Heterologous Biosynthesis of Kauralexin A1 in Saccharomyces cerevisiae through Metabolic and Enzyme Engineering.

Kauralexin A1 (KA1) is a key intermediate of the kauralexin A series metabolites of maize phytoalexins. However, their application is severely limited by their low abundance in maize. In this study, an efficient biosynthetic pathway was constructed to produce KA1 in Saccharomyces cerevisiae. Also, metabolic and enzyme engineering strategies were applied to construct the high-titer strains, such as chassis modification, screening synthases, the colocalization of enzymes, and multiple genomic integrations. First, the KA1 precursor ent-kaurene was synthesized using the efficient diterpene synthase GfCPS/KS from Fusarium fujikuroi, and optimized to reach 244.36 mg/L in shake flasks, which displayed a 200-fold increase compared to the initial strain. Then, the KA1 was produced under the catalysis of ZmCYP71Z18 from Zea mays and SmCPR1 from Salvia miltiorrhiza, and the titer was further improved by integrating the fusion protein into the genome. Finally, an ent-kaurene titer of 763.23 mg/L and a KA1 titer of 42.22 mg/L were achieved through a single-stage fed-batch fermentation in a 5 L bioreactor. This is the first report of the heterologous biosynthesis of maize diterpene phytoalexins in S. cerevisiae, which lays a foundation for further pathway reconstruction and biosynthesis of the kauralexin A series maize phytoalexins.

Nano-Confined Effect and Heterojunction Promoted Exciton Separation for Light-Boosted Osmotic Energy Conversion.

The osmotic energy conversion properties of biomimetic light-stimulated nanochannels have aroused great interest. However, the power output performance is limited by the low light-induced current and energy conversion efficiency. Here, nanochannel arrays with simultaneous modification of ZnO and di-tetrabutylammonium cis-bis(isothiocyanato)bis(2,20-bipyridyl-4,40-dicarboxylato) ruthenium (II) (N719) onto anodic aluminum oxide (AAO) to combine the nano-confined effect and heterojunction is designed, which demonstrate rectified ion transport behavior due to the asymmetric composition, structure and charge. High cation selectivity and ion flux contribute to the high power density of ≈7.33 W m-2 by mixing artificial seawater and river water. Under light irradiation, heterojunction promoted the production and separation of exciton, enhanced cation selectivity, and improved the utilization efficiency of osmotic energy, providing a remarkable power density of ≈18.49 W m-2 with an increase of 252% and total energy conversion efficiency of 30.43%. The work opens new insights into the biomimetic nanochannels for high-performance energy conversion.

Ultrathin H-MXM as An "Ion Freeway" for High-Performance Osmotic Energy Conversion.

Nanofluidic membranes are currently being explored as potential candidates for osmotic energy harvesting. However, the development of high-performance nanofluidic membranes remains a challenge. In this study, the ultrathin MXene membrane (H-MXM) is prepared by ultrathin slicing and realize the ion horizontal transportation. The H-MXM membrane, with a thickness of only 3 µm and straight subnanometer channels, exhibits ultrafast ion transport capabilities resembling an "ion freeway". By mixing artificial seawater and river water, a power output of 93.6 W m-2 is obtained. Just as cell membranes have an ultrathin thickness that allows for excellent penetration, this straight nanofluidic membrane also possesses an ultrathin structure. This unique feature helps to shorten the ion transport path, leading to an increased ion transport rate and improveS performance in osmotic energy conversion.

Toehold-Containing Three-Way Junction-Initiated Multiple Exponential Amplification and CRISPR/Cas14a Assistant Magnetic Separation Enhanced Visual Detection of Mycobacterium Tuberculosis.

Rapid and simple nucleic acid detection is significant for disease diagnosis and pathogen screening, especially under specific conditions. However, achieving highly sensitive and specific nucleic acid detection to meet the time and equipment demand remains technologically challenging. In this study, we proposed a magnetic separation enhanced colorimetry biosensor based on a toehold-containing three-way junction (TWJ) induced multiple isothermal exponential amplification and the CRISPR/Cas14a (C-TEC) biosensor. The TWJ template was designed as a Y-X-Y structure. In the presence of the target, the formation of toehold-containing TWJ complex induced primer extension, leading to the generation of amplified single-stranded DNA; this amplified DNA could then bind to either the free TWJ template for EXPAR reaction or the toehold of the TWJ complex for toehold-mediated strand displacement, thereby enabling the recycling of the target. The amplification products could trigger CRISPR/Cas14a for efficient trans-cleavage and release the magnetically bound gold nanoparticle probes for colorimetry detection. Using Mycobacterium tuberculosis 16S rDNA as the target, the proposed C-TEC could detect 16S rDNA down to 50 fM by the naked eye and 20.71 fM by UV-vis detector at 520 nm within 90 min under optimal conditions. We successfully applied this biosensor to clinical isolates of Mycobacterium tuberculosis. In addition, the C-TEC biosensor also showed feasibility for the detection of RNA viruses. In conclusion, the proposed C-TEC is a convenient, fast, and versatile platform for visual detection of pathogen DNA/RNA and has potential clinical applications.

Subchondral bone in knee osteoarthritis: bystander or treatment target?

The subchondral bone is an important structural component of the knee joint relevant for osteoarthritis (OA) incidence and progression once disease is established. Experimental studies have demonstrated that subchondral bone changes are not simply the result of altered biomechanics, i.e., pathologic loading. In fact, subchondral bone alterations have an impact on joint homeostasis leading to articular cartilage loss already early in the disease process. This narrative review aims to summarize the available and emerging imaging techniques used to evaluate knee OA-related subchondral bone changes and their potential role in clinical trials of disease-modifying OA drugs (DMOADs). Radiographic fractal signature analysis has been used to quantify OA-associated changes in subchondral texture and integrity. Cross-sectional modalities such as cone-beam computed tomography (CT), contrast-enhanced cone beam CT, and micro-CT can also provide high-resolution imaging of the subchondral trabecular morphometry. Magnetic resonance imaging (MRI) has been the most commonly used advanced imaging modality to evaluate OA-related subchondral bone changes such as bone marrow lesions and altered trabecular bone texture. Dual-energy X-ray absorptiometry can provide insight into OA-related changes in periarticular subchondral bone mineral density. Positron emission tomography, using physiological biomarkers of subchondral bone regeneration, has provided additional insight into OA pathogenesis. Finally, artificial intelligence algorithms have been developed to automate some of the above subchondral bone measurements. This paper will particularly focus on semiquantitative methods for assessing bone marrow lesions and their utility in identifying subjects at risk of symptomatic and structural OA progression, and evaluating treatment responses in DMOAD clinical trials.

High-output soft-contact fiber-structure triboelectric nanogenerator and its sterilization application.

Infectious diseases are spreading rapidly with the flow of the world's population, and the prevention of epidemic diseases is particularly important for public and personal health. Therefore, there is an urgent need to develop a simple, efficient and non-toxic method to control the spread of bacteria and viruses. The newly developed triboelectric nanogenerator (TENG) can generate a high voltage, which inhibits bacterial reproduction. However, the output performance is the main factor limiting real-world applications of TENGs. Herein, we report a soft-contact fiber-structure TENG to avoid insufficient friction states and to improve the output, especially at a high rotation speed. Rabbit hair, carbon nanotubes, polyvinylidene difluoride film and paper all contain fiber structures that are used to guarantee soft contact between the friction layers and improve the contact state and abrasion problem. Compared with a direct-contact triboelectric nanogenerator, the outputs of this soft-contact fiber-structure TENG are improved by about 350%. Meanwhile, the open-circuit voltage can be enhanced to 3440 V, which solves the matching problems when driving high-voltage devices. A TENG-driven ultraviolet sterilization system is then developed. The bactericidal rate of this sterilization system can reach 91%, which significantly reduces the risk of disease spread. This work improves a forward-looking strategy to improve the output and service life of the TENG. It also expands the applications of self-powered TENG sterilization systems.

Room-Temperature Synthesis of a COFs Membrane Via LBL Self-Assembly Strategy for Energy Harvesting.

The covalent organic frameworks (COFs) membrane with ordered and confined one-dimensional channel has been considered as a promising material to harvest the salinity gradient energy from the seawater and river water. However, the application of the COFs in the field of energy conversion still faces the challenges in membrane preparation. Herein, energy harvesting is achieved by taking advantage of a COFs membrane where TpDB-HPAN is synthesized via layer-by-layer self-assembly strategy at room temperature. The carboxy-rich TpDB COFs can be expediently assembled onto the substrate with an environmental-friendly method. The increased open-circuit voltage (Voc ) endows TpDB-HPAN membrane with a remarkable energy harvesting performance. More importantly, the application perspective is also illuminated by the cascade system. With the advantages of green synthesis, the TpDB-HPAN membrane can be considered as a low-cost and promising candidate for energy conversion.

Targeted Therapy of Non-Small Cell Lung Cancer and Liver Cancer: Functional Nanocarriers for the Delivery of Cisplatin and Tissue Factor Pathway Inhibitor-2.

INTRODUCTION: The aim of the study was to construct folic acid-modified PEGylated paramagnetic nanoparticles (MNPs) co-carrying tissue factor pathway inhibitor-2 (TFPI-2) and cisplatin (CDDP), and to study the molecular-targeting and inhibitory effects of the nanocomposite on non-small cell lung cancer (NSCLC) and liver cancer. METHODS: Nanocomposites were prepared using amino-modified iron oxide nanoparticles as carriers, co-loading CDDP and PEGylated FA/TFPI-2. Transmission electron microscopy, UV absorption spectrum, and dynamic light scattering were employed to characterize the morphology, structure, particle size, and zeta potential of the nanocomposite. The phenylenediamine method was used to detect the loading of CDDP, and the CCK-8 assay was used to detect the toxic effect of the nanocomposite on HUVECs, A549, and NCI-H460 cells. In tumor-bearing mice models, the antitumor effects of the nanocomposites were assessed using TUNEL staining (at the molecular level), reverse transcriptase quantitative polymerase chain reaction (at the gene level), hematoxylin and eosin staining (at the cellular level), and the appearance of the mice models. RESULTS: The synthesized FA-MNP/CDDP/TFPI-2 nanocomposite was uniformly dispersed and spherical in shape (approximate diameter: 10 nm). The zeta potential of particles was -9.44 mV, and the average particle size was 25 nm. The loading amount of CDDP was 70.24 µg/mL (23.33%). The nanocomposite was nontoxic to HUVECs, while it showed a favorable inhibitory effect on A549 and NCI-H460 cells. In vivo experiments in mice demonstrated satisfactory imaging properties and therapeutic effects of nanocomposite against liver cancer. DISCUSSION: FA-MNP/CDDP/TFPI-2 may provide insights for the development of new chemotherapeutic drugs.

Application of functional training on physical fitness in basketball / Aplicação do treinamento funcional sobre a aptidão física no basquetebol / Aplicación del entrenamiento funcional en la aptitud física en el baloncesto

ABSTRACT Introduction: Basketball is a predominant competitive sport among the masses. Its practice requires scoring as many points as possible within a specific time limit, manifesting a short-duration, high-intensity intermittent training session. To meet the sport's requirements, the athlete must have ample directional control, rapid changes in speed, and good jumping ability. Objective: Verify the effects of functional training on basketball players aiming to improve explosive power, stability, and agility. Methods: 18 college basketball players were randomly selected as volunteers for the investigation. They were randomly divided into experimental and control groups. Only to the experimental one was functional physical training added during routine training. The trial lasted for eight weeks. All participants were tested for agility, strength, speed, endurance, power, and cartilage repair before and after the experiment. Finally, a comprehensive statistical data analysis was performed. Results: There were significant differences between the experimental group and the control group in push-ups, 3200-meter run, physical acuity detection, 17 sidelines, and running items, and touch height (P<0.05). In the experimental group, there was no significant difference in high school grades (P>0.05). There was significant statistical significance in the supine project, the 3200-meter athletics project, the 17 sideline projects, and the touchdown project (P<0.05). Conclusion: The physical fitness of the experimental group improved significantly after functional physical training. After routine physical training, the control group athletes had significantly positive absolute strength and endurance results. Overall, functional fitness training is superior to conventional fitness training. Level of evidence II; Therapeutic studies - investigation of treatment outcomes.

RESUMO Introdução: O basquetebol é um esporte de competição predominante entre as massas. Sua prática requer o maior número possível de pontos dentro de um limite de tempo específico, manifestando uma sessão de treinamento intermitente de curta duração e de alta intensidade. Para atender aos requisitos esportivos, é necessário que o atleta tenha um amplo controle direcional, mudanças rápidas de velocidade e boa capacidade de salto. Objetivo: Verificar os efeitos do treinamento funcional em jogadores de basquetebol visando melhorar o poder explosivo, estabilidade e agilidade. Métodos: Foram selecionados aleatoriamente 18 jogadores universitários de basquetebol como voluntários para a investigação. Divididos aleatoriamente em grupos experimental e controle. Apenas ao experimental foi adicionado o treinamento físico funcional durante o treinamento de rotina. O ensaio durou oito semanas. Todos os participantes foram testados quanto a agilidade, força, velocidade, resistência, potência e reparo de cartilagem antes e depois do experimento. Finalmente, efetuou-se uma abrangente análise estatística de dados. Resultados: Verificou-se diferenças significativas entre o grupo experimental e o grupo de controle em flexões, 3200 metros de corrida, detecção de acuidade física, 17 itens de linha lateral e itens de corrida e altura de toque (P<0,05). No grupo experimental, não houve diferença significativa nas notas do ensino médio (P>0,05). Houve significância estatística significativa no projeto de supino, no projeto de atletismo de 3200 metros, nos 17 projetos de linha lateral, e no projeto de retoque (P<0,05). Conclusão: A aptidão física do grupo experimental melhorou significativamente após o treinamento físico funcional. Após o treinamento físico de rotina, os atletas do grupo de controle tiveram resultados significativamente positivos sobre força e resistência absolutas. Em geral, o treinamento de aptidão física funcional é superior ao treinamento de aptidão física convencional. Nível de evidência II; Estudos terapêuticos - investigação dos resultados do tratamento.

Resumen Introducción: El baloncesto es un deporte de competición predominante entre las masas. Su práctica requiere el mayor número posible de puntos dentro de un límite de tiempo específico, manifestando una sesión de entrenamiento intermitente de corta duración y alta intensidad. Para cumplir con los requisitos deportivos, es necesario que el atleta tenga un amplio control direccional, rápidos cambios de velocidad y una buena capacidad de salto. Objetivo: Verificar los efectos del entrenamiento funcional en jugadores de baloncesto con el objetivo de mejorar la potencia explosiva, la estabilidad y la agilidad. Métodos: 18 jugadores de baloncesto universitario fueron seleccionados al azar como voluntarios para la investigación. Se dividieron aleatoriamente en grupos experimentales y de control. Sólo al experimental se le añadió el entrenamiento físico funcional durante el entrenamiento rutinario. La prueba duró ocho semanas. Todos los participantes fueron sometidos a pruebas de agilidad, fuerza, velocidad, resistencia, potencia y reparación del cartílago antes y después del experimento. Por último, se realizó un exhaustivo análisis estadístico de los datos. Resultados: Hubo diferencias significativas entre el grupo experimental y el grupo de control en las flexiones de brazos, la carrera de 3200 metros, la detección de la agudeza física, los 17 elementos de la banda y la carrera y la altura del toque (P<0,05). En el grupo experimental, no hubo diferencias significativas en las calificaciones de la escuela secundaria (P>0,05). Hubo una significación estadística significativa en el proyecto de decúbito supino, el proyecto de 3200 metros de atletismo, los 17 proyectos de banda y el proyecto de touchdown (P<0,05). Conclusión: La aptitud física del grupo experimental mejoró significativamente tras el entrenamiento físico funcional. Tras el entrenamiento físico rutinario, los atletas del grupo de control obtuvieron resultados significativamente positivos en cuanto a fuerza y resistencia absolutas. En general, el entrenamiento de aptitud física funcional es superior al entrenamiento de aptitud física convencional. Nivel de evidencia II; Estudios terapéuticos - investigación de los resultados del tratamiento.

Development and evaluation of a rapid and sensitive multienzyme isothermal rapid amplification with a lateral flow dipstick assay for detection of Acinetobacter baumannii in spiked blood specimens.

Purpose: This study aimed to establish the multienzyme isothermal rapid amplification with a lateral flow dipstick (MIRA-LFD) assay and evaluate its performance in detection of A. baumannii in spiked blood specimens. Methods: The study was divided into two stages: a pilot study to establish the methodology and a clinical validation study to evaluate its performance. In the first step, we designed primers specific to detect A. baumannii, optimized the MIRA-LFD assay and analyzed its performance regarding limits of detection, reproducibility, specificity, and efficiency of detection using real-time PCR method. In the second step, we obtained 50 spiked blood isolates and detected these pathogens by MIRA-LFD assay. The MIRA-LFD time was 15 min from DNA sample amplification to complete pathogen detection. Results: The developed MIRA-LFD assay displayed a detection limit of 6 CFU/mL for detecting A. baumannii, which was significantly better than that of real-time PCR method, and no cross-reactivity was observed in other non-A. baumannii studied. The results obtained with 50 spiked blood isolates suggested that the developed MIRA-LFD assay had high specificity and sensitivity for identifying A. baumannii. Conclusions: This study demonstrates that the established MIRA-LFD assay is time-saving, more effective and sensitive, which may become a powerful tool for rapid and reliable diagnosis of bloodstream infection caused by A. baumannii in primary hospitals.

An engineered quorum-sensing-based whole-cell biosensor for active degradation of organophosphates.

The environmental accumulation of organophosphates is a serious threat to public health. To detect these xenobiotics, a broad range of sensors has been developed in past decades. However, sensors with high sensitivity and a capability for degrading organophosphates are rare. In this study, "smart" whole-cell biosensors were created by combining synthetic biology approaches with the bacterial quorum sensing (QS) mechanism. The engineered whole-cell biosensor pUC57-QS-DSF-F42 L/E coli DH5α can sense a wide array of phenolic compounds including phenol and p-nitrophenol (p-NP). By optimizing the genetic circuits, the phenol and p-NP detection limits reached 0.1 and 1 µM, respectively. Importantly, by replacing the fluorescence-generated reporter sfGFP with MP-degrading enzyme PoOPHM2, the whole-cell biosensor pUC57-OPH-QS-DSF-F42 L/E coli DH5α actively degraded 10 and 100 µM methyl parathion (MP), a typical organophosphate pesticide, which was artificially added to the cell culture at different time points in five consecutive degrading experiments, demonstrating its MP sensing and degrading capabilities. The universal design of this new biosensor can be used to create more efficient biosensors to detect and degrade various pollutants in the environment for rapid testing and bioremediation.

Large-Area Covalent Organic Polymers Membrane via Sol-Gel Approach for Harvesting the Salinity Gradient Energy.

Many materials with nanofluidic channels are exploited to achieve salinity gradient energy conversion. However, most materials are fragile, difficult to process, or only prepared into a limited size, which greatly restricts their practical application in the future. Herein, a covalent organic polymers membrane with high mechanical property and stability is fabricated, which can keep integrity in harsh conditions for up to 1 month. In addition, by using the sol-gel approach, a large-area membrane with an area of 26 × 26 cm is expediently fabricated in lab conditions. When the membrane is applied to salinity gradient energy conversion, the maximum output power density is up to 6.21 W m-2 . This work provides a simple method for the fabrication of large-area membrane for salinity gradient energy conversion in future real-world applications.

Investigation of the chemical structure of anti-amyloidogenic constituents extracted from Thamnolia vermicularis.

ETHNOPHARMACOLOGICAL RELEVANCE: Thamnolia vermicularis (Sw.) Schaer (T. vermicularis) is known to have therapeutic effects on various diseases in Southwest China. Recent research has highlighted that T. vermicularis may suppress Aß level and Tau hyperphosphorylation to improve the pathological characteristics of Alzheimer's disease, indicating that it might have the potential to treat Alzheimer's disease. AIM OF THE STUDY: The objective of this study was to evaluate the inhibitory effect of T. vermicularis on the fibril formation of a typical amyloidogenic protein, hen egg white lysozyme (HEWL), and to identify the effective components that could potentially enable an extract of T. vermicularis to be used in the development of novel therapeutic agents. MATERIALS AND METHODS: A water extract was prepared from T. vermicularis (TVWE) and its inhibitory effect on amyloid fibrillation in vitro was investigated using thioflavin T and 8-anilinonapthalene-1-sulfonic acid spectrofluorometric analyses. The anti-amyloidogenic components of TVWE were separated and qualitatively analyzed using thin layer chromatography (TLC), supercritical carbon dioxide extraction (SFE-CO2), and liquid chromatography-mass spectrometry. Finally, the effect of the bioactive components on the structure of HEWL in the early stages of fibrillogenesis was determined by molecular docking simulation. RESULTS: TVWE strongly inhibited the ability of HEWL to form an amyloid fibril, yielding an IC50 of 0.018 mg/mL for the inhibition of fibrillogenesis. The chemical constituents in the various TVWE fractions resolved by TLC were qualitatively identified by liquid chromatography-quadrupole/time-of-flight mass spectrometry (LC-Q-TOF-MS). The target components were predicted by reviewing the existing literature on T. vermicularis, in which the components of T. vermicularis, along with three small molecules (molecular weight: 182) were preliminarily identified. Molecular docking simulation showed that these small molecules were bound to the core region of HEWL, affecting its stability. Finally, the active anti-amyloidogenic components were extracted from whole T. vermicularis using SFE-CO2 and then identified. CONCLUSION: The potential components of TVWE that could prevent HEWL fibrillogenesis were primarily identified using TLC, LC-Q-TOF-MS, and SFE-CO2. The candidate small-molecule compounds were further predicted by combining the LC-Q-TOF-MS results with molecular docking analysis. The effective components of T. vermicularis were extracted using SFE-CO2. Together, these methods could constitute a practical strategy for the isolation and identification of anti-amyloidogenic components from a traditional Chinese medicine.

Comparative transcriptomic analysis-based identification of the regulation of foreign proteins with different stabilities expressed in Pichia pastoris.

Introduction: The industrial yeast Pichia pastoris is widely used as a cell factory to produce proteins, chemicals and advanced biofuels. We have previously constructed P. pastoris strains that overexpress protein disulfide isomerase (PDI), which is a kind of molecular chaperone that can improve the expression of an exogenous protein when they are co-expressed. Chicken cystatin (cC) is a highly thermostable cysteine protease inhibitor and a homologous protein of human cystatin C (HCC). Wild-type cC and the two mutants, I66Q and ΔW (a truncated cC lacking the á-helix 2) represent proteins with different degrees of stability. Methods: Wild-type cC, I66Q and ΔW were each overexpressed in P. pastoris without and with the coexpression of PDI and their extracellular levels were determined and compared. Transcriptomic profiling was performed to compare the changes in the main signaling pathways and cell components (other than endoplasmic reticulum quality control system represented by molecular chaperones) in P. pastoris in response to intracellular folding stress caused by the expression of exogenous proteins with different stabilities. Finally, hub genes hunting was also performed. Results and discussion: The coexpression of PDI was able to increase the extracellular levels of both wild-type cC and the two mutants, indicating that overexpression of PDI could prevent the misfolding of unstable proteins or promote the degradation of the misfolded proteins to some extent. For P. pastoris cells that expressed the I66Q or ΔW mutant, GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) analyses of the common DEGs in these cells revealed a significant upregulation of the genes involved in protein processing, but a significant downregulation of the genes enriched in the Ribosome, TCA and Glycolysis/Gluconeogenesis pathways. Hub genes hunting indicated that the most downregulated ribosome protein, C4QXU7 in this case, might be an important target protein that could be manipulated to increase the expression of foreign proteins, especially proteins with a certain degree of instability. Conclusion: These findings should shed new light on our understanding of the regulatory mechanism in yeast cells that responds to intracellular folding stress, providing valuable information for the development of a convenient platform that could improve the efficiency of heterologous protein expression in P. pastoris.

Defining the mechanism of PDI interaction with disulfide-free amyloidogenic proteins: Implications for exogenous protein expression and neurodegenerative disease.

Protein disulfide isomerase (PDI) is an important molecular chaperone capable of facilitating protein folding in addition to catalyzing the formation of a disulfide bond. To better understand the distinct substrate-screening principles of Pichia pastoris PDI (Protein disulfide isomerase) and the protective role of PDI in amyloidogenic diseases, we investigated the expression abundance and intracellular retention levels of three archetypal amyloidogenic disulfide bond-free proteins (Aß42, α-synuclein (α-Syn) and SAA1) in P. pastoris GS115 strain without and with the overexpression of PpPDI (P. pastoris PDI). Intriguingly, amyloidogenic Aß42 and α-Syn were detected only as intracellular proteins whereas amyloidogenic SAA1 was detected both as intracellular and extracellular proteins when these proteins were expressed in the PpPDI-overexpressing GS115 strain. The binding between PpPDI and each of the three amyloidogenic proteins was investigated by molecular docking and simulations. Three different patterns of PpPDI-substrate complexes were observed, suggesting that multiple modes of binding might exist for the binding between PpPDI and its amyloidogenic protein substrates, and this could represent different specificities and affinities of PpPDI toward its substrates. Further analysis of the proteomics data and functional annotations indicated that PpPDI could eliminate the need for misfolded proteins to be partitioned in ER-associated compartments.

Preliminary comparison of the efficacy of several surgical treatments based on maxillomandibular advancement procedures in adult patients with obstructive sleep apnoea: a systematic review and network meta-analysis.

PURPOSE: To evaluate the efficacy of eight different surgical treatments based on maxillomandibular advancement (MMA), which has emerged in recent years, for adult obstructive sleep apnoea (OSA) patients. METHODS: The literature was searched from January 2010 to May 2020 for studies of adult OSA patients with different types of MMA procedures to perform a network meta-analysis. The outcomes were changes in the apnoea-hypopnoea index (AHI), the lowest pulse oxygen saturation (SpO2 min) and the Epworth Sleepiness Scale (ESS). Treatment hierarchy was summarized according to the rank charts. RESULTS: Eight studies were included and encompassed a total of 227 adult patients diagnosed with OSA. Among them, 225 patients underwent combined surgery or simple MMA surgery, including modified maxillomandibular advancement (MMMA),counterclockwise maxillomandibular advancement (CMMA), drug-induced sleep endoscopy and maxillomandibular advancement (MMA + DISE), transoral robotic surgery and maxillomandibular advancement (MMA + TORS), uvulopalatopharyngoplasty (UPPP), maxillomandibular advancement and uvulopalatopharyngoplasty (MMA + UPPP), uvulopalatopharyngoplasty with uvula preservation and maxillomandibular advancement (MMA + HUPPP); MMA consisting of Le Fort I osteotomy and bilateral inverted-L osteotomy (ILOs), genioplasty and iliac bone grafting; and MMA consisting of Le Fort I osteotomy, bilateral sagittal split ramus osteotomies and genioplasty. The results showed that the most effective surgical treatment is MMA + HUPPP [- 56.79 (WMD); 95% confidence interval (CI): - 113.02 to - 3.33] (P < 0.00001), which was far superior to other approaches. CONCLUSION: MMA combined with HUPPP had the highest efficacy. The MMA consisted of Le Fort I osteotomy, bilateral sagittal split ramus osteotomies and genioplasty; CMMA and MMA + TORS are likely also great choices.

Smart plant-wearable biosensor for in-situ pesticide analysis.

Inspired by the wearable sensors and to meet the demand for rapid and nondestructive detection, we developed a smart plant-wearable biosensor, which can be applied for in-situ analysis of organophosphorus pesticide on crop surfaces. Herein, the serpentine three-electrode system was prepared via the laser-induced graphene (LIG) technology. After transferred by polydimethylsiloxane (PDMS), the stretchable and flexible LIG-based electrode was obtained, which can be well adapt to the irregular surface of crops, such as leaves and fruits. After modified with organophosphorus hydrolase (OPH) and equipped with biocompatible semisolid electrolyte, our plant-wearable biosensor can selectively capture and recognize the methyl parathion and the data can be transmitted to a smartphone device wirelessly, which enable the real-time and in-situ electrochemical analysis of pesticide on the surface of agricultural products. To further enhance the electrochemical performance, gold nanoparticles (AuNPs) were modified on the surface of three-dimensional (3D) porous LIG. Such smart plant-wearable biosensor could be a transformative approach for the in-situ analysis of pesticide residue on crops, which could also promote the development of precision agriculture in the future.

Epigenetics of osteoarthritis: Histones and TGF-ß1.

Osteoarthritis (OA) is the most common musculoskeletal and joint disorder. However, no disease-modifying therapy for OA is currently available, and the etiology of OA is poorly understood. Epigenetics has emerged as a new and important area of research on OA. Differing from genetics, Epigenetic factors are known to be tissue-specific and highly dynamic, being dependent on environmental stimuli and developmental stages. Therefore, human studies into OA epigenetics are sensitive to confounding and reverse causation. Here, we will review the epigenetic mechanism in OA onset and progression by focusing on the opposing action of two families of enzymes: histone methyltransferases and histone demethylases, such as DOT1L, KDM4B, KDM6A, KDM6B, EZH2, and LSD1. Moreover, the TGF-ß1 signaling pathway has proven to be one of the key factors in cartilage and bone formation, and in recent research, was found to initiate and develop OA disease by TGF-ß1 overexpression. Besides the introduction of enzymes and TGF-ß1 signaling, some special epigenetic regulation mechanisms associated with key transcription factors (e.g. RUNX2, NFAT1, and SOX9) in OA disease are also reviewed here in detail to clarify the OA epigenetic mechanism. The overall understanding of these epigenetic mechanisms underlying the issues will accelerate the development of novel therapeutic strategies for OA.

Therapeutic Delivery of Polymeric Tadpole Nanostructures with High Selectivity to Triple Negative Breast Cancer Cells.

Targeted delivery of therapeutic drugs using nanoparticles to the highly aggressive triple negative breast cancer cells has the potential to reduce side effects and drug resistance. Cell entry into triple negative cells can be enhanced by incorporating cell binding receptor molecules on the surface of the nanoparticles to enhance receptor-mediated entry pathways, including clatherin or caveolae endocytosis. However, for highly aggressive cancer cells, these pathways may not be effective, with the more rapid and high volume uptake from macropinocytosis or phagocytosis being significantly more advantageous. Here we show, in the absence of attached cell binding receptor molecules, that asymmetric polymer tadpole nanostructure coated with a thermoresponsive poly(N-isopropylacrylamide) polymer with approximately 50% of this polymer in a globular conformation resulted in both high selectivity and rapid uptake into the triple breast cancer cell line MDA-MB-231. We found that the poly(N-isopropylacrylamide) surface coating in combination with the tadpole's unique shape had an almost 15-fold increase in cell uptake compared to spherical particles with the same polymer coating, and that the mode of entry was most likely through phagocytosis. Delivery of the tadpole attached with doxorubicin (a prodrug, which can be released at pHs < 6) showed a remarkable 10-fold decrease in the IC50 compared to free doxorubicin. It was further observed that cell death was primarily through late apoptosis, which may allow further protection from the body's own immune system. Our results demonstrate that by tuning the chemical composition, polymer conformation and using an asymmetric-shaped nanoparticle, both selectivity and effective delivery and release of therapeutics can be achieved, and such insights will allow the design of nanoparticles for optimal cancer outcomes.