Association between sex hormones and gout: An analysis of the UK Biobank cohort.

OBJECTIVES: To investigate the associations between sex hormones and gout. METHODS: A total of 448,836 individuals free of gout at baseline were included from the UK Biobank. Cox regression models were used to estimate hazard ratios (HRs) for gout. Besides, we investigated the causal relationship between bioavailable testosterone (BAT) and gout using mendelian randomization (MR). RESULTS: There were differential effects in different testosterone active states in gout. One-unit higher log-transformed total testosterone (TT) was associated with a 52 % [95 % CI, 0.39-0.58] lower risk of gout in males. In contrast, free testosterone (FT) and BAT were associated with a 74 % [95 % CI, 1.38-2.20] and a 78 % [95 % CI, 1.41-2.25] higher risk of gout in males respectively. For MR, the weighted median [OR, 1.70; 95 % CI, 1.14-2.56;] and inverse variance-weighted [OR, 1.25; 95 % CI, 0.96-1.62; P = 0.09] method revealed significant and approximately significant positive effect of genetic liability to BAT levels on the risk of gout respectively. CONCLUSIONS: Sex hormones were potentially associated with gout. Notably, we were the first to explore different testosterone states on gout and found that FT and BAT may increase the risk of gout in males, which is opposite to TT. And the former are active states of androgens, may be more accurately reflect the association between androgens and gout.

TaWRKY50-TaSARK7 module-mediated cysteine-rich protein phosphorylation suppresses the programmed cell death response to Chinese wheat mosaic virus infection.

WRKY transcription factors are widely involved in plant responses to biotic and abiotic stresses. However, there is currently a limited understanding of the regulation of viral infection by WRKY transcription factors in wheat (Triticum aestivum). The WRKY transcription factor TaWRKY50 in group IIb wheat exhibited a significant response to Chinese wheat mosaic virus infection. TaWRKY50 is localized in the nucleus and is an activating transcription factor. Interestingly, we found that silencing TaWRKY50 induces cell death following inoculation with CWMV. The protein kinase TaSAPK7 is specific to plants, whereas NbSRK is a closely related kinase with high homology to TaSAPK7. The transcriptional activities of both TaSAPK7 and NbSRK can be enhanced by TaWRKY50 binding to their promoters. CRP is an RNA silencing suppressor. Furthermore, TaWRKY50 may regulate CWMV infection by regulating the expression of TaSAPK7 and NbSRK to increase CRP phosphorylation and reduce the amount of programmed cell death (PCD).

Regulation of Disease-Resistance Genes against CWMV Infection by NbHAG1-Mediated H3K36ac.

Post-translational modification of proteins plays a critical role in plant-pathogen interactions. Here, we demonstrate in Nicotiana benthamiana that knockout of NbHAG1 promotes Chinese wheat mosaic virus (CWMV) infection, whereas NbHAG1 overexpression inhibits infection. Transcriptome sequencing indicated that a series of disease resistance-related genes were up-regulated after overexpression of NbHAG1. In addition, cleavage under targets and tagmentation (Cut&Tag)-qPCR results demonstrated that NbHAG1 may activate the transcription of its downstream disease-resistance genes by facilitating the acetylation level of H3K36ac. Therefore, we suggest that NbHAG1 is an important positive regulator of resistance to CWMV infestation.

Long-Acting Heterodimeric Paclitaxel-Idebenone Prodrug-Based Nanomedicine Promotes Functional Recovery after Spinal Cord Injury.

After spinal cord injury (SCI), successive systemic administration of microtubule-stabilizing agents has been shown to promote axon regeneration. However, this approach is limited by poor drug bioavailability, especially given the rapid restoration of the blood-spinal cord barrier. There is a pressing need for long-acting formulations of microtubule-stabilizing agents in treating SCI. Here, we conjugated the antioxidant idebenone with microtubule-stabilizing paclitaxel to create a heterodimeric paclitaxel-idebenone prodrug via an acid-activatable, self-immolative ketal linker and then fabricated it into chondroitin sulfate proteoglycan-binding nanomedicine, enabling drug retention within the spinal cord for at least 2 weeks and notable enhancement in hindlimb motor function and axon regeneration after a single intraspinal administration. Additional investigations uncovered that idebenone can suppress the activation of microglia and neuronal ferroptosis, thereby amplifying the therapeutic effect of paclitaxel. This prodrug-based nanomedicine simultaneously accomplishes neuroprotection and axon regeneration, offering a promising therapeutic strategy for SCI.

ADP-Hep-Induced Liquid Phase Condensation of TIFA-TRAF6 Activates ALPK1/TIFA-Dependent Innate Immune Responses.

The ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with fork head-associated domain)-TRAF6 signaling pathway plays a pivotal role in regulating inflammatory processes, with TIFA and TRAF6 serving as key molecules in this cascade. Despite its significance, the functional mechanism of TIFA-TRAF6 remains incompletely understood. In this study, we unveil that TIFA undergoes liquid-liquid phase separation (LLPS) induced by ALPK1 in response to adenosine diphosphate (ADP)-ß-D-manno-heptose (ADP-Hep) recognition. The phase separation of TIFA is primarily driven by ALPK1, the pT9-FHA domain, and the intrinsically disordered region segment. Simultaneously, TRAF6 exhibits phase separation during ADP-Hep-induced inflammation, a phenomenon observed consistently across various inflammatory signal pathways. Moreover, TRAF6 is recruited within the TIFA condensates, facilitating lysine (K) 63-linked polyubiquitin chain synthesis. The subsequent recruitment, enrichment, and activation of downstream effectors within these condensates contribute to robust inflammatory signal transduction. Utilizing a novel chemical probe (compound 22), our analysis demonstrates that the activation of the ALPK1-TIFA-TRAF6 signaling pathway in response to small molecules necessitates the phase separation of TIFA. In summary, our findings reveal TIFA as a sensor for upstream signals, initiating the LLPS of itself and downstream proteins. This process results in the formation of membraneless condensates within the ALPK1-TIFA-TRAF6 pathway, suggesting potential applications in therapeutic biotechnology development.

New Nanofibrous Structured CsAg5Te3 Exhibiting Ultralow Thermal Conductivity and High Figure of Merit.

Low-thermal-conductivity materials are ideal candidates for high-performance thermoelectric materials. CsAg5Te3 is a new metal-rich chalcogenide with an inherent low-thermal conductivity. However, due to its complex crystal structure, obtaining high-purity CsAg5Te3 poses a serious challenge. In addition, the high price of pure metals Cs, Ag, and Te leads to the high cost of traditional solid-state methods for preparing CsAg5Te3. To address these issues, the preparation of CsAg5Te3 with a nanostructured fiber morphology was carried out using a low-energy-intensity scalable microwave method. The CsAg5Te3 nanofibers were then assembled using spark plasma sintering technology to prepare CsAg5Te3 bulk with a layered structure. The lattice thermal conductivity of the CsAg5Te3 nanostructured material is 0.19 W m-1 K-1, which is almost the lowest among the state-of-the-art thermoelectric materials. Finally, at 673 K, the maximum zT value of CsAg5Te3 can reach ∼0.67. This study provides a feasible pathway for low-cost preparation of nanostructured thermoelectric materials.

Large-scale phosphoproteome analysis in wheat seedling leaves provides evidence for extensive phosphorylation of regulatory proteins during CWMV infection.

BACKGROUND: Chinese wheat mosaic virus (CWMV) often causes severe damage to wheat (Triticum aestivum L.) growth and yield. It is well known that a successful infection in plants depends on a complex interaction between the host plant and the pathogen. Post-translational modification (PTM) of proteins is considered to be one of the main processes that decides the outcome of the plant-pathogen arms race during this interaction. Although numerous studies have investigated PTM in various organisms, there has been no large-scale phosphoproteomic analysis of virus-infected wheat plants. We therefore aimed to investigate the CWMV infection-induced phosphoproteomics changes in wheat by high-resolution liquid chromatography-tandem mass spectroscopy (LC-MS/MS) using affinity-enriched peptides followed by comprehensive bioinformatics analysis. RESULTS: Through this study, a total of 4095 phosphorylation sites have been identified in 1968 proteins, and 11.6% of the phosphorylated proteins exhibited significant changes (PSPCs) in their phosphorylation levels upon CWMV infection. The result of Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that most of the PSPCs were associated with photosynthesis, plant-pathogen interactions, and MAPK signaling pathways. The protein-protein interaction (PPI) network analysis result showed that these PSPCs were mainly participated in the regulation of biosynthesis and metabolism, protein kinase activities, and transcription factors. Furthermore, the phosphorylation levels of TaChi1 and TaP5CS, two plant immunity-related enzymes, were significantly changed upon CWMV infection, resulting in a significant decrease in CWMV accumulation in the infected plants. CONCLUSIONS: Our results indicate that phosphorylation modification of protein plays a critical role in wheat resistance to CWMV infection. Upon CWMV infection, wheat plants will regulate the levels of extra- and intra-cellular signals and modifications of enzyme activities via protein phosphorylation. This novel information about the strategies used by wheat to resist CWMV infection will help researchers to breed new CWMV-resistant cultivars and to better understand the arms race between wheat and CWMV.

A papain-like cysteine protease-released small signal peptide confers wheat resistance to wheat yellow mosaic virus.

Wheat yellow mosaic virus (WYMV), a soil-borne pathogen, poses a serious threat to global wheat production. Here, we identify a WYMV resistance gene, TaRD21A, that belongs to the papain-like cysteine protease family. Through genetic manipulation of TaRD21A expression, we establish its positive role in the regulation of wheat to WYMV resistance. Furthermore, our investigation shows that the TaRD21A-mediated plant antiviral response relies on the release of a small peptide catalyzed by TaRD21A protease activity. To counteract wheat resistance, WYMV-encoded nuclear inclusion protease-a (NIa) suppress TaRD21A activity to promote virus infection. In resistant cultivars, a natural variant of TaRD21A features a glycine-to-threonine substitution and this substitution enables the phosphorylation of threonine, thereby weakening the interaction between NIa and TaRD21A, reinforcing wheat resistance against WYMV. Our study not only unveils a WYMV resistance gene but also offers insights into the intricate mechanisms underpinning resistance against WYMV.

Flexible Capacitive Sensors Based on Liquid Crystal Elastomer.

The disordered transformation of the ordered aligned polar liquid crystal molecules in liquid crystal elastomers (LCEs) under the influence of an external field imbues them with the unique property of thermally reversible shape memory, making them highly valuable for various applications, particularly in actuators. In this study, we examined the high dielectric constant exhibited by the orientation polarization of polar liquid crystal molecules in RM257-LCE films, which holds significant potential for developing flexible capacitive sensors. By manipulating the flexibility of the molecular chain network and introducing hydrogen bonds and metal ions into the main chain, we were able to enhance the relative dielectric constant of LCEs to an impressive value of 62 (at 100 Hz), which is approximately 23 times higher than for polydimethylsiloxane (PDMS). This elevated dielectric constant displays a noteworthy positive temperature coefficient within a specific temperature range, starting from room temperature and extending to the clearing point. Using this property, we fabricated highly sensitive capacitive, flexible temperature sensors. Moreover, we successfully engineered a flexible pressure sensor with an excellent pressure-sensing range of 0-2 MPa by combining the porous structure of the prepared LCEs with mushroom electrodes. Additionally, the sensor showcases a remarkable capacitance recovery time of 0.8 s at 90 °C. These outstanding features collectively contribute to the excellent pressure-sensing characteristics of our sensor. The findings of this study offer valuable insights and serve as a reference for the design of innovative flexible sensors, enabling advancements in sensor technology.

Monodomain liquid crystal elastomer bionic muscle fibers with excellent mechanical and actuation properties.

Monodomain liquid crystal elastomers (m-LCEs) exhibit large reversible deformations when subjected to light and heat stimuli. Herein, we developed a new method for the large-scale continuous preparation of m-LCE fibers. These m-LCE fibers exhibit a reversible contraction ratio of 55.6%, breaking strength of 162 MPa (withstanding a load of 1 million times its weight), and maximum output power density of 1250 J/kg, surpassing those of previously reported m-LCEs. These excellent mechanical properties are mainly attributed to the formation of a homogeneous molecular network. Furthermore, the fabrication of m-LCEs with permanent plasticity using m-LCEs with impermanent instability without external intervention was realized by the synergistic effects of the self-restraint of mesogens and the prolonged relaxation process of LCEs. The designed LCE fibers, which are similar to biological muscle fibers and can be easily integrated, exhibit broad application prospects in artificial muscles, soft robots, and micromechanical systems.

Skin-friendly and antibacterial monodomain liquid crystal elastomer actuator.

Monodomain liquid crystal elastomers (mLCEs) are flexible and biocompatible smart materials that show unique behaviors of soft elasticity, anisotropy, and reversible shape changes above the nematic-isotropic transition temperature. Therefore, it has great potential for application in wearable devices and biologically. However, most of the reported mLCEs have nematic-isotropic transition temperature (TNI) higher than 60 °C; and above this TNI, the tensile strength of the mLCEs decreases by orders of magnitude. These issues have received little attention, limiting their application in humans. Herein, the TNI of mLCEs was reduced from 78.4 °C to 23.5 °C by substituting part of the rigid LC mesogens with a flexible backbone. The physical entanglement of hydrogen bonds between molecular chains alleviated the molecular chain slip caused by the long flexible backbone. The tensile strength remained constant during the phase transformation. Furthermore, dynamic disulfide bonds were used to modify the LC polymer network, imparting it with excellent antimicrobial, programmable, and self-healing properties. To realize its application in the closure of skin wounds, a porous PHG-mLCE/hydrogel patch that was breathable and waterproof was designed to increase skin adhesion (262 N/m).

Design and Characterization of a Natural Arf-GEFs Inhibitor Prodrug CHNQD-01255 with Potent Anti-Hepatocellular Carcinoma Efficacy In Vivo.

Brefeldin A (BFA), a well-known natural Arf-GEFs inhibitor, is effective against hepatocellular carcinoma (HCC), while the poor solubility, serious toxicity, and short half-life limit its potential. Herein, distinct corresponding prodrugs of BFA, including esters 1-15, carbonates 16-24 and 30-32, and carbamates 25-29, were synthesized and evaluated. CHNQD-01255 (16) with improved aqueous solubility (15-20 mg/mL) demonstrated favorable pharmacokinetic profiles. It behaved as expected by undergoing rapid conversion to BFA in vivo, and achieved sufficient high plasma exposure, prolonged half-life, as well as the improved bioavailability of BFA (F = 18.96%). Meanwhile, CHNQD-01255 significantly suppressed tumor growth (TGI = 61.0%) at a dose of 45 mg/kg (p.o.) in the xenograft model. Notably, the improved safety profile of CHNQD-01255 (MTD > 750 mg/kg, p.o.) was confirmed to be superior to that of BFA (MTD < 506 mg/kg). Overall, CHNQD-01255 may serve as a safe and effective new anti-HCC prodrug.

Microcrystals of Ketal-Linked Paliperidone Prodrugs for Long-Acting Antipsychotics.

Intramuscularly injectable long-acting prodrug-based microcrystals (MCs) are of particular interest for chronic disease management. Nevertheless, current prevalently used linkers degraded by enzymes have the potential drawback of substantial differences in enzyme levels between individuals. Here, we reported the synthesis of a stearyl-modified paliperidone prodrug (SKP) with an acid-sensitive ketal linker for developing long-acting MC antipsychotics. SKP-MCs of three different sizes were prepared and systematically examined. We found that paliperidone exposure in SKP-MC-treated rats was prolonged compared with that in rats treated with the commercial antipsychotic Invega Sustenna and that the drug release rate decreased with increasing MC size. In inflammation-inhibition-model rats, paliperidone release from the SKP-MCs was considerably decreased, indicating that the immune-mediated foreign-body response after intramuscular administration boosted paliperidone release. Our findings will provide valuable insights into in vivo drug release from prodrug-based MC formulations. The ketal-linked prodrug strategy might be a new solution for developing long-acting prodrug formulations of hydroxyl-group-bearing drugs.

A fluorescence biosensor based on double-stranded DNA and a cationic conjugated polymer coupled with exonuclease III for acrylamide detection.

As a toxic substance on human health produced in food thermal treatment, simple analytical approaches are highly desired for the detection of acrylamide (ACR) in foods. With the aid of exonuclease III (Exo III), a simple fluorescence sensor was proposed based on carboxyfluorescein-labeled double-stranded DNA (FAM-dsDNA) and a cationic conjugated polymer (PFP). Fluorescence resonance energy transfer (FRET) efficiency between FAM and PFP was changed with and without ACR. When ACR was present, ACR and single-stranded DNA (P1, ssDNA) formed an adduct, allowing free FAM-labeled complementarity strand DNA (P2, FAM-csDNA) to appear in the solution and avoiding the digestion of P2 by Exo III. After the addition of PFP, the interaction of PFP and FAM induced strong FRET. Under optimized conditions, ACR was detected with a limit of detection (LOD) of 0.16 µM. According to this biosensor, a LOD of 1.3 µM in water extract samples was observed with a good recovery rate (95-110 %).

Central Role of Ubiquitination in Wheat Response to CWMV Infection.

Ubiquitination is a major post-translational modification (PTM) involved in almost all eukaryotic biological processes and plays an essential role in plant response to pathogen infection. However, to date, large-scale profiling of the changes in the ubiquitome in response to pathogens, especially viruses, in wheat has not been reported. This study aimed to identify the ubiquitinated proteins involved in Chinese wheat mosaic virus (CWMV) infection in wheat using a combination of affinity enrichment and high-resolution liquid chromatography-tandem mass spectroscopy. The potential biological functions of these ubiquitinated proteins were further analyzed using bioinformatics. A total of 2297 lysine ubiquitination sites in 1255 proteins were identified in wheat infected with CWMV, of which 350 lysine ubiquitination sites in 192 proteins were differentially expressed. These ubiquitinated proteins were related to metabolic processes, responses to stress and hormones, plant-pathogen interactions, and ribosome pathways, as assessed via Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Furthermore, we found that the ubiquitination of Ta14-3-3 and TaHSP90, which are essential components of the innate immune system, was significantly enhanced during CWMV infection, which suggested that ubiquitination modification plays a vital role in the regulatory network of the host response to CWMV infection. In summary, our study puts forward a novel strategy for further probing the molecular mechanisms of CWMV infection. Our findings will inform future research to find better, innovative, and effective solutions to deal with CWMV infection in wheat, which is the most crucial and widely used cereal grain crop.

New brefeldin A-cinnamic acid ester derivatives as potential antitumor agents: Design, synthesis and biological evaluation.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and ranks third in mortality rate worldwide. Brefeldin A (BFA, 1), a natural Arf1 inhibitor, qualifies extremely superior antitumor activity against HCC while its low aqueous solubility, poor bioavailability, and high toxicity have greatly hindered its translation to the clinic. Herein, a series of BFA-cinnamic acid ester derivatives was rationally designed and synthesized via introducing active cinnamic acid and its analogues into the structure of 1. Their in vitro cytotoxic activities on five cancer cell lines, including HepG2, BEL-7402, HeLa, Eca-109 and PANC-1, were evaluated using MTT assay. As expected, favorable cytotoxic activity was observed on majority of the mono-substituted derivatives. Especially, the most potent brefeldin A 4-O-(4)-dimethylaminocinnamate (CHNQD-01269, 33) with improved aqueous solubility, demonstrated the strong cytotoxic activity against HepG2 and BEL-7402 cell lines with IC50 values of 0.29 and 0.84 µM, respectively. More importantly, 33 performed low toxicity on normal liver cell line L-02 with the selectivity index (SI) of 9.69, which was more than 17-fold higher than that of 1. Results from mechanistic studies represented that 33 blocked the cell cycle in the G1 phase, and induced apoptosis via elevating reactive oxygen species (ROS) production and increasing expression of apoptosis-related proteins of HepG2 cells. Docking experiment also suggested 33 a promising Arf1 inhibitor, which was confirmed by the cellular thermal shift assay that 33 displayed a significant effect on the stability of Arf1 protein. Furthermore, 33 possessed high safety profile (MTD >100 mg/kg, ip) and favorable pharmacokinetic properties. Notably, the superior antiproliferative activity was verified in HepG2 tumor-bearing xenograft model in which 33 markedly suppressed the tumor growth (TGI = 46.17%) in nude mice at a dose of 10 mg/kg once a day for 16 d. The present study provided evidence of exploiting this series of highly efficacious derivatives, especially 33, for the treatment of HCC.

De Novo SMARCC2 Variant in a Chinese Woman with Coffin-Siris Syndrome 8: a Case Report with Mild Intellectual Disability and Endocrinopathy.

Coffin-Siris syndrome (CSS) is a neurodevelopmental disorder characterized by cognitive disability, coarse facial features, hypertrichosis, and somatic dysmorphic features. It is caused by mutations in the BAF-complex or SOX gene. Here, a Chinese woman presenting with neurodevelopmental delay, mild intellectual disability, speech delay, dysmorphic features, obesity, scoliosis, hypotonia, seizures, skin problems, hypokalemia, and endocrine dysfunction is described. Whole exome sequencing (WES) identified a heterozygous missense variant, c.2074G > C (p. Ala692Pro), in the SMARCC2 gene of the proband. Affecting chromatin structure, SMARCC2 plays an essential role in modulating cortical neurogenesis, and controlling cortical size and thickness. Moreover, it is associated with tumor suppression, and SMARCC2 mutations have been observed with high frequency in human cancers. While this is the second report of SMARCC2 mutations in patients with detailed phenotypes, this is the first describing the observation of electrolyte disturbances and endocrinopathy. These findings expanded the genetic and clinical spectrum of SMARCC2-related Coffin-Siris syndrome.

A High-Fidelity Preparation Method for Liquid Crystal Elastomer Actuators.

Three-dimensional (3D) structural actuators based on monodomain liquid crystal elastomers (mLCEs) show a wide range of potential applications. A direct ink writing technique has been developed to print LCE structures. It is still a challenge to print high-precision 3D-mLCE actuators. Here, a method of wet 3D printing combined with freeze-drying is proposed. The coagulation bath is designed to restrain the nascent fiber disturbance of the capillary wave and weight by adjusting the ink viscosity and printing speed to control the LC molecular order, enabling uniform (B = 1.02) fibers with a high degree of orientational alignment (S = 0.45) of the mesogens. Furthermore, dynamic disulfide bond formation was used as the cross-linking point, which can allow the LCE network structure to be continuously cured to ensure adjacent layers are effectively bonded and, in combination with freeze-drying, produce the 3D-mLCE actuators of fidelity architecture (98.37 vol %) by printing. The actuators have excellent actuating strain (45.12%), and the dynamic disulfide bond makes them programmable. Finally, a printed bionic starfish and a printed bionic hand can easily grab regular and irregular objects. This work provides a feasible scheme for fabricating complex 3D-mLCEs with reversible changes in shape.

High-Strength, Large-Deformation, Dual Cross-Linking Network Liquid Crystal Elastomers Based on Quadruple Hydrogen Bonds.

Liquid crystal elastomers (LCEs) with large deformation under external stimuli have attracted extensive attention in various applications such as soft robotics, 4D printing, and biomedical devices. However, it is still a great challenge to reduce the damage to collimation and enhance the mechanical and actuation properties of LCEs simultaneously. Here, we construct a new method of a double cross-linking network structure to improve the mechanical properties of LCEs. The ureidopyrimidinone (UPy) group with quadruple hydrogen bonds was used as the physical cross-linking unit, and pentaerythritol tetra(3-mercaptopropionate) was used as the chemical cross-link. The LCEs showed a strong mechanical tensile strength of 8.5 MPa and excellent thermally induced deformation (50%). In addition, the introduction of quadruple hydrogen bonds endows self-healing ability to extend the service life of LCEs. This provides a generic strategy for the fabrication of high-strength LCEs, inspiring the development of actuators and artificial muscles.