Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy.

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of YarsE196K mice modelling DI-CMT. We determined that YarsE196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRSE196K, but not TyrRSWT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.

Combination immunotherapy of PEG-modified preladenant thermosensitive liposomes and PD-1 inhibitor effectively enhances the anti-tumor immune response and therapeutic effects.

Immunotherapy is a promising cancer treatment strategy. In contrast, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors are associated with low response rates and are only useful in a small group of cancer patients. A combination of treatments may be effective for overcoming this clinical issue. Preladenant is an adenosine (ADO) receptor inhibitor that can block the ADO pathway and improve the tumor microenvironment (TME), thereby enhancing the immunotherapeutic effect of PD-1 inhibitors. However, its poor water solubility and low targeting limit its clinical applications. We designed a PEG-modified thermosensitive-liposome (pTSL) loaded with ADO small molecule inhibitor preladenant (P-pTSL) to overcome these problems and enhance the effect of PD-1 inhibitor on breast cancer immunotherapy. The prepared P-pTSL was round and uniformly distributed with a particle size of (138.9 ± 1.22) nm, PDI: 0.134 ± 0.031, and zeta potential (-10.1 ± 1.63) mV; preladenant was released slowly at 37 °C but released fast at 42 °C from P-pTSL, which was 76.52 ± 0.44%. P-pTSL has good long-term and serum stability and excellent tumor-targeting ability in mice. Moreover, the combination with PD-1 inhibitor significantly enhanced the anti-tumor effect, and the improvement of related factors in serum and lymph was more obvious under the condition of 42 °C thermotherapy in vitro.

A randomized, controlled, split-face study of botulinum toxin and broadband light for the treatment of erythematotelangiectatic rosacea.

To study the efficacy and safety of botulinum toxin (BTX) combined with broadband light (BBL) in the treatment of rosacea-related erythema and flushing. A randomized, single-blind, split-face controlled study including 22 patients with erythemato telangiectatic rosacea were enrolled. Both cheeks were randomly divided into experimental group and control group. They were treated three times with an interval of 1 month. In the first treatment, the experimental group received BBL treatment and intradermal injection of BTX, and the control group received BBL treatment and intradermal injection of the same amount of normal saline; in the second and third treatments were both groups received the same BBL treatment. The patients were evaluated before the first treatment and 1, 2, 3, and 6 months after the treatment. Compared with the control group, the hydration in the experimental group increased and the global flushing symptom score (GFSS), VISIA red value, erythema index, transepidermal water loss, and sebum secretion decreased. The differences were statistically significant (p < 0.05). In the experimental group, at 3 months after the first treatment, compared with before treatment, the GFSS, VISIA red value, erythema index, transepidermal water loss and sebum secretion decreased the hydration increased. The sebum secretion returned to the pretreatment level in 6 months after treatment, and the other indexes maintained the level in 3 months after treatment. One patient had a slight lifting limitation of the corners of his mouth after 10 days of BTX injection, without special treatment, and recovered after 1 month. BTX intradermal injection combined with BBL has a definite therapeutic effect on the improvement of rosacea related erythema and flushing, which is better than simple BBL, and has high safety. It is worthy of clinical promotion.

Boosting BDNF in muscle rescues impaired axonal transport in a mouse model of DI-CMTC peripheral neuropathy.

Charcot-Marie-Tooth disease (CMT) is a genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which transfer amino acids to partner tRNAs for protein synthesis, represent the largest protein family genetically linked to CMT aetiology, suggesting pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that human DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for several mutant glycyl-tRNA synthetases linked to CMT type 2D (CMT2D). We then performed temporal neuromuscular assessments of YarsE196K mice modelling DI-CMT. We determined that YarsE196K homozygotes display a selective, age-dependent impairment in in vivo axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. This impairment is replicated by injection of recombinant TyrRSE196K, but not TyrRSWT, into muscles of wild-type mice. Augmenting BDNF in DI-CMTC muscles, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a non-cell autonomous pathomechanism common to ARS-related neuropathies, and highlights the potential of boosting BDNF levels in muscles as a therapeutic strategy.

Atropine-eluting silicone contact lenses for myopia control.

Myopia, also known as nearsightedness, is one of the prime reasons for vision impairment worldwide. Atropine in topical ophthalmic solutions (e.g., 0.01% atropine sulfate eye drops) is the primary medical treatment for controlling myopia, especially for pseudomyopia or true myopia in rapid progress. However, aqueous atropine solution is unstable and easily breaks down to tropic acid, which will result in vision blur. Drug-eluting contact lenses (CLs) have been explored as a potentially superior alternative to effectively control the drug release and improve the drug efficacy. In this work, an atropine-eluting contact lens was developed by encapsulating an atropine implant in a silicon-based contact lens, towards functioning in vision correction and controlling myopia. The safety and effectiveness of this atropine-eluting contact lens were verified with rabbit and guinea pig models. The results showed that the lenses reduced the side effects like mydriasis and no other adverse events were observed in rabbit eyes. More importantly, atropine-loaded lenses could effectively delay the progress of form-deprivation myopia with guinea pig eyes as the model. Thus, we concluded that atropine-eluting CLs prepared by implantation technology may be an option for the treatment of myopia.

NiCo2S4 combined 3D hierarchical porous carbon derived from lignin for high-performance supercapacitors.

Metal sulfides with the nature of low electronegativity and high electrochemical activity are potentially considered effective electrode materials for supercapacitors. Meanwhile, hierarchical porous carbon (HPC) materials derived from eco-friendly enzymatic hydrolysis lignin are the ideal matrix for holding nanoparticles (NP) that allows the overall NP/HPC composite to achieve outstanding electrochemical performance. In this study, NiCo2S4 nanoparticles were in-situ synthesized on the inner surface of 3D HPC that derived from enzymatic hydrolysis lignin with a simple one-step solvothermal method, thus forming a high-performance composite electrode material for supercapacitor applications. As a result, the NiCo2S4/HPC composite yields an outstanding specific capacity of 1264.2 F g-1 at 1 A g-1 and also exhibits remarkable rate performance. Such remarkable property is attributed to the effective combination of NiCo2S4 plus HPC and their strong chemical bonds, which enable excellent electronic conductivity and abundant exposed electroactive sites. The asymmetric supercapacitor assembled by utilizing NiCo2S4/HPC and active carbon as the positive and negative electrodes, respectively, provide an excellent energy density of 32.05 Wh kg-1 at a power density of 193.9 W kg-1. This work puts forward a practical optimization strategy for metal sulfides used in electrochemical energy storage devices.

Boosting peripheral BDNF rescues impaired in vivo axonal transport in CMT2D mice.

Gain-of-function mutations in the housekeeping gene GARS1, which lead to the expression of toxic versions of glycyl-tRNA synthetase (GlyRS), cause the selective motor and sensory pathology characterizing Charcot-Marie-Tooth disease (CMT). Aberrant interactions between GlyRS mutants and different proteins, including neurotrophin receptor tropomyosin receptor kinase receptor B (TrkB), underlie CMT type 2D (CMT2D); however, our pathomechanistic understanding of this untreatable peripheral neuropathy remains incomplete. Through intravital imaging of the sciatic nerve, we show that CMT2D mice displayed early and persistent disturbances in axonal transport of neurotrophin-containing signaling endosomes in vivo. We discovered that brain-derived neurotrophic factor (BDNF)/TrkB impairments correlated with transport disruption and overall CMT2D neuropathology and that inhibition of this pathway at the nerve-muscle interface perturbed endosome transport in wild-type axons. Accordingly, supplementation of muscles with BDNF, but not other neurotrophins, completely restored physiological axonal transport in neuropathic mice. Together, these findings suggest that selectively targeting muscles with BDNF-boosting therapies could represent a viable therapeutic strategy for CMT2D.

Construction of nickel ferrite nanoparticle-loaded on carboxymethyl cellulose-derived porous carbon for efficient pseudocapacitive energy storage.

The preparation of biomass-derived carbon electrode materials with abundant active sites is suitable for development of energy-storage systems with high energy and power densities. Herein, a hybrid material consisting of highly-dispersed nickel ferrite nanoparticle on 3D hierarchical carboxymethyl cellulose-derived porous carbon (NiFe2O4/CPC) was prepared by simple annealing treatment. The synergistic effects of NiFe2O4 species with multiple oxidation states and 3D porous carbon with a large specific surface area offered abundant active centers, fast electron/ion transport, and robust structural stability, thereby showing the excellent performance of the electrochemical capacitor. The best performing sample (NiFe2O4/CPC-800) exhibited a superior capacitance of 2894F g-1 at a current density of 0.5 A g-1. Encouragingly, an asymmetric supercapacitor with NiFe2O4/CPC-800 as a positive electrode and activated carbon as a negative electrode delivered a high energy density of 135.2 W h kg-1 along with an improved power density of 10.04 kW kg-1. Meanwhile, the superior cycling stability of 90.2% over 10,000 cycles at 5 A g-1 was achieved. Overall, the presented work offers a guideline for the design and preparation of advanced electrode materials for energy-storage systems.

[Effects of Plastic Mulch Film on Soil Nutrients and Ecological Enzyme Stoichiometry in Farmland].

Ecological enzyme stoichiometry can be used to evaluate the limit of soil microbial energy and nutrient resources. To illustrate the effects of plastic mulch film on soil ecological enzyme stoichiometry in farmland, this study collected soil with different amounts of mulching film residual and used the fluorescence analysis to determine the activities of key enzymes for the carbon, nitrogen, and phosphorus cycle processes including ß-1,4-glycosidase (BG), ß-1,4-N-acetyl amino glycosidase (NAG), and phosphatase (ACP) activity. This study investigated the effects of plastic mulch film on soil nutrient cycling and supply in farmland. The results showed that in the soil with chemical fertilizer, plastic film mulching decreased soil Olsen-P and NO3--N contents to 48%-62% and 16%-24% of those in the soil without plastic film mulching, respectively. In the soil with the combined application of organic-chemical fertilizers, plastic film mulching increased Olsen-P and NO3--N contents by 144%-203% and 1.9-5.1 times, respectively. In the organic-chemical fertilization soils, plastic film mulching decreased SOC:TN in soils by 6.6%-25.8%, whereas it increased SOC:TP and TN:TP significantly. MBC, MBN, and MBP contents in the soil with plastic film mulching were significantly lower than that in non-plastic film mulching farmland, and there were no significant differences in MBC:MBN and MBC:MBP between soil with and without plastic film mulching. The MBN:MBP was reduced by 36.6% and 23.8% in S1 and S2, and 5.4 and 1.3 times in S3 and S4 by plastic film mulching, respectively. The change pattern of NAG:ACP in soil was similar to that of the corresponding elements ratio in microbial biomass. In the soil from plastic film mulching, the ratio of BG:NAG was 1.3-15 times higher in organic-chemical fertilization soils than that with only chemical fertilizer. In conclusion, plastic film mulching reduced the availability of soil nutrients, and organic-chemical fertilization alleviated the limitation of soil nutrients to a certain extent. This study deepened the understanding of the response of soil microorganisms to nutrient cycling after plastic film mulching. It provides a theoretical basis for optimizing the farmland management in the use of plastic film.

Sustainable removal of soil arsenic by naturally-formed iron oxides on plastic tubes.

Arsenic (As) pollution in paddy fields is a major threat to rice safety. Existing As remediation techniques are costly, require external chemical addition and degrade soil properties. Here, we report the use of plastic tubes as a recyclable tool to precisely extract As from contaminated soils. Following insertion into flooded paddy soils, polyethylene tube walls were covered by thin but massive Fe coatings of 76.9-367 mg Fe m-2 in 2 weeks, which adsorbed significant amounts of As. The formation of tube-wall Fe oxides was driven by local Fe-oxidizing bacteria with oxygen produced by oxygenic phototrophs (e.g., Cyanobacteria) or diffused from air through the tube wall. The tubes with As-bound Fe oxides can be easily separated from soil and then washed and reused. We tested the As removal efficiency in a pot experiment to remove As from ~ 20 cm depth/40 kg soils in a 2-year experiment and achieved an overall removal efficiency of 152 mg As m-2 soil year-1, comparable to phytoremediation with the As hyperaccumulator Pteris vittata. The cost of Fe hooks was estimated at 8325 RMB ha-1 year-1, and the profit of growing rice (around 16080 RMB ha-1 year-1 can be still maintained. The As accumulated in rice tissues was markedly decreased in the treatment (>11.1 %). This work provides a low-cost and sustainable soil remediation method for the targeted removal of As from soils and a useful tool for the study and management of the biogeochemical Fe cycle in paddy soils.

Three-dimensional hierarchical porous carbon derived from lignin for supercapacitors: Insight into the hydrothermal carbonization and activation.

Three-dimensional hierarchical porous carbon is prepared by utilizing enzymatic hydrolysis lignin as a carbon source via hydrothermal carbonization and activation. The complicated operational parameters including temperature, time, concentration and pH in the hydrothermal carbonization are systemically investigated. We employed the hydrochar as electrode for supercapacitors. Accordingly, we not only achieve a high-performance specific capacitance for supercapacitors but also rationalize the effects of hydrothermal conditions on the specific capacitance via various characterizations. The activation process of hydrochar is also studied by comparing various activators and the activator/hydrochar ratios. The obtained materials possess a three-dimensional interconnected hierarchical structure with rational pore size distribution and a specific surface area reach up to 1504 m2 g-1. Then the corresponding supercapacitors achieve a large specific capacitance of 324 F g-1 as the current density is 0.5 A g-1. These supercapacitors acquire an outstanding cycling stability with 99.7% capacitance retention after 5000 cycles. The assembled symmetrical supercapacitors also show a high energy density of 17.9 W h kg-1 and can maintain at 5.6 W h kg-1 even at an ultra-high power density of 50,400 W kg-1.

Three-dimensional hierarchical porous lignin-derived carbon/WO3 for high-performance solid-state planar micro-supercapacitor.

The development of advanced energy storage systems, such as rechargeable batteries and supercapacitors (SCs), is one of the great challenges related to energy demand with the rapid development of world economy. Herein, a three-dimensional hierarchical porous lignin-derived carbon/WO3 (HPC/WO3) was prepared by carbonization and solvothermal process. This electrode material for supercapacitor can be operated at a wide voltage window range of -0.4 V to 1.0 V. More importantly, 3HPC/WO3 with ultrahigh mass loading (~3.56 mg cm-2) has excellent specific capacitance of 432 F g-1 at 0.5 A g-1 and cycling stability of 86.6% after 10,000 cycles at 10 A g-1. The as-assembled asymmetrical supercapacitor shows an energy density of 34.2 W h kg-1 at a power density of 237 W kg-1 and energy density of 16 W h kg-1 at a power density is 14,300 W kg-1. A solid-state planar micro-supercapacitor (MSC) was fabricated using HPC/WO3 nanocomposites. Moreover, the calculated specific capacity of MSC was 20 mF cm-2 in polyvinyl alcohol-sulfuric acid gel electrolyte. Overall, through the reasonable design of HPC/WO3 nanocomposite materials and the efficient assembly of MSCs, the performance of the device was greatly improved, thus providing a clear strategy for the development of energy storage devices.

Green construction of Fe3O4@GC submicrocubes for highly sensitive magnetic dispersive solid-phase extraction of five phthalate esters in beverages and plastic bottles.

A well-designed core-shelled Fe3O4@graphitic carbon (Fe3O4@GC) submicrocube was in situ constructed in a simple, relatively green and eco-friendly ways basing on one-step pyrolysis of low-cost waste napkins-coated Fe2O3 submicrocubes. The Fe3O4@GC submicrocubes showed unique architectures where in situ generated thin graphitic carbon layer wrapped on the surface of Fe3O4, resulting in excellent affinity to five phthalate esters (PAEs), good reusability and rapid magnetic separation, therefore were employed as magnetic dispersive solid-phase extraction material combined with HPLC to simultaneously detect five trace PAEs in beverages and plastic bottles. Under optimized conditions, recoveries (80.0%-112.8%), precision (RSDs ≤ 8.8%), and limits of detection (LODs) for beverages (0.09-0.28 µg L-1) and plastic bottles (0.01-0.03 µg g-1) were obtained. This work not only establishes an effective method for simultaneous determination of five PAEs, but also opens up a new strategy to design/construct magnetic graphitic carbon-encapsulated core-shell materials using low-cost/recyclable napkins as carbon source.

A Macrophage-Magnesium Hybrid Biomotor: Fabrication and Characterization.

Magnesium (Mg)-based micromotors are combined with live macrophage (MΦ) cells to create a unique MΦ-Mg biohybrid motor system. The resulting biomotors possess rapid propulsion ability stemming from the Mg micromotors and the biological functions provided by the live MΦ cell. To prepare the biohybrid motors, Mg microparticles coated with titanium dioxide and poly(l-lysine) (PLL) layers are incubated with live MΦs at low temperature. The formation of such biohybrid motors depends on the relative size of the MΦs and Mg particles, with the MΦ swallowing up Mg particles smaller than 5 µm. The experimental results and numerical simulations demonstrate that the motion of MΦ-Mg motors is determined by the size of the Mg micromotor core and the position of the MΦ during the attachment process. The MΦ-Mg motors also perform biological functions related to free MΦs such as endotoxin neutralization. Cell membrane staining and toxin neutralization studies confirm that the MΦs maintain their viability and functionality (e.g., endotoxin neutralization) after binding to the Mg micromotors. This new MΦ-Mg motor design can be expanded to different types of living cells to fulfill diverse biological tasks.

Synthesis of amphoteric curdlan derivatives for delivery of therapeutic nucleic acids.

Cationic polymers are powerful carriers for intracellular delivery of therapeutic nucleic acids. However, the positively charged macromolecules have considerable cytotoxicity and often induce irreversible damages to the cells and tissues, which greatly negate the clinical application of such materials as drug delivery system. Herein, we report the synthesis of novel amphoteric polymers based on curdlan, and the evaluation of their cytotoxicity as well as the nucleic acid delivery efficiency. ß-(1,3)-polyglucuronic acid, a TEMPO-oxidized derivative of curdlan, was chemically modified by conjugation of tetraethylenepentamine. The resulting amphoteric polymers, denoted tetraethylenepentamine-curdlan (TEPAC) polymers have the degree of substitution (DS) ranging from 25% to 48%. The result of MTT assay indicated that TEPAC polymers have negligible cytotoxicity on HeLa cells and A549 cells. The novel amphoteric polymers efficiently bound with plasmid DNA and delivered pcDNA-eGFP plasmid to 293T cells and induced expression of GFP 48h after the transfection. Moreover, TEPAC polymers delivered siRNA to HeLa cells and HepG2 cells in high efficiency, and induced significant RNAi for the expression of an endogenous gene. Collectively, our data demonstrate that the novel curdlan-based amphoteric polymers are biocompatible and may provide a highly efficient system for the delivery of therapeutic nucleic acids.

Low pressure steam expansion pretreatment as a competitive approach to improve diosgenin yield and the production of fermentable sugar from Dioscorea zingiberensis C.H. Wright.

Development of efficient pretreatment methods which can disrupt the peripheral lignocellulose and even the parenchyma cells is of great importance for production of diosgenin from turmeric rhizomes. It was found that low pressure steam expansion pretreatment (LSEP) could improve the diosgenin yield by more than 40% compared with the case without pretreatment, while simultaneously increasing the production of fermentable sugar by 27.37%. Furthermore, little inhibitory compounds were produced in LSEP process which was extremely favorable for the subsequent biotransformation of fermentable sugar to other valuable products such as ethanol. Preliminary study showed that the ethanol yield when using the fermentable sugar as carbon source was comparable to that using glucose. The liquid residue of LSEP treated turmeric tuber after diosgenin production can be utilized as a quality fermentable carbon source. Therefore, LSEP has great potential in industrial application in diosgenin clean production and comprehensive utilization of turmeric tuber.

Dendrobium officinale polysaccharides ameliorate the abnormality of aquaporin 5, pro-inflammatory cytokines and inhibit apoptosis in the experimental Sjögren's syndrome mice.

Sjögren's syndrome (SS) is a chronic autoimmune disease with exocrine glands disorder. Our previous work demonstrated the protective effect of Dendrobium officinale polysaccharides (DP) both on the phenotypes of patients and animal model with SS. In this study, we expand these observations to explore the possible mechanisms. The experimental SS mice model was established with or without the administration of DP (20mg/ml). The time frame of lymphocytes infiltration, apoptotic indicators such as Bax, Bcl-2 and caspase-3 were determined in submandibular gland (SG), as well as the subsequent mRNA expression of cytokines such as TNF-α, IL-1 beta and IL-6. The expression and localization of aquaporin-5 (AQP-5) was examined by Western blot and immunofluorescent staining. As the result, DP could suppress the progressive lymphocytes infiltration and apoptosis, and balance the chaos of pro-inflammatory cytokines in the SG. Further, DP ameliorated the abnormalities of AQP-5 and maintained its functional importance of saliva secretion. In addition, the protection of AQP-5 by DP from human TNF-α was supported by an in vitro study on A-253 cell line. Our study further supported the efficacy of DP as the promising candidate for the therapy of SS.