Reducing Cholesterol Level in Live Macrophages Improves Delivery Performance by Enhancing Blood Shear Stress Adaptation.

In recent years, live-cell-based drug delivery systems have gained considerable attention. However, shear stress, which accompanies blood flow, may cause cell death and weaken the delivery performance. In this study, we found that reducing cholesterol in macrophage plasma membranes enhanced their tumor targeting ability by more than 2-fold. Our study demonstrates that the reduced cholesterol level deactivated the mammalian target of rapamycin (mTOR) and consequently promoted the nuclear translocation of transcription factor EB (TFEB), which in turn enhanced the expression of superoxide dismutase (SOD) to reduce reactive oxygen species (ROS) induced by shear stress. A proof-of-concept system using low cholesterol macrophages attached to MXene (e.g., l-RX) was fabricated. In a melanoma mouse model, l-RX and laser irradiation treatments eliminated tumors with no recurrences observed in mice. Therefore, cholesterol reduction is a simple and effective way to enhance the targeting performance of macrophage-based drug delivery systems.

An investigation of the growth status of 19-year-old Idesia polycarpa 'Yuji' plantation forest in the mountainous region of Henan, China.

Plantation forests play an important role in the mitigation of greenhouse gas emissions. Idesia polycarpa Maxim is an emerging woody oil tree species in most Asian countries. The 19-year-old Idesia polycarpa 'Yuji' plantation forest was selected as a sample site. The nutrient contents of the understory soil total carbon (TC), total nitrogen (TN), nitrate nitrogen (NN), organic carbon (OC), available phosphorus (AP), available potassium (AK), and pH were analyzed. Several metrics were measured to quantify the growth status of the forest, such as tree heights (H), clear bole heights (CBH), diameters at breast height (DBH), and male-to-female ratios (MFR). In addition, we harvested the fruits to analyze oil content and fatty acid composition. The results found that the nutrient content of the soil was TC (4.93%), TN (0.42%), NN (43.08 mg kg-1), OC (4.90 g kg-1), AP (13.66 mg kg-1), AK (30.48 mg kg-1), and pH (7.90). The growth characteristics were H (11.75 m), DBH (12.79 cm), and CBH (6.17 m). The MFR was close to 1:1. Besides, the oil content of the fruit and unsaturated fatty acids was 24.08% and 68.49%, respectively. As an alternative tree species, the plantation of Idesia polycarpa offers great potential in artificial afforestation in some particular places with specific forest site conditions.

Cuproptosis-immunotherapy using PD-1 overexpressing T cell membrane-coated nanosheets efficiently treats tumor.

The cuproptosis cell death pathway brings fresh opportunities for tumor therapy. However, efficient and targeted cuproptosis induction in tumors is still a challenge. Unfortunately, the well-known cuproptosis initiator, disulfiram and copper complex (DSF/Cu2+), also increases PD-L1 level in tumors, which may diminish the final therapeutic outcome. In this study, DSF/Cu2+-loading MXene nanosheets are coated with PD-1 overexpressing T cell membrane to generate CuX-P system. CuX-P could recognize and stick to PD-L1 on tumor cells like a patch, which promotes the endocytosis of both CuX-P and PD-L1 by tumor cells. Following internalization and release of DSF/Cu2+ in the cytoplasm, PD-L1 expression is upregulated. However, due to the presence of CuX-P in the tumor microenvironment, the then supplemented PD-L1 on tumor surface again binds CuX-P for internalization. This feedback loop keeps blocking and consuming the PD-L1 on tumor surface and promotes the enrichment of CuX-P in tumors to induce cuproptosis. After CuX-P treatment with laser irradiation, strong anti-tumor immune responses are stimulated in a mouse model with triple-negative breast cancer. Thus, this study develops a tumor-targeted biomimetic system that offers simultaneous cuproptosis killing, photothermal therapy (PTT) and immunotherapy in mice.

Cholesterol removal improves performance of a model biomimetic system to co-deliver a photothermal agent and a STING agonist for cancer immunotherapy.

Biological membranes often play important functional roles in biomimetic drug delivery systems. We discover that the circulation time and targeting capability of biological membrane coated nanovehicles can be significantly improved by reducing cholesterol level in the coating membrane. A proof-of-concept system using cholesterol-reduced and PD-1-overexpressed T cell membrane to deliver a photothermal agent and a STING agonist is thus fabricated. Comparing with normal membrane, this engineered membrane increases tumor accumulation by ~2-fold. In a melanoma model in male mice, tumors are eliminated with no recurrence in >80% mice after intravenous injection and laser irradiation; while in a colon cancer model in male mice, ~40% mice are cured without laser irradiation. Data suggest that the engineered membranes escape immune surveillance to avoid blood clearance while keeping functional surface molecules exposed. In summary, we develop a simple, effective, safe and widely-applicable biological membrane modification strategy. This "subtractive" strategy displays some advantages and is worth further development.

Degradable Temperature-Sensitive Hydrogel Loaded with Heparin Effectively Prevents Post-Operative Tissue Adhesions.

Tissue adhesions could occur following surgeries, and severe tissue adhesions can lead to serious complications. Medical hydrogels could be applied at surgical sites as a physical barrier to prevent tissue adhesion. For practical reasons, spreadable, degradable, and self-healable gels are highly demanded. To meet these requirements, we applied carboxymethyl chitosan (CMCS) to poloxamer-based hydrogels to generate low Poloxamer338 (P338) content gels displaying low viscosity at refrigerator temperature and improved mechanical strength at body temperature. Heparin, an effective adhesion inhibitor, was also added to construct P338/CMCS-heparin composite hydrogel (PCHgel). PCHgel presents as a flowable liquid below 20 °C and could rapidly transform into gel when spread on the surface of damaged tissue due to temperature change. The introduction of CMCS enabled hydrogels to form a stable self-healable barrier at injured positions and slowly release heparin during the wound healing period before being degraded after ∼14 days. Ultimately, PCHgel significantly reduced tissue adhesion in model rats and displayed higher efficiency than P338/CMCS gel without heparin. Its adhesion suppression mechanism was verified, and it also displayed good biosafety. Therefore, PCHgel showed good clinical transformation potential with high efficacy, good safety, and ease of use.

Quercetin-ferrum nanoparticles enhance photothermal therapy by modulating the tumor immunosuppressive microenvironment.

Photothermal therapy (PTT) was reported to induce synergistic immunogenic cell death (ICD) which may convert tumor cells into "therapeutic vaccines". However, this is often insufficient to prevent tumor recurrence, in part because of the immunosuppressive microenvironment in tumors. Therefore, remodeling tumor microenvironment is of great importance to enhance the therapeutic efficacy of PTT. We herein fabricated a versatile nano-photosensitizer by assembling quercetin and Ferrum ion (QFN). The released quercetin from QFN could reduce programmed death ligand 1 (PD-L1) in tumor cells by inhibiting the phosphorylation of JAK2 and STAT3, and reshape extracellular matrix (ECM) by down-regulating α-SMA+ fibroblast in tumors. Moreover, QFN could capture tumor antigen and deliver it to the tumor-draining lymph nodes after PTT, which further enhanced the activation of antigen-presenting cells. As a result, QFN-based PTT eliminated melanoma and induced long-term immune memory to prevent tumor metastasis and recurrence. This study provides an effective and translationally feasible photothermic agent for photothermal/immunotherapy. STATEMENT OF SIGNIFICANCE: The efficacy of photothermal therapy (PTT) in cancer treatment is often limited by the immunosuppressive microenvironment in tumors. Herein, we prepared a versatile photosensitizer by assembling quercetin and Ferrum ion (QFN). Upon near-infrared light irradiation, QFN-PTT induced cancer cells destruction and tumor antigen release. QFN then captured antigen and delivered it to the tumor-draining lymph nodes, thus promoting dendritic cell maturation and T cells activation. Quercetin released from QFN in tumors improved T cells infiltration and activation in tumor by regulating immunosuppressive microenvironment. The QFN-PTT-treated mice exhibited significantly elongated survival time, and gained strong anti-tumor immune memory to prevent tumor metastasis and recurrence. Thus, this work provided a simple and versatile photothermic agent, and it has important implications for designing effective and translationally feasible photosensitizers for PTT.

Effect of Yttrium on the Microstructure and Mechanical Properties of PH13-8Mo Stainless Steels Produced by Selective Laser Melting.

In the present work, PH13-8Mo stainless steel parts without yttrium and with yttrium (Y) were manufactured by selective laser melting (SLM). The microstructure, phase composition and grain orientation of the stainless steels parts with Y and without Y were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), electron-backscatter diffraction (EBSD), transmission electron microscopy (TEM) and high-resolution transmission electron microscopy (HRTEM). The characterization results revealed that the addition of Y clearly refined the grain size of the PH13-8Mo steel formed part, resulting in more equiaxed massive grains and in a less anisotropic microstructure. PH13-8Mo stainless steel formed parts were mainly composed of martensite and retained austenite. The addition of Y could significantly increase the content of retained austenite and also generate nano-sized precipitates containing Y. The mechanical test results showed that both strength and toughness of the shaped parts containing Y were improved synergistically. The yield strength reached 1443 MPa, the elongation was 12.2%, and the room temperature impact energy reached 124.25 J/cm2. The strengthening and toughening by Y of the formed parts were mainly attributed to grain refinement, higher volume fraction of the retained austenite and the formation of nano-sized precipitates containing Y.

CH/π-interaction-driven self-assembly of tetraphenylethylene derivatives into the face to face arrangement.

For tetraphenylethene (TPE) derivatives, it is difficult to determine the arrangement of the molecules in the aggregation state because disordered aggregation usually occurs. To solve the problem, we have explored a novel and facile strategy to investigate the aggregation mode of a TPE derivative framework in which the two neighboring ortho carbons of two phenyl moieties at the same ethylene carbon were linked with an alkoxyl chain (C4) (denoted as TPEC4). The XRD measurements on the particles obtained in a DMSO/H2O mixture (f w = 60%) showed sharp peaks which is consistent with the simulated XRD patterns on the basis of a single crystal structure of TPEC4, indicating well-ordered molecular packing in the aggregated state. The CH/π-interaction and solvophobicity driven self-assembly behaviour of the compound was observed in the DMSO/H2O mixture. A face to face molecular packing structure that arises from quadruple intermolecular CH/π-interactions of the tetraphenylethylenes is the key motif for self-assembly in solution. The unique blue-red shifted emission in the DMSO/H2O mixture associated with aggregated behaviour of the compound was also investigated. This discovery will provide the basis for theoretical research and the rational design of TPE-based luminogens.

Clinical research linking Traditional Chinese Medicine constitution types with diseases: a literature review of 1639 observational studies.

OBJECTIVE: To analyze clinical studies on correlations between Traditional Chinese Medicine (TCM) body constitution types and diseases published in the past 10 years, and to provide an evidence base to support the use of such correlations for health maintenance and disease prevention. METHODS: We searched five databases for the period April 2009 to December 2019: China National Knowledge Infrastructure Database, Wanfang Database, China Science and Technology Journal Database, PubMed and Embase. Three types of observational studies on correlation between constitution types and diseases were included: cross-sectional, case-control and cohort studies. Descriptive statistical methods were employed for data analysis. RESULTS: A total of 1639 clinical studies were identified: 1452 (88.59%) cross-sectional studies, 115 (7.02%) case-control studies and 72 (4.39%) cohort studies covering 30 regions of China and five other countries (Malaysia, South Korea, Singapore, Thailand and France). The collection of studies comprised 19 disease categories and 333 different diseases. The 10 most commonly studied diseases were hypertension, diabetes, stroke, coronary atherosclerotic heart disease (CAHD), sleep disorders, neoplasm of the breast, dysmenorrhea, fatty liver disease, chronic viral hepatitis B and dyslipidemia. We found high distributions for each biased constitution type in different patient populations as follows: Qi-deficiency constitution in stroke, diabetes, chronic obstructive pulmonary disease, acquired immunodeficiency syndrome and hypertension; Yang-deficiency constitution in female infertility, osteoporosis, irritable bowel syndrome, gonarthrosis and dysmenorrhea; Yin-deficiency constitution in hypertension, diabetes, constipation, female climacteric states and osteoporosis; phlegm- dampness constitution in hypertension, stroke, fatty liver disease, diabetes and metabolic syndrome; damp-heat constitution in acne, chronic gastritis, chronic viral hepatitis B, human papillomavirus infection and hyperuricemia; blood-stasis constitution in CAHD, endometriosis and stroke; Qi-stagnation constitution in hyperplasia and neoplasms of the breast, insomnia, depression and thyroid nodules; and inherited-special constitution in asthma and allergic rhinitis. CONCLUSION: Eight biased TCM constitutions were closely related to specific diseases, and could be used to guide individualized prevention and treatment. More rigorously designed studies are recommended to further verify the constitution-disease relationship.

Tuning the fluorescence based on the combination of TICT and AIE emission of a tetraphenylethylene with D-π-A structure.

A simple D-π-A structured tetraphenylethylene with two electron-rich methyloxy groups and two electron withdrawing cyano groups, which features both twisted intramolecular charge-transfer (TICT) and aggregation-induced emission (AIE) properties, namely TPEOMeCN has been prepared. The emission of TPEOMeCN examined in various solvents is dependent on the polarities of solvents, which indicates the TICT character. The emission intensity of the compound also enhances with the increasing water fraction in H2O-DMSO mixtures, demonstrating the typical AIE property. Excitingly, the TICT and AIE emission could be observed separately or simultaneously by adjusting the water fraction or viscosity of the solvent. Encouragingly, the combined emission of the TPEOMeCN derived from this single molecule could be readily tuned via regulating the viscosity of the system, resulting in a broad emission peak which covers the visible spectrum (400-700 nm). This work provides a general strategy for designing molecules combining TICT emission and AIE for application as full-color emitters.

Quality appraisal of gestational diabetes mellitus guidelines with AGREE II: a systematic review.

BACKGROUND: Several societies and associations have produced and disseminated clinical practice guidelines (CPGs) for gestational diabetes mellitus (GDM). However, the quality of such guidelines has not been appraised so far. This study aims to evaluate the quality of CPGs for GDM published in the last decade using the AGREE II instrument. METHODS: A systematic search of the National Institute for Health and Care Excellence, New Zealand Guidelines Group, Scottish Intercollegiate Guidelines Network, Medlive, American Diabetes Association, Canadian Diabetes Association, International Diabetes Federation, as well as PubMed, Web of Science, Embase, China National Knowledge Infrastructure, Wanfang Chinese Periodical Database, and VIP Chinese Periodical Database was conducted from inception to June 2018. The quality was assessed by four trained researchers independently, using the AGREE IIinstrument. RESULTS: A total of 13 guidelines, published from 2009 to 2018, were finally included. Among them, 11 guidelines were evidence-based guidelines, and 2 were expert consensus. Scores for each of the six AGREE II domains(Median ± IQR) were 94 ± 11, 89 ± 53, 58 ± 37, 100 ± 6, 79 ± 48, 100 ± 71 and 67% ± 42%, and guidelines based on expert consensus generally scored lower than evidence-based guidelines (Z = -2.201, p = 0.028). Overall score of 10 guidelines were 5 points and above, and four guidelines were 7 points. Among six domains, two domains: Scope and Purpose, and Clarity of Presentation, had high scores; however, the domains of Rigor of Development, Stakeholder Involvement and Editorial Independence received lower scores. CONCLUSIONS: In general, the methodological quality of GDM guidelines is high, and evidence-based guidelines are superior to expert consensus. However, the domains of Rigor of Development, Stakeholder Involvement and Editorial Independence still need improvement. A systematic approach in the development of these guidelines and updating timely is needed. In some regions, more attention for guideline adaptation is recommended.

Current guidelines on the management of gestational diabetes mellitus: a content analysis and appraisal.

BACKGROUND: Despite many guidelines for the management of gestational diabetes available internationally, little work has been done to summarize and assess the content of existing guidelines. A paucity of analysis guidelines within in a unified system may be one explanatory factor. So this study aims to analyze and evaluate the contents of all available guidelines for the management of gestational diabetes. METHOD: Relevant clinical guidelines were collected through a search of relevant guideline websites and databases (PubMed, Web of Science, Embase, etc.). Fourteen guidelines were identified, and each guideline was assessed for quality using the Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Two independent reviewers extracted guideline recommendations using a "recommendation matrix" through which basic guideline information and consistency between search strategy and selection of evidence, between selected evidence and interpretation, and between interpretation and resulting recommendations were analyzed. RESULTS: Fourteen documents were analyzed, and a total of 361 original recommendations for gestational diabetes mellitus (GDM) management were assessed. In all guidelines included, the recommendations were developed in five domains, namely, diagnosis of GDM, prenatal care, intrapartum care, neonatal care and postpartum care. Different guidelines appeared to have significant discrepancy in consistency of guideline content, but overall, there was consistency between search strategy and selection of evidence, between selected evidence and interpretation, and between interpretation and resulting recommendations (scilicet 49.31, 57.20 and 58.17%, respectively). CONCLUSION: Although commonality in most recommendations existed, there were still some discrepancies between guidelines. Consistency of guidelines on the management of GDM in pregnancy is highly variable and needs to be improved.

Regulating the emission of tetraphenylethenes by changing the alkoxyl linkage length between two neighboring phenyl moieties.

Alkoxyl linkages with different carbon lengths are employed to link the two neighboring ortho carbons of the two phenyl moieties at the same ethylene carbon of the tetraphenylethene framework, resulting in successful regulation of the molecular conformation and in turn the emission properties.

3D Nitrogen-Anion-Decorated Nickel Sulfides for Highly Efficient Overall Water Splitting.

Developing non-noble-metal electrocatalysts with high activity and low cost for both the oxygen evolution reaction (OER) and hydrogen evolution reaction (HER) is of paramount importance for improving the generation of H2 fuel by electrocatalytic water-splitting. This study puts forward a new N-anion-decorated Ni3 S2 material synthesized by a simple one-step calcination route, acting as a superior bifunctional electrocatalyst for the OER/HER for the first time. The introduction of N anions significantly modifies the morphology and electronic structure of Ni3 S2 , bringing high surface active sites exposure, enhanced electrical conductivity, optimal HER Gibbs free-energy (ΔGH* ), and water adsorption energy change (ΔGH2O* ). Remarkably, the obtained N-Ni3 S2 /NF 3D electrode exhibits extremely low overpotentials of 330 and 110 mV to reach a current density of 100 and 10 mA cm-2 for the OER and HER in 1.0 m KOH, respectively. Moreover, an overall water-splitting device comprising this electrode delivers a current density of 10 mA cm-2 at a very low cell voltage of 1.48 V. Our finding introduces a new way to design advanced bifunctional catalysts for water splitting.

Regulating Water-Reduction Kinetics in Cobalt Phosphide for Enhancing HER Catalytic Activity in Alkaline Solution.

Electrochemical water splitting to produce hydrogen renders a promising pathway for renewable energy storage. Considering limited electrocatalysts have good oxygen-evolution reaction (OER) catalytic activity in acid solution while numerous economical materials show excellent OER catalytic performance in alkaline solution, developing new strategies that enhance the alkaline hydrogen-evolution reaction (HER) catalytic activity of cost-effective catalysts is highly desirable for achieving highly efficient overall water splitting. Herein, it is demonstrated that synergistic regulation of water dissociation and optimization of hydrogen adsorption free energy on electrocatalysts can significantly promote alkaline HER catalysis. Using oxygen-incorporated Co2 P as an example, the synergistic effect brings about 15-fold enhancement of alkaline HER activity. Theory calculations confirm that the water dissociation free energy of Co2 P decreases significantly after oxygen incorporation, and the hydrogen adsorption free energy can also be optimized simultaneously. The finding suggests the powerful effectiveness of synergetic regulation of water dissociation and optimization of hydrogen adsorption free energy on electrocatalysts for alkaline HER catalysis.

Roaming-Mediated CH2NH Elimination from the Ionization of Aromatic Ethylamines.

The ionization of aromatic ethylamines by photons or electrons leads to elimination of CH2NH fragments, supposedly deriving from the McLafferty rearrangement involving intramolecular γ-hydrogen transfer. Using tryptamine and phenethylamine as examples, the results reported here suggest that the McLafferty mechanism is inadequate for interpreting the observations of CH2NH elimination due to much higher calculated appearance energy than experimentally measured values. Furthermore, by considering the roaming-mediated effect, the calculated appearance energy for the elimination of CH2NH fragments is reduced and matches well with the experimental results and verifies the existence of roaming-mediated effect. This effect could potentially be extended to explain the general CH2NH elimination of aromatic ethylamines. Due to the similar hydrogen transfer to that of the McLafferty mechanism, the roaming-mediated effect was taken into account to suggest a novel mechanism, termed the "roaming-modified McLafferty rearrangement", that explains the observations of CH2NH elimination in the ionization of aromatic ethylamines. This is a reasonable modification of the McLafferty rearrangement mechanism.