Melatonin alleviates endoplasmic reticulum stress to improve ovarian function by regulating the mTOR pathway in aged laying hens.

Granular cell apoptosis is a key factor leading to follicular atresia and decreased laying rate in aged laying hens. Endoplasmic reticulum stress (ERS) induced cell apoptosis is a new type of apoptosis pathway. Previous studies have shown that the ERS pathway is involved in the regulation of follicular development and atresia, and can be regulated by mTOR. Melatonin (MEL) can protect the normal development of follicles, but the precise mechanism by which MEL regulates follicular development is not yet clear. So, we investigated the potential relationship between MEL and ERS and mTOR signaling pathway in vivo through intraperitoneal injection of MEL in aged laying hens. The results show that the laying rate, ovarian follicle number, plasma MEL, E2, LH, FSH concentrations, as well as the mRNA expression of mTOR signaling-associated genes TSC1, TSC2, mTOR, 4E-BP1, and S6K in old later-period chicken control (Old-CN) group was significantly decreased (P < 0.01). In contrast, the ERS-related of plasma and granular cell layer mRNA expression of Grp78, CHOP, and Caspase-3 was significantly increased (P < 0.01). While both of the effects were reversed by MEL. Then, aging granulosa cells were treated with MEL in vitro, followed by RNA seq analysis, and it was found that 259 and 322 genes were upregulated and downregulated. After performing GO enrichment analysis, it was found that DEGs significantly contribute to the biological processes including cell growth and apoptosis. Using pathway enrichment analysis, we found significant overrepresentation of cellular processes related to mTOR signaling and endoplasmic reticulum (ER) stress, involving genes such as GRB10, SGK1, PRKCA, RPS6KA2, RAF1, PIK3R3, FOXO1, DERL3, HMOX1, TLR7, VAMP7 and INSIG2. The obtained results of RT-PCR showed consistency with the RNA-Seq data. In summary, the underlined results revealed that MEL has significantly contributed to follicular development via activating the mTOR signaling pathway-related genes and alleviating ERS-related genes in laying hens. The current study provides a theoretical background for enhancing the egg-laying capability of hens and also providing a basis for elucidating the molecular mechanism of follicular selection.

Melatonin alleviates endoplasmic reticulum stress and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens.

Follicular atresia in chickens reduces the number of follicles that can further develop, leading to decrease egg laying. Endoplasmic reticulum stress (ERS) can initiate a unique pathway inducing the apoptosis of follicular granulosa cells, thus reducing egg laying. Melatonin (MEL) is involved in the regulation of follicle development, ovulation, and oocyte maturation, and is closely related to follicle fate. Mammalian target of Rapamycin (mTOR) signaling pathway plays an important role in cell growth regulation, and that there is a possible crosstalk between melatonin and mTOR activity in granular cells maturation and ovulation. This study aimed to investigate whether MEL inhibits ERS and follicular granulosa cell apoptosis by regulating ATF4 to activate mTOR signaling pathway in chickens. Frist, we established an in vitro ERS cell model using tunicamycin (TM). The results showed that different concentrations of TM exhibited dose-dependent inhibition of cell activity and induction of granulosa cells (P<0.01). Therefore, we chose 5 µg/mL of TM and a treatment time for 6 h as the optimal concentration for the following experiments. Then we investigate whether melatonin can inhibit ERS. TM treatment decreased the cell viability and Bcl-2 expression, increasing ROS levels and the mRNA expression of Grp78, ATF4, CHOP, PERK, eIF-2α, and BAX (P<0.01), whereas TM+MEL treatment significantly inhibited these changes (P<0.01). Then we explored whether melatonin protects follicular granulosa cells from ERS-induced apoptosis through the mammalian target of rapamycin (mTOR) signaling pathway by regulating ATF4, we found that ATF4 knockdown inhibited ERS by decreasing the expression of ERS-related genes and proteins and activating mTOR signaling pathway by increasing the protein expression of p4E-BP1 and pT389-S6K (P<0.001), while these changes were promoted by TM+si-ATF4+MEL treatment (P<0.01). These results indicate that MEL could alleviate TM-induced ERS by regulating ATF4 to activate mTOR signaling pathway in follicular granulosa cells, thus providing a new perspective for prolonging the laying cycle in chickens.

Diallyl disulfide antagonizes DJ-1 mediated proliferation, epithelial-mesenchymal transition, and chemoresistance in gastric cancer cells.

Diallyl disulfide (DADS), an organic component of allicin abstracted from garlic, possesses multi-target antitumor activity. DJ-1 performs a vital function in promoting AKT aberrant activation via down-regulating phosphatase and tensin homologue (PTEN) in tumors. It is unknown the involvement of DJ-1 in epithelial-mesenchymal transition (EMT) of gastric cancer (GC) cells. The purpose of this study is to investigate whether diallyl disulfide (DADS) intervenes in the role of DJ-1 in GC. Based on the identification that the correlation between high DJ-1 and low PTEN expression in GC was implicated in clinical progression, we illuminated that down-regulation of DJ-1 by DADS aided in an increase in PTEN expression and a decrease in phosphorylated AKT levels, which was in line with the results manifested in the DJ-1 knockdown and overexpressed cells, concurrently inhibiting proliferation, EMT, migration, and invasion. Furthermore, the antagonistic effects of DADS on DJ-1 were observed in in vivo experiments. Additionally, DADS mitigated the DJ-1-associated drug resistance. The current study revealed that DJ-1 is one of potential targets for DADS, which hopefully provides a promising strategy for prevention and adjuvant chemotherapy of GC.

PROTAC EZH2 degrader-1 overcomes the resistance of podophyllotoxin derivatives in refractory small cell lung cancer with leptomeningeal metastasis.

BACKGROUND: Leptomeningeal metastasis (LM) of small cell lung cancer (SCLC) is a highly detrimental occurrence associated with severe neurological disorders, lacking effective treatment currently. Proteolysis-targeting chimeric molecules (PROTACs) may provide new therapeutic avenues for treatment of podophyllotoxin derivatives-resistant SCLC with LM, warranting further exploration. METHODS: The SCLC cell line H128 expressing luciferase were mutated by MNNG to generate H128-Mut cell line. After subcutaneous inoculation of H128-Mut into nude mice, H128-LM and H128-BPM (brain parenchymal metastasis) cell lines were primarily cultured from LM and BPM tissues individually, and employed to in vitro drug testing. The SCLC-LM mouse model was established by inoculating H128-LM into nude mice via carotid artery and subjected to in vivo drug testing. RNA-seq and immunoblotting were conducted to uncover the molecular targets for LM. RESULTS: The SCLC-LM mouse model was successfully established, confirmed by in vivo live imaging and histological examination. The upregulated genes included EZH2, SLC44A4, VEGFA, etc. in both BPM and LM cells, while SLC44A4 was particularly upregulated in LM cells. When combined with PROTAC EZH2 degrader-1, the drug sensitivity of cisplatin, etoposide (VP16), and teniposide (VM26) for H128-LM was significantly increased in vitro. The in vivo drug trials with SCLC-LM mouse model demonstrated that PROTAC EZH2 degrader-1 plus VM26 or cisplatin/ VP16 inhibited H128-LM tumour significantly compared to VM26 or cisplatin/ VP16 alone (P < 0.01). CONCLUSION: The SCLC-LM model effectively simulates the pathophysiological process of SCLC metastasis to the leptomeninges. PROTAC EZH2 degrader-1 overcomes chemoresistance in SCLC, suggesting its potential therapeutic value for SCLC LM.

Changes of Mycobacterium tuberculosis specific antigen-stimulated CD27-CD38+IFN-γ+CD4+ T cells before and after anti-tuberculosis treatment.

BACKGROUND: The aim of the study was to investigate whether the expression of CD27-CD38+ in interferon (IFN)-γ+CD4+ T cells stimulated by the specific antigen early secreted antigenic target-6 (ESAT-6)/culture filter protein-10 (CFP-10) could be a potential new therapeutic evaluation indicator for anti-tuberculosis (TB) treatment. METHODS: Newly diagnosed active pulmonary TB patients, latent TB infection (LTBI) and healthy controls were enrolled from January 2021 to December 2021. PTB patients were treated by standard anti-TB regimen 2HREZ/4HR (2 months of isoniazid (H), rifampin (R), ethambutol (E), and pyrazinamide (Z) followed by 4 months of isoniazid (H) and rifampin (R)). The difference of CD27-CD38+ expression in IFN-γ+CD4+ T cells before treatment, 2 months after treatment, and 6 months after treatment were compared. RESULTS: Total 45 PTB patients, 38 LTBI cases and 43 healthy controls were enrolled. The expression of CD27-CD38+ decreased significantly after anti-TB treatment and was comparable with that in LTBI and healthy controls when the 6-month anti-TB treatment course was completed. The decline rate of CD27-CD38+ between 6 months after treatment and baseline was positively correlated with erythrocyte sedimentation rate (r = 0.766, P < 0.0001), C-reactive protein (r = 0.560, P = 0.003) and chest computerized tomography severity score (r = 0.632, P = 0.0005). The area under receiver operator characteristic curve of CD27-CD38+ in distinguish pulmonary TB patients before and after treatment was 0.779. CONCLUSION: The expression of CD27-CD38+ in ESAT-6/CFP-10 stimulated IFN-γ+CD4+T cells can well reflect the changes of the disease before and after anti-TB treatment, which is expected to be a potential new therapeutic evaluation index. Clinical Registry number chiCTR1800019966.

Methyltransferase METTL3-mediated maturation of miR-4654 facilitates high glucose-induced apoptosis and oxidative stress in lens epithelial cells via decreasing SOD2.

N6-methyladenosine (m6 A) modification has been reported to have roles in modulating the development of diabetic cataract (DC). Methyltransferase-like 3 (METTL3) is a critical m6 A methyltransferase involving in m6 A modification activation. Here, we aimed to explore the action and mechanism of METTL3-mediated maturation of miR-4654 in DC progression. Human lens epithelial cells (HLECs) were exposed to high glucose (HG) to imitate DC condition in vitro. Levels of genes and proteins were tested via qRT-PCR and western blotting assays. The proliferation and apoptosis of HLECs were evaluated by cell counting kit-8, 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry assays, respectively. Oxidative stress was analyzed by detecting the contents of reactive oxygen species (ROS), superoxide dismutase (SOD) and malondialdehyde (MDA). The binding of miR-4654 and SOD2 was confirmed by dual-luciferase reporter assay. The m6 A-RNA immunoprecipitation (MeRIP) assay detected the m6 A modification profile. Thereafter, we found that miR-4654 expression was elevated in DC samples and HG-induced HLECs. MiR-4654 knockdown reversed HG-mediated apoptosis and oxidative stress in HLECs. Mechanistically, miR-4654 directly targeted SOD2, silencing of SOD2 abolished the protective effects of miR-4654 knockdown on HLECs under HG condition. In addition, METTL3 induced miR-4654 maturation through promoting pri-miR-4654 m6 A modification, thereby increasing miR-4654 content in HLECs. METTL3 was highly expressed in DC samples and HG-induced HLECs, METTL3 deficiency protected HLECs against HG-mediated apoptotic and oxidative injury via down-regulating miR-4654. In all, METTL3 induced miR-4654 maturation in a m6 A-dependent manner, which was then reduced SOD2 expression, thus promoting apoptosis and oxidative stress in HLECs, suggesting a novel path for DC therapy.

Image registration for in situ X-ray nano-imaging of a composite battery cathode with deformation.

The structural and chemical evolution of battery electrodes at the nanoscale plays an important role in affecting the cell performance. Nano-resolution X-ray microscopy has been demonstrated as a powerful technique for characterizing the evolution of battery electrodes under operating conditions with sensitivity to their morphology, compositional distribution and redox heterogeneity. In real-world batteries, the electrode could deform upon battery operation, causing challenges for the image registration which is necessary for several experimental modalities, e.g. XANES imaging. To address this challenge, this work develops a deep-learning-based method for automatic particle identification and tracking. This approach was not only able to facilitate image registration with good robustness but also allowed quantification of the degree of sample deformation. The effectiveness of the method was first demonstrated using synthetic datasets with known ground truth. The method was then applied to an experimental dataset collected on an operating lithium battery cell, revealing a high degree of intra- and interparticle chemical complexity in operating batteries.

GDI2 deletion alleviates neurodegeneration and memory loss in the 5xFAD mice model of Alzheimer's disease.

Accumulation of insoluble deposits of amyloid ß-peptide (Aß), derived from amyloid precursor protein (APP) processing, represents one of the major pathological hallmarks of Alzheimer's disease (AD). Perturbations in APP transport and hydrolysis could lead to increased Aß production. However, the precise mechanisms underlying APP transport remain elusive. The GDP dissociation inhibitor2 (GDI2), a crucial regulator of Rab GTPase activity and intracellular vesicle and membrane trafficking, was investigated for its impact on AD pathogenesis through neuron-specific knockout of GDI2 in 5xFAD mice. Notably, deficiency of GDI2 significantly ameliorated cognitive impairment, prevented neuronal loss in the subiculum and cortical layer V, reduced senile plaques as well as astrocyte activation in 5xFAD mice. Conversely, increased activated microglia and phagocytosis were observed in GDI2 ko mice. Further investigation revealed that GDI2 knockout led to more APP co-localized with the ER rather than the Golgi apparatus and endosomes in SH-SY5Y cells, resulting in decreased Aß production. Collectively, these findings suggest that GDI2 may regulate Aß production by modulating APP intracellular transport and localization dynamics. In summary, our study identifies GDI2 as a pivotal regulator governing APP transport and process implicated in AD pathology; thus highlighting its potential as an attractive pharmacological target for future drug development against AD.

Exploring terahertz spectral characteristics of L-sorbose and D-melibiose in solid and liquid states.

Saccharides are essential organic compounds that perform critical functions in sustaining life processes. As biomolecules, their vibrational frequencies predominantly fall in the terahertz (THz) range, making them amenable to analysis using THz techniques. In this study, L-sorbose and D-melibiose were measured using a THz time-domain spectroscopy system covering a frequency range of 0.1-2.0 THz, and their crystal structures were simulated using density functional theory. The experimental results demonstrated significant agreement with the simulation findings. In addition, the spectral properties of the two saccharides in solution were determined using microfluidic chip technology, thereby facilitating a comparison between the solid and aqueous states. The results demonstrate that the intramolecular and intermolecular interactions of the saccharides were weakened by the presence of water molecules, and the THz absorption spectrum of the same substance solution was found to be correlated with its concentration and temperature.

Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer.

OBJECTIVES: Histological transformation to small cell lung cancer (SCLC) has been identified as a mechanism of TKIs resistance in EGFR-mutant non-small cell lung cancer (NSCLC). We aim to explore the prevalence of transformation in EGFR-wildtype NSCLC and the mechanism of SCLC transformation, which are rarely understood. METHODS: We reviewed 1474 NSCLC patients to investigate the NSCLC-to-SCLC transformed cases and the basic clinical characteristics, driver gene status and disease course of them. To explore the potential functional genes in SCLC transformation, we obtained pre- and post-transformation specimens and subjected them to a multigene NGS panel involving 416 cancer-related genes. To validate the putative gene function, we established knocked-out models by CRISPR-Cas 9 in HCC827 and A549-TP53-/- cells and investigated the effects on tumor growth, drug sensitivity and neuroendocrine phenotype in vitro and in vivo. We also detected the expression level of protein and mRNA to explore the molecular mechanism involved. RESULTS: We firstly reported an incidence rate of 9.73% (11/113) of SCLC transformation in EGFR-wildtype NSCLC and demonstrated that SCLC transformation is irrespective of EGFR mutation status (P = 0.16). We sequenced 8 paired tumors and identified a series of mutant genes specially in transformed SCLC such as SMAD4, RICTOR and RET. We firstly demonstrated that SMAD4 deficiency can accelerate SCLC transition by inducing neuroendocrine phenotype regardless of RB1 status in TP53-deficient NSCLC cells. Further mechanical experiments identified the SMAD4 can regulate ASCL1 transcription competitively with Myc in NSCLC cells and Myc inhibitor acts as a potential subsequent treatment agent. CONCLUSIONS: Transformation to SCLC is irrespective of EFGR status and can be accelerated by SMAD4 in non-small cell lung cancer. Myc inhibitor acts as a potential therapeutic drug for SMAD4-mediated resistant lung cancer. Video Abstract.

Vibrational spectroscopic detection and analysis of salicylic acid and aspirin binary cocrystal.

Salicylic acid is a raw material for preparing aspirin and holds an important position in medical history. Studying the crystallization of these two drugs is of great significance in improving their dissolution rate, bioavailability, and physical stability. Although various techniques have been used for structural characterization, there is still a lack of information on the collective vibrational behavior of aspirin and salicylic acid eutectic compounds. Firstly, two starting materials (salicylic acid and aspirin) were ground in a 1:1 M ratio to prepare eutectic compounds. The eutectic composition was studied using vibrational spectroscopy techniques, such as X-ray powder diffusion (XRPD), terahertz time-domain spectroscopy (THz-TDS), and Raman spectroscopy. Additionally, the structure of the aspirin and salicylic acid eutectic was simulated and optimized using density functional theory. It was found that the eutectic type II was the most consistent with the experiment, and the corresponding vibration modes of each peak were provided. These results offer a unique method for characterizing the structural composition of eutectic crystals, which can be utilized to enhance the physical and chemical properties, as well as the pharmacological activity, of specific drugs at the molecular level.

Nanotextured titanium inhibits bacterial activity and supports cell growth on 2D and 3D substrate: A co-culture study.

Medical implant-associated infections pose a significant challenge to modern medicine, with aseptic loosening and bacterial infiltration being the primary causes of implant failure. While nanostructured surfaces have demonstrated promising antibacterial properties, the translation of their efficacy from 2D to 3D substrates remains a challenge. Here, we used scalable alkaline etching to fabricate nanospike and nanonetwork topologies on 2D and laser powder-bed fusion printed 3D titanium. The fabricated surfaces were compared with regard to their antibacterial properties against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, and mesenchymal stromal cell responses with and without the presence of bacteria. Finite elemental analysis assessed the mechanical properties and permeability of the 3D substrate. Our findings suggest that 3D nanostructured surfaces have potential to both prevent implant infections and allow host cell integration. This work represents a significant step towards developing effective and scalable fabrication methods on 3D substrates with consistent and reproducible antibacterial activity, with important implications for the future of medical implant technology.

Integration of land ecological consolidation and ecosystem product value realization: A case from the Yangtze riverside industrial park in Changzhou, China.

Traditional industries and industrialization have led to widespread environmental pollution and ecosystem degradation in major river basins globally. Strategies centered on ecological restoration and ecological economy are emerging as essential tools for effective environmental governance. This study aims to investigate how a multifaceted framework for land ecological consolidation, with various developmental goals, can effectively support ecological restoration and sustainability. Through quantitative analysis and in-depth interviews, we investigated the case of Yangtze riverside chemical industrial park in Changzhou. This park pursues ecological and economic sustainability through chemical industry transformation, ecological restoration and protection, ecological management, and ecological industry development. The results show that this practice established a multi-objective action framework rooted in urban renewal, land consolidation, ecological restoration, industrial transformation, and rural revitalization. Through multiplanning integration, integrated implementation and full-cycle profit distribution, the aim of ecological protection has been initially achieved, offering a crucial guarantee for sustainable development. A total of 96.47 ha ecological space expanded, which can generate ecological product worth CNY 7.283 billion, alongside a net economic benefit of CNY 978 million over three decades. The top-down ecological responsibilities, coupled with local developmental demands, have stimulated collaborations within a bottom-up endogenous network comprising government, enterprises, and residents.

Global occurrence characteristics, drivers, and environmental risk assessment of microplastics in lakes: A meta-analysis.

Microplastic (MP) pollution in lakes has received much attention as an increasing amount of plastic waste enters aquatic ecosystems. However, there is still a lack of comprehensive understanding of the global distribution patterns, environmental hazards, factors driving their presence, and the relationships between sources and sinks of MPs. In this study, we conducted a meta-analysis of drivers of lake MP pollution based on 42 articles on MP pollution from three different aspects: geographical distribution, driving factors and environmental risks. The results revealed differences in the MP pollution levels across the different sampling sites in the global lakes. Moreover, there is significant heterogeneity in the abundance of MPs among various lakes, whose distribution pattern is affected by geographical location, sampling method and extraction method. The size of the MPs differed significantly between water and sediment, and the proportion of small (<1 mm) MPs in sediment was significantly greater than that in water (72% > 46%). Environmental risk assessment reveals that the risk level of MP pollution in most lakes worldwide is low, and the environmental risk of pollution in lake water is higher than that in sediment. Based on the risk assessment and geographical location of the lake, the risk of MP pollution is related not only to human activities and economic development but also to local waste management practices, which directly impact the accumulation of MPs. Therefore, we suggest that the production of biodegradable low-risk polymer plastics instead of high-risk materials, and plastic solid waste recycling management should be strengthened to effectively mitigate the presence of MPs in the environment.

Bacterial Surface Appendages Modulate the Antimicrobial Activity Induced by Nanoflake Surfaces on Titanium.

Bioinspired nanotopography is a promising approach to generate antimicrobial surfaces to combat implant-associated infection. Despite efforts to develop bactericidal 1D structures, the antibacterial capacity of 2D structures and their mechanism of action remains uncertain. Here, hydrothermal synthesis is utilized to generate two 2D nanoflake surfaces on titanium (Ti) substrates and investigate the physiological effects of nanoflakes on bacteria. The nanoflakes impair the attachment and growth of Escherichia coli and trigger the accumulation of intracellular reactive oxygen species (ROS), potentially contributing to the killing of adherent bacteria. E. coli surface appendages type-1 fimbriae and flagella are not implicated in the nanoflake-mediated modulation of bacterial attachment but do influence the bactericidal effects of nanoflakes. An E. coli ΔfimA mutant lacking type-1 fimbriae is more susceptible to the bactericidal effects of nanoflakes than the parent strain, while E. coli cells lacking flagella (ΔfliC) are more resistant. The results suggest that type-1 fimbriae confer a cushioning effect that protects bacteria upon initial contact with the nanoflake surface, while flagella-mediated motility can lead to elevated membrane abrasion. This finding offers a better understanding of the antibacterial properties of nanoflake structures that can be applied to the design of antimicrobial surfaces for future medical applications.

Insulin-Dendrimer Nanocomplex for Multi-Day Glucose-Responsive Therapy in Mice and Swine.

The management of diabetes in a manner offering autonomous insulin therapy responsive to glucose-directed need, and moreover with a dosing schedule amenable to facile administration, remains an ongoing goal to improve the standard of care. While basal insulins with reduced dosing frequency, even once-weekly administration, are on the horizon, there is still no approved therapy that offers glucose-responsive insulin function. Herein, a nanoscale complex combining both electrostatic- and dynamic-covalent interactions between a synthetic dendrimer carrier and an insulin analogue modified with a high-affinity glucose-binding motif yields an injectable insulin depot affording both glucose-directed and long-lasting insulin availability. Following a single injection, it is even possible to control blood glucose for at least one week in diabetic swine subjected to daily oral glucose challenges. Measurements of serum insulin concentration in response to challenge show increases in insulin corresponding to elevated blood glucose levels, an uncommon finding even in preclinical work on glucose-responsive insulin. Accordingly, the subcutaneous nanocomplex that results from combining electrostatic- and dynamic-covalent interactions between a modified insulin and a synthetic dendrimer carrier affords a glucose-responsive insulin depot for week-long control following a single routine injection.

Schizophrenia in the genetic era: a review from development history, clinical features and genomic research approaches to insights of susceptibility genes.

Schizophrenia is a devastating neuropsychiatric disorder affecting 1% of the world population and ranks as one of the disorders providing the most severe burden for society. Schizophrenia etiology remains obscure involving multi-risk factors, such as genetic, environmental, nutritional, and developmental factors. Complex interactions of genetic and environmental factors have been implicated in the etiology of schizophrenia. This review provides an overview of the historical origins, pathophysiological mechanisms, diagnosis, clinical symptoms and corresponding treatment of schizophrenia. In addition, as schizophrenia is a polygenic, genetic disorder caused by the combined action of multiple micro-effective genes, we further detail several approaches, such as candidate gene association study (CGAS) and genome-wide association study (GWAS), which are commonly used in schizophrenia genomics studies. A number of GWASs about schizophrenia have been performed with the hope to identify novel, consistent and influential risk genetic factors. Finally, some schizophrenia susceptibility genes have been identified and reported in recent years and their biological functions are also listed. This review may serve as a summary of past research on schizophrenia genomics and susceptibility genes (NRG1, DISC1, RELN, BDNF, MSI2), which may point the way to future schizophrenia genetics research. In addition, depending on the above discovery of susceptibility genes and their exact function, the development and application of antipsychotic drugs will be promoted in the future.

Bio-inspired nacre-like zirconia/PMMA composites for chairside CAD/CAM dental restorations.

OBJECTIVES: To introduce a versatile fabrication process to fabricate zirconia/PMMA composites for chairside CAD/CAM dental restorations. These zirconia composites have nacre-like lamellar microstructures, competent and tooth-matched mechanical properties, as well as crack resistance behaviours. METHODS: Bi-directional freeze casting was used to fabricate ceramic green bodies with highly aligned lamellar structure. Pressure was then applied to control the ceramic volume fraction. PMMA was infiltrated into the ceramic scaffold. Mechanical tests including 3-point bending, Vickers hardness, and fracture toughness were performed on the composites. The machinability of the composites was also characterised. RESULTS: Two types of nacre-like zirconia/PMMA composites, i.e., 3Y-YZP/PMMA and 5Y-PSZ/PMMA composites were fabricated. The microstructure created was similar to the 'brick and mortar' structure of nacre. Excellent flexural strength (up to 400 MPa and 290 MPa for 3Y-TZP/PMMA and 5Y-PSZ/PMMA composite, respectively), tuneable hardness and elastic modulus within the range similar to enamel, along with improved crack-resistance behaviour were demonstrated on both zirconia composites. In addition, both zirconia/PMMA composites showed acceptable machinability, being easy to mill, as would be required to produce a dental crown. SIGNIFICANCE: Nacre-like zirconia/PMMA composites therefore exhibit the potential for use in the production of chairside CAD/CAM dental restorations.

Sedimentary record of microplastics in coastal wetland, eastern China.

Microplastic (MP) dynamics can reflect history of plastic production and waste management in nearby areas. However, the stratigraphy of MPs in coastal wetlands and their link to policy and economic pattern changes are currently unclear. Here, MP stratigraphic records in sediment core from coastal wetlands in Yancheng, China, were used to reconstruct plastic pollution history. Neural network models simulated how policy intervention and economic development affected MP accumulation over time. We showed that MP abundance curves with boundaries from 1920 to 2019 had four stages. MP growth slowed or even decreased in the mid-to-late 1980s due to improved waste management and wastewater treatment since the late 1980s. Human activities were the primary factor affecting MP abundance and shape, followed by sediment properties. We predict that the environmental impact of MPs will continue to increase in the next decade. Current plastic policy measures focus on predictable waste emissions, but hidden sources like clothing fibers and tire wear that significantly contribute to MP pollution require further attention.