Uptight responses between clenching and forearm raising with factors of visual feedback and maintenance effort in healthy young women: An experimental study on factorial design.

BACKGROUND: To achieve different central preset force levels requires various fine-tuning efforts and may elicit different uptight responses. The mandibular lever system has a distinct regularity in the fine-tuning function of the upper limbs. The purpose of the present study was to detect whether the uptight responses elicited from motivating clenching differ from those induced by motivating forearm raising at different force levels. METHODS: Twenty-five healthy females were enrolled in this study. The target was low, medium, and maximum force levels with or without visual feedback and/or maintenance effort. Surface electromyographic (SEMG) activity was recorded from the bilateral anterior temporalis and masseter or left biceps brachii muscle (BicL), and the T-Scan III System synchronously recorded the sensitive force values. The uptight responses and task difficulties were recorded for occlusal and left forearm lifting tasks using a unique visual analogue scale. RESULTS: The highest uptight response value was achieved at a low clenching force level with visual feedback requiring no maintenance effort but at a maximum forearm-raising force level with visual feedback and maintenance effort. The SEMG activities of both jaw-closing muscles and BicL were associated with the central preset force level (P < 0.001). However, the maintenance effort only increased the jaw-closing muscles' SEMG activity at the maximal force level (P < 0.001). CONCLUSIONS: Clenching at the central preset lower force level with visual feedback is prone to elicit a higher degree of uptight response. The constant need for a low-intensity bite can have a negative effect on an individual's mood.

Sustained release of collagen VI potentiates sciatic nerve regeneration by modulating macrophage phenotype.

Although the peripheral nervous system has an intrinsic ability for repair and regeneration after injury, bridging long peripheral nerve defects remains a challenge. Functional nerve regeneration depends on interactions among axons, Schwann cells, fibroblasts and immune cells. Macrophages, as immune cells recruited early in this process, show polarization toward phenotypes that are detrimental or beneficial to tissue remodeling depending on the microenvironment of the scaffolds. In this study, we investigated the effects of macrophage phenotypes modulated by collagen VI on axonal regeneration and functional recovery by bridging a 15-mm-long sciatic nerve defect in rats. Our results showed that local delivery of collagen VI within a polycaprolactone (PCL) electrospun conduit increased the recruitment of macrophages and their polarization toward the pro-healing (M2) phenotype. In addition, the axonal regeneration and neurologic functional recovery in the PCL/collagen VI conduit group are equivalent to that of an autograft. In conclusion, the present study confirmed that PCL/collagen VI conduits with sustained release of collagen VI in the local microenvironment may, through triggering macrophage M2 polarization to enhance the nerve regeneration, suggest that our combined biomaterial-immunomodulatory system may be an attractive candidate for peripheral nerve regeneration.

Allosteric peptides bind a caspase zymogen and mediate caspase tetramerization.

The caspases are a family of cytosolic proteases with essential roles in inflammation and apoptosis. Drug discovery efforts have focused on developing molecules directed against the active sites of caspases, but this approach has proved challenging and has not yielded any approved therapeutics. Here we describe a new strategy for generating inhibitors of caspase-6, a potential therapeutic target in neurodegenerative disorders, by screening against its zymogen form. Using phage display to discover molecules that bind the zymogen, we report the identification of a peptide that specifically impairs the function of caspase-6 in vitro and in neuronal cells. Remarkably, the peptide binds at a tetramerization interface that is uniquely present in zymogen caspase-6, rather than binding into the active site, and acts via a new allosteric mechanism that promotes caspase tetramerization. Our data illustrate that screening against the zymogen holds promise as an approach for targeting caspases in drug discovery.

Tuning the iridescence of chiral nematic cellulose nanocrystal films with a vacuum-assisted self-assembly technique.

Iridescent films composed of the chiral nematic liquid crystal phase of cellulose nanocrystals (CNC) have attracted significant interest due to their fascinating optical properties. However, the current fabrication method, i.e., solution casting with a subsequent evaporation process, has significant limitations and therefore hinders the application of CNC iridescent films. In the present study, we demonstrate, for the first time, that vacuum-assisted self-assembly (VASA) can be used to fabricate highly oriented, large area, smooth, and structurally homogeneous CNC iridescent films. It was found that a long ultrasonic pretreatment is necessary for obtaining CNC iridescent films via VASA. Furthermore, it was also found that the iridescent color of the CNC films can be tuned by the sonication time, suspension volume, and degree of vacuum. By combining CD spectroscopy, SEM, and WAXD techniques, the internal structure of CNC iridescent films prepared by VASA has been investigated in detail. Moreover, the origin of the ultrasonic pretreatment effect on the self-assembly behavior of CNCs is also discussed.

Construction of targeting-clickable and tumor-cleavable polyurethane nanomicelles for multifunctional intracellular drug delivery.

New strategies for the construction of versatile nanovehicles to overcome the multiple challenges of targeted delivery are urgently needed for cancer therapy. To address these needs, we developed a novel targeting-clickable and tumor-cleavable polyurethane nanomicelle for multifunctional delivery of antitumor drugs. The polyurethane was synthesized from biodegradable poly(ε-caprolactone) (PCL) and L-lysine ethyl ester diisocyanate (LDI), further extended by a new designed L-cystine-derivatized chain extender bearing a redox-responsive disulfide bond and clickable alkynyl groups (Cys-PA), and finally terminated by a detachable methoxyl-poly(ethylene glycol) with a highly pH-sensitive benzoic-imine linkage (BPEG). The obtained polymers show attractive self-assembly characteristics and stimuli-responsiveness, good cytocompatibility, and high loading capacity for doxorubicin (DOX). Furthermore, folic acid (FA) as a model targeting ligand was conjugated to the polyurethane micelles via an efficient click reaction. The decoration of FA results in an enhanced cellular uptake and improved drug efficacy toward FA-receptor positive HeLa cancer cells in vitro. As a proof-of-concept, this work provides a facile approach to the design of extracellularly activatable nanocarriers for tumor-targeted and programmed intracellular drug delivery.

Liquid-crystalline assembly of spherical cellulose nanocrystals.

Rod-shaped cellulose nanocrystals (CNCs), also called cellulose nanorods (CNRs), possess anisotropic properties that allow for their self-organization into chiral nematic liquid crystals. Interestingly, spherical cellulose nanocrystals (cellulose nanospheres, CNSs) have also been shown to form a chiral liquid-crystalline phase in recent years. Herein, to understand how the similar assembly takes places as particle dimension changes, the organization features of CNSs were investigated. Results of this study demonstrate that above a critical concentration in suspension, CNSs organize into a liquid-crystal phase consisting of periodically parallel-aligned layer structures. This structure persists after suspension drying. In comparison with CNRs, the alignment of CNSs exhibits a shorter layer distance, lower order degree, and weaker long-range orientation. To explain the early stages of tactoid formation, a "caterpillar-like" model was proposed, which was captured by freezing the CNS suspension in an intermediate aggregation state. This structure serves as the fundamental unit for further liquid-crystal assembly.

Controllable self-assembly of cellulose nanospheres through phosphoric acid triggered dissolution-regeneration and degradation.

Phosphoric acid has been utilized as a favorable alternative to strong acids for the production of cellulose nanospheres (CNS) in recent years, partly owing to the reduced reliance on mechanical assistance. In the present study, phosphoric acid hydrolysis was applied to synthesize CNS from natural cotton pulp. Compared to reported long-time hydrolysis over 12 h, reduced time of 4 h is achieved for CNS production. Particle size from 530 nm to 1.3 µm was further controlled by changing the hydrolysis time in 4-11 h. Powdered sample was obtained after freeze-drying. CNS prepared in this work exhibits a cellulose II structure. Crystallinity index of the samples locates in 70-75 % which is higher than the reported 43-60 % for the acid-hydrolyzed medical cotton. Moreover, compared to the sulphuric-acid hydrolyzed CNS with higher crystallinity, thermal stability of the CNS generated from phosphoric-acid hydrolysis is significantly greater. A cooperative dissolution-regeneration and degradation is proposed to induce CNS self-assembly. Initial cellulose microfibrils are completely dissolved as exposed to phosphoric acid. Partial chains aggregate as a result while the remaining chains assemble onto the aggregates in a layer-by-layer manner. Acid degradation to cellulose with time affects length of the molecular chains. CNS size is controlled accordingly.

Rapidly regenerated CNC/TiO2/MnO2 porous microspheres for high-efficient dye removal.

The cellulose nanocrystal (CNC)/transition metal oxide hybrid porous microspheres usually have high adsorption performance and degradability, and show promising applications in the field of wastewater treatment. However, single metal oxides are limited by the forbidden band width and electron-hole complexation, and often fail to achieve good effluent treatment. Herein, a CNC/manganese dioxide/titanium dioxide porous microspheres are prepared by the combination of bubble template and ionic crosslinking between sodium alginate and Ca2+ ions as a matrix. Based on the synergistic effect of two kinds of transition metal oxide, the degradation efficiency of CNC/MnO2/TiO2 porous microspheres for methylene blue is as high as 97.0%, showing easy recovery process and rapid regeneration of this material. Besides, its maximum removal of dyes reaches up to 310.2 mg/g, which is much higher than most CNC based adsorption materials. The concept of concerted catalysis can to explain the origin for excellent performance of as-prepared hybrid microspheres.

Green fabrication of porous microspheres containing cellulose nanocrystal/MnO2 nanohybrid for efficient dye removal.

Microspheres based on cellulose nanocrystal (CNC)/metal oxide hybrid materials have great application prospects in wastewater treatment due to simultaneously adsorption, degradation ability, easily separation and recycling properties. However, the relatively small porosity and specific surface area of the CNC-based microspheres limit their adsorption ability. Herein, we reported a facile strategy to prepare porous microsphere based on CNC/MnO2 by freeze-drying the air-bubble templated emulsion, in which the sodium alginate (SA) was used as the crosslinked matrix. Thus-obtained CNC/MnO2/SA microspheres showed low density of 0.027 g/cm3 and high porosity of 98.23%. Benefiting from the high porosity, synergetic effect of CNC electrostatic adsorption and oxidative degradation ability of MnO2, the decolorization ratio of methylene blue (800 mg/mL) could be up to 95.4% in 10 min, and the equilibrium decolorization could reach 114.5 mg/g. This study provides a green and facile strategy to design porous CNC-based material for dye wastewater treatment.

Therapeutic vaccination against leukaemia via the sustained release of co-encapsulated anti-PD-1 and a leukaemia-associated antigen.

Therapeutic leukaemia vaccines have shown modest potency. Here, we show that the co-encapsulation of a leukaemia-associated epitope peptide highly expressed in leukaemia patients and of the immune checkpoint inhibitor anti-programmed-cell-death-protein-1 (anti-PD-1) in degradable poly(lactic acid) microcapsules resulted in the sustained release of the peptide and of the antibody, which led to the recruitment of activated antigen-presenting cells to the injection site, their uptake of the peptide and the transportation of the anti-PD-1 antibody to lymph nodes, enhancing the expansion of epitope-specific T cells and the activation of cytotoxic T cells. After single subcutaneous injections of vaccine formulations with different epitope peptides, mice bearing leukaemia xenografts derived from humanized cell lines or from primary cells from patients showed better therapeutic outcomes than mice receiving repeated injections of free antigen, antibody and a commercial adjuvant. The sustained release of a tumour-associated peptide and of anti-PD-1 may represent a generalizable strategy for boosting antitumour immune responses to leukaemia.

Simultaneous improvement of thermal stability and redispersibility of cellulose nanocrystals by using ionic liquids.

Cellulose nanocrystals (CNCs) are predominantly obtained by the traditional sulfuric acid hydrolysis process. However, as-prepared CNCs powder features low thermal stability and poor redispersibility due to the existence of sulfonate groups and the hydrogen bond interaction among particles. Herein, by mixing the ionic liquid [BMIm][BF4] with freshly prepared CNCs without dialysis through a simple rotary evaporate procedure, the simultaneous improvement of thermal stability and redispersibility of CNCs has been achieved. By combining FTIR, TGA and DLS measurements, the critical role of rotary evaporates process for improving the thermal stability of CNCs has been discussed. Furthermore, the poly(lactic acid) (PLLA)/IL-CNC nanocomposites with enhanced mechanical properties were prepared by the melt-mixing method. This study provides a green and simple strategy for preparing dried CNC powders, which has a great potential in large-scale production of fully bio-based nanocomposites.

Association Between Contact from an Overerupted Third Molar and Bilaterally Redistributed Electromyographic Activity of the Jaw Closing Muscles.

AIMS: To determine whether the facial side of an overerupted third molar and/or the side exhibiting symptoms of temporomandibular disorders (TMD) has an association with the bilateral distribution of occlusal contact number, occlusal force, or surface electromyographic (SEMG) activity of the anterior temporalis (TA) and masseter muscles. METHODS: Nineteen patients with unilateral TMD symptoms and one overerupted mandibular third molar were enrolled. Occlusal contacts and the SEMG activity of the anterior temporalis and masseter muscles were recorded simultaneously during maximal voluntary clenching (MVC) in the intercuspal position (ICP-MVC) and in the protrusive edge-to-edge position (Pro-MVC). The associations between the side of overeruption/TMD symptoms and the Δvalues of the differences between the right- and left-side values for the number of occlusal contacts, sectional force value (defined as the ratio of the anterior or posterior sectional arch bite force of the right or left side to the total arch force [SFV]), and SEMG activity of the temporalis and masseter muscles were analyzed. RESULTS: The overeruption side (P < .050), but not the symptomatic side (P > .050), showed an association with the Δvalues, with higher SFVs of the posterior arch and lower values for temporalis SEMG activity in the 100%, 75%, and 50% protrusive clenching positions and larger numbers of occlusal contacts in the posterior arch in the 100% and 75% protrusive clenching positions than the non-overeruption side. CONCLUSION: The pattern of occlusion, but not TMD symptoms, had an association with the number and distribution of the occlusal contacts, occlusal force, and temporalis SEMG activity.

An investigation on the simultaneously recorded occlusion contact and surface electromyographic activity for patients with unilateral temporomandibular disorders pain.

The present study examined if unilateral pain from temporomandibular disorders (TMD) was associated with the occlusion contacts and surface electromyographic (SEMG) activities of jaw-closing muscles. Eleven patients with unilateral TMD pain and 20 healthy volunteers who all had Angle's Class-I occlusions were enrolled. The numbers and load distributions of the occlusion contacts and the SEMG activities of the anterior temporalis (TA) muscles and masseters muscles (MM) during maximal voluntary clenching (MVC) in the centric and eccentric positions were simultaneously recorded on both sides. The pain was not associated with occlusal contact numbers or load distributions. The SEMG activities of the pain-side TA and bilateral MM were lower during centric MVC compared with controls. The SEMG activities of the non-pain-side TA and the normalized SEMG activities of the bilateral TAs and MMs were higher during protrusive MVC (p<0.05). During pain-side MVC, the normalized SEMG activities of the working-side MM and balancing-side TA were higher than those of the controls. In conclusion, the TMD pain side was not associated with the occlusal contacts, but the patients with TMD had TA and MM SEMG activities during different tasks that differed from controls and that did not seem related to the pain side.

Inspired by nonenveloped viruses escaping from endo-lysosomes: a pH-sensitive polyurethane micelle for effective intracellular trafficking.

A multifunctional drug delivery system (DDS) for cancer therapy still faces great challenges due to multiple physiological barriers encountered in vivo. To increase the efficacy of current cancer treatment a new anticancer DDS mimicking the response of nonenveloped viruses, triggered by acidic pH to escape endo-lysosomes, is developed. Such a smart DDS is self-assembled from biodegradable pH-sensitive polyurethane containing hydrazone bonds in the backbone, named pHPM. The pHPM exhibits excellent micellization characteristics and high loading capacity for hydrophobic chemotherapeutic drugs. The responses of the pHPM in acidic media, undergoing charge conversion and hydrophobic core exposure, resulting from the detachment of the hydrophilic polyethylene glycol (PEG) shell, are similar to the behavior of a nonenveloped virus when trapped in acidic endo-lysosomes. Moreover, the degradation mechanism was verified by gel permeation chromatography (GPC). The endo-lysosomal membrane rupture induced by these transformed micelles is clearly observed by transmission electron microscopy. Consequently, excellent antitumor activity is confirmed both in vitro and in vivo. The results verify that the pHPM could be a promising new drug delivery tool for the treatment of cancer and other diseases.

Toward the next-generation nanomedicines: design of multifunctional multiblock polyurethanes for effective cancer treatment.

Specific accumulation of therapeutics at tumor sites to improve in vivo biodistribution and therapeutic efficacy of anticancer drugs is a major challenge for cancer therapy. Herein, we demonstrate a new generation of intelligent nanosystem integrating multiple functionalities in a single carrier based on multifunctional multiblock polyurethane (MMPU). The smart nanocarriers equipped with stealth, active targeting, and internalizable properties can ferry paclitaxel selectively into tumor tissue, rapidly enter cancer cells, and controllably release their payload in response to an intracellular acidic environment, thus resulting in an improved biodistribution and excellent antitumor activity in vivo. Our work provides a facile and versatile approach for the design and fabrication of smart intracellular targeted nanovehicles for effective cancer treatment, and opens a new era in the development of biodegradable polyurethanes for next-generation nanodelivery systems.

The degradation and biocompatibility of pH-sensitive biodegradable polyurethanes for intracellular multifunctional antitumor drug delivery.

To obtain controllable stepwise biodegradable polymer for multifunctional antitumor drug carriers, pH-sensitive biodegradable polyurethanes were firstly synthesized using poly(ε-caprolactone) (PCL) and pH-sensitive poly(ε-caprolactone)-hydrazone-poly(ethylene glycol)-hydrazone-poly(ε-caprolactone) macrodiol (PCLH) as soft segment; l-lysine ethyl ester diisocyanate (LDI), l-lysine derivative tripeptide and 1,4-butandiol (BDO) as hard segment; and hydrazone-linked methoxyl-poly(ethylene glycol)(m-PEG-Hyd) as end-capper. Then, an extensive degradation process of the prepared pH-sensitive polyurethanes was investigated in vitro with proton nuclear magnetic resonance spectra ((1)H NMR), gel permeation chromatograph (GPC), scanning electron microscopy (SEM), and weight loss. It was found that the degradation of these polyurethanes occurred via the random hydrolytic ester cleavage along the PCL segments close to PEG segments in enzymatic solutions while the hydrazone bond in the polymer chain was more easily cleaved in acidic media, which was accelerated with decreasing pH value. Furthermore, the biocompatibility in vivo was evaluated in an intramuscular implantation model on Sprague-Dawley rats, using SEM and light microscopy. The result showed that the prepared polyurethanes can be easily degraded and the degradation products do not induce any adverse response from surrounding muscle tissues. Our work suggests that the prepared pH-sensitive polyurethanes could be promising materials as controllable biodegradable and non-cyctotoxic multifunctional carriers for active intracellular drug delivery.

Molecular engineered super-nanodevices: smart and safe delivery of potent drugs into tumors.

A super-nanodevice engineered at molecular level integrates various desired properties in a smart and coordinated way, and can "switch on" or "turn off" certain functionalities as required. Importantly, it can break through complex physiological barriers, and then precisely ferry potent toxic triptolide into tumor cells in vivo, thus significantly maximizing the therapeutic efficacy and reducing the drug toxicity.

Synthesis and characterization of novel biodegradable folate conjugated polyurethanes.

In order to obtain targeting polyurethane micelle drug carriers, a series of biodegradable folate conjugated polyurethanes (FPUs) were synthesized using poly(ethylene glycol) (PEG) and poly(ε-caprolactone) (PCL) as soft segments, L-lysine ethyl ester diisocyanate (LDI) and 1,3-propanediol (PDO) as hard segments, and folic acid-ethylenediamine conjugate (FA-EDA) as an end-capping reagent. The resultant FPUs were fully characterized by (1)H NMR, Fourier-transform infrared (FTIR) spectroscopy, ultraviolet spectrophotometry (UV), gel permeation chromatography (GPC), and differential scanning calorimetry (DSC). These polymers can self-assemble into micelles in aqueous solutions confirmed by dynamic light scattering (DLS), pyrene fluorescence probe techniques, and transmission electron microscopy (TEM). The results indicated that the bulk structures and micellar properties of the prepared polyurethanes could be controlled by varying the PEG content in the soft segments. The present work provides a facile approach to prepare amphiphilic multiblock copolymers with tumor targeting moiety, which is a good candidate as biodegradable carriers for active intracellular drug delivery.