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Transarterial chemoembolization (TACE) has emerged as the mainstay treatment for patients suffering from unresectable intermediate hepatocellular carcinoma and also holds the potential to treat other types of hypervascular cancers such as renal cell carcinoma. However, an in vitro model for evaluating both embolic performance and drug-release kinetics of the TACE embolic agents is still lacking since the current models greatly simplified the in vivo vascular systems as well as the extracellular matrices (ECM) in the organs. Here, we developed a decellularized organ model with preserved ECM and vasculatures as well as a translucent appearance to investigate chemoembolization performances of a clinically widely used embolic agent, i.e., a doxorubicin-loaded ethiodised oil (EO)-based emulsion. We, for the first time, utilized an ex vivo model to evaluate the liquid-based embolic agent in two organs, i.e., liver and kidneys. We found that the EO-based emulsion with enhanced stability by incorporating an emulsifier, i.e., hydrogenated castor oil-40 (HCO), showed an enhanced occlusion level and presented sustained drug release in the ex vivo liver model, suggesting an advantageous therapeutic effect for TACE treatment of hepatocellular carcinoma. In contrast, we observed that drug-release burst happened when applying the same therapy in the kidney model even with the HCO emulsifier, which may be explained by the presence of the specific renal vasculature and calyceal systems, indicating an unfavorable effect in the renal tumor treatment. Such an ex vivo model presents a promising template for chemoembolization evaluation before in vivo experiments for the development of novel embolic agents.

The field of two-dimensional (2D) nanomaterial-based cancer immunotherapy combines research from multiple subdisciplines of material science, nano-chemistry, in particular nano-biological interactions, immunology, and medicinal chemistry. Most importantly, the “biological identity” of nanomaterials governed by bio-molecular corona in terms of bimolecular types, relative abundance, and conformation at the nanomaterial surface is now believed to influence blood circulation time, bio-distribution, immune response, cellular uptake, and intracellular trafficking. A better understanding of nano-bio interactions can improve utilization of 2D nano-architectures for cancer immunotherapy and immunotheranostics, allowing them to be adapted or modified to treat other immune dysregulation syndromes including autoimmune diseases or inflammation, infection, tissue regeneration, and transplantation. The manuscript reviews the biological interactions and immunotherapeutic applications of 2D nanomaterials, including understanding their interactions with biological molecules of the immune system, summarizes and prospects the applications of 2D nanomaterials in cancer immunotherapy., Graphical abstract The two-dimensional nanomaterials would affect and could modulate immune system via specific design, which endows them great potential in cancer immunotherapy.Image 1

Maternal severe zinc (Zn) deficiency resulted in growth retardation and high mortality during embryonic development in human. Therefore, this study is aimed at evaluating the effect of maternal marginal Zn deficiency on the development and redox status to avoid severe Zn deficiency using an avian model. A total of 324 laying duck breeders at 214 days old were randomly allotted into 3 dietary Zn levels with 6 replicates of 18 ducks per replicate. The birds were fed experimental diets including 3 dietary supplemental Zn levels of 0 mg/kg (maternal Zn-deficient group, 29.2 mg Zn/kg diet), 60 mg/kg (maternal Zn-adequate group), and 120 mg/kg (maternal Zn-high group) for 6 weeks. Dietary Zn levels had on effect on egg production and fertility ( P > 0.05 ), whereas dietary Zn deficiency decreased breeder plasma Zn concentration and erythrocytic alkaline phosphatase activity at week 6 and inhibited erythrocytic 5 ′ -nucleotidase (5 ′ -NT) activity at weeks 2, 4, and 6 ( P < 0.05 ), indicating that marginal Zn-deficient status occurred after Zn depletion. Maternal marginal Zn deficiency increased embryonic mortality and contents of superoxide anion radical, MDA, and PPC and reduced MT content and CuZnSOD activity in duck embryonic livers on E29. The MDA content was positively correlated with embryonic mortality. Maternal marginal Zn deficiency increased BCL2-associated X protein and Caspase-9 mRNA expressions as well as decreased B-cell lymphoma-2 and MT1 mRNA and signal AKT1 and ERK1 protein expressions ( P < 0.05 ). Breeder plasma Zn concentration and erythrocytic 5 ′ -NT activities at week 6 were positively correlated with GSH-Px activity and GPx, MT1, and BCL2 mRNA expressions in embryonic livers on E29. In conclusion, erythrocytic 5 ′ -NT activity could be more rapid and reliable to monitor marginal Zn-deficient status. Marginal Zn deficiency impaired hatchability and antioxidant defense system and then induced oxidative damage and apoptosis in the embryonic liver, contributing to the greater loss of duck embryonic death.

Summary Oral delivery of insulin is of great convenience in treating diabetes but is still subject to the harsh gastrointestinal tract. Herein, we developed an intelligent oral insulin platform based on glucose-responsive polymeric nanoparticles (NPs), which possess the following advantages: (1) protect the integrity and bioavailability of loaded insulin against gastrointestinal tract, (2) overcome the intestinal epithelial barriers via neonatal Fc receptor-mediated transport, and (3) on-demand release of insulin dependent solely on blood glucose levels to avoid hyperglycemia and hypoglycemia caused by unsafe doses of insulin. Notably, our oral NPs extended the therapeutic effect to up to 16 h in type 1 diabetic mice. To our knowledge, this is the longest effective time among such types of oral insulin platforms reported to date and may reduce the frequency of insulin administration to once daily. This platform might be useful for the oral delivery of biologics in treating diabetes and related complications.

In contrast to the external shells in bivalves and gastropods, most cephalopods are missing this external protection. The cuttlefish, belonging to class cephalopod, has an internal biomineralized structure made of mainly calcium carbonate for controlling buoyancy. However, the macromolecules, especially proteins that control cuttlebone mineral formation, are not sufficiently understood, limiting our understanding of the evolution of this internal shell. In this study, we extracted proteins from the cuttlebone of pharaoh cuttlefish Sepia pharaonis and performed liquid chromatography-tandem mass spectrometry to identify the shell matrix proteins (SMPs). In total, 41 SMPs were identified. Among them, hemocyanin, an oxygen-carrying protein, was the most abundant SMP. By comparison with SMPs of other marine biominerals, hemocyanin, apolipophorin, soul domain proteins, transferrin, FL-rich, and enolase were found to be unique to the cuttlebone. In contrast, typical SMPs of external shells such as carbonic anhydrase complement control protein, fibronectin type III, and G/A-rich proteins were lacking from the cuttlebone. Furthermore, the cluster analysis of biomineral SMPs suggests that the SMP repertoire of the cuttlebone does not resemble that of other species with external shells. Taken together, this study implies a potential relationship of the cuttlefish internal shell with other internal biominerals, which highlights a unique shell evolutionary pathway in invertebrates.

The N-ethylmaleimide-sensitive fusion protein attachment protein receptor YKT6 is a key protein that controls the release of exosomes, was reported to play important roles in multiple cancers. Howe...

Introduction It will be challenging to develop high-performance organic chromophores for light-triggered thermal ablation of the tumor. Besides, the mechanisms of organic chromophores for tumor therapy remain unclear. Herein, an acceptor-π-donor (A-π-D) structured organic chromophore based on 2-dicyanomethylenethiazole named PTM was developed for photothermal therapy (PTT) of tumors. Methods and Results Biocompatible PTM nanoparticles (PTM NPs) were fabricated by enclosing PTM with Pluronic F-127. The results of optical and photothermal properties of PTM NPs showed robust near-infrared (NIR) absorption, excellent photostability and high photothermal conversion efficiency (56.9%). The results of flow cytometry, fluorescence microscopy, apoptosis, CCK-8 assays and animal experiments showed that PTM NPs had a good killing effect on tumors under NIR laser irradiation. Furthermore, mechanistic studies, RNA-seq and biological analysis revealed that PTM NPs can cause tumor cell death via DNA damage-mediated apoptosis. Conclusion Light-induced thermal ablation effects of PTM NPs in vitro and vivo were surveyed. Collectively, our studies provided a new approach to developing a safe and effective photothermal agent for cancer treatment., Graphical Abstract

This research investigated a novel folic acid(FA)-modified zirconium core metal-organic framework(MOF) Uio-66 as a nanocarrier to deliver indocyanine green(ICG) and Sunitinib to cancer cells for combination therapy. Platinum-loaded Uio-66 nanoparticles(Pu) were synthesized via a one-pot method, followed by the modification with FA on their surfaces. This afforded FPu that enabled subsequent loading of ICG and Sunitinib to achieve dualmodal cancer therapy. Drug loading/release test and singlet oxygen detection were also conducted in vitro, and the nanoparticles showed considerable drug loading efficiency for both ICG and Sunitinib, coupled with a high singlet oxygen generation rate. Specifically, drug loading and encapsulation efficiency of Sunitinib were 2.30% and 72.67%, while those for ICG were 2.87% and 90.28%, respectively. Additionally, cytotoxicity test on HepG2 human hepatocellular carcinoma cancer cell line revealed that the fully functional nanoparticles possess excellent biocompatibility and as such could be further investigated as a potential drug delivery system for effectual carcinoma cancer treatment.

Unlike stable atherosclerotic plaques, vulnerable plaques are very likely to cause serious cardio-cerebrovascular diseases. Meanwhile, how to non-invasively identify vulnerable plaques at early stages has been an urgent but challenging problem in clinical practices. Here, we propose a macrophage-targeted and in situ stimuli-triggered T1–T2 switchable magnetic resonance imaging (MRI) nanoprobe for the non-invasive diagnosis of vulnerable plaques. Precisely, single-dispersed iron oxide nanoparticles (IONPs) modified with hyaluronic acid (HA), denoted as IONP-HP, show macrophage targetability and T1 MRI enhancement (r2/r1 = 3.415). Triggered by the low pH environment of macrophage lysosomes, the single-dispersed IONP-HP transforms into a cluster analogue, which exhibits T2 MRI enhancement (r2/r1 = 13.326). Furthermore, an in vivo switch of T1–T2 enhancement modes shows that the vulnerable plaques exhibit strong T1 enhancement after intravenous administration of the nanoprobe, followed by a switch to T2 enhancement after 9 h. In contrast, stable plaques show only slight T1 enhancement but without T2 enhancement. It is therefore imperative that the intelligent and novel nanoplatform proposed in this study achieves a substantial non-invasive diagnosis of vulnerable plaques by means of a facile but effective T1–T2 switchable process, which will significantly contribute to the application of materials science in solving clinical problems.

Motivation Tumor stratification has a wide range of biomedical and clinical applications, including diagnosis, prognosis and personalized treatment. However, cancer is always driven by the combination of mutated genes, which are highly heterogeneous across patients. Accurately subdividing the tumors into subtypes is challenging. Results We developed a network-embedding based stratification (NES) methodology to identify clinically relevant patient subtypes from large-scale patients’ somatic mutation profiles. The central hypothesis of NES is that two tumors would be classified into the same subtypes if their somatic mutated genes located in the similar network regions of the human interactome. We encoded the genes on the human protein–protein interactome with a network embedding approach and constructed the patients’ vectors by integrating the somatic mutation profiles of 7344 tumor exomes across 15 cancer types. We firstly adopted the lightGBM classification algorithm to train the patients’ vectors. The AUC value is around 0.89 in the prediction of the patient’s cancer type and around 0.78 in the prediction of the tumor stage within a specific cancer type. The high classification accuracy suggests that network embedding-based patients’ features are reliable for dividing the patients. We conclude that we can cluster patients with a specific cancer type into several subtypes by using an unsupervised clustering algorithm to learn the patients’ vectors. Among the 15 cancer types, the new patient clusters (subtypes) identified by the NES are significantly correlated with patient survival across 12 cancer types. In summary, this study offers a powerful network-based deep learning methodology for personalized cancer medicine. Availability and implementation Source code and data can be downloaded from https://github.com/ChengF-Lab/NES. Supplementary information Supplementary data are available at Bioinformatics online.

Summary Checkpoint blocking-based immunotherapy has been proved to be effective for the treatment of cancer, but its dependence on T cell infiltration has limited its effectiveness across patients. Radiotherapy (RT) is becoming the most common method of clinical tumor treatment but can occasionally cause systemic tumor rejection. Here, we demonstrate a simple one-pot hydrothermal method to synthesize tellurium (Te) nanostars (GTe-RGD) and offer a treatment strategy that combines GTe-RGD-potentiated RT with checkpoint blockade immunotherapy for efficient and systemic tumor elimination. In mouse models of breast cancer, GTe-RGD-potentiated RT not only eradicated primary tumors but also elicited antitumor immunity to inhibit growth at distant sites by enhancing cytotoxic T lymphocytes when combined with an immune checkpoint inhibitor. Furthermore, the triggered release of tumor-associated antigens and cytokines can effectively reduce the percentage of M2 macrophages with enhanced antitumor activity. Thus, this simply synthesized Te-based nanomedicine, with radiation-driven immunotherapy, offers an attractive clinical alternative for tumor treatment.

Diabetes mellitus is a lifelong metabolic disease that requires frequent subcutaneous injections of insulin. However, this method of administration can be associated with patient discomfort and local tissue infection. Oral delivery of insulin has been pursued as a more convenient method for diabetes treatment, given its likely superior patient compliance and convenience as well as cost-effectiveness. However, various biological barriers hinder the clinical translation of oral insulin. The rapid development of nanotechnology over the last decade offers great promise in improving the bioavailability of oral insulin. This Minireview provides an overview of biological barriers to oral insulin delivery, summarizes significant technological advances, and outlines future perspectives in oral insulin formulations as well as their hypoglycaemic effects.

A method is developed to fabricate tumor microenvironment (TME) stimuli-responsive nanoplatform for fluorescence (FL) imaging and synergistic cancer therapy via assembling photosensitizer (chlorine e6, Ce6) modified carbon dots (CDs-Ce6) and Cu2+ . The as-obtained nanoassemblies (named Cu/CC nanoparticles, NPs) exhibit quenched FL and photosensitization due to the aggregation of CDs-Ce6. Their FL imaging and photodynamic therapy (PDT) functions are recovered efficiently once they entering tumor sites by the stimulation of TME. Introducing of Cu2+ not only provides extra chemodynamic therapy (CDT) function through reaction with hydrogen peroxide (H2 O2 ), but also depletes GSH in tumors by a redox reaction, thus amplifying the intracellular oxidative stress and enhancing the efficacy of reactive oxygen species (ROS) based therapy. Cu/CC NPs can act as a FL imaging guided trimodal synergistic cancer treatment agent by photothermal therapy (PTT), PDT, and thermally amplified CDT.

Background Management of distal humerus metaphyseal-diaphyseal junction (MDJ) region fractures can be very challenging mainly because of the higher location and characteristics of the fracture lines. Loss of reduction is relatively higher in MDJ fractures treated with classical supracondylar humerus fractures (SHFs) fixation techniques. Methods Three different fracture patterns including transverse, medial oblique and lateral oblique fractures were computationally simulated in the coronal plane in the distal MDJ region of a pediatric humerus and fixated with Kirschner Wires (K-wires), elastic stable intramedullary nails (ESIN), and lateral external fixation system (EF). Stiffness values in flexion, extension, valgus, varus, internal, and external rotations for each fixation technique were calculated. Results In the transverse fracture model, 3C (1-medial, 2-lateral K-wires) had the best stiffness in flexion, varus, internal, and external rotations, while 3L (3-divergent lateral K-wires) was the most stable in extension and valgus. In the medial oblique fracture model, EF had the best stiffness in flexion, extension, valgus, and varus loadings, while the best stiffness in internal and external rotations was generated by 3MC (2-medial, 1-lateral K-wires). In the lateral oblique fracture model, 3C (1-medial, 2-lateral K-wires) had the best stiffness in flexion and internal and external rotations, while ESIN had the best stiffness in extension and valgus and varus loadings. Conclusion The best stability against translational forces in lateral oblique, medial oblique, and transverse MDJ fractures would be provided by ESIN, EF, and K-wires, respectively. K-wires are however superior to both ESIN and EF in stabilizing all three fracture types against torsional forces, with both 2-crossed and 3-crossed K-wires having comparable stability. Depending on the fracture pattern, a 3-crossed configuration with either 2-divergent lateral and 1-medial K-wires or 2-medial and 1-lateral K-wires may offer the best stability.

At present, cancer is obviously a major threat to human health worldwide. Accurate diagnosis and treatment are in great demand and have become an effective method to alleviate the development of cancer and improve the survival rate of patients. A large number of theranostic probes that combine diagnosis and treatment methods have been developed as promising tools for tumor precision medicine. Among them, fluorescent theranostic probes have developed rapidly in the frontier research field of precision medicine with their real time, low toxicity, and high-resolution merit. Therefore, this review focuses on recent advances in the development of fluorescent theranostic probes, as well as their applications for cancer diagnosis and treatment. Initially, small-molecule fluorescent theranostic probes mainly including tumor microenvironment-responsive fluorescent prodrugs and phototherapeutic probes were introduced. Subsequently, nanocomposite probes are expounded based on four types of nano-fluorescent particles combining different therapies (chemotherapy, photothermal therapy, photodynamic therapy, gene therapy, etc.). Then, the capsule-type "all in one" probes, which occupy an important position in theranostic probes, are summarized according to the surface carrier type. This review aims to present a comprehensive guide for researchers in the field of tumor-related theranostic probe design and development.

As nanomedicine-based clinical strategies have continued to develop, the possibility of combining chemotherapy and singlet oxygen-dependent photodynamic therapy (PDT) to treat pancreatic cancer (PaC) has emerged as a viable therapeutic modality. The efficacy of such an approach, however, is likely to be constrained by the mechanisms of drug release and tumor oxygen levels. In the present study, we developed an Fe(III)-complexed porous coordination network (PCN) which we then used to encapsulate PTX (PCN-Fe(III)-PTX) nanoparticles (NPs) in order to treat PaC via a combination of chemotherapy and PDT. The resultant NPs were able to release drug in response to both laser irradiation and pH changes to promote drug accumulation within tumors. Furthermore, through a Fe(III)-based Fenton-like reaction these NPs were able to convert H2O2 in the tumor site to O2, thereby regulating local hypoxic conditions and enhancing the efficacy of PDT approaches. Also these NPs were suitable for use as a T1-MRI weighted contrast agent, making them viable for monitoring therapeutic efficacy upon treatment. Our results in both cell line and animal models of PaC suggest that these NPs represent an ideal agent for mediating effective MRI-guided chemotherapy-PDT, giving them great promise for the clinical treatment of PaC.

The emerging properties of mimicking enzymes open up new horizons for nanomaterials. Regulating their enzyme-like activity and exploiting their applications are currently the hot topics for nanozymes. Among their activities, the pro-oxidant and antioxidant capabilities of nanozymes are important to determine their unique physiological functions. In this paper, we demonstrate that PtRu NPs exhibit multiple enzyme-like activities (e.g. peroxidase, oxidase, ferroxidase, catalase and SOD) and 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity. The PtRu bimetallic nanozymes therefore show pro-oxidant and anti-oxidant functions. It was found that the enzyme-like activities of PtRu NPs are highly dependent on the Pt/Ru molar ratio and show a similar trend in the order of activity: Pt90Ru10 > Pt75Ru25 > Pt > Pt40Ru60, indicating that proper alloying of Pt with Ru can enhance both pro- and anti-oxidant capabilities. By employing the ferroxidase-like activity and catalase-like activity, we verified the applications of PtRu nanozymes in the detection of Fe2+ ions, and tried for the first time to protect Monascus pigments (MPs) from hydrogen peroxide oxidation. These results not only provide an effective way to optimize the pro- and anti-oxidant capabilities of nanozymes, but also provide prospects for the applications of nanozymes in protecting biologically active natural products.

Temperature-sensitive liposomes (TSLs) have received constant attention due to the release of contents around the physiological temperature, which holds great potential in the treatment of tumors. However, the development of TSLs is limited by the long-term biotoxicity and low photothermal conversion efficiency of heat-generation materials. In this study, we develop a new D-A (donor-acceptor) structure NIR absorbing dye (C720) which exhibits a high photothermal conversion efficiency (62%), good photostability, and photothermal reproducibility. Then C720 is doped in the lipid bilayer and DOX (doxorubicin) is wrapped in the core of temperature sensitive liposomes to construct a C720 and DOX-loaded thermosensitive nanoplatform (CDTSL). The as-prepared CDTSL achieves NIR light controlled drug release and can be applied for photoacoustic imaging. In vitro and in vivo studies confirm that CDTSL exhibits high tumor suppressive efficiency by synergistic photothermal therapy and chemotherapy. Our research provides fundamental insights for the rational design and preparation of a promising nanoplatform for photoacoustic imaging and chemo-photothermal therapy.

The neuroprotective effect of electroacupuncture (EA) treatment has been well studied; growing evidence suggests that changes in lipid composition may be involved in the pathogenesis of posttraumatic stress disorder (PTSD) and may be a target for treatment. However, the influence of early EA intervention on brain lipid composition in patients with PTSD has never been investigated. Using a modified single prolonged stress (mSPS) model in mice, we assessed the anti-PTSD-like effects of early intervention using EA and evaluated changes in lipid composition in the hippocampus and prefrontal cortex (PFC) using a mass spectrometry-based lipidomic approach. mSPS induced changes in lipid composition in the hippocampus, notably in the content of sphingolipids, glycerolipids, and fatty acyls. These lipid changes were more robust than those observed in the PFC. Early intervention with EA after mSPS ameliorated PTSD-like behaviors and partly normalized mSPS-induced lipid changes, notably in the hippocampus. Cumulatively, our data suggest that EA may reverse mSPS-induced PTSD-like behaviors due to region-specific regulation of the brain lipidome, providing new insights into the therapeutic mechanism of EA.

Echovirus 11 (Echo 11) is a serotype of Enterovirus B (EV-B) belonging to the genus Enterovirus in the family Picornaviridae . Echo 11 infections are associated with viral encephalitis (VE), viral meningitis (VM), and viral meningo-encephalitis (VME). Echo 11 was reported to cause severe illnesses in neonates or infants, with high morbidity and mortality. In addition, Echo 11 has frequently been identified as the causative agent of outbreaks, greatly threatens public health. For example, in early 2019, an Echo 11 outbreak occurred in a hospital of Guangdong Province in China, leading to nineteen infections of newborns and five of them died. CD55 has been designated an attaching receptor of several echoviruses in the 1990s. But CD55 alone is unable to help the virus to complete its whole entry process. In our earlier work, we found that the human neonatal Fc receptor (FcRn) is the cellular uncoating receptor for Enterovirus B and illustrated the entry mechanism taking Echo 6 as an example. We proposed the coordination of attaching and uncoating “dual-receptor system” in the entry pathways. Here, we analyzed 10 cryo-electron microscopy (Cryo-EM) structures of Echo 11 viral particles in three different forms (free, “A-particle” and empty particle), and Echo 11 in complex with receptor CD55 or FcRn, under both neutral (pH 7.4) and acidic (pH 5.5) conditions. With atomic or near-atomic resolutions (2.32−3.4 A), we obtained detailed characterization of the molecular events during Echo 11 entry. The structures revealed that CD55 is the attaching receptor of Echo 11, which facilitates the viral attachment to cell surface. Similar to Echo 12 and Echo 7, Echo 11 uses its VP2 and VP3 domain to bind short consensus repeat (SCR) module SCR 3 and SCR4 domains of CD55. FcRn is the uncoating receptor, which uses the α2 domain of its heavy chain FCGRT to insert into and bind the “canyon” of Echo 11 VP1 domain. The binding induced the extrusion of “pocket factor” and resulted in virus uncoating and genome release. FcRn induced Echo 11 viral particle conformational change and “pocket factor” release started at neutral pH, which is different from Echo 6, there the “pocket factor” release occurs at low pH. This hints us that acidic treatment might not be an essential requirement for the uncoating of all Enterovirus B which uses FcRn as their uncoating receptor. The uncoating process is able to start in early endosomes. SPR (Surface plasmon resonance) analysis certified that, Echo 11 can bind to both receptors, but has a higher affinity with FcRn than to CD55. FcRn-mediated Echo 11 uncoating was further confirmed with an FcRn-decorated liposome model, which induced the structural transitions of Echo 11 into empty particles. This work provided a molecular and structural basis for our understanding of the mechanisms of Echo 11 entry. And it is an important progress in dissecting the mechanism of the “dual-receptor system” in non-enveloped virus entry.

Summary Apoptotic cell clearance by macrophages (efferocytosis) promotes resolution signaling pathways, which can be triggered by molecules derived from the phagolysosomal degradation of apoptotic cells. We show here that nucleotides derived from the hydrolysis of apoptotic cell DNA by phagolysosomal DNase2a activate a DNA−PKcs−mTORC2/Rictor pathway that increases Myc to promote non-inflammatory macrophage proliferation. Efferocytosis-induced proliferation expands the pool of resolving macrophages in vitro and in mice, including zymosan-induced peritonitis, dexamethasone-induced thymocyte apoptosis, and atherosclerosis regression. In the dexamethasone-thymus model, hematopoietic Rictor deletion blocked efferocytosing macrophage proliferation, apoptotic cell clearance, and tissue resolution. In atherosclerosis regression, silencing macrophage Rictor or DNase2a blocked efferocyte proliferation, apoptotic cell clearance, and plaque stabilization. In view of previous work showing that other types of apoptotic cell cargo can promote resolution in individual efferocytosing macrophages, the findings here suggest that signaling-triggered apoptotic cell-derived nucleotides can amplify this benefit by increasing the number of these macrophages.

BACKGROUND Fermented soya bean meal (FSBM) is believed to have improved nutritional qualities compared with soya bean meal (SBM) and is also cheaper than soya protein concentration (SPC) and fish meal (FM). Therefore, the present study was conducted to compare the effects of FSBM replacing SBM, SPC and FM in diets on growth performance, serum biochemistry profile, short-chain fatty acid concentrations in digesta, intestinal mucosal enzyme activities, intestinal proinflammatory cytokine concentrations and morphology in weaned piglets. One hundred and twenty 28-day-old piglets (Duroc × Landrace × Yorkshire, body weight: 6.73 ± 1.14 kg) were randomly allocated to four treatment diets (six replicate pens with five piglets per pen) containing SBM, SPC, FM or FSBM as the protein source, respectively. RESULTS Dietary FSBM supplementation improved average daily gain (p

The existence of cancer stem cells (CSCs) poses a major obstacle for the success of current cancer therapies, especially the fact that non-CSCs can spontaneously turn into CSCs, which lead to the failure of the treatment and tumor relapse. Therefore, it is very important to develop effective strategies for the eradication of the CSCs. In this work, we have developed a CSCs-specific targeted, retinoic acid (RA)-loaded gold nanostars-dendritic polyglycerol (GNSs-dPG) nanoplatform for the efficient eradication of CSCs. The nanocomposites possess good biocompatibility and exhibit effective CSCs-specific multivalent targeted capability due to hyaluronic acid (HA) decorated on the multiple attachment sites of the bioinert dendritic polyglycerol (dPG). With the help of CSCs differentiation induced by RA, the self-renewal of breast CSCs and tumor growth were suppressed by the high therapeutic efficacy of photothermal therapy (PTT) in a synergistic inhibitory manner. Moreover, the stemness gene expression and CSC-driven tumorsphere formation were significantly diminished. In addition, the in vivo tumor growth and CSCs were also effectively eliminated, which indicated superior anticancer activity, effective CSCs suppression, and prevention of relapse. Taken together, we developed a CSCs-specific targeted, RA-loaded GNSs-dPG nanoplatform for the targeted eradication of CSCs and for preventing the relapse.

The modulation of intracellular reactive oxygen species (ROS) levels is crucial for cellular homeostasis and determination of cellular fate. A sublethal level of ROS sustains cell proliferation, differentiation and promotes tumor metastasis, while a drastic ROS burst directly induces apoptosis. Herein, surface-oxidized arsenene nanosheets (As/AsxOy NSs) with type II heterojunction are fabricated with efficient ·O2− and 1O2 production and glutathione consumption through prolonging the lifetime of photo-excited electron-hole pairs. Moreover, the portion of AsxOy with oxygen vacancies not only catalyzes a Fenton-like reaction, generating ·OH and O2 from H2O2, but also inactivates main anti-oxidants to cut off the “retreat routes” of ROS. After polydopamine (PDA) and cancer cell membrane (M) coating, the engineered As/AsxOy@PDA@M NSs serve as an intelligent theranostic platform with active tumor targeting and long-term blood circulation. Given its narrow-band-gap-enabled in vivo fluorescence imaging properties, As/AsxOy@PDA@M NSs could be applied as an imaging-guided non-invasive and real-time nanomedicine for cancer therapy., Multifunctional materials with a number of effects are important for dealing with the complex environment in cancer therapy. Here, the authors report on surface-oxidized arsenene nanosheets coated with polydopamine and cancer cell membrane as a multi theranostic tumour targeting cancer therapy.

Ozone (O3) stress severely affects the normal growth of grape (Vitis vinifera L.) leaves. Melatonin (MT) plays a significant role in plant response to various abiotic stresses, but its role in O3 stress and related mechanisms are poorly understood. In order to understand the mechanism of MT in alleviate O3 stress in grape leaves, we perform a transcriptome analyses of grapes leaves under O3 stress with or without MT treatment. Transcriptome analysis showed that the processes of ethylene biosynthesis and signaling were clearly changed in “Cabernet Sauvignon” grapes under O3 and MT treatment. O3 stress induced the expression of genes related to ethylene biosynthesis and signal transduction, while MT treatment significantly inhibited the ethylene response mediated by O3 stress. Further experiments showed that both MT and aminoethoxyvinylglycine (AVG, an inhibitor of ethylene biosynthesis) enhanced the photosynthetic and antioxidant capacities of grape leaves under O3 stress, while ethephon inhibited those capacities. The combined treatment effect of MT and ethylene inhibitor was similar to that of MT alone. Exogenous MT reduced ethylene production in grape leaves under O3 stress, while ethephon and ethylene inhibitors had little effect on the MT content of grape leaves after O3 stress. However, overexpression of VvACO2 (1-aminocyclopropane-1-carboxylate oxidase2) in grape leaves endogenously induced ethylene accumulation and aggravated O3 stress. Overexpression of the MT synthesis gene VvASMT1 (acetylserotonin methyltransferase1) in tobacco (Nicotiana tabacum L.) alleviated O3 stress and reduced ethylene biosynthesis after O3 stress. In summary, MT can alleviate O3 stress in grape leaves by inhibiting ethylene biosynthesis.

Magnetic resonance imaging (MRI) has received significant attention as the noninvasive diagnostic technique for complex diseases. Image-guided therapeutic strategy for diseases such as cancer has also been at the front line of biomedical research, thanks to the innovative MRI, enhanced by the prior delivery of contrast agents (CAs) into patients' bodies through injection. These CAs have contributed a great deal to the clinical utility of MRI but have been based on metal-containing compounds such as gadolinium, manganese, and iron oxide. Some of these CAs have led to cytotoxicities such as the incurable Nephrogenic Systemic Fibrosis (NSF), resulting in their removal from the market. On the other hand, CAs based on organic nitroxide radicals, by virtue of their structural composition, are metal free and without the aforementioned drawbacks. They also have improved biocompatibility, ease of functionalization, and long blood circulation times, and have been proven to offer tissue contrast enhancement with longitudinal relaxivities comparable with those for the metal-containing CAs. Thus, this Review highlights the recent progress in metal-based CAs and their shortcomings. In addition, the remarkable goals achieved by the organic nitroxide radical CAs in the enhancement of MR images have also been discussed extensively. The focal point of this Review is to emphasize or demonstrate the crucial need for transition into the use of organic nitroxide radicals-metal-free CAs-as against the metal-containing CAs, with the aim of achieving safer application of MRI for early disease diagnosis and image-guided therapy.

Microcystins (MCs) pose a great threat to human health due to their toxicity. In this study, photoelectrocatalysis was applied as an effective technology to degrade MCs. The effects of different dimensionally stable anodes and cathodes were evaluated. Detoxification effects were investigated using a luminescence inhibition assay, a micronucleus assay of Vicia faba root tips and a single cell gel electrophoresis assay. The results show that RuO2-TiO2/Ti and stainless steel were the best among the six anodes and four cathodes tested for MCLR degradation. Compared to photodegradation, photocatalysis and electrocatalysis, photoelectrocatalysis obtained the highest efficiency on MCLR degradation, nearly 100% at 254 nm and 5.0 mA/cm2. The degradation kinetics agreed with the Langmuir-Hinshelwood kinetic model. When NaCl was used as an electrolyte, the degradation efficiency of MCLR reached 100% even under 0.002 mol/L, which was much better than that of Na2SO4, Na2HPO4 and NaNO3. The toxicity assays showed that although MCLR was completely degraded, acute toxicity still occurred in the solution at relative luminosities from 0 to 9.37%. However, the micronucleus efficiency and DNA damage of cells returned to normal levels at the end of the reaction. This indicates that genotoxicity and cytotoxicity were eliminated with the degradation of MCLR.

Prostate cancer (PCa) is one of the major cancers affecting males with high mortality around the world. Recent studies have found that some long noncoding RNAs play a critical part in the cellular processes of PCa. In our study, aberrant expressed lymphoid enhancer-binding factor-1 antisense RNA 1 (LEF1-AS1), microRNA-330-5p (miR-330-5p), and lymphoid enhancer-binding factor-1 (LEF1) were screened out from a microarray database, the role of the novel noncoding RNA regulatory circuitry in the initiation and development of PCa was investigated. LEF1-AS1 and LEF1 were highly expressed while miR-330-5p was poorly expressed in PCa. Following that, the PCa PC-3 cell line was adopted for subsequently experiments, in which the expression of LEF1-AS1 and miR-330-5p was subsequently altered by means of exogenous transfection. After that, the effects of up- or downregulation of LEF1-AS1 and miR-330-5p on epithelial-mesenchymal transition (EMT) and the cell ability for proliferation, invasion, migration in vitro, and tumorigenesis and lymph node metastasis (LNM) in vivo were evaluated. RNA crosstalk revealed that LEF1-AS1 bound to miR-330-5p and LEF1 was the target gene of miR-330-5p. Silenced LEF1-AS1 or elevated miR-330-5p exhibited inhibited EMT processes, reduced ability of proliferation, invasion and migration, coupling with decreased tumorigenesis and LNM in nude mice. The key findings of this study collectively propose downregulation of LEF1-AS1 competing with miR-330-5p to inhibit EMT, invasion and migration of PCa by LEF1 repression.

Steam reforming of toluene, a model tar compound, was carried out at low temperature of 600 °C using Cu–Ni and Fe–Ni bimetallic catalysts with different molar ratios supported on activated carbon (AC). For the Cu–Ni/AC catalysts, the carbon conversion of toluene rose and then decreased with the content of Cu increasing, and the best performance was achieved at the molar ratio of 0.2. However, the Fe–Ni/AC catalyst with the optimum composition of Fe/Ni = 0.1 had a better catalytic performance for toluene steam reforming than the Cu–Ni/AC catalyst (Cu/Ni = 0.2). During the duration test of 20 h, the Fe–Ni/AC (Fe/Ni = 0.1) catalyst showed higher activity for the average carbon conversion of toluene (93.8% vs. 92.9%) and better resistance. to carbon deposition than those of Ni/AC catalyst. Moreover, the metal average sizes of the spent Ni/AC and 0.1-Fe–Ni/AC were estimated to be 30.0 nm and 19.0 nm, respectively. Based on a variety of physiochemical characterization results, it is demonstrated that the addition of iron into Ni/AC catalyst led to good dispersion of Ni, and few coke formation and limited aggregation of nickel particles during reaction.

This study aimed to explore the relationship of loneliness, perceived stress, and depressive symptoms among the Chinese rural empty nest elderly. The role of sense of coherence (SOC) as a moderating variable was investigated in a representative sample of older adults in Henan, China, from November 2016 to February 2017. Results indicated that perceived stress mediated the relationship between loneliness and depressive symptoms, and SOC acted as a moderator on this mediating model. The mediation effect of perceived stress was significant only when SOC was lower. The results emphasized the importance of perceived stress in older adults. SOC was a protective factor with regard to depressive symptoms, and improving SOC should be a focus of health promotion with the elderly.

A correlative materials analysis approach reveals perturbed bone growth in a mouse model of premetastatic breast cancer., Breast cancer frequently metastasizes to bone, causing osteolytic lesions. However, how factors secreted by primary tumors affect the bone microenvironment before the osteolytic phase of metastatic tumor growth remains unclear. Understanding these changes is critical as they may regulate metastatic dissemination and progression. To mimic premetastatic bone adaptation, immunocompromised mice were injected with MDA-MB-231–conditioned medium [tumor-conditioned media (TCM)]. Subsequently, the bones of these mice were subjected to multiscale, correlative analysis including RNA sequencing, histology, micro–computed tomography, x-ray scattering analysis, and Raman imaging. In contrast to overt metastasis causing osteolysis, TCM treatment induced new bone formation that was characterized by increased mineral apposition rate relative to control bones, altered bone quality with less matrix and more carbonate substitution, and the deposition of disoriented mineral near the growth plate. Our study suggests that breast cancer–secreted factors may promote perturbed bone growth before metastasis, which could affect initial seeding of tumor cells.

The design and synthesis of near-infrared (NIR) emissive fluorophores for the imaging of organelles and photodynamic therapy have received enormous attention. Hence, the development of NIR emissive fluorophores for high-fidelity lysosome targeting, two-photon fluorescence imaging, and the inducing of photo-triggered cancer-cell apoptosis is highly desirable. In this study, a novel lysosome-targeting two-photon fluorescent photosensitizer (TTRh-CN) is prepared and comprehensively investigated. TTRh-CN demonstrates near-infrared (NIR) emission, good biocompatibility, and superior photostability, and it can act as a two-photon fluorescent agent for the clear visualization of living cells and the vascular system within tissue, with deep-tissue penetration abilities. Furthermore, TTRh-CN can efficiently produce ROS in conjunction with lysosomes in situ upon light irradiation, which can damage lysosomes, up-regulate LC3 and Beclin1, increase BAX release, and induce cell apoptosis. The efficacy of TTRh-CN as a photosensitizer is explored in vivo. All these results confirm that TTRh-CN can serve as a potential platform for the two-photon fluorescence imaging of cells/tissue and for organelle-specific photodynamic therapy.

Antibody-dependent enhancement (ADE) has been reported for SARS-CoV and MERS-CoV, suggesting the risk of ADE for antibody-based SARS-CoV-2 vaccines and therapeutics. Understanding the underlying molecular mechanisms behind ADE of SARS-CoV-2 is critical for development of safe and effective therapies. Here, we report that two neutralizing mAbs MW01 and MW05 could enhance the infection of SARS-CoV-2 on FcγRIIB-expressing B cells. Enhancing the interaction of Fc with FcγRIIB could increase the ADE activity mediated by MW01 and MW05. Expression of other FcγRs, such as FcγRIA and FcγRIIA, could decrease ADE activity of these two mAbs by competing with FcγRIIB. X-ray crystal structure determination and S trimer-binding modeling showed that MW01 and MW05 can bind to RBDs in S trimer with both “up” and “down” states. While, the neutralizing mAb MW07, which has no ADE activity only binds to RBD in S trimer with “up” state. Monovalent MW01 and MW05 completely diminished the ADE activity compared with their bivalent counterparts. Moreover, both macropinocytosis and endocytosis are confirmed involving in ADE of SARS-CoV-2 infection. Blocking endosome transportation and lysosome acidification could inhibit the ADE activity mediated by MW05. Together, our results identified a novel ADE mechanism of SARS-CoV-2, FcγRIIB-mediated uptake of SARS-CoV-2/mAb complex with bivalent interaction. These findings provide a novel perspective on the mechanism of ADE of SARS-CoV-2, which is informative to the development of safer therapeutics and vaccines. Funding Information: This work was supported by National Key R&D Program (2020YFC0848600 to S.W. and 2020YFC0860700 to L.W.). Declaration of Interests: X.G., S.W., S.J., W.J. and C.G. are listed as inventors on the licensed patents for MW05 and MW07. S.W., S.J., W.J., M.W., Z.L., C.G., B.C., H.C., A.W., G.L., C.G., X.G., J.Z. and D.L. are employees of Mabwell (Shanghai) Bioscience Co., Ltd. and may hold shares in Mabwell (Shanghai) Bioscience Co., Ltd. The other authors declare no competing interests.