A highly flexible Ni-Co MOF nanosheet coated Au/PDMS film based wearable electrochemical sensor for continuous human sweat glucose monitoring.

The development of flexible substrate materials and nanomaterials with high electrochemical performance is of great significance for constructing efficient wearable electrochemical sensors for real-time health monitoring. Herein, a wearable electrochemical sweat sensor based on a Ni-Co MOF nanosheet coated Au/polydimethylsiloxane (PDMS) film was prepared for continuous monitoring of the glucose level in sweat with high sensitivity. First, a stretchable Au/PDMS film based three-electrode system was prepared by chemical deposition of a gold layer on the hydrophilic treated PDMS. Then, Ni-Co MOF nanosheets with high electrocatalytic activity were synthesized by a facile solvothermal method and modified on the Au/PDMS electrode. The electrocatalytic activity of the Ni-Co MOF nanosheets synthesized under different Ni : Co ratios was investigated. The Ni-Co MOF/Au/PDMS (NCAP) film electrode showed excellent electrochemical performance for glucose detection with a wide linear range of 20 µM to 790 µM and a high sensitivity of 205.1 µA mM-1 cm-2. In addition, the flexible sensor shows high stability and a good electrochemical response to glucose when stretched and bent to different levels. Moreover, it maintained long-term stability and high selectivity for glucose monitoring. Lastly, a sweat-absorbent cloth was used to cover the working area of the sensor and was fixed with a needle and thread to form a wearable sweat glucose sensor. The sensor can be attached to the skin for stable, accurate and continuous monitoring of glucose levels in human sweat for one day. This work validates the potential of our high-performance wearable sensor for out-of-clinic health monitoring.

Metal Phenolic Network-Integrated Multistage Nanosystem for Enhanced Drug Delivery to Solid Tumors.

Metal-phenolic networks (MPNs) are an emerging class of supramolecular surface modifiers with potential use in various fields including drug delivery. Here, the development of a unique MPN-integrated core-satellite nanosystem (CS-NS) is reported. The "core" component of CS-NS comprises a liposome loaded with EDTA (a metal ion chelator) in the aqueous core and DiR (a near-infrared photothermal transducer) in the bilayer. The "satellite" component comprises mesoporous silica nanoparticles (MSNs) encapsulating doxorubicin and is coated with a Cu2+ -tannic acid MPN. Liposomes and MSNs self-assemble into the CS-NS through adhesion mediated by the MPN. When irradiated with an 808 nm laser, CS-NS liberated the entrapped EDTA, leading to Cu2+ chelation and subsequent disassembly of the core-satellite nanostructure. Photo-conversion from the large assembly to the small constituent particles proceeded within 5 min. Light-triggered CS-NS disassembly enhanced the carrier and cargo penetration and accumulation in tumor spheroids in vitro and in orthotopic murine mammary tumors in vivo. CS-NS is long circulating in the blood and conferred improved survival outcomes to tumor-bearing mice treated with light, compared to controls. These results demonstrate an MPN-integrated multistage nanosystem for improved solid tumor treatment.

Oral microbiota alteration associated with oral cancer and areca chewing.

Oral cancer is among most common neoplasm of oral cavity; in many cases, it develops at the site of premalignant lesion. Areca nut has been identified as a carcinogen, which was proved to promote the inflammation level and contributes to oral malignancy. Chewing areca nut is the main cause of the premalignant disease oral submucous fibrosis (OSF). Bacterial alterations were suggested to be assonated with oral cancer progression. Therefore, the present study was carried out to determine the changes of microbiota in the mucosa along stage of development of oral cancer with areca nut chewing. 162 participants, reporting to department of oral medical center, were enrolled into the study which includes 45 patients each of OSF, 42 of oral cancer, 29 healthy controls (HC) with areca nut chewing, and 46 healthy controls (HC) never chewing areca nut. Oral swabbing of tongue dorsum, buccal mucosa, and gingiva was evaluated by MiSeq platform of the V3-V4 region of the 16S rRNA gene. These data revealed microbial changes that may mirror oral cancer progression and reflect clinical preconditions such as areca nut chewing. Consequently, revealing microbial changes in patients with oral squamous cell carcinomas and the premalignant disease oral submucous fibrosis (OSF) with areca nut chewing might improve our understanding of the pathobiology of the disease and help in the design of novel diagnostic and treatment strategies.

Nanobowl-Supported Liposomes Improve Drug Loading and Delivery.

Liposomal drug delivery for cancer therapy can be limited due to drug leakage in circulation. Here, we develop a new method to enhance the stability of actively loaded liposomal doxorubicin (DOX) through embedding a stiff nanobowl in the liposomal water cavity. Nanobowl-supported liposomal DOX (DOX@NbLipo) resists the influence of plasma protein and blood flow shear force to prevent drug leakage. This approach yields improved drug delivery to tumor sites and enhanced antitumor efficacy. Compared to alternative methods of modifying liposome surface and composition for stability, this approach designs a physical support for an all-aqueous nanoliposomal cavity. Nanobowl stabilization of liposomes is a simple and effective method to improve carrier stability and drug delivery.

Edge-Localized Biodeterioration and Secondary Microplastic Formation by Papiliotrema laurentii Unsaturated Biofilm Cells on Polyurethane Films.

Painted environmental surfaces are prone to microbiological colonization with potential coating deterioration induced by the microorganisms. Accurate mechanistic models of these interactions require an understanding of the heterogeneity in which the deterioration processes proceed. Here, unsaturated biofilms (i.e., at air/solid interfaces) of the yeast Papiliotrema laurentii were prepared on polyether polyurethane (PEUR) and polyester-polyether polyurethane (PEST-PEUR) coatings and incubated for up to 33 days at controlled temperature and humidity with no additional nutrients. Transmission micro-Fourier transform infrared microscopy (µFTIR) confirmed preferential hydrolysis of the ester component by the biofilm. Atomic force microscopy combined with infrared nanospectroscopy (AFM-IR) was used to analyze initial PEST-PEUR coating deterioration processes at the single-cell level, including underlying surfaces that became exposed following cell translocation. The results revealed distinct deterioration features that remained localized within ∼10 µm or less of the edges of individual cells and cell clusters. These features comprised depressions of up to ∼300 nm with locally reduced ester/urethane ratios. They are consistent with a formation process initiated by enzymatic ester hydrolysis followed by erosion from water condensation cycles. Further observations included particle accumulation in the broader biofilm vicinity. AFM-IR spectroscopy indicated these to be secondary microplastics consisting of urethane-rich oligomeric aggregates. Overall, multiple contributing factors have been identified that can facilitate differential deterioration rates across the PEST-PEUR surface. Effects of the imposed nutrient conditions on Papiliotrema laurentii physiology were also apparent, with cells developing the characteristics of starvation response, despite the availability of polyester metabolites as a carbon source. The combined results provide new laboratory insights into field-relevant microbiological polymer deterioration mechanisms and biofilm physiology at polymer coating interfaces.

Modification of Tracheal Cuff Shape and Continuous Cuff Pressure Control to Prevent Microaspiration in an Ex Vivo Pig Tracheal Two-Lung Model.

OBJECTIVES: Microaspiration of subglottic secretions plays a pivotal role in ventilator-associated pneumonia. Impact of endotracheal tube cuff material and shape on tracheal sealing performance remains debated. The primary objective was to compare the tracheal sealing performance of polyvinyl chloride tapered, cylindrical and spherical cuffs. Secondary objectives were to determine the impact of continuous cuff pressure control on sealing performance and pressure variability. DESIGN: Prospective randomized ex vivo animal study. SETTING: French research laboratory. SUBJECTS: Seventy-two ex vivo pig tracheal two-lung blocks. INTERVENTIONS: Blocks were randomly intubated with cylindrical (n = 26), tapered (n = 24), or spherical (n = 22) polyvinyl chloride endotracheal tube cuffs. Two milliliter of methylene blue were instilled above the cuff to quantify microaspirations, and lungs were ventilated for 2 hours. Continuous cuff pressure control was implemented in 33 blocks. MEASUREMENTS AND MAIN RESULTS: Cuff pressures were continuously recorded, and after 2 hours, a microaspiration score was calculated. Tapered cuffs improved cuff sealing performance compared with spherical cuffs with or without continuous cuff pressure control. Compared with spherical cuffs, tapered cuffs reduced the microaspiration score without and with continuous pressure control by 65% and 72%, respectively. Continuous cuff pressure control did not impact sealing performance. Tapered cuffs generated higher cuff pressures and increased the time spent with overinflation compared with spherical cuffs (median [interquartile range], 77.9% [0-99.8] vs. 0% [0-0.5]; p = 0.03). Continuous cuff pressure control reduced the variability of tapered and spherical cuffs likewise the time spent with overinflation of tapered and cylindrical cuffs. CONCLUSIONS: Polyvinyl chloride tapered cuffs sealing enhanced performance at the cost of an increase in cuff pressure and in time spent with overinflation. Continuous cuff pressure control reduced the variability and normalized cuff pressures without impacting sealing performance.

Characteristics and mechanisms of acrylate polymer damage to maize seedlings.

Superabsorbent acrylate polymers (SAPs) have been widely used to maintain soil moisture in agricultural management, but they may cause damage to plants, and the mechanisms are not well understood. In this study, seed germination, soil pot culture, hydroponic experiments, and SAPs degradation were conducted to investigate damage characteristics and mechanisms associated with SAPs application. The Results showed that SAPs inhibited maize growth and altered root morphology (irregular and loose arrangement of cells and breakage of cortex parenchyma), and the inhibitory effects were enhanced at higher SAPs rates. After 1h SAP hydrogels treatment, root malondialdehyde (MDA) content was significantly increased, while superoxide dismutase (SOD) and catalase (CAT) content were significantly decreased. Hydroponics experiment indicated that root and shoot growth was inhibited at 2.5mgL(-1) acrylic acid (AA), and the inhibition was enhanced with increasing AA rates. This effect was exacerbated by the presence of Na(+) at a high concentration in the hydrogels. Release and degradation of AA were enhanced at higher soil moisture levels. A complete degradation of AA occurred between 15 and 20 days after incubation (DAI), but it took longer for Na(+) concentration to decrease to a safe level. These results indicate that high concentration of both AA and Na(+) present in the SAPs inhibits plant growth. The finding of this study may provide a guideline for appropriate application of SAPs in agriculture.

Ternary nylon-3 copolymers as host-defense peptide mimics: beyond hydrophobic and cationic subunits.

Host-defense peptides (HDPs) are produced by eukaryotes to defend against bacterial infection, and diverse synthetic polymers have recently been explored as mimics of these natural peptides. HDPs are rich in both hydrophobic and cationic amino acid residues, and most HDP-mimetic polymers have therefore contained binary combinations of hydrophobic and cationic subunits. However, HDP-mimetic polymers rarely duplicate the hydrophobic surface and cationic charge density found among HDPs ( Hu , K. ; et al. Macromolecules 2013 , 46 , 1908 ); the charge and hydrophobicity are generally higher among the polymers. Statistical analysis of HDP sequences ( Wang , G. ; et al. Nucleic Acids Res. 2009 , 37 , D933 ) has revealed that serine (polar but uncharged) is a very common HDP constituent and that glycine is more prevalent among HDPs than among proteins in general. These observations prompted us to prepare and evaluate ternary nylon-3 copolymers that contain a modestly polar but uncharged subunit, either serine-like or glycine-like, along with a hydrophobic subunit and a cationic subunit. Starting from binary hydrophobic-cationic copolymers that were previously shown to be highly active against bacteria but also highly hemolytic, we found that replacing a small proportion of the hydrophobic subunit with either of the polar, uncharged subunits can diminish the hemolytic activity with minimal impact on the antibacterial activity. These results indicate that the incorporation of polar, uncharged subunits may be generally useful for optimizing the biological activity profiles of antimicrobial polymers. In the context of HDP evolution, our findings suggest that there is a selective advantage to retaining polar, uncharged residues in natural antimicrobial peptides.

Antimicrobial efficacy of cyclic α- and ß-peptides incorporated in polyurethane coatings.

Microbial growth on surfaces poses health concerns and can accelerate the biodegradation of engineered materials and coatings. Cyclic peptides are promising agents to combat biofouling because they are more resistant to enzymatic degradation than their linear counterparts. They can also be designed to interact with extracellular targets and intracellular targets and/or self-assemble into transmembrane pores. Here, we determine the antimicrobial efficacy of two pore-forming cyclic peptides, α-K3W3 and ß-K3W3, against bacterial and fungal liquid cultures and their capacity to inhibit biofilm formation on coated surfaces. These peptides display identical sequences, but the additional methylene group in the peptide backbone of ß-amino acids results in a larger diameter and an enhancement in the dipole moment. In liquid cultures, ß-K3W3 exhibited lower minimum inhibitory concentration values and greater microbicidal power in reducing the number of colony forming units (CFUs) when exposed to a gram-positive bacterium, Staphylococcus aureus, and two fungal strains, Naganishia albida and Papiliotrema laurentii. To evaluate the efficacy against the formation of fungal biofilms on painted surfaces, cyclic peptides were incorporated into polyester-based thermoplastic polyurethane. The formation of N. albida and P. laurentii microcolonies (105 per inoculation) for cells extracted from coatings containing either peptide could not be detected after a 7-day exposure. Moreover, very few CFUs (∼5) formed after 35 days of repeated depositions of freshly cultured P. laurentii every 7 days. In contrast, the number of CFUs for cells extracted from the coating without cyclic peptides was >8 log CFU.

Tailoring and application of a multi-responsive cellulose nanofibre-based 3D nanonetwork wound dressing.

The rapid loss of drugs and the weak curative effects due to cyclical urination are the main reasons why wound heal with difficulty after bladder tumour resection. Here, a bioinspired cellulose nanofibre (CNF)-based magnetic 3D nanonetwork wound dressing with excellent tissue adhesion and biocompatibility is designed by the assembly of pH- and near infrared-responsive CNF nanoskeletons, magnetic switching Fe3O4 nanoparticles, and temperature switching Pluronic®F-127. The dressing with high loading capacity for mitomycin and indocyanine green can form a sticky 3D nanonetwork at the wound site and remain for a long time to release drugs through an external magnetic field. Interestingly, the dressing possessed excellent antibacterial activity, bacterial biofilm elimination, T24 tumour cell killing, and wound healing promotion through photothermal, photodynamic, and chemotherapy. Therefore, it has promising application for bladder postoperative infected wound healing to avoid rapid loss of drugs due to cyclical urination.

O-GlcNAcylation of MORC2 at threonine 556 by OGT couples TGF-ß signaling to breast cancer progression.

MORC family CW-type zinc finger 2 (MORC2) is a newly identified chromatin-remodeling enzyme involved in DNA damage response and gene transcription, and its dysregulation has been linked with Charcot-Marie-Tooth disease, neurodevelopmental disorder, and cancer. Despite its functional importance, how MORC2 is regulated remains enigmatic. Here, we report that MORC2 is O-GlcNAcylated by O-GlcNAc transferase (OGT) at threonine 556. Mutation of this site or pharmacological inhibition of OGT impairs MORC2-mediated breast cancer cell migration and invasion in vitro and lung colonization in vivo. Moreover, transforming growth factor-ß1 (TGF-ß1) induces MORC2 O-GlcNAcylation through enhancing the stability of glutamine-fructose-6-phosphate aminotransferase (GFAT), the rate-limiting enzyme for producing the sugar donor for OGT. O-GlcNAcylated MORC2 is required for transcriptional activation of TGF-ß1 target genes connective tissue growth factor (CTGF) and snail family transcriptional repressor 1 (SNAIL). In support of these observations, knockdown of GFAT, SNAIL or CTGF compromises TGF-ß1-induced, MORC2 O-GlcNAcylation-mediated breast cancer cell migration and invasion. Clinically, high expression of OGT, MORC2, SNAIL, and CTGF in breast tumors is associated with poor patient prognosis. Collectively, these findings uncover a previously unrecognized mechanistic role for MORC2 O-GlcNAcylation in breast cancer progression and provide evidence for targeting MORC2-dependent breast cancer through blocking its O-GlcNAcylation.

Design of Near-Infrared-Triggered Cellulose Nanocrystal-Based In Situ Intelligent Wound Dressings for Drug-Resistant Bacteria-Infected Wound Healing.

Postoperative infected wound complications caused by residual tumor cells, bacterial biofilms, and drug-resistant bacteria have become the main challenge in postsurgical skin regeneration. Herein, a bionic cellulose nanocrystal (CNC)-based in situ intelligent wound dressing with near-infrared (NIR)-, temperature-, and pH-responsive functions was designed by using NIR-responsive CNC as the network skeleton, dynamic imine bonds between dialdehyde cellulose nanocrystals and doxorubicin, chitosan oligosaccharide as the pH-responsive switch, and temperature-sensitive poly(N-isopropyl acrylamide) as the temperature-responsive in situ formation switch. The as-prepared wound dressing with the intertwining three-dimensional (3D) network structure possessed high drug loadability of indocyanine green (30 mg/g) and doxorubicin (420 mg/g) simultaneously. The temperature-, NIR-, and pH-responsive switches endowed the wound dressing with controllable on-demand drug release behavior. In particular, the temperature switch endowed the dressing with a shape-adaptable ability on irregularly infected wounds. Interestingly, the wound dressing showed excellent antitumor activity for A375 tumor cells, antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and bacterial biofilm removal ability. Therefore, the developed wound dressing can provide an ideal synergistic treatment strategy combined with chemotherapy and photodynamic and photothermal therapy for postoperative drug-resistant bacteria-infected wound healing.

Dual light-responsive cellulose nanofibril-based in situ hydrogel for drug-resistant bacteria infected wound healing.

In situ hydrogels with rapid hemostasis and antibacterial activity have received considerable attention in the field of wound healing. Herein, a white light and NIR dual light-responsive cellulose nanofibril (CNF)-based in situ hydrogel wound dressing is tailored by using white light-responsive CNF and endogenous antibacterial CNF as the skeleton, Prussian blue nanoparticles, Pluronic® F127 and hydroxypropyl methyl cellulose as the NIR, temperature-responsive switch and binder, respectively. The dressing exhibits rapid hemostasis properties in rat liver injury model with low blood loss of 286.4 mg and short hemostasis time of 63 s. Meanwhile, the antibacterial activity of the dressing with white and NIR irradiation against Escherichia coli, Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) is higher than 99.9 %. Interestingly, the dressing with biocompatibility can promote MRSA infection wound healing and can be removed on demand without secondary injury to skin. Therefore, it has promising applications for first-aid hemostasis and wound healing.

Poly(caffeic acid)-coated molecularly imprinted magnetic nanoparticles for specific and ultrasensitive detection of glycoprotein.

Molecularly imprinted polymers (MIPs) are artificial chemical receptors, and can recognize template molecules with a high selectivity and affinity. As "antibody mimics", MIPs have been widely studied in various fields. However, the general applicability of MIPs is limited by the type of functional monomers. Herein, we developed caffeic acid (CA, a natural polyphenol) as novel a functional monomer. An innovative poly(caffeic acid)-coated molecularly imprinted magnetic nanoparticles (PCA-MIMN) with transferrin (TRF) as a model glycoprotein template was fabricated by autoxidation of CA with hexamethylenediamine (HMDA) in an aerobic environment as imprinted layer. The successful fabrication of PCA-MIMN was proved in detail by diversified characterization. The PCA-MIMN exhibited not only outstanding binding affinity and specificity for target glycoprotein, but also excellent hydrophilicity due to the externally generous hydrophilic groups. To evaluate the preeminent performance, the PCA-MIMN was linked with pH-triggered allochroic-graphene oxide (AGO), which was used for determination of TRF in real samples. The proposed PCA-MIMN linked AGO strategy exhibited ultrahigh sensitivity with limit of detection of 0.38 pg mL-1 for TRF. Finally, the proposed strategy was successfully applied in determination of TRF in spiked human serum sample with recovery and relative standard deviation in the range of 97.2%-103.9% and 4.6%-5.8%, respectively. This work demonstrates that the "autoxidation of CA with HMDA" may be a universal tool for synthesis of highly specific MIPs, and the type of functional monomers will increase exponentially due to the presence of numerous polyphenols in nature.

Bioinspired Multifunctional Cellulose Nanofibril-Based In Situ Liquid Wound Dressing for Multiple Synergistic Therapy of the Postoperative Infected Wound.

A smart in situ-formed wound dressing with excellent antibacterial ability against drug-resistance bacterial, antitumor, and biofilm-eliminating activities to promote effective wound closure is highly desirable in therapeutic and clinical applications. Herein, we designed and developed a multifunctional; shape-adaptable; and pH, temperature, and near-infrared radiation (NIR) multiple responsive cellulose nanofibril (CNF)-based in situ liquid wound dressing, using a pH-sensitive CNF grafted with terminated amino hyperbranched polyamines (HBP-NH2) as a substrate, along with poly(N-isopropylacrylamide) and indocyanine green (ICG) loaded as the temperature and NIR on/off switches, respectively. The 3D nanocage network structure of CNF and the nanocavities in the hyperbranched structure of HBP-NH2 endow the dressing with a high loading capacity for active drugs (doxorubicin and ICG) simultaneously. Moreover, the responsiveness of the dressing to multiple stimuli enables controllable and efficient drug release to the wound area. The bioinspired dressing demonstrates excellent antibacterial activity against common bacteria and methicillin-resistant Staphylococcus aureus, antitumor activity against A375 tumor cells, and biofilm-eliminating capability. In addition, the developed dressing synergistically combines multiple therapeutic strategies for effective wound healing, specifically photothermal therapy, photodynamic therapy, and chemotherapy. The design provides an ideal clinical intervention strategy for irregular tumor postoperative infected wounds.

Biomimetic Liposomal Nanoplatinum for Targeted Cancer Chemophototherapy.

Photodynamic therapy (PDT) of cancer is limited by tumor hypoxia. Platinum nanoparticles (nano-Pt) as a catalase-like nanoenzyme can enhance PDT through catalytic oxygen supply. However, the cytotoxic activity of nano-Pt is not comprehensively considered in the existing methods to exert their multifunctional antitumor effects. Here, nano-Pt are loaded into liposomes via reverse phase evaporation. The clinical photosensitizer verteporfin (VP) is loaded in the lipid bilayer to confer PDT activity. Murine macrophage cell membranes are hybridized into the liposomal membrane to confer biomimetic and targeting features. The resulting liposomal system, termed "nano-Pt/VP@MLipo," is investigated for chemophototherapy in vitro and in vivo in mouse tumor models. At the tumor site, oxygen produced by nano-Pt catalyzation improves the VP-mediated PDT, which in turn triggers the release of nano-Pt via membrane permeabilization. The ultrasmall 3-5 nm nano-Pt enables better penetration in tumors, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy. Chemophototherapy with a single injection of nano-Pt/VP@MLipo and light irradiation inhibits the growth of aggressive 4T1 tumors and their lung metastasis, and prolongs animal survival without overt toxicity.

The Identification and Genetic Characterization of Parechovirus Infection Among Pediatric Patients With Wide Clinical Spectrum in Chongqing, China.

Human parechoviruses (HPeVs) are important causes of infection in children. However, without a comprehensive and persistent surveillance, the epidemiology and clinical features of HPeV infection remain ambiguous. We performed a hospital-based surveillance study among three groups of pediatric patients with acute respiratory infection (Group 1), acute diarrhea (Group 2), and hand, foot and mouth disease (Group 3) in Chongqing, China, from 2009 to 2015. Among 10,212 tested patients, 707 (6.92%) were positive for HPeV, with the positive rates differing significantly among three groups (Group 1, 3.43%; Group 2, 14.94%; Group 3, 3.55%; P < 0.001). The co-infection with other pathogens was detected in 75.2% (531/707) of HPeV-positive patients. Significant negative interaction between HPeV and Parainfluenza virus (PIV) (P = 0.046, OR = 0.59, 95% CI = 0.34-0.98) and positive interactions between HPeV and Enterovirus (EV) (P = 0.015, OR = 2.28, 95% CI = 1.23-4.73) were identified. Among 707 HPeV-positive patients, 592 (83.73%) were successfully sequenced, and 10 genotypes were identified, with HPeV1 (n = 396), HPeV4 (n = 86), and HPeV3 (n = 46) as the most frequently seen. The proportion of genotypes differed among three groups (P < 0.001), with HPeV1 and HPeV4 overrepresented in Group 2 and HPeV6 overrepresented in Group 3. The spatial patterns of HPeV genotypes disclosed more close clustering of the currently sequenced strains than those from other countries/regions, although they were indeed mixed. Three main genotypes (HPeV1, HPeV3, and HPeV4) had shown distinct seasonal peaks, highlighting a bi-annual cycle of all HpeV and two genotypes (HPeV 1 and HPeV 4) with peaks in odd-numbered years and with peaks in even-numbered years HPeV3. Significantly higher HPeV1 viral loads were associated with severe diarrhea in Group 2 (P = 0.044), while associated with HPeV single infection than HPeV-EV coinfection among HFMD patients (P = 0.001). It's concluded that HPeV infection was correlated with wide clinical spectrum in pediatric patients with a high variety of genotypes determined. Still no clinical significance can be confirmed, which warranted more molecular surveillance in the future.

USP9X stabilizes BRCA1 and confers resistance to DNA-damaging agents in human cancer cells.

BRCA1, a multifunctional protein with an important role in DNA double-strand break repair by homologous recombination (HR), is subjected to ubiquitin-dependent degradation. To date, several E3 ubiquitin ligases have been identified to govern BRCA1 stability, but the deubiquitinase that counteracts its turnover remains undefined. In this study, we report that the ubiquitin-specific protease 9X (USP9X) is a bona fide deubiquitinase for BRCA1 in human cancer cells. Reciprocal immunoprecipitation assays demonstrated that USP9X interacted with BRCA1. Depletion of USP9X by short interfering RNAs or inhibition of USP9X by the small-molecular inhibitor WP1130 significantly reduced BRCA1 protein abundance, without affecting its mRNA levels. In contrast, overexpression of wild-type USP9X, but not its deubiquitinase activity-defective mutant (C1566S), resulted in an upregulation of BRCA1 protein levels. Moreover, USP9X depletion reduced the half-life of BRCA1, accompanied by an increase in its ubiquitination. HR assays showed that knockdown of USP9X significantly reduced HR efficiency, which was partially rescued by reintroduction of BRCA1 into USP9X-depleted cells. In support of these findings, USP9X knockdown significantly enhanced sensitivity to PARP inhibitor Olaparib and methyl methanesulfonate (MMS). Collectively, these results establish USP9X as a deubiquitinase for BRCA1 and reveal a previously unrecognized role of USP9X in the regulation of HR repair and the sensitivity of cancer cells to DNA-damaging agents.

[Advances in the study of excipient inhibitors of intestinal P-glycoprotein].

P-glycoprotein (P-gp) located in the apicalmembranes of intestinal absorptive cells is an energy-dependent efflux pump which can reduce the bioavailability of a wide range of substrate drugs. There is increasingly interest in enhancing the bioavailability of these molecules by inhibiting intestinal P-gp. A classification of excipient inhibitors of intestinal P-gp nonionic surfactants, poly (ethylene glycol), derivates of beta-cyclodextrin and thiolated chitosan will be presented and then the inhibition mechanism will be discussed. Compared with traditional P-gp inhibitor, excipient inhibitors appear to have minimal nonspecific pharmacological activity, thus potential side effects can be mostly avoided. These excipient inhibitors, which hold the promise of replacing the traditional ones, will be extensively employed to significantly improve the intestinal absorption of poorly soluble and absorbed drugs as a result of P-gp inhibition, and thus to enhance the bioavailability of these drugs. However, the further studies of both the mechanism and clinical application are urgently needed.

[Effect of polyoxyl ether analogous surfactants on the activity of cytochromes P450 3A in rats in vivo].

To evaluate the effects of p-octyl polyethylene glycol phenyl ether (Triton X-100), polyoxyl 35 caster oil (EL35) and polyoxyl 40 hydrogenated caster oil (RH40) on the activity of Cytochrome P450 3A (CYP3 As) in vivo. Rats were administered with saline, ketoconazole (75 mg x kg(-1) x d(-1)), Triton X-100 (30 mg x kg(-1) x d(-1)), EL35 (150 mg x kg(-1) x d(-1)) and RH40 (150 mg x kg(-1) x d(-1)) intragastrically for 5 consecutive days, and then given midazolam 10 mg x kg(-1) 20 min after the last treatment of ketoconazole or three surfactants with the same dose through duodenal administration. Pharmacokinetics parameters for midazolam and its metabolite 1'-hydroxymidazolam were estimated from the plasma concentration-time data by a noncompartmental approach. The results showed that multiple dose administration of Triton X-100, EL35 and RH40 decreased the ratios of 1'-hydroxymidazolam and midazolam AUC0-infinity from 1.14 to 0.90, 1.03 and 0.64, respectively. In contrast, multiple dose administration of ketoconazole caused the ratios of 1'-hydroxymidazolam and midazolam a significant decrease to 0.50. This study indicated that Triton X-100 and EL35 would have no inhibition on CYP3A, while RH40 had significant inhibition on CYP3A. Therefore, RH40 might be used to prepare drug formulations in pharmaceutical industry and would increase the bioavailability of some drugs transformed by CYP3As and further lead to significant clinical pharmacologic effects.