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CoRNR motif of HBXIP is required for co-activation of LXRs in a ligand-independent manner.

Supplementary Materials and Methods. Table S1. The positive rate of HBXIP is 87.5% (329/376) in 3 groups of atypical duct hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive breast cancer (IBC). Table S2. The expression levels of HBXIP were shown in the tumor tissues. Table S3. The expression and pathological features of HBXIP were shown in 236 clinical breast cancer tissues. Table S4. Cross tabulation analysis of HBXIP and FAS is shown in cancer tissues. Table S5. Primers for promoter of lipid metabolism genes are shown in the table. Table S6. Antibodies are used in this paper. Table S7. Detailed information of tumor tissues was shown in this table.

Episodic memory is thought to be preferentially encoded by sparsely distributed memory-eligible “primed” neurons in memory-related regions. Based onin vivocalcium imaging on freely behaving mice, we developed an analytical method to determine neuronal activity hierarchy and establish hippocampal primed neurons. Neurons with high activity and memory-associated burst synchronization are identified as primed neurons. When a trace fear memory is being formed or retrieved, the major pattern of the calcium dynamics is predominantly mediated by primed neurons and highly correlated with mouse freezing behaviors. In cilia knockout mice that exhibit severe learning deficits, the percentage of their primed neurons is drastically reduced, and any burst synchronization is strongly suppressed. Consistently, the first principal pattern of cilia knockout neurons does not fully distinguish itself from other minor components or correlate with mouse freezing behaviors. To reveal how a portion of neurons get primed, we developed a numerical model of a simplified neural network that incorporates simulations of linear and non-linear weighted postsynaptic conductance, modeling AMPAR- and NMDAR-mediated conductances respectively. Moderate non-linear to linear conductance ratios can naturally lead to the emergence of primed neurons. In such cases, the neuronal firing averages show a right-skewed log-distribution, similar to the distributions of hippocampal c-Fos expression and the activity levels measured by calcium imaging. Together, this study reveals a novel method to determine neuronal activity hierarchy. Our simulation suggests that the accumulation of biased synaptic transmission mediated by the non-linear synaptic component represents an important mechanism for neuronal priming.

Inducing mitochondrial malfunction is an appealing strategy to overcome tumor multidrug resistance (MDR). Reported here a versatile mitochondrial-damaging molecule, vitamin E succinate (VES), is creatively utilized to assist MDR reversal of doxorubicin hydrochloride (DOX·HCl) via a nanovesicle platform self-assembled from amphiphilic polyphosphazenes containing pH-sensitive 1H-benzo-[d]imidazol-2-yl) methanamine (BIMA) groups. Driven by multiple non-covalent interactions, VES is fully introduced into the hydrophobic membrane of DOX·HCl-loaded nanovesicles with loading content of 23.5%. The incorporated VES also offers robust anti-leakage property toward DOX·HCl under normal physiological conditions. More importantly, upon release within acidic tumor cells, VES can target mitochondria and result in various dysfunctions including excessive generation of reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) loss, and inhibited adenosine triphosphate (ATP) synthesis, which contribute to cell apoptosis and insufficient energy supply for drug efflux pumps. Consequently, the killing-effect of DOX·HCl is significantly enhanced toward drug resistant cancer cells at the optimal mass ratio of DOX·HCl to VES. Further in vivo antitumor investigation on nude mice bearing xenograft drug-resistant human chronic myelogenous leukemia K562/ADR tumors verifies the extremely enhanced anti-tumor efficacy of the dual drug-loaded nanovesicle with the tumor inhibition rate (TIR) of 82.38%. Collectively, this study provides a s safe, facile and promising strategy for both precise drug delivery and MDR eradication to improve cancer therapy.

The in vivo delivery of nanomedicine is severely hampered by the limited enhanced permeability and retention effect (EPR) in tumors. Aiming at overcoming this limitation and achieving high anti-tumor effect of chemotherapeutics, we specially addressed an available strategy from a viewpoint of increasing the drug loading of nano-carriers. Here, we constructed a novel pH-responsive polymersome based on the drug-driven self-assembly of amphiphilic polyphosphazenes PAP containing the ortho ester group ABD and mPEG2000. Due to the non-covalent attractive forces between PAP and doxorubicin hydrochloride (DOX·HCl), DOX·HCl can induce the self-assembly of PAP via embedding itself in the lamella to form vesicles and the subsequent location in the center aqueous chamber of the resultant nano-vesicles, which resulted in the high drug loading content of 35.77 wt%. In addition, with the incorporation of cholesteryl hemisuccinate (CholHS), the premature leakage of DOX·HCl was significantly inhibited under physiological conditions. Meanwhile, the pH-sensitive drug release occurred at pH 5.5 by the advantage of the pH-sensitive biodegradation of ABD in PAP. Consequently, this CholHS-incorporated DOX·HCl-driven PAP vesicle achieved excellent anti-tumor effect with tumor growth inhibition up to 82.4% in S180 tumor-bearing mice. Taken together, our newly developed drug-driven vesicles may promote the development of efficient drug delivery systems for application in cancer therapy.

Background: Traumatic dental injuries (TDIs) are considered a public health problem as it occurs frequently and negatively impacts quality of life. The aim of this study was to assess the knowledge of preschool staff in Shanghai with regard to TDIs first-aid and the management of broken teeth.Methods: A cross-sectional survey was carried out among the staff at selected preschools. A stratified random sampling method was first used to identify suitable subjects. Data were obtained using a self-completed questionnaire. Results: A total of 1,069 subjects completed the questionnaire. According to the survey, 25% of teachers correctly answered that the tooth should be replanted in the original alveolar. 48% of teachers knew that avulsed teeth should be stored in a liquid environment, 66% knew that broken teeth should be stored in saline, and 11.8% knew that broken teeth could be stored in fresh milk. 35.4% of teachers with college degree or above chose to store the avulsed teeth in a liquid environment, and 5.9% of teachers with a high school degree or below made the same choice (χ2=2.890, p=0.009). Conclusions: The level of first-aid knowledge among preschool teachers in Shanghai regarding TDIs was low.

Objective. It is imperative to popularize the tertiary prevention of chronic obstructive pulmonary disease (COPD) and to improve the diagnosis and treatment. Methods. COPD patients were divided into mild (n = 18), moderate (n = 20), severe (n = 24), and extremely severe (n = 22) groups for performing high-resolution computed tomography (HRCT) and pulmonary function test. Serum procalcitonin (PCT) and high-sensitivity C-reactive protein (hs-CRP) were detected, and the occurrence rate of acute exacerbation COPD (AECOPD) was recorded during a 12-months follow-up period. Results. With an increase in the severity grade, the HRCT indexes, including emphysema index (EI), 1st and 15th percentile of inspiratory attenuation distribution (Perc1 and Perc15), ratio of expiratory/inspiratory mean lung density (MLDex/in) and lung volume (LVex/in), and ratio of the wall thickness to the outer diameter of the lumen (TDR), as well as percentage of the wall area to the total cross-sectional area (WA%) were increased with a decreased change in relative lung volume with attenuation values between −860 and −950 HU (RVC−860to −950) and lumen area (Ai). These were correlated with the ratio of forced expiratory volume in 1 sec (FEV1) over forced vital capacity (FVC) (FEV1/FVC), the percentage of FEV1 the predicted value (FEV1%), and ratio of residual volume to total lung volume (RV/TLC). Body mass index, MLDex/in, FEV1%, FEV1/FVC, and PCT had a predictive value to AECOPD, with the combined AUC of 0.812. Conclusions. HRCT imaging effectively classifies the severity of COPD, which combined with BMI, PFT, and serum PCT can predict the risk of AECOPD.

Aimed at evoking an adequate anti-tumor immune response via oral administration route, this study constructed functionally and structurally mimicking-bacteria-membrane (MBM) nano-vesicle (RGD-PEOP) to orally deliver ovalbumin (OVA) antigen. In terms of simulating bacterial membrane structure, we creatively designed this nano-vesicle to have phospholipid-like octadecylphosphoethanolamine groups in vesicle membrane to improve OVA loading by means of specific interactions including salt bridge and hydrogen bond interaction. For simulating bacterial membrane function, the RGD peptide was modified onto the nano-vesicle surface, and the resulting vector displayed a good transport ability with a 3.4-fold higher than free OVA. In vitro and in vivo assay showed that the expression of co-stimulatory molecules and MHC class II complexes was significantly enhanced by MBM nano-vesicle. IFN-γ and IL-4 levels also increased several folds in the MBM nano-vesicle group. Consequently, MBM nano-vesicle achieved the highest in vivo inhibition rate of 69% against E.G7-OVA tumors among all the oral groups. These results suggest that this MBM nano-vesicle may be a promising vector to orally deliver OVA antigen for cancer immunotherapy. STATEMENT OF SIGNIFICANCE: Developing an effective non-bacterial carrier for oral cancer immunotherapy remains challenging. This work constructed a mimicking-bacteria-membrane nano-vesicle based on phospholipid-like amphiphilic polyphosphazenes for oral delivery of ovalbumin antigen. With the considerable capability to load ovalbumin antigen and target M cells, the nano-vesicle produced remarkable tumor suppression in vivo by evoking anti-tumor immune response.

It is well-recognized that primary cilia regulate embryonic neurodevelopment, but little is known about their roles in postnatal neurodevelopment. The striatum pyramidal (SP) of hippocampal CA1 consists of superficial and deep sublayers, however, it is not well understood how early- and late-born pyramidal neurons position to two sublayers postnatally. Here we show that the axonemes of primary cilia of early-born pyramidal neurons point to the stratum oriens (SO), whereas late-born neuronal cilia orient toward the stratum radiatum (SR), reflecting an inside-out lamination pattern. Neuronal primary cilia in SP undergo marked changes in morphology and orientation from postnatal day 5 (P5) to P14, concurrent with pyramidal cell positioning to the deep and superficial sublayers and with neuronal maturation. Transgenic overexpression of Arl13B, a protein regulating ciliogenesis, not only elongates primary cilia and promotes earlier cilia protrusion, but also affects centriole positioning and cilia orientation in SP. The centrioles of late-born neurons migrate excessively to cluster at SP bottom before primary cilia protrusion and a reverse movement back to the main SP. Similarly, this backward movement of centriole/cilia is also manifested on late-born cortical pyramidal neurons, although early- and late-born cortical neurons display the same cilia orientation. Together, this study provides the first evidence demonstrating that late-born pyramidal neurons exhibit a reverse movement for cell positioning, and primary cilia regulate pyramidal neuronal positioning to the deep and superficial sublayers in the hippocampus.Significance Statement1.Because the axonemes of primary cilia of early-born neurons point to the stratum oriens (SO), whereas late-born neuronal cilia orient toward the opposite direction, neuronal primary cilia orientation can be used as a marker to distinguish early- and late-born pyramidal neurons in the CA1.2.This work is the first to show that neuronal primary cilia modulate pyramidal neuronal positioning to the deep and superficial sublayers of the hippocampal CA1.3.Transgenic overexpression of Arl13B not only elongates primary cilia and promotes earlier cilia protrusion, but also affects centriole positioning and cilia orientation in the CA1.4.We have identified a novel “reverse movement” of late-born CA1 and cortical pyramidal neurons for cell positioning, which may affect the maturation and formation of synaptic connectivity of late-born neurons.

Background: Nasopharyngeal carcinoma (NPC) is the most prevalent cancer in China, accounting for an incidence rate of 12.5/37 in Guangxi, which is the highest in the world. Although chemoradiotherapy offers more effective cancer treatment, it also causes a variety of acute and chronic side effects, seriously affecting the quality of life. NPC has evolved into a chronic disease with most patients opting for home-based rehabilitation. Therefore, efforts on improving the home-based extended care services to improve the quality of life of patients are booming. The Chinese government encourages the use of internet technology for expanding the prospect of nursing. Methods: An experimental design was applied for this study. The study enrolled 116 discharged patients who were re-examined in the Radiotherapy Department of the First Affiliated Hospital of Guangxi Medical University from November 2019 to February 2020. The patients were divided into a test and a control group (n = 58 cases in each group) using the IBM SPSS STATISTICS 20.0 random number generation method. The control group was subjected to routine discharge guidance and follow-up, while the experimental group was implemented with a mobile health (mHealth)-based continuous nursing intervention model. The scores of the side effects, cancer fatigue, and quality of life were compared between the two groups of patients for 3, 6, and 12 months, respectively after discharge from the hospital.Results: This study included a total of 114 patients, and there was no significant difference in the baseline data between the two groups. After 6 and 12 months of intervention, the severity of radiation toxicity and side effects, scores of cancer-related fatigue, and quality of life (symptom field) of the patients in the interventional group were significantly lowered statistically compared to those in the control group.Conclusion: This study is based on the mHealth continuous nursing intervention model, which can better guide discharged patients to master the correct rehabilitation nursing methods, and reduce the side effects of radiotherapy and cancer fatigue.Trial registration: This study was retrospectively registered as a randomized controlled trial in the Chinese Clinical Trial Center. Registration Date: January 12, 2021, Registration Number: ChiCTR2100042027.

L-arginine (L-Arg) is an important nitric oxide (NO) donor, and its exploration in NO gas therapy has received widespread attention. Application of nano-platforms that can efficiently deliver L-Arg and induce its rapid conversion to NO becomes a predominant strategy to achieve promising therapeutic effects in tumor treatment. Herein, an enhanced nano-vesicular system of ternary synergistic treatment combining NO therapy, photodynamic therapy (PDT) along with mild photothermal therapy (MPTT) was developed for cancer therapy. We integrated photosensitizer PEGylated indocyanine green (mPEG-ICG) into polyphosphazene PEP nano-vesicles through co-assembly and simultaneously encapsulated NO donor L-Arg into the vesicle center chambers to form mPEG-ICG/L-Arg co-loaded system IA-PEP. The unique nanostructure of vesicle provided considerable loading capacity for mPEG-ICG and L-Arg with 15.9% and 17.95% loading content, respectively, and efficiently prevented mPEG-ICG and L-Arg from leaking. Significantly, the reactive oxygen species (ROS) was produced by IA-PEP under 808 nm laser irradiation to perform PDT against tumors, which concurrently reacted with L-Arg to release NO and arouse gas therapy effectively. Moreover, the mild heat produced by IA-PEP could exhibit cooperative anti-tumor effect with minimal damage. As a consequence, in vivo antitumor investigation on nude mice bearing xenograft MCF-7 tumors verified the potent anti-tumor efficacy of IA-PEP under 808 nm laser irradiation with complete tumor elimination. Taken together, the IA-PEP nano-vesicle system designed in this work may provide a promising treatment paradigm for synergistic cancer treatment. STATEMENT OF SIGNIFICANCE: Nitric oxide (NO) gas therapy has drawn widespread attention due to its "green" treatment paradigm with negligible side effects. L-arginine (L-Arg) is an important NO donor. However, how to efficiently deliver L-Arg and induce NO generation remains a big challenge since L-Arg is a water-soluble small molecule. Herein, we developed a nano-vesicle system IA-PEP to integrate photosensitizer PEGylated indocyanine green and L-Arg with high loading content and to produce a ternary synergistic treatment combining NO therapy, photodynamic therapy (PDT) along with mild-temperature photothermal therapy (MPTT) under 808 nm laser irradiation. The in vivo investigation on nude mice bearing xenograft MCF-7 tumors verified its potent anti-tumor efficacy with complete tumor elimination.

Background Nasopharyngeal carcinoma (NPC) is one of the most common head and neck malignancies, having a high incidence in Guangxi, China. Although chemoradiotherapy offers more effective cancer treatment, it also causes a variety of acute and chronic side effects, seriously affecting the quality of life. NPC has evolved into a chronic disease with most patients opting for home-based rehabilitation. Therefore, efforts on improving the home-based extended care services to improve the quality of life of patients are booming. The Chinese government encourages the use of internet technology for expanding the prospect of nursing. This study aimed to evaluate the impact of a mHealth-based care model on the health outcomes of discharged patients with nasopharyngeal carcinoma. Methods An experimental design was applied for this study. The study enrolled 116 discharged patients who were re-examined in the Radiotherapy Department of the First Affiliated Hospital of Guangxi Medical University from November 2019 to February 2020. These patients were randomized into control and intervention groups (n = 58 per group), but during the implementation of the project, there was one dropout in the control group due to the loss of follow-up, and one dropout in the intervention group due to distant metastasis. In the end, 57 patients in the control and intervention groups completed the trial. The control group was subjected to routine discharge guidance and follow-up, while the experimental group was implemented with a mobile health (mHealth)-based continuous nursing intervention model. The scores of the side effects, cancer fatigue, and quality of life were compared between the two groups of patients for 3, 6, and 12 months, respectively after discharge from the hospital. Results This study included 114 patients and there were no significant differences in the baseline data between the two groups. After 6 and 12 months of intervention, the severity of radiation toxicity and side effects, the scores of cancer-related fatigue, and quality of life (symptom field) of the patients in the interventional group were significantly lowered statistically compared to those in the control group. Conclusion This study is based on the mHealth continuous nursing intervention model, which can reduce the side effects of radiotherapy and cancer fatigue, and improve the quality of life. Trial registration This study was retrospectively registered as a randomized controlled trial in the Chinese Clinical Trial Center. Registration Date: January 12, 2021, Registration Number: ChiCTR2100042027.

Magnetite is a major corrosion product of carbon steel that forms deposits in the steam generators in water-cooled nuclear reactors. Sulfate is present as an impurity in the steam generator feed water and accumulates in the magnetite deposits, leading to formation of acidic crevices, corrosion and stress corrosion cracking of steam generator tubing. Reliable adsorption data are required to understand material degradation of steam generator tubing. Sulfate adsorption onto magnetite has been studied at temperatures from 25 to 300 °C as a function of pH, and chloride and sulfate concentrations. The results show that adsorption decreases with increasing pH and ionic strength, and adsorption followed the Langmuir adsorption isotherm. Overall, sulfate adsorption onto magnetite is endothermic and the enthalpy of adsorption depends on the pH and ionic strength of the solutions. The adsorption behavior of sulfate onto magnetite is explained through outer-sphere and inner-sphere adsorption.

To explore effective therapeutic strategy on nonalcoholic fatty liver disease (NAFLD), the amphiphilic oligochitosan derivative containing ursodeoxycholic acid (UDCA) was synthesized and named as UBC, which could self-assemble and encapsulate exenatide (Exe) to obtain Exe-UBC nano-vesicle. Exe-UBC could be uptaken by fatty-acid cultured cells and release UDCA and Exe responsive to the high esterase concentration. In vitro experiments demonstrated that Exe-UBC activated the expression level of SIRT1 with inhibited expression of PGC-1β and PPAR-γ and consequently exerted synergistic bioaction immediately on reducing lipidosis. After a month of Exe-UBC treated through intravenous injection, the body weight of high-fat diet feeding C57BL/6 mice recovered to ordinary level, and their lipid contents in the liver declined significantly. The recovery in hepatic function indexes like TG, AST, and ALT further revealed the superiority of Exe-UBC vesicles. These results suggested that the co-delivery of UDCA and Exe via Exe-UBC could be a potent platform for NAFLD treatment.

Hemophilia A (HA), an X-linked recessive congenital bleeding disorder, affects 80%–85% of patients with hemophilia. Nearly half of severe cases of hemophilia are caused by a 0.6-Mb genomic inversion (Inv22) that disrupts F8. Although viral-based gene therapy has shown therapeutic effects for hemophilia B (HB), this promising approach is not applicable for HA at the present stage; this limitation is mainly due to the large size of F8 cDNA, which far exceeds the adeno-associated virus (AAV) packaging capacity. We previously reported an in situ genetic correction of Inv22 in HA patient-specific induced pluripotent stem cells (HA-iPSCs) by using TALENs. We also investigated an alternative strategy for targeted gene addition, in which cDNA of the B-domain deleted F8 (BDDF8) was targeted at the rDNA locus of HA-iPSCs using TALENickases to restore FVIII function. Mesenchymal stem cells (MSCs) have low immunogenicity and can secrete FVIII under physiological conditions; in this study, MSCs were differentiated from F8-corrected iPSCs, BDDF8-iPSCs, and HA-iPSCs. Differentiated MSCs were characterized, and FVIII expression efficacy in MSCs was verified in vitro. The three types of MSCs were introduced into HA mice via intravenous injection. Long-term engraftment with restoration of FVIII function and phenotypic rescue was observed in HA mice transplanted with F8-corrected iMSCs and BDDF8-iMSCs. Our findings suggest that ex vivo gene therapy using iMSCs derived from F8-modified iPSCs can be feasible, effective, and promising for the clinical translation of therapeutic gene editing of HA and other genetic birth defects, particularly those that involve large sequence variants.

Vitamin E succinate (VES), a succinic acid ester of vitamin E, is one of the most effective anticancer compounds of the vitamin E family. VES can inhibit tumor growth by multiple pathways mainly involve tumor proliferation inhibition, apoptosis induction, and metastasis prevention. More importantly, the mitochondrial targeting and damaging property of VES endows it with great potential in exhibiting synergetic effect with conventional chemotherapeutic drugs and overcoming multidrug resistance (MDR). Given the lipophilicity of VES that hinders its bioavailability and therapeutic activity, nanotechnology with multiple advantages has been widely explored to deliver VES and opened up new avenues for its in vivo application. This review aims to introduce the anticancer mechanisms of VES and summarize its delivery strategies using nano-drug delivery systems. Specifically, VES-based combination therapy for synergetic anticancer effect, MDR-reversal, and oral chemotherapy improvement are highlighted. Finally, the challenges and perspectives are discussed.

Background Epilepsy is one of the most common neurological problems among children. The aim of this survey was to assess the knowledge and attitude among preschool staff in Shanghai regarding epilepsy. Methods A cross-sectional survey was carried out among the staff at selected preschools. A stratified random sampling method was first used to identify suitable subjects. Data were obtained using a self-completed questionnaire. A standardized collection of demographic information was performed, and participants were given a questionnaire about their knowledge and attitudes regarding epilepsy. Results A total of 1069 subjects completed the questionnaire. In this survey, 387 (36.2%) staff members had previously participated in related training. 17.6% of teachers knew how to provide appropriate first aid for seizures. Correct responses regarding first aid for seizures, such as laying the person on his or her side (24.9%), moving harmful objects out of the way (20.7%), protecting the head (36.1%), waiting until the seizure ends (7.9%), and dialing the emergency number (40.1%), were low. The staff members had different attitudes towards children with epilepsy: some subjects had a positive attitude, some had a negative attitude. Conclusions The level of first-aid knowledge among preschool staff in Shanghai relevant to epilepsy was low. There is an urgent need to educate staff about epilepsy and appropriate first-aid practices for seizures.

Combretastatin A4 phosphate (CA4P), the water-soluble phosphate pro-drug of combretastatin A4 (CA4), acts as a novel vascular disrupting agent (VDA). It strongly inhibits tubulin polymerization and selectively exerts action against tumor blood vessels. However, its quite short half-life (∼30 min) results in a short action time and consequently limits its application. Therefore, it is beneficial to develop a sustained-release preparation of CA4P for relatively long action duration. On the other hand, conventional PLGA microspheres display poor encapsulation capability for water-soluble small molecules due to rapid diffusion outside. Hence, we developed CA4P-loaded microspheres (CA4P-MS) composed of methoxy poly(ethylene glycol)-b-polylactide (PELA) reverse micelles and PLGA with a nano-in-micro sea-island structure. The CA4P encapsulation efficiency of CA4P-MS reached 92.88%. More interestingly, sustained drug release was achieved, which contributed to the prolonged inhibition effect on S180 tumor during a 30-day period with one-time subcutaneous administration. In conclusion, our study established a biodegradable polymer based platform to construct microspheres for water-soluble small molecular compounds with sustained release and a long-lasting action.

To date few polymeric vesicles have been investigated to improve oral insulin (INS) absorption due to their limited loading capacity. Therefore, an amphiphilic polyphosphazene (PEOP) containing lipid-like octadecylphosphoethanolamine (OPA) groups and amino-modified poly(ethylene glycol) at the proper ratio was designed and synthesized in this study. It was found that PEOP can self-assemble into nano-vesicles, which displayed considerable loading capability for INS by taking advantage of the synergetic effect of the interaction between OPA and INS and the physical encapsulation by the aqueous lumen of the vesicles. Furthermore, PEOP vesicles can promote INS absorption across the subsequent lymphatic transport of PEOP vesicles after their uptake by the enterocytes in the gastrointestinal tract, and consequently achieve better hypoglycemic effects

Additional file 3:. Knowledge and attitudes among preschools staff in Shanghai, China, regarding epilepsy of STROBE

Additional file 1:. Knowledge and attitudes among preschools staff in Shanghai, China, regarding epilepsy of questionnaire

Additional file 2:. Knowledge and attitudes among preschools staff in Shanghai, China, regarding epilepsy of data

Additional file 4:. Knowledge and attitudes among preschools staff in Shanghai, China, regarding epilepsy of editorial certificate

On the basis of immuno-modulating effect and upregulating the activity of thymidine phosphorylase (TP), interferon-γ (IFN-γ) as a cooperative attacker was explored to enhance the anticancer activity of 5-FU. We designed and prepared a self-assembled nano-vesicular system IFN-γ-EDP formulated by amphiphilic poly((polyethylene glycol)(dodecylphospho-ethanolamine)phosphazene) (EDP) to entrap IFN-γ in the hydrophilic cavity. The IFN-γ-EDP vesicles allowed IFN-γ to accumulate at the tumor site and be taken up by tumor cells, resulting in significantly upregulated expression level of TP, distinct inhibition of cell growth, more cellular apoptosis and more serious cell cycle arrest when administrated combined with 5-FU. Moreover, IFN-γ-EDP could normalize the tumor microenvironment by enhancing the CD4+ and CD8+ T cell populations, promoting the IL-12 secretion and suppressing the IL-10 secretion in tumor. As a consequence, the combination therapy of IFN-γ-EDP with 5-FU achieved remarkably enhanced tumor inhibition rate of 56.9% against CT26 colorectal cancer.

Supramolecular structures have received growing attention and been widely applied in many fields. Herein, we synthesized hydrophobic β-cyclodextrin-contained poly(β-amino ester) (PAE-β-CD) and hydrophilic adamantyl-terminated poly (ethylene glycol) (PEG-AD) to form a supramolecular micelle via the host-guest interaction. The micelle displayed pH responsive structure change due to the transform of hydrophobic PAE core to hydrophilic form in weakly acid condition. After the anticancer drug curcumin (Cur) was loaded into the micelle, the drug release behavior of the Cur-loaded micelle was studied, and it turned out that the Cur-loaded supramolecular micelle could effectively unload the drug at pH 5.5. Furthermore, the antitumor efficiency of the Cur-loaded micelle was also examined both in vitro and in vivo, indicating considerable inhibition ratio as high as 62.14% against mouse sarcoma 180.

Radioactive cesium, strontium and europium can be released as fission products during nuclear incidents and pose a major concern to contamination control because of their biological activity and long decay half-lives. Experiments were performed to study the kinetics and equilibrium of the adsorption of inactive Cs(I), Sr(II) and Eu(III) ions on a natural sandy soil. It was found that the adsorption of Cs(I), Sr(II) and Eu(III) had a second order reaction kinetics and generally reached equilibrium within 7 days. The adsorption equilibria of Cs(I) follows a Freundlich isotherm, while those of Sr(II) and Eu(III) follows a Langmuir isotherm. Adsorption increases with increasing pH for these cations studied at temperatures from 25 to 50°C. In general, the temperature effect on cation adsorption is small under these test conditions suggesting that the enthalpy change for adsorption is not significant. Tests of mixed Cs(I) and Sr(II) adsorption suggested that these cations likely adsorb on different sites on the surface of sandy soil. The desorption tests in NaCl and CaCl2 solutions show that Eu(III) and Cs(I) are more tightly bound and less mobile in natural sandy soil than Sr(II) under the same test conditions. Tests of Cs(I), Sr(II) and Eu(III) in a column under a flowing condition revealed that these cations mainly adsorbed within the depth of 2 cm below the surface of sandy soil.

In this work, we report a supramolecular polymer based on the host–guest interaction between β-cyclodextrin groups in β-CD-PEG and azobenzene groups in PAE-g-Azo. The supramolecular polymer PAE-g-Azo@β-CD-PEG could self-assemble into a regular nanostructure in aqueous solution due to its proper amphiphilicity. Benefiting from the pH-responsiveness of PAE and the photo-responsive trans-to-cis isomerization of Azo, the supramolecular assemblies apparently show pH and photo responsive properties. Furthermore, the combination of the pH regulation and the irradiation of UV light or visible light induced the recurrent disassembly and reassembly of the supramolecular polymer. This dual-responsive supramolecular polymer has great prospects in various practical applications such as intelligent nanomaterials and nanotechnology.

Aiming at the path planning problem for searching static target by autonomous underwater vehicles (AUVs) in ocean environment, this paper proposes a hierarchical method based on the maximum cumulative detection reward or search efficiency. First, the mission sea region is described in the form of target probability map, and the subregions with high search value are extracted by the method of expectation-maximization (EM). For multiple AUVs, we propose the bidirectional negotiation with biased min-consensus (BN-BMC) algorithm to determine the allocation and prioritization of subregions to be searched. On this basis, we utilize an adaptive oval spiral coverage (AOSC) strategy to plan the coverage path within each subregion, and take the Dubins path satisfying the AUV kinematic constraint as the transition path between subregions. Finally, the simulation results validate the advantage of our method.

Polymeric graft polyphosphazene containing 4-aminobenzoic acid diethylaminoethyl ester (DEAAB) as hydrophobic side groups was rationally designed and named PDEP. PDEP can self-assemble into a nanovesicle in water. More importantly, when compared with the amphiphile poly[(methoxy-poly(ethylene glycol))(ethyl p-aminobenzoate)]phosphazene (PEP) copolymer containing benzene rings and the amphiphile poly[(methoxy-poly(ethylene glycol)(N,N-diisopropylethylenediamine)]phosphazene (PDP) copolymer containing tertiary amino groups, the coexistence of benzene and tertiary amino groups in PDEP enabled it to effectively load water-soluble small-molecule doxorubicin hydrochloride (DOX·HCl) into the vesicle and efficiently induce in situ transformation of gold tetrachloroaurate (HAuCl4) to gold nanoparticles (AuNPs) as both a reductant and a stabilizer. By optimizing the reduction conditions, such as the temperature, reaction time, and hydrophobic group in polymer/HAuCl4 molar ratio, the AuNP complex PDEP vesicles signi...

Carboplatin is one of the few platinum-based antitumor drugs used worldwide. Unfortunately, systemic carboplatin therapy is limited by its dose-related myelosuppression. In this study, a viable way to reduce the serious myelotoxicity of carboplatin while improving its therapeutic efficacy using amino-functionalized polyphosphazene vesicles is reported. First, three polyphosphazenes with different amino content were synthesized by amidating hydrophobic side groups; these polyphosphazenes could self-assemble into polymersomes with similar particle size and morphology. Based on FTIR analysis, hydrogen bonding interactions between the polymeric carriers and carboplatin were validated and shown to predominantly contribute to the significant improvement of drug loading in polymersomes. Therefore, it turned out that the amino level of polymers played a substantial role in carboplatin encapsulation. Then, PEAP-2-C polymersomes were optimized for further experimental verification to achieve depressed carboplatin-induced myelotoxicity as well as promote curative effects against CT-26 colon adenocarcinoma. These results in vitro and in vivo proved that amino-functionalized polyphosphazene vesicles have great potential for carboplatin delivery in the application of cancer therapy.

Objectives This study aimed to evaluate that the polymersomes (Ps-DOX-CA4P) dual-loaded with combretastatin-A4 phosphate (CA4P) and doxorubicin (DOX) overcame drug resistance and sensitized tumour cells to chemotherapeutic drugs. Methods Ps-DOX-CA4P were prepared by solvent evaporation method using mPEG-b-PLA as carriers. The potential capability of CA4P to reverse DOX resistance was verified by cytotoxicity test, apoptosis assay and cellular uptake of DOX. The comparison between free drugs and drug-loaded polymersomes was also made on a single-layer cell model and multicellular tumour spheroids to display the superiority of the drug vehicles. Furthermore, we put the emphasis on the investigation into underlying mechanisms for CA4P overcoming DOX resistance. Key findings Results showed Ps-DOX-CA4P achieved increased uptake of DOX, enhanced cytotoxicity and apoptotic rate in MCF-7/ADR cells as well as MCF-7/ADR tumour spheroids. The potential molecular mechanisms may be related to inhibiting P-glycoprotein function by downregulating protein kinase Cα, stimulating ATPase activity, depleting ATP and increasing intracellular reactive oxygen species levels. Conclusions The findings validated the sensitization property of CA4P on DOX independent of its well-known angiogenesis effect, which would provide a novel and promising strategy for drug-resistant cancer therapy.

Oral administration of BCS Class IV drugs still faces great challenges owing to their poor dissolubility in the gastro-intestinal (GI) tract and low permeation capacity across the GI membrane. Here, we constructed a β-cyclodextrin-based polymeric micelle (PELC) to effectively deliver docetaxel (DTX), a typical BCS Class IV drug, by oral administration. Cellular uptake and bidirectional transport studies of PELC/DTX on MDCK-MDR1 cells revealed significantly enhanced absorption of DTX through inhibition of P-glycoprotein mediated efflux. In vivo pharmacokinetic studies showed that the relative oral bioavailability of PELC/DTX was 4.6-fold higher than free DTX. Correspondingly, orally administered PELC/DTX achieved superior anti-cancer efficacy against mouse sarcoma 180 tumor in vivo than free DTX with decreased subacute toxicity. Furthermore, we confirmed the vital effect of β-cyclodextrin on various functions of PELC throughout this study. These findings indicate that PELC copolymer displays great potential for the effective oral delivery of DTX.

Acids can disturb the ecosystem of wild animals through altering their olfaction and olfaction-related survival behaviors. It is known that the main olfactory epithelia (MOE) of mammals rely on odorant receptors and type III adenylyl cyclase (AC3) to detect general odorants. However, it is unknown how the olfactory system sense protons or acidic odorants. Here, we show that while the MOE of AC3 knockout (KO) mice failed to respond to an odor mix in electro-olfactogram (EOG) recordings, it retained a small fraction of acid-evoked EOG responses. The acetic acid-induced EOG responses in wild-type (WT) MOE can be dissected into two components: the big component dependent on the AC3-mediated cAMP pathway and the much smaller component not. The small acid-evoked EOG response of the AC3 KOs was blocked by diminazene, an inhibitor of acid-sensing ion channels (ASICs), but not by forskolin/IBMX that desensitize the cAMP pathway. AC3 KO mice lost their sensitivity to detect pungent odorants but maintained sniffing behavior to acetic acid. Immunofluorescence staining demonstrated that ASIC1 proteins were highly expressed in olfactory sensory neurons (OSNs), mostly enriched in the knobs, dendrites, and somata, but not in olfactory cilia. Real-time polymerase chain reaction further detected the mRNA expression of ASIC1a, ASIC2b, and ASIC3 in the MOE. Additionally, mice exhibited reduced preference to attractive objects when placed in an environment with acidic volatiles. Together, we conclude that the mouse olfactory system has a non-conventional, likely ASIC-mediated ionotropic mechanism for acid sensing.

Using novel biodegradable elastomer particles (BEP) prepared by the technologies of melt polycondensation, emulsification, and irradiation vulcanization, we successfully prepared advanced poly(lactic acid) (PLA)/BEP composites with higher toughness, higher biodegradability, and better cytocompatibility than neat PLA by means of the melt blending technology. The experimental results revealed that the elongation at break of the PLA/BEP composites containing 8 parts per hundred rubber (phr) by weight BEP increased dramatically from 2.9% of neat PLA to 67.1%, and the notched impact strength increased from 3.01 to 7.24 kJ/m2. Meanwhile, the biodegradation rate of the PLA/BEP composites increased dramatically in both soil environment and lipase solution, and the crystallization rate and crystallinity of the PLA/BEP composites increased significantly compared to those of neat PLA. The methyl thiazolyl tetrazolium (MTT) assay also showed that the viability of L929 cells in the presence of extracts of PLA/BEP composites was more than 75%, indicating that the PLA/BEP composites were not cytotoxic and had better cytocompatibility than neat PLA. Research on advanced PLA/BEP composites opens up new potential avenues for preparing advanced PLA products, especially for advanced biomedical materials.

Plasmid DNA gp100 is able to act as an available vaccine against metastatic melanoma, but its administration is usually limited to parenteral route. Since oral delivery of plasmid DNA is intervened by various physical obstacles, here we constructed a nanogel (Alg-Tat-gp100) with multi-faceted functions through blending-by-blending method. Due to the cooperation of alginate and Tat peptide, Alg-Tat-gp100 demonstrated the significant improvement of stability in the stomach, mucus penetration ability in intestine, and transport across mucus layer and MDCK cells. Moreover, the bone marrow-derived cells were activated with an enhanced co-stimulatory molecule expression. Following immunization using Alg-Tat-gp100 nanogels in C57BL/6 mice, the secretion of IFN-γ and the activation of cytotoxic T cells were significantly improved. Benefiting from those cases, the B16F10 tumor inhibition rate achieved 42.5% by this oral DNA vaccine, suggesting that this multi-faceted nanogel prepared by simple blending-by-blending method may provide a new strategy for oral DNA vaccine delivery.

Using the melt polycondensation of five bio-based aliphatic monomers (succinic acid, sebacic acid, fumaric acid, 1,3-propanediol, and 1,4-butanediol), we first synthesized the more flexible and biodegradable polyester diols (BPD) with an average molecular weight of 3825. Then, the BPD was polymerized with excessive 4,4&prime, diphenylmethane diisocyanate (MDI). Finally, the molecular chain extender of 1,4-butanediol (BDO) was used to fabricate the biodegradable thermoplastic polyurethane elastomer (BTPU), comprising the soft segment of BPD and the hard segment polymerized by MDI and BDO. Atomic force microscope (AFM) images showed the two-phase structure of the BTPU. The tensile strength of the BTPU containing 60% BPD was about 30 MPa and elongation at break of the BTPU was over 800%. Notably, the BTPU had superior biodegradability in lipase solution and the biodegradation weight loss ratio of the BTPU containing 80% BPD reached 36.7% within 14 days in the lipase solution.

Polymersomes, also called polymeric vesicles, are self-assembled by amphiphilic copolymers. Due to their unique characters, polymersomes are attracting more and more interest as an important class of vehicles for nanopharmaceuticals. In this chapter, various methods to prepare and characterize polymersomes are introduced systematically with several applicable examples. In addition, the advantages and disadvantages of each method were compared and analyzed with the aim to help readers choose the appropriate method in the process of experiments. Although some methods we introduced here are effective in preparing and characterizing polymersomes, the remaining challenge in this filed is to develop new tools. The reason is that polymersome is a kind of complex nanostructure, and some minor factors can affect the formation of polymersome. Meanwhile, more advanced technology should be developed to precisely determine the structure of some complex polymersomes such as multilayer polymersomes.

Type III adenylyl cyclase (AC3, ADCY3) is predominantly enriched in neuronal primary cilia throughout the central nervous system (CNS). Genome-wide association studies in humans have associated ADCY3 with major depressive disorder and autistic spectrum disorder, both of which exhibit sexual dimorphism. To date, it is unclear how AC3 affects protein phosphorylation and signal networks in central neurons, and what causes the sexual dimorphism of autism. We employed a mass spectrometry (MS)-based phosphoproteomic approach to quantitatively profile differences in phosphorylation between inducible AC3 knockout (KO) and wild type (WT), male and female mice. In total, we identified 4,655 phosphopeptides from 1,756 proteins, among which 565 phosphopeptides from 322 proteins were repetitively detected in all samples. Over 46% phosphopeptides were identified in at least three out of eight biological replicas. Comparison of AC3 KO and WT datasets revealed that phosphopeptides with motifs matching proline-directed kinases' recognition sites had a lower abundance in the KO dataset than in WTs. We detected 14 phosphopeptides restricted to WT dataset (i.e., Rabl6, Spast and Ppp1r14a) and 35 exclusively in KOs (i.e., Sptan1, Arhgap20, Arhgap44, and Pde1b). Moreover, 95 phosphopeptides (out of 90 proteins) were identified only in female dataset and 26 only in males. Label-free MS spectrum quantification using Skyline further identified phosphopeptides that had higher abundance in each sample group. In total, 204 proteins had sex-biased phosphorylation and 167 of them had increased expression in females relative to males. Interestingly, among the 204 gender-biased phosphoproteins, 31% were found to be associated with autism, including Dlg1, Dlgap2, Syn1, Syngap1, Ctnna1, Ctnnd1, Ctnnd2, Pkp4, and Arvcf. Therefore, this study also provides the first phosphoproteomics evidence suggesting that gender-biased post-translational phosphorylation may be implicated in the sexual dimorphism of autism.