment.

To date, the development of highly selective and efficient glycoproteins/peptides enrichment is still a challenge for mass spectrometry-based proteomic analysis. In this work, we reported a novel strategy to prepare a magnetic amide-linked covalent organic framework functionalized by benzoboroxole (denoted as Fe3O4@COF-ABB), which was then used as an adsorbent for the enrichment of glycoproteins. The physical and adsorption properties of Fe3O4@COF-ABB were fully investigated. The Fe3O4@COF-ABB presents a regular core-shell spherical structure, quick magnetic response performance, regular porosity, and multiple binding sites of phenylboronic acid. Taking advantage of these benefits, the synthesized magnetic composites exhibited a superior adsorption capacity (565.8 mg g-1) and high selectivity towards glycoprotein immunoglobulin G (IgG) under physiological state (pH 7.4). Additionally, the adsorbent Fe3O4@COF-ABB could be easily regenerated and reused 5 times with no reduction of enrichment performance. More importantly, the practical applications of Fe3O4@COF-ABB were further demonstrated by the selective adsorption of IgG from human serum. The present work represents a rational design of versatile functionalization of magnetic COFs, which demonstrates an avenue for the selective enrichment and analysis of IgG from real biological sample matrices.

An ultrasensitive label-free biosensor based on aptamer functionalized two-dimensional photonic crystal for kanamycin detection in milk.

A novel photonic crystal aptamer biosensor SiO2-Au-ssDNA two-dimensional photonic crystal (2D PC), allowing label-free and highly sensitive to kanamycin (KANA), is successfully manufactured. This 2D PC biosensor was prepared via a needle tip flow method, using electrostatic adsorption to introduce negatively charged gold nanoparticles (Au NPs) into the 2D PC, combined with sulfhydryl-modified ssDNA for the rapid measurement. Benefiting from the localized surface plasmon resonance effect of Au NPs and optical response capability of PC, the biosensor has an excellent performance on quantitative analysis of KANA ranging from 5 pg∙mL-1 to 5 µg∙mL-1, with a limit of detection of 1.10 pg∙mL-1. The recovery of KANA is between 97 % and 110 % in the milk samples with relative standard deviation less than 4.8 %, which revealing that the 2D PC biosensor has the excellent performance on the KANA detection in complex conditions.

Tumor acid microenvironment-activated self-targeting & splitting gold nanoassembly for tumor chemo-radiotherapy.

Low accumulation and penetration of nanomedicines in tumor severely reduce therapeutic efficacy. Herein, a pH-responsive gold nanoassembly is designed to overcome these problems. Polyethylene glycol linked raltitrexed (RTX, target ligand and chemotherapy drug) and two tertiary amine molecules (1-(2-aminoethyl) pyrrolidine and N, N-dibutylethylenediamine) are modified on the surface of the 6-nm gold nanoparticles by lipoic acid to form gold nanoassembly defined as Au-NNP(RTX). The Au-NNP (RTX) nanoassembly could remain at about 160 nm at the blood circulation (pH 7.4), while split into 6-nm gold nanoparticles due to tertiary amine protonation at tumor extracellular pH (pH 6.8). This pH-responsive disassembly behavior endows Au-NNP(RTX) better tumor tissue permeability through the better diffusion brought by the size reduction. Meanwhile, after disassembly, more RTXs on the surface of gold nanoparticles are exposed from the shielded state of assembly along with 2.25-fold augment of cellular uptake capability. Most importantly, the results show that Au-NNP(RTX) possesses of high tumor accumulation and effective tumor penetration, thereby enhancing the tumor chemo-radiotherapy efficiency.

A pH-responsive Pt-based nanoradiosensitizer for enhanced radiotherapy via oxidative stress amplification.

Tumor radioresistance is a major issue in radiotherapy. To address it, a pH-responsive nanoradiosensitizer was synthesized employing a simple method. Initially, chloroplatinic acid was reduced by human serum albumin (HSA) to form HSA-wrapped Pt@HSA nanoparticles (NPs). Subsequently, cinnamicaldehyde (CA) was grafted on Pt@HSA via aldimine condensation to obtain nanoradiosensitizer Pt@HSA/CA NPs. CA would be released in tumor cells (pH = 5.5) to induce the production of reactive oxygen species, including H2O2, ˙OH, etc. The increased decomposition of H2O2 catalyzed by the NPs resulted in enhanced production of oxygen, leading to hypoxia relief of the tumor cells, which is beneficial for radiotherapy. Due to the high X-ray attenuation coefficient of Pt, Pt@HSA/CA NPs enhance the energy deposition of radiation. Cytotoxicity assay revealed that Pt@HSA/CA NPs resulted in a cell death rate of 77%, which was 24.4% higher than that of Pt@HSA NPs even under low-dose X-ray irradiation of 4 Gy. Colony formation assay demonstrated that the sensitization enhancement ratio was 1.37, indicating that Pt@HSA/CA NPs displayed remarkable radiosensitizing ability. Notably, in vivo results indicated that the NPs could increase the tumor inhibition rate to 91.2% with negligible side effects to normal tissues. These results demonstrate that Pt@HSA/CA NPs had outstanding tumor curative efficacy and hypotoxicity.

An oxidation responsive nano-radiosensitizer increases radiotherapy efficacy by remolding tumor vasculature.

As an excellent candidate material for nano-sensitizers, gold nanostructures have shown great potential in radiotherapy. Nevertheless, severe hypoxia and low accumulation of nanomedicine caused by poor perfusion at the tumor site have significantly reduced radiotherapy efficacy. Vascular normalization has gained attention owing to its ability to relieve hypoxia and increase perfusion. The synergistic therapy of tumor vascular normalization and radiotherapy has become a new option to increase anti-cancer efficacy. However, the commonly used strategy of suppressing a single growth factor to induce vascular normalization is limited by tumor compensatory effects. In this work, we developed a strategy to inhibit oxidative stress in tumors by generating chelating agents in response to hydrogen peroxide, thereby inhibiting multi-angiogenic factors simultaneously to normalize blood vessels. Concretely, sodium alginate (SA) reacted with 8-quinoline boric acid (QBA) to form SA-QBA. Then gold nanoparticles (Au NPs) were modified with SA-QBA to obtain Au@SA-QBA. The system was simple in structure and could generate 8HQ in response to H2O2in vitro to inhibit oxidative stress and reduce the expression of VEGF, bFGF, and Ang-2. In vivo, the perfusion unit (PU) increased by 78% after Au@SA-QBA treatment, and the coverage of pericytes increased by 32%, which in turn induced vascular normalization. In addition, blood routine and blood biochemical tests confirmed its good biocompatibility and 8HQ was not detected in the supernatant after homogenization of major organs. More importantly, after the synergistic treatment of vascular normalization and radiotherapy (4 Gy), the tumor growth inhibition rate was increased by 38.6% compared to the Au@SA-treated group with negligible side effects to normal tissues.

Construction of a pH/TGase "Dual Key"-Responsive Gold Nano-radiosensitizer with Liver Tumor-Targeting Ability.

The method of tumor microenvironment (TME)-responsive aggregation has become a promising approach to enhance treatment effect by improving the accumulation of nanoparticles in tumors. The enzymatic cross-linking strategy has widely attracted attention owing to its good aggregation stability and biocompatibility. However, the enzymes in nontumor tissue can also catalyze the cross-linking reaction and reduce accumulation of nanoparticles in tumor. In this work, a "dual key"-responsive strategy is utilized to construct a transglutaminase (TGase)/pH-responsive radiosensitizer (Au@TAcoGal) with specific aggregation behavior in hepatic tumor cells. Au@TAcoGal can retain its stability in blood circulation (pH 7.4) even in the presence of TGase in plasma. On reaching tumor sites, it can be endocytosed by hepatoma cells by the active targeting of phenylboronic acid (PBA) and aggregated under acidity and overexpression of TGase in cells. Due to its specific accumulation in hepatoma cells, radiotherapy can be operated under a lower dose of X-ray. The results show that the cellular accumulation of Au@TAcoGal increases by 30-70%, and the cell survival rate is less than 25% under X-ray irradiation. The antineoplastic results show that Au@TAcoGal exhibits a higher therapeutic effect, and the tumor inhibition rate can reach 84.21%.

In situ self-assembled biosupramolecular porphyrin nanofibers for enhancing photodynamic therapy in tumors.

Due to the complicated environment and high tissue hydraulic pressure in tumors that easily pumps the nanomedicines back to the systemic circulation, the concentration of released photosensitizers (PSs) retained in a tumor by a traditional nano-delivery system is very low, causing an unsatisfactory photodynamic therapy (PDT) effect. Therefore, we prepared a pH/H2O2-responsive nano-system (ZnP-OC-M) through modified porphyrin PS units with a long-unsaturated oleoyl chloride chain, and by the further introduction of hydrophilic hydroxyl groups and MnO2 through a cis-addition reaction between the unsaturated double bonds of oleoyl chloride and dilute KMnO4 solution. Making use of the sensitivity of MnO2 to the H2O2 in the acid environment of tumor cells, ZnP-OC-M selectively realized responsive disintegration and O2 generation. More importantly, the rich amphiphilic PS units were shedded simultaneously and spontaneously completed the self-assembly into nanofibers in situ by helical stacking, which displayed a 1.85-fold higher retention effect of PSs in vivo compared with free PS groups and showed a great tumor inhibition effect in enhancing PDT. This nanosystem effectively solves the problem of the low retention abilities leading to a poor PS concentration in a tumor, prolonging the treatment time window efficiently after only a single administration and achieving the purpose of PDT enhancement.

Clinical Efficacy and Safety of Combination Therapy with Amlodipine and Olmesartan or an Olmesartan/Hydrochlorothiazide Compound for Hypertension: A Prospective, Open-Label, and Multicenter Clinical Trial in China.

BACKGROUND: Amlodipine (AML) is the initial therapy most commonly prescribed for patients with hypertension in China. However, AML monotherapy is often less effective in achieving blood pressure (BP) control than other agents. OBJECTIVE: We performed a clinical study to evaluate efficacy and safety of a combination therapy with AML, olmesartan (OLM), or an OLM/hydrochlorothiazide (HCTZ) compound for Chinese patients with mild-to-moderate hypertension. METHODS: In the clinical trial, patients were initially treated with OLM 20 mg/d combined with AML 5 mg/d. Then OLM was uptitrated to 40 mg/d or changed to an OLM/HCTZ (20/12.5 mg/d) compound if the patients did not reach the target of seated diastolic BP <90 mm Hg (<80 mm Hg in patients with diabetes) after 8 weeks. RESULTS: The overall response rate of the combination therapy was 59.2% (95% CI, 54.23%-63.97%) at Week 2 and gradually increased to 97.1% (95% CI, 94.93%-98.47%) at the end of the study (Week 16). CONCLUSIONS: The combination therapy with OLM or OLM/HCTZ was well tolerated. The total incidence of adverse events was 42.9% (n = 176). Most of the adverse events were mild in severity (39.5%; n = 162) and not associated with the drugs (33.2%). In conclusion, combination therapy with AML, OLM, or OLM/HCTZ can significantly lower BP safely and achieve a high BP control rate in patients with mild-to-moderate hypertension in China. ClinicalTrial.org identifier: ChiCTR-ONC-12001963.

Single NIR Laser-Activated Multifunctional Nanoparticles for Cascaded Photothermal and Oxygen-Independent Photodynamic Therapy.

Inconvenient dual-laser irradiation and tumor hypoxic environment as well as limited judgment of treating region have impeded the development of combined photothermal and photodynamic therapies (PTT and PDT). Herein, Bi2Se3@AIPH nanoparticles (NPs) are facilely developed to overcome these problems. Through a one-step method, free radical generator (AIPH) and phase transition material (lauric acid, LA, 44-46 °C) are encapsulated in hollow bismuth selenide nanoparticles (Bi2Se3 NPs). Under a single 808-nm laser irradiation at the tumor area, hyperthermia produced by Bi2Se3 not only directly leads to cell death, but also promotes AIPH release by melting LA and triggers free radical generation, which could further eradicate tumor cells in hypoxic environments. Moreover, Bi2Se3 with high X-ray attenuation coefficient endows the NPs with high computed tomography (CT) imaging capability, which is important for treating area determination. The results exhibit that Bi2Se3@AIPH NPs possesses 31.2% photothermal conversion efficiency for enhanced PTT, ideal free radical generation for oxygen-independent PDT, and 37.77 HU mL mg-1 X-ray attenuation coefficient for CT imaging with high quality. Most importantly, the tumor growth inhibition rate by synergistic PTT, PDT, and following immunotherapy is 99.6%, and even one tumor disappears completely, which demonstrates excellent cascaded synergistic effect of Bi2Se3@AIPH NPs for the tumor therapy.

Vector sparse representation of color image using quaternion matrix analysis.

Traditional sparse image models treat color image pixel as a scalar, which represents color channels separately or concatenate color channels as a monochrome image. In this paper, we propose a vector sparse representation model for color images using quaternion matrix analysis. As a new tool for color image representation, its potential applications in several image-processing tasks are presented, including color image reconstruction, denoising, inpainting, and super-resolution. The proposed model represents the color image as a quaternion matrix, where a quaternion-based dictionary learning algorithm is presented using the K-quaternion singular value decomposition (QSVD) (generalized K-means clustering for QSVD) method. It conducts the sparse basis selection in quaternion space, which uniformly transforms the channel images to an orthogonal color space. In this new color space, it is significant that the inherent color structures can be completely preserved during vector reconstruction. Moreover, the proposed sparse model is more efficient comparing with the current sparse models for image restoration tasks due to lower redundancy between the atoms of different color channels. The experimental results demonstrate that the proposed sparse image model avoids the hue bias issue successfully and shows its potential as a general and powerful tool in color image analysis and processing domain.