H-type blood vessels participate in alveolar bone remodeling during murine tooth extraction healing.

OBJECTIVES: We aimed to investigate whether skeletal-specific H-type blood vessels exist in alveolar bone and how they function in alveolar bone remodeling. MATERIALS AND METHODS: H-type vessels with high expression of CD31 and Endomucin (CD31hi Emcnhi ) were immunostained in alveolar bone. Abundance and age-related changes in CD31hi Emcnhi endothelial cells (H-ECs) were detected by flow cytometry. Osteoprogenitors association with H-type vessels and bone mass were detected in tooth extraction model of alveolar bone remodeling by immunohistofluorescence and micro-CT, respectively. Transcription and expression of H-EC feature genes during in vitro Notch inhibition were measured by RT-qPCR and immunocytofluorescence. RESULTS: We verified that H-type vessels existed in alveolar bone, the abundance of which was highest at infancy age, then decreased but maintained a constant level during aging. In tooth extraction model, H-ECs significantly increased with concomitant perivascular accumulation of Runx2+ osteoprogenitors and gradually augmentation of bone mass. Notch inhibition of in vitro cultured H-ECs resulted in decreased expression levels of Emcn and hes1, but not Pecam1 or Kdr genes, with decreased expression levels of H-EC numbers, accordingly. CONCLUSIONS: The present study suggests that H-type vessels promote osteogenesis during alveolar bone remodeling. Notch signaling pathway regulates expression of Emcn and possibly determines fate and functions of alveolar H-ECs.

Three-dimensional polymer coated 45S5-type bioactive glass scaffolds seeded with human mesenchymal stem cells show bone formation in vivo.

45S5-type bioactive glasses are a promising alternative to established substitutes for the treatment of bone defects. Because the three-dimensional (3D) structure of bone substitutes is crucial for bone ingrowth and formation, we evaluated the osteoinductive properties of different polymer coated 3D-45S5 bioactive glass (BG) scaffolds seeded with human mesenchymal stem cells (hMSC) in vivo. BG scaffolds coated with gelatin, cross-linked gelatin, and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) were seeded with hMSC prior to implantation into severe combined immunodeficiency mice. Newly formed bone was evaluated with histomorphometry and micro-computed tomography. Bone formation was detectable in all groups, whereas the gelatin-coated BG scaffolds showed the best results and should be considered in further studies.

Light-Controlled Ion Transport through Biomimetic DNA-Based Channels.

Light-controlled nanochannels are fabricated through self-assembling azobenzene-incorporated DNA (Azo-DNA) strands to regulate ion transport. By switching between collapsed and relaxed states using visible and ultraviolet light alternately, the Azo-DNA channels can be opened and closed because the conformation of Azo-DNA changes, that is, Azo-DNA is used as switchable controlling unit. In addition to sharing short response time and reversibility with other photoresponsive apparatuses, the Azo-DNA-based nanochannel system has advantages in good biocompatibility and versatile design, which could potentially be applied in light-controlled drug release, optical information storage, and logic networks.

Highly responsive ultrathin GaS nanosheet photodetectors on rigid and flexible substrates.

The first GaS nanosheet-based photodetectors are demonstrated on both mechanically rigid and flexible substrates. Highly crystalline, exfoliated GaS nanosheets are promising for optoelectronics due to strong absorption in the UV-visible wavelength region. Photocurrent measurements of GaS nanosheet photodetectors made on SiO2/Si substrates and flexible polyethylene terephthalate (PET) substrates exhibit a photoresponsivity at 254 nm up to 4.2 AW(-1) and 19.2 AW(-1), respectively, which exceeds that of graphene, MoS2, or other 2D material-based devices. Additionally, the linear dynamic range of the devices on SiO2/Si and PET substrates are 97.7 dB and 78.73 dB, respectively. Both surpass that of currently exploited InGaAs photodetectors (66 dB). Theoretical modeling of the electronic structures indicates that the reduction of the effective mass at the valence band maximum (VBM) with decreasing sheet thickness enhances the carrier mobility of the GaS nanosheets, contributing to the high photocurrents. Double-peak VBMs are theoretically predicted for ultrathin GaS nanosheets (thickness less than five monolayers), which is found to promote photon absorption. These theoretical and experimental results show that GaS nanosheets are promising materials for high-performance photodetectors on both conventional silicon and flexible substrates.

[Ectopic osteogenesis in vivo using bone morphogenetic protein-2 derived peptide loaded biodegradable hydrogel].

We investigated the development of an injectable, biodegradable hydrogel composite of poly(trimethylene carbonate)-F127-poly(trimethylene carbonate)(PTMC11-F127-PTMC11 )loaded with bone morphogenetic protein-2 (BMP-2) derived peptide P24 for ectopic bone formation in vivo and evaluated its release kinetics in vitro. Then we evaluated P24 peptide release kinetics from different concentration of PTMC11-F127-PTMC11 hydrogel in vitro using bicinchoninic acid (BCA)assay. P24/ PTMC11-F127-PTMC11 hydrogel was implanted into each rat's erector muscle of spine and ectopic bone formation of the implanted gel in vivo was detected by hematoxylin and eosin stain (HE). PTMC11-F127-PTMC11 hydrogel with concentration more than 20 percent showed sustained slow release for one month after the initial burst release. Bone trabeculae surround the P24/ PTMC11-F127-PTMC11 hydrogel was shown at the end of six weeks by hematoxylin and eosin stain. These results indicated that encapsulated bone morphogenetic protein (BMP-2) derived peptide P24 remained viable in vivo, thus suggesting the potential of PTMC11-F127-PT- MC11 composite hydrogels as part of a novel strategy for localized delivery of bioactive molecules.

Homomultivalent Polymeric Nanotraps Disturb Lipid Metabolism Homeostasis and Tune Pyroptosis in Cancer.

Genetic manipulations and pharmaceutical interventions to disturb lipid metabolism homeostasis have emerged as an attractive approach for the management of cancer. However, the research on the utilization of bioactive materials to modulate lipid metabolism homeostasis remains constrained. In this study, heptakis (2,3,6-tri-O-methyl)-ß-cyclodextrin (TMCD) is utilized to fabricate homomultivalent polymeric nanotraps, and surprisingly, its unprecedented ability to perturb lipid metabolism homeostasis and induce pyroptosis in tumor cells is found. Through modulation of the density of TMCD arrayed on the polymers, one top-performing nanotrap, PTMCD4, exhibits the most powerful cholesterol-trapping and depletion capacity, thus achieving prominent cytotoxicity toward different types of tumor cells and encouraging antitumor effects in vivo. The interactions between PTMCD4 and biomembranes of tumor cells effectively enable the reduction of cellular phosphatidylcholine and cholesterol levels, thus provoking damage to the biomembrane integrity and perturbation of lipid metabolism homeostasis. Additionally, the interplays between PTMCD4 and lysosomes also induce lysosomal stress, activate the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasomes, and subsequently trigger tumor cell pyroptosis. To sum up, this study first introduces dendronized bioactive polymers to manipulate lipid metabolism and has shed light on another innovative insight for cancer therapy.

Quantitative comparison of the delignification performance of lignocellulosic biomass pretreatment technologies for enzymatic saccharification.

Pretreatments for delignification are required for the enzymatic saccharification of lignocellulosic biomasses. However, in the current literature, various pretreatment approaches have been applied for the same kinds of biomass. To find the optimum pretreatments for biomaterials containing various lignin contents, in this study, a quantitative comparison was carried out on the delignification performance of 15 categories of pretreatments. In total, 1729 sets of biomass, cellulose, hemicellulose, and lignin recovery data were collected from 214 relevant studies. Box plots and Cate-Nelson-like graphs were applied for analyses. The results showed that alkali, oxidation, organic solvent, and multistep pretreatments generally were better at removing lignin and recovering cellulose. Moreover, among these four categories, alkali pretreatments had the best performance, increasing the saccharification efficiency by approximately five-fold. Considering both delignification performance and saccharification improvement, alkali pretreatments are currently considered to be the optimum pretreatment methods for enzymatic saccharification.

Targeted Drug/Gene/Photodynamic Therapy via a Stimuli-Responsive Dendritic-Polymer-Based Nanococktail for Treatment of EGFR-TKI-Resistant Non-Small-Cell Lung Cancer.

Yes-associated protein (YAP) has been identified as a key driver for epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance. Inhibition of YAP expression could be a potential therapeutic option for treating non-small-cell lung cancer (NSCLC). Herein, a nanococktail therapeutic strategy is proposed by employing amphiphilic and block-dendritic-polymer-based nanoparticles (NPs) for targeted co-delivery of EGFR-TKI gefitinib (Gef) and YAP-siRNA to achieve a targeted drug/gene/photodynamic therapy. The resulting NPs are effectively internalized into Gef-resistant NSCLC cells, successfully escape from late endosomes/lysosomes, and responsively release Gef and YAP-siRNA in an intracellular reductive environment. They preferentially accumulate at the tumor site after intravenous injection in both cell-line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of Gef-resistant NSCLC, resulting in potent antitumor efficacy without distinct toxicity after laser irradiation. Mechanism studies reveal that the cocktail therapy could block the EGFR signaling pathway with Gef, inhibit activation of the EGFR bypass signaling pathway via YAP-siRNA, and induce tumor cell apoptosis through photodynamic therapy (PDT). Furthermore, this combination nanomedicine can sensitize PDT and impair glycolysis by downregulating HIF-1α. These results suggest that this stimuli-responsive dendritic-polymer-based nanococktail therapy may provide a promising approach for the treatment of EGFR-TKI resistant NSCLC.

Targeted delivery by pH-responsive mPEG-S-PBLG micelles significantly enhances the anti-tumor efficacy of doxorubicin with reduced cardiotoxicity.

Stimuli-responsive nanotherapeutics hold great promise in precision oncology. In this study, a facile strategy was used to develop a new class of pH-responsive micelles, which contain methoxy polyethylene glycol (mPEG) and poly(carbobenzoxy-l-glutamic acid, BLG) as amphiphilic copolymer, and ß-thiopropionate as acid-labile linkage. The mPEG-S-PBLG copolymer was synthesized through one-step ring-opening polymerization (ROP) and thiol-ene click reaction, and was able to efficiently encapsulate doxorubicin (DOX) to form micelles. The physicochemical characteristics, cellular uptake, tumor targeting, and anti-tumor efficacy of DOX-loaded micelles were investigated. DOX-loaded micelles were stable under physiological conditions and disintegrated under acidic conditions. DOX-loaded micelles can be internalized into cancer cells and release drugs in response to low pH in endosomes/lysosomes, resulting in cell death. Furthermore, the micellar formulation significantly prolonged the blood circulation, reduced the cardiac distribution, and selectively delivered more drugs to tumor tissue. Finally, compared with free DOX, DOX-loaded micelles significantly improved the anti-tumor efficacy and reduced systemic and cardiac toxicity in two different tumor xenograft models. These results suggest that mPEG-S-PBLG micelles have translational potential in the precise delivery of anti-cancer drugs.

LHRH-Targeted Redox-Responsive Crosslinked Micelles Impart Selective Drug Delivery and Effective Chemotherapy in Triple-Negative Breast Cancer.

Systemic chemotherapy is efficacious against triple-negative breast cancer (TNBC), but it is often associated with serious side effects. Here, a luteinizing hormone-releasing hormone (LHRH) receptor-targeted and tumor microenvironment-responsive nanoparticle system to selectively deliver chemotherapeutic drugs to TNBC cells, is reported. This delivery system (termed "LHRH-DCMs") contains poly(ethylene glycol) and dendritic cholic acid as a micellar carrier, reversible intra-micellar disulfide bond as a redox-responsive crosslink, and synthetic high-affinity (D-Lys)-LHRH peptide as a targeting moiety. LHRH-DCMs exhibit high drug loading efficiency, optimal particle size, good colloidal stability, and glutathione-responsive drug release. As expected, LHRH-DCMs are more efficiently internalized into human TNBC cells through receptor-mediated endocytosis, resulting in stronger cytotoxicity against these cancer cells than the non-targeted counterpart when encapsulated with paclitaxel (PTX). Furthermore, near-infrared fluorescence and magnetic resonance imaging demonstrate that LHRH-DCMs facilitate the tumor distribution and penetration of payloads in three different animal models of breast cancer, including cell line-derived xenograft (CDX), patient-derived xenograft (PDX), and transgenic mammary carcinoma. Finally, in vivo therapeutic studies show that PTX-LHRH-DCMs outperform both the corresponding nontargeted PTX-DCMs and the current clinical formulation (Taxol) in an orthotopic TNBC model. These results provide new insights into approaches for precise drug delivery of TNBC.

Well-defined, size-tunable, multifunctional micelles for efficient paclitaxel delivery for cancer treatment.

We have developed a well-defined and biocompatible amphiphilic telodendrimer system (PEG-b-dendritic oligo-cholic acid) which can self-assemble into multifunctional micelles in aqueous solution for efficient delivery of hydrophobic drugs such as paclitaxel. In this telodendrimer system, cholic acid is essential for the formation of stable micelles with high drug loading capacity, owing to its facial amphiphilicity. A series of telodendrimers with variable length of PEG chain and number of cholic acid in the dendritic blocks were synthesized. The structure and molecular weight of each of these telodendrimers were characterized, and their critical micellization concentration (CMC), drug-loading properties, particle sizes, and cytotoxicity were examined and evaluated for further optimization for anticancer drug delivery. The sizes of the micelles, with and without paclitaxel loading, could be tuned from 11.5 to 21 nm and from 15 to 141 nm, respectively. Optical imaging studies in xenograft models demonstrated preferential uptake of the smaller paclitaxel-loaded micelles (17-60 nm) by the tumor and the larger micelles (150 nm) by the liver and lung. The toxicity and antitumor efficacy profiles of these paclitaxel-loaded micelles in xenograft models were found to be superior to those of Taxol and Abraxane.

Bioinspired Ionic Sensory Systems: The Successor of Electronics.

All biological systems, including animals and plants, communicate in a language of ions and small molecules, while the modern information infrastructures and technologies rely on a language of electrons. Although electronics and bioelectronics have made great progress in the past several decades, they still face the disadvantage of signal transformation when communicating with biology. To narrow the gap between biological systems and artificial-intelligence systems, bioinspired ion-transport-based sensory systems should be developed as successor of electronics, since they can emulate biological functionality more directly and communicate with biology seamlessly. Herein, the essential principles of (accurate) ion transport are introduced, and the recent progress in the development of three elements of an ionic sensory system is reviewed: ionic sensors, ionic processors, and ionic interfaces. The current challenges and future developments of ion-transport-based sensory systems are also discussed.

Artificial light-driven ion pump for photoelectric energy conversion.

Biological light-driven ion pumps move ions against a concentration gradient to create a membrane potential, thus converting sunlight energy directly into an osmotic potential. Here, we describe an artificial light-driven ion pump system in which a carbon nitride nanotube membrane can drive ions thermodynamically uphill against an up to 5000-fold concentration gradient by illumination. The separation of electrons and holes in the membrane under illumination results in a transmembrane potential which is thought to be the foundation for the pumping phenomenon. When used for harvesting solar energy, a sustained open circuit voltage of 550 mV and a current density of 2.4 µA/cm2 can reliably be generated, which can be further scaled up through series and parallel circuits of multiple membranes. The ion transport based photovoltaic system proposed here offers a roadmap for the development of devices by using simple, cheap, and stable polymeric carbon nitride.

[Concentration of biyankang extracts using multi-stage membranes separation].

Multi-stage membranes processes, including ultrafiltration and nanofiltration are used in concentration of Biyankang extracts at room temperature, and the concentrations of main active ingredient in retentions after membrane processes were determined by HPLC. The results showed that the removal rate of water is about 45%, and the cost is only one fourth of the vacuum heating method. The retention rates of buddleoside and ephedrine hydrochloride are above 80% and 90% respectively, which meet the efficient concentration and energy-saving needs. The concentration method of Biyankang with multi-stage membranes processes provides some instructive theories and experimental foundations.

Uptake, distribution, clearance, and toxicity of iron oxide nanoparticles with different sizes and coatings.

Iron oxide nanoparticles (IONPs) have been increasingly used in biomedical applications, but the comprehensive understanding of their interactions with biological systems is relatively limited. In this study, we systematically investigated the in vitro cell uptake, cytotoxicity, in vivo distribution, clearance and toxicity of commercially available and well-characterized IONPs with different sizes and coatings. Polyethylenimine (PEI)-coated IONPs exhibited significantly higher uptake than PEGylated ones in both macrophages and cancer cells, and caused severe cytotoxicity through multiple mechanisms such as ROS production and apoptosis. 10 nm PEGylated IONPs showed higher cellular uptake than 30 nm ones, and were slightly cytotoxic only at high concentrations. Interestingly, PEGylated IONPs but not PEI-coated IONPs were able to induce autophagy, which may play a protective role against the cytotoxicity of IONPs. Biodistribution studies demonstrated that all the IONPs tended to distribute in the liver and spleen, and the biodegradation and clearance of PEGylated IONPs in these tissues were relatively slow (>2 weeks). Among them, 10 nm PEGylated IONPs achieved the highest tumor uptake. No obvious toxicity was found for PEGylated IONPs in BALB/c mice, whereas PEI-coated IONPs exhibited dose-dependent lethal toxicity. Therefore, it is crucial to consider the size and coating properties of IONPs in their applications.

"One-Pot" Fabrication of Highly Versatile and Biocompatible Poly(vinyl alcohol)-porphyrin-based Nanotheranostics.

Nanoparticle-based theranostic agents have emerged as a new paradigm in nanomedicine field for integration of multimodal imaging and therapeutic functions within a single platform. However, the clinical translation of these agents is severely limited by the complexity of fabrication, long-term toxicity of the materials, and unfavorable biodistributions. Here we report an extremely simple and robust approach to develop highly versatile and biocompatible theranostic poly(vinyl alcohol)-porphyrin nanoparticles (PPNs). Through a "one-pot" fabrication process, including the chelation of metal ions and encapsulation of hydrophobic drugs, monodispersenanoparticle could be formed by self-assembly of a very simple and biocompatible building block (poly(vinyl alcohol)-porphyrin conjugate). Using this approach, we could conveniently produce multifunctional PPNs that integrate optical imaging, positron emission tomography (PET), photodynamic therapy (PDT), photothermal therapy (PTT) and drug delivery functions in one formulation. PPNs exhibited unique architecture-dependent fluorescence self-quenching, as well as photodynamic- and photothermal- properties. Near-infrared fluorescence could be amplified upon PPN dissociation, providing feasibility of low-background fluorescence imaging. Doxorubicin (DOX)-loaded PPNs achieved 53 times longer half-life in blood circulation than free DOX. Upon irradiation by near infrared light at a single excitation wavelength, PPNs could be activated to release reactive oxygen species, heat and drugs simultaneously at the tumor sites in mice bearing tumor xenograft, resulting in complete eradication of tumors. Due to their organic compositions, PPNs showed no obvious cytotoxicity in mice via intravenous administration during therapeutic studies. This highly versatile and multifunctional PPN theranostic nanoplatform showed great potential for the integration of multimodal imaging and therapeutic functions towards personalized nanomedicine against cancers.

Machine Learning Algorithms for Risk Prediction of Severe Hand-Foot-Mouth Disease in Children.

The identification of indicators for severe HFMD is critical for early prevention and control of the disease. With this goal in mind, 185 severe and 345 mild HFMD cases were assessed. Patient demographics, clinical features, MRI findings, and laboratory test results were collected. Gradient boosting tree (GBT) was then used to determine the relative importance (RI) and interaction effects of the variables. Results indicated that elevated white blood cell (WBC) count > 15 × 109/L (RI: 49.47, p < 0.001) was the top predictor of severe HFMD, followed by spinal cord involvement (RI: 26.62, p < 0.001), spinal nerve roots involvement (RI: 10.34, p < 0.001), hyperglycemia (RI: 3.40, p < 0.001), and brain or spinal meninges involvement (RI: 2.45, p = 0.003). Interactions between elevated WBC count and hyperglycemia (H statistic: 0.231, 95% CI: 0-0.262, p = 0.031), between spinal cord involvement and duration of fever ≥3 days (H statistic: 0.291, 95% CI: 0.035-0.326, p = 0.035), and between brainstem involvement and body temperature (H statistic: 0.313, 95% CI: 0-0.273, p = 0.017) were observed. Therefore, GBT is capable to identify the predictors for severe HFMD and their interaction effects, outperforming conventional regression methods.

Engineered Asymmetric Composite Membranes with Rectifying Properties.

Asymmetric composite membranes with rectifying properties are developed by grafting pH-stimulus-responsive materials onto the top layer of the composite structure, which is prepared by two novel block copolymers using a phase-separation technique. This engineered asymmetric composite membrane shows potential applications in sensors, filtration, and nanofluidic devices.

A Bioinspired Multifunctional Heterogeneous Membrane with Ultrahigh Ionic Rectification and Highly Efficient Selective Ionic Gating.

A bioinspired multifunctional heterogeneous membrane composed of a block copolymer (PS-b-P4VP) membrane and a porous anodic alumina membrane is fabricated. The ionic rectification is so strong that the maximum ratio is ≈489, and the chemical actuation of the anion or cation gate from the "OFF" to the "ON" state promotes a 98.5% increase in the channel conductance.

Pharmacokinetic Behaviors of Intravenously Administered siRNA in Glandular Tissues.

The pharmacokinetics of small interfering RNAs (siRNAs) is a pivotal issue for siRNA-based drug development. In this study, we comprehensively investigated the behavior of siRNAs in vivo in various tissues and demonstrated that intravenously-injected naked siRNA accumulated remarkably in the submandibular gland, bulbourethral gland, and pancreas, with a respective half-life of ~22.7, ~45.6, and ~30.3 h. This was further confirmed by gel separation of tissue homogenates and/or supernatants. In vivo imaging and cryosectioning suggested that delivery carriers significantly influence the distribution and elimination profiles of siRNA. Gene-silencing assays revealed that neither naked nor liposome-formulated siRNA resulted in gene knockdown in the submandibular and bulbourethral glands after systemic administration, suggesting that these glands function as drug reservoirs that enable slow siRNA release into the circulation. But robust gene-silencing was achieved by local injection of liposome-encapsulated siRNA into the submandibular gland. Our results enhance understanding of the pharmacokinetic properties of siRNAs and we believe that they will facilitate the development of siRNA therapy, especially for the submandibular gland.