Model-based precision dosing and remedial dosing recommendations for delayed or missed doses of isoniazid in Chinese patients with tuberculosis.

AIMS: Isoniazid (INH) has been used as a first-line drug to treat tuberculosis (TB) for more than 50 years. However, large interindividual variability was found in its pharmacokinetics, and effects of nonadherence to INH treatment and corresponding remedy regime remain unclear. This study aimed to develop a population pharmacokinetic (PPK) model of INH in Chinese patients with TB to provide model-informed precision dosing and explore appropriate remedial dosing regimens for nonadherent patients. METHODS: In total, 1012 INH observations from 736 TB patients were included. A nonlinear mixed-effects modelling was used to analyse the PPK of INH. Using Monte Carlo simulations to determine optimal dosage regimens and design remedial dosing regimens. RESULTS: A 2-compartmental model, including first-order absorption and elimination with allometric scaling, was found to best describe the PK characteristics of INH. A mixture model was used to characterize dual rates of INH elimination. Estimates of apparent clearance in fast and slow eliminators were 28.0 and 11.2 L/h, respectively. The proportion of fast eliminators in the population was estimated to be 40.5%. Monte Carlo simulations determined optimal dosage regimens for slow and fast eliminators with different body weight. For remedial dosing regimens, the missed dose should be taken as soon as possible when the delay does not exceed 12 h, and an additional dose is not needed. delay for an INH dose exceeds 12 h, the patient only needs to take the next single dose normally. CONCLUSION: PPK modelling and simulation provide valid evidence on the precision dosing and remedial dosing regimen of INH.

Complete response in patient with locally advanced lung large cell neuroendocrine carcinoma under sintilimab plus platinum-based chemotherapy: A case report.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is an uncommon subtype of lung cancer with bleak prognosis. Its optimal treatment remains undetermined due to its malignancy. A 66-year-old man diagnosed with unresectable locally advanced LCNEC exhibited partial radiographic response to chemo-immunotherapy. He underwent salvage surgery after 4 rounds of docetaxel/nedaplatin (DP) regimen plus sintilimab, a highly selective monoclonal antibody which targets human anti-programmed death-ligand 1 (PD-L1). In addition, the pathologic examination of the excision demonstrated that there were no viable residuary tumor cells. This case indicates that neoadjuvant chemo-immunotherapy might benefit patients with locally advanced LCNEC, which deserves further investigation.

Monolithic Integration of GaN-Based Transistors and Micro-LED.

Micro-LED is considered an emerging display technology with significant potential for high resolution, brightness, and energy efficiency in display applications. However, its decreasing pixel size and complex manufacturing process create challenges for its integration with driving units. Recently, researchers have proposed various methods to achieve highly integrated micro-structures with driving unit. Researchers take advantage of the high performance of the transistors to achieve low power consumption, high current gain, and fast response frequency. This paper gives a review of recent studies on the new integration methods of micro-LEDs with different types of transistors, including the integration with BJT, HEMT, TFT, and MOSFET.

Development, Validation, and Clinical Application of an Ultra-High-Performance Liquid Chromatography Coupled With Tandem Mass Spectrometry Method for the Determination of 10 Antituberculosis Drugs in Human Serum.

INTRODUCTION: Linezolid, moxifloxacin, rifapentine, rifabutin, cycloserine, clofazimine, bedaquiline, levofloxacin, prothionamide, and ethionamide are commonly used second-line antituberculosis (anti-TB) drugs. To support therapeutic drug monitoring in regular clinical practice, the authors sought to develop a method based on ultra-high-performance liquid chromatography coupled with tandem mass spectrometry (UHPLC-MS/MS) that would allow for the simultaneous quantification of multiple second-line anti-TB drugs in human serum. METHODS: Analytes were extracted from human serum by protein precipitation. UHPLC-MS/MS was performed using a gradient at a flow rate of 0.3 mL/min, and each sample was taken for 7.5 minutes. The mass spectrometry scanning mode used was electrospray ionization with multiple reaction monitoring in the positive mode. RESULTS: Validation showed that endogenous substances in the sample did not interfere with the assay, and the relationship between X and Y was highly linear, with a coefficient of determination (R2) >0.9954 for each curve. The accuracy (85.0%-114.7%) and precision (intraday: 0.27%-9.32%; interday: 0.20%-7.66%) were less than 15.0%, and the internal standard-normalized matrix effects were consistent (coefficient of variation ≤4.40%). The analytes were stable in the final extract and human serum under various storage conditions (recovery: 87.0%-115.0%). The clinical applicability of the method was demonstrated by quantitative determination of analytes in serum samples obtained from patients with TB. Reproducibility of the drug concentrations measured in clinical samples was confirmed by incurred sample reanalysis. CONCLUSIONS: A simple and reliable analytical method was developed and validated for the simultaneous determination of 10 anti-TB drugs in human serum using UHPLC-MS/MS. Quantitation of anti-TB drugs in clinical samples confirmed that the assay is suitable for therapeutic drug monitoring in regular clinical practice.

Investigation of highly reflective p-electrodes for AlGaN-based deep-ultraviolet light-emitting diodes.

We proposed a "Ni sacrifice" method to fabricate Al-based highly reflective p-electrode in the ultraviolet spectral region for AlGaN-based deep-ultraviolet light-emitting diodes (DUV-LEDs). The "Ni sacrifice" p-electrode could have a high optical reflectivity of around 90% at the DUV spectral region below 300 nm. Compared to Ni/Au, indium tin oxide (ITO), and Pd p-contacts, the "Ni sacrifice" led to a higher resistivity of p-contacts and a slightly higher operated voltage of the DUV-LEDs (within 0.6 V at 20 mA). Although the electrical performance was degraded slightly, the light output power and external quantum efficiency of the DUV-LEDs could be improved by utilizing the "Ni sacrifice" p-electrode. Besides, we introduced a grid of vias in the device mesa and reduced the diameter of the vias to achieve an enhanced peak external quantum efficiency (EQE) up to 1.73%. And the wall-plug efficiency (WPE) of DUV-LEDs with a "Ni sacrifice" p-electrode was higher than that of Ni/Au p-electrode DUV-LEDs at low currents. These results highlight the great potential of the proposed "Ni sacrifice" reflective p-electrode for use in DUV-LEDs.

Gooseberry anthocyanins alleviate insulin resistance by regulating ceramide metabolism in high fat diet mice.

Background/aim: Obesity is the fifth largest risk factor of death in the world. The ceramide produced by obesity is closely related to insulin resistance (IR) caused by obesity. At present, the commercially available weight loss products have large side effects and limited therapeutic effects. Therefore, it is particularly important to find effective natural nontoxic products to treat obesity and explore its possible pathways and mechanisms. Materials and methods: In this paper, a high-fat diet (HFD) mice model was established by intragastric administration of high-fat emulsion to investigate the intervention effect of Gooseberry anthocyanins (GA) on IR in HFD mice. We used molecular docking technology to find the binding sites and binding energy of anthocyanins on CerS6. Real-time PCR was used to detect the effect of GA on the expression of IL-6 and TNF-α mRNA in HFD mice. The expression of S1P/Cer signaling pathway in HFD mice with IR was detected by Western Blot. Results: The results showed that GA could effectively inhibit visceral fat, liver index, the level of TC, TG and the level of LDL-C (p < 0.05), and improved HDL-C, GSH-Px and SOD (p < 0.05). GA decreased the level of insulin sensitivity index from -5.15 to -4.54 and improved insulin sensitivity and IR in HFD mice. The binding energy of anthocyanins on CerS6 was in the range of -8.2 to 5.2 kcal/mol, with low energy parameters and good binding positions. GA could reduce mRNA levels of inflammatory factors IL-6 and TNF-α (p < 0.05), inhibit the expression of CerS6, PKCζ, PPARγ, CD36 (p < 0.05), and enhance the expression of SphK2, Akt, p-Akt/Akt, ISR (p < 0.05). Conclusion: This study investigated the effect and mechanism of GA on reducing ceramide content and reducing IR in mice, and provided an experimental basis for the prevention and treatment of obesity-related diseases.

Encoding Coacervate Droplets with Paramagnetism for Dynamical Reconfigurability and Spatial Addressability.

It is an ongoing endeavor in chemistry and materials science to regulate coacervate droplets on a physiologically relevant spatiotemporal scale to ultimately match or even surpass living cells' precision, complexity, and functionality. Herein, we develop a magnetic strategy orthogonal to the thermal, pH, light, or chemical counterparts that are commonly employed by biotic or artificial systems; its successful implementation thus adds a missing piece to the current arsenal of manipulative methodologies. Specifically, we paramagnetize the otherwise diamagnetic coacervate droplets by cooperatively combining paramagnetic ingredients (including organic radicals, metal ions, and Fe3O4 nanoparticles) and coacervate ingredients to obtain "MagCoa" droplets. A simple model is derived theoretically to account for migration and division of MagCoa droplets in an uneven magnetic field. Experimentally, we produce an array of compartmentalized and monodispersed droplets using microfluidics and magnetically steer them with uniformity and synchronicity. We design and fabricate spatial magnetic modulators to engineer the landscape of a magnetic field that, in turn, directs the MagCoa droplets into predesigned patterns in a reconfigurable fashion. These programmable liquid patterns can be potentially extended to dynamic assembly and information encryption. We envision that the toolbox established here is of generality and multitudes to serve as a practical guide to control droplets magnetically.

Extended Kalman filter algorithm for non-roughness and moving damage identification.

It is a promising method to identify structural damage using bridge dynamic response under moving vehicle excitation, but the lack of accurate information about road roughness and vehicle parameters will lead to the failure of this method. The paper proposed a step-by-step EKF damage identification method, which transforms the inversion problem of unknown structural parameters under unknown loads (vehicle and road roughness) into two separate inversion problems: moving contact force identification and damage parameters identification. Firstly, the VBI model is converted into bridge vibration model under a moving contact force, and the moving contact force covering the information of road roughness and vehicle parameters can be calculated by EKF iteration. Secondly, the moving contact force identified in the first step is loaded on the bridge as a known condition, and the bridge damage problem is also solved by the EKF method. Numerical analyses of a simply-supported bridge under the moving vehicle are conducted to investigate the accuracy and efficiency of the proposed method. Effects of the vehicle speed, the damage cases, the measurement noise, and the roughness levels on the accuracy of the identification results are investigated. The results demonstrate the proposed algorithm is efficient and robust, and the algorithm can be developed into an effective tool for structural health monitoring of bridges.

gw2.1, a new allele of GW2, improves grain weight and grain yield in rice.

Grain weight is an important characteristic of grain shape and a key contributing factor to the grain yield in rice. Here, we report that gw2.1, a new allele of the Grain Width and Weight 2 (GW2) gene, regulates grain size and grain weight. A single nucleotide substitution in the coding sequence (CDS) of gw2.1 resulted in the change of glutamate to lysine (E128K) in GW2.1 protein. Complementation tests and GW2 overexpression experiments demonstrated that the missense mutation in gw2.1 was responsible for the phenotype of enlarged grain size in the mutant line jf42. The large grain trait of the near-isogenic line NIL-gw2.1 was found to result from increased cell proliferation during flower development. Meanwhile, NIL-gw2.1 was shown to increase grain yield without compromising the grain quality. The GW2 protein was localized to the cell nucleus and membrane, and interacted with CHB705, a subunit of the chromatin remodeling complex. Finally, the F1 hybrids from crosses of NIL-gw2.1 with 7 cytoplasmic male-sterile lines exhibited large grains and desirable grain appearance. Thus, gw2.1 is a promising allele that could be applied to improve grain yield and grain appearance in rice. AVAILABILITY OF DATA AND MATERIALS: The datasets generated and/or analyzed in the study are available from the corresponding author on reasonable request.

Construction of a double-responsive modified guar gum nanoparticles and its application in oral insulin administration.

The use of intelligent insulin delivery systems has become more important for treating diabetes. In this study, a dual-responsive oral insulin delivery nanocarrier that responds to glucose and pH has been developed. First, the oleic acid hydrophobic modified guar gum (GG) was synthesized by the esterification reaction, and the γ-polyglutamic acid (γ-PGA) was coupled with GG by the amidation reaction. The obtained pH-responsive copolymer (γ-PGA-GG) was cross-linked by concanavalin A to obtain pH/glucose dual-responsive nanocarriers, and insulin was effectively loaded into the dual-responsive nanocarriers. The insulin-loaded nanoparticles can achieve effective pH and glucose responses, releasing insulin on demand. In vitro and in vivo studies demonstrated the dual-responsive nanoparticles can protect insulin against the pH changes in the digestive tract and deliver insulin into the body to exert a hypoglycemic effect. Moreover, the dual-responsive nanoparticles have significant potential to be employed for oral insulin delivery.

Preventive Effect and Mechanism of Anthocyanins from Aronia Melanocarpa Elliot on Hepatic Fibrosis Through TGF-ß/Smad Signaling Pathway.

In order to explore the effect and mechanism of Aornia mealnocarpa Elliot anthocyanins (AMA) at the cellular level on hepatic fibrosis (HF), molecular docking, RT-PCR and Western Blotting were used to explore the molecular mechanism and the effects of different doses AMA on HSC-T6 cells by TGF-ß1 induction. The results showed that the binding energy of anthocyanins on TGF-ß1 (PDB ID: 3KFD) was in the range of -9.5 to 8.6 kcal/mol, with good low energy parameters and binding positions. AMA could effectively inhibit the expressions of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total serum bilirubin (TSB), and improved the expressions of total protein (TP) and albumin (ALB). RT-PCR and Western bloting results showed that AMA could inhibited the secretion of inflammatory cytokines IL-1, IL-6, TNF-α and COX-2, and inhibit the expression of TGF-ß1, P-Smad2, α-SMA and Collagen I in TGF-ß /Smad signaling pathway. This study revealed the AMA's inhibition effects and mechanism of malignant biological behavior of HSC-T6 cells, in order to provide theoretical basis for the prevention and treatment of HF by Aronia melanocarpa Elliot.

Natural variation of the BRD2 allele affects plant height and grain size in rice.

MAIN CONCLUSION: The zqdm1 identified from a rice mutant is a novel allele of BRD2 and is responsible for regulating rice plant height, grain size and appearance, which has possibilities on improving rice quality. Plant height is an important agronomic trait related to rice yield, and grain size directly determines grain yield in rice (Oryza sativa L.). With the development of molecular biotechnology and genome sequencing technology, more and more key genes associated with plant height and grain size have been cloned and identified in recent years. This study identified the zqdm1 gene from a mutant with reduced plant height and grain size. The zqdm1 gene was revealed to be a new allele of BRASSINOSTEROID DEFICIENT DWARF 2 (BRD2), encoding a FAD-linked oxidoreductase protein involved in the brassinosteroid (BR) biosynthesis pathway, and regulates plant height by reducing cell number of longitudinal sections of the internode and regulates grain size by altering cell expansion. A 369-bp DNA fragment was found inserted at the first exon, resulting in protein-coding termination. This mutation has not been discovered in previous studies. Complementation tests have confirmed that 369-bp insertion in BRD2 was responsible for the plant height and grain size changing in the zqdm1 mutant. Over-expression of BRD2 driven by different promoters into indica rice variety Jiafuzhan (JFZ) results in slender grains, suggesting its function on regulating grain shape. In summary, the current study has identified a new BRD2 allele, which facilitated the further research on the molecular mechanism of this gene on regulating growth and development.

The functional microbiota of on- and off-year moso bamboo (Phyllostachys edulis) influences the development of the bamboo pest Pantana phyllostachysae.

BACKGROUND: Development of Pantana phyllostachysae, a moso bamboo pest, is affected by its diet. Understanding the mechanism underlying the different insect-resistant capacities of on- and off-year moso bamboo fed by P. phyllostachysae is crucial for managing pest outbreaks. As microbes were proven to influence plant immunity, we compared gut microbial communities of P. phyllostachysae with different diets by metabarcoding sequencing. By using sterilization assay, microbes were removed from leaf surfaces, and thus we confirmed that microbes inhabiting moso bamboo leaves impact the weight of P. phyllostachysae larva. Furthermore, the gut microbial communities of P. phyllostachysae fed on on- and off-year bamboo leaves were compared, to identify the functional microbial communities that impact the interaction between bamboo leaves and P. phyllostachysae. RESULTS: We found that species from orders Lactobacillales and Rickettsiales are most effective within functional microbiota. Functional prediction revealed that gut microbes of larva fed on on-year leaves were related to naphthalene degradation, while those fed on off-year leaves were related to biosynthesis of ansamycins, polyketide sugar unit biosynthesis, metabolism of xenobiotics, and tetracycline biosynthesis. Most functional microbes are beneficial to the development of larva that feed on on-year bamboo leaves, but damage the balance of intestinal microenvironment and immune systems of those larva that feed on off-year leaves. CONCLUSIONS: This work developed an efficient strategy for microbiome research of Lepidopteran insects and provided insights into microbiota related to the interaction between host plants and P. phyllostachysae. We provided microbial candidates for the ecological control of P. phyllostachysae according to the function of effective microbiota.

High Luminous Efficacy Phosphor-Converted Mass-Produced White LEDs Achieved by AlN Prebuffer and Transitional-Refraction-Index Patterned Sapphire Substrate.

Constant advance in improving the luminous efficacy (ηL) of nitride-based light-emitting diodes (LEDs) plays a critical role for saving measurable amounts of energy. Further development is motivated to approach the efficiency limit for this material system while reducing the costs. In this work, strategies of using thin AlN prebuffer and transitional-refraction-index patterned sapphire substrate (TPSS) were proposed, which pushed up the efficiency of white LEDs (WLEDs). The AlN prebuffer was obtained through physical vapor deposition (PVD) method and TPSS was fabricated by dry-etched periodic silica arrays covered on sapphire. Devices in mass production confirmed that PVD AlN prebuffer was able to improve the light output power (φe) of blue LEDs (BLEDs) by 2.53% while increasing the productivity by ~8% through shortening the growth time. Additionally, BLEDs on TPSS exhibited an enhanced top ηext of 5.65% in contrast to BLEDs on the conventional PSS through Monte Carlo ray-tracing simulation. Consequently, φe of BLEDs was experimentally enhanced by 10% at an injected current density (Jin) of 40 A/cm2. A peak ηL of 295.2 lm/W at a Jin of 0.9 A/cm2 and the representative ηL of 282.4 lm/W at a Jin of 5.6 A/cm2 for phosphor-converted WLEDs were achieved at a correlated color temperature of 4592 K.

Integration of transcriptomic and proteomic analyses reveals several levels of metabolic regulation in the excess starch and early senescent leaf mutant lses1 in rice.

BACKGROUND: The normal metabolism of transitory starch in leaves plays an important role in ensuring photosynthesis, delaying senescence and maintaining high yield in crops. OsCKI1 (casein kinase I1) plays crucial regulatory roles in multiple important physiological processes, including root development, hormonal signaling and low temperature-treatment adaptive growth in rice; however, its potential role in regulating temporary starch metabolism or premature leaf senescence remains unclear. To reveal the molecular regulatory mechanism of OsCKI1 in rice leaves, physiological, transcriptomic and proteomic analyses of leaves of osckI1 allele mutant lses1 (leaf starch excess and senescence 1) and its wild-type varieties (WT) were performed. RESULTS: Phenotypic identification and physiological measurements showed that the lses1 mutant exhibited starch excess in the leaves and an obvious leaf tip withering phenotype as well as high ROS and MDA contents, low chlorophyll content and protective enzyme activities compared to WT. The correlation analyses between protein and mRNA abundance are weak or limited. However, the changes of several important genes related to carbohydrate metabolism and apoptosis at the mRNA and protein levels were consistent. The protein-protein interaction (PPI) network might play accessory roles in promoting premature senescence of lses1 leaves. Comprehensive transcriptomic and proteomic analysis indicated that multiple key genes/proteins related to starch and sugar metabolism, apoptosis and ABA signaling exhibited significant differential expression. Abnormal increase in temporary starch was highly correlated with the expression of starch biosynthesis-related genes, which might be the main factor that causes premature leaf senescence and changes in multiple metabolic levels in leaves of lses1. In addition, four proteins associated with ABA accumulation and signaling, and three CKI potential target proteins related to starch biosynthesis were up-regulated in the lses1 mutant, suggesting that LSES1 may affect temporary starch accumulation and premature leaf senescence through phosphorylation crosstalk ABA signaling and starch anabolic pathways. CONCLUSION: The current study established the high correlation between the changes in physiological characteristics and mRNA and protein expression profiles in lses1 leaves, and emphasized the positive effect of excessive starch on accelerating premature leaf senescence. The expression patterns of genes/proteins related to starch biosynthesis and ABA signaling were analyzed via transcriptomes and proteomes, which provided a novel direction and research basis for the subsequent exploration of the regulation mechanism of temporary starch and apoptosis via LSES1/OsCKI1 in rice.

Glucose sensitive konjac glucomannan/concanavalin A nanoparticles as oral insulin delivery system.

Compared with injection, oral drug delivery is a better mode of administration because of its security, low pain and simplicity. Insulin is the first choice for clinical treatment of type 1 diabetes, but, because insulin inability to resist gastrointestinal (GI) digestion results in poor oral bioavailability of insulin. Herein, we developed a targeted oral delivery system for diabetes. ConA-INS-KGM nanoparticles were prepared, loaded with insulin, fabricated from konjac glucomannan (KGM) and concanavalin A (ConA) through a crosslinking method, as an insulin oral delivery system in response to different blood glucose levels. The size of nanoparticles was characterized by TEM, which showed that these nanoparticles were formed spherical particles with a diameter of about 500 nm. In vitro release of insulin from these nanoparticles was studied, which indicated that insulin release is reversible at different glucose concentrations. In vivo tests demonstrated that they are safe and have high biocompatibility. Using the nanoparticles to treat diabetic mice, we found that they can control blood sugar levels for 6 h, retaining their glucose-sensitive properties during this time. Therefore, these nanoparticles have significant potential as glucose-responsive systems for diabetes and show great applications in biomedical fields.

Unidirectional-emitting GaN-based micro-LED for 3D display.

Naked-eye 3D micro-LED display combines the 3D characteristics and advantages of micro-LED simultaneously. A conventional micro-LED device emission exhibits Lambertian distribution, and it requires stacking of multiple optical components into a 3D display, resulting in bulky systems, low efficiency, and a limited viewing zone and points. We propose and investigate a single-chip micro-LED with unidirectional emission through an in-situ integrated resonant cavity and metasurface, which has great potential to be used for an efficient naked-eye 3D display with a wide viewing angle and multiple viewpoints. This Letter promotes the application of GaN-based micro-LEDs in a display, especially a 3D display.

Circularly polarized light emission from a GaN micro-LED integrated with functional metasurfaces for 3D display.

This Letter proposes a circularly polarized (CP) light GaN micro-LED which is integrated with functional metasurfaces. The one-dimensional metallic nanograting can achieve a high transverse electric (TE) reflectivity (${{\rm{R}}_{\rm{TE}}}$) and extinction ratio (ER) of TE and transverse magnetic (TM) waves, which is highly polarized output for micro-LEDs. Besides, the nanograting, which is integrated on the bottom of the GaN layer, can also support a resonant cavity, together with the top distributed Bragg reflector, which can shape the radiation pattern. By optimizing the structure parameters of nanograting, the ${{\rm{R}}_{\rm{TE}}}$ achieves over 80%, and the ER reaches higher than 38 dB at 450 nm for the GaN micro-LED. Additionally, the metasurface, which acts as a quarter-wave plate, was investigated to control the phase delay between the polarization state of the electric wave in two orthogonal components. Finally, the circular shape of the transmitted pattern denotes the high performance of the metasurface which is integrated in the micro-LED for CP light emission. The work reported in this Letter might provide potential application in a 3D polarized light display.

Multiplexing multifoci optical metasurfaces for information encoding in the ultraviolet spectrum.

Recently, optical metasurfaces have attracted much attention due to their versatile features in manipulating phase, polarization, and amplitude of both reflected and transmitted light. Because it controls over four degrees of freedom: phase, polarization, amplitude, and wavelength of light wavefronts, optical cryptography is a promising technology in information security. So far, information encoding can be implemented by the metasurface in one-dimensional (1D) mode (either wavelength or polarization) and in a two-dimensional (2D) mode of both wavelength and polarization. Here, we demonstrate multiplexing multifoci optical metasurfaces for information encoding in the ultraviolet spectrum both in the 1D and 2D modes in the spatial zone, composed of high-aspect-ratio aluminum nitride nanorods, which introduce discontinuous phases through the Pancharatnam-Berry phase to realize multifoci in the spatial zone. Since the multiplexed multifocal optical metasurfaces are sensitive to the helicity of the incident light and the wavelength is within the ultraviolet spectrum, the security of the information encrypted by it would be guaranteed.

Synthesis of Double Interfering Biodegradable Nano-MgO Micelle Composites and Their Effect on Parkinson's Disease.

Although gene therapy targeting the α-synuclein gene (SNCA) has achieved outstanding results in the treatment of Parkinson's disease (PD), the lack of a suitable gene delivery system and inadequate therapeutic effects remains a tremendous obstacle for RNAi therapy. Here, a degradable nano-MgO micelle composite (MgO(pDNA)-INS-Plu-mRNA-NGF) with double interference (mediated by RNAi and α-synuclein (α-syn)-targeted mRNA) was constructed. Binding mRNA treatment significantly increased the inhibitory effect compared to the reduction of α-syn expression by RNAi alone. Moreover, the cell experiments demonstrated that the viability of the PD cell model can be significantly improved by nano-MgO micelle composite treatment. More importantly, the composite has the ability to penetrate the blood brain barrier and deliver genes and mRNA to neurons through endocytosis mediated by the nerve growth factor and its receptors, thus significantly downregulating the expression of α-syn in the PD mice model without causing damage to other major organs. Overall, this work provides a novel insight into the design of biomaterials for gene therapy for PD.