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Activating cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) holds great potential for cancer immunotherapy by eliciting type-I interferon (IFN-I) responses. Yet, current approaches to cGAS-STING activation rely on STING agonists, which suffer from difficult formulation, poor pharmacokinetics, and marginal clinical therapeutic efficacy. Here, we report nature-inspired oligonucleotide, Svg3, as a cGAS agonist for cGAS-STING activation in tumor combination immunotherapy. The hairpin-shaped Svg3 strongly binds to cGAS and enhances phase separation to form Svg3-cGAS liquid-like droplets. This results in cGAS-specific immunoactivation and robust IFN-I responses. Remarkably, Svg3 outperforms several state-of-the-art STING agonists in murine and human cells/tissues. Nanoparticle-delivered Svg3 reduces tumor immunosuppression and potentiates immune checkpoint blockade therapeutic efficacy of multiple syngeneic tumor models in wild-type mice, but in neither cGas−/− nor Sting−/− mice. Overall, these results demonstrate the great potential of Svg3 as a cGAS agonistic oligonucleotide for cancer combination immunotherapy.

USH type 2 (USH2) is an autosomal recessive disorder that is characterized by inherited retinopathies and sensorineural hearing loss. USH type 2 (USH2) is frequently caused by USH2A mutations, which account for 74–90% of USH2 cases. We used peripheral blood mononuclear cells (PBMCs) from a USH2 patient with a USH2A gene mutation (c.8559-2A > G) to create an induced pluripotent stem (iPS) cell line. The patient-specific iPS cell line with the specific point mutation exhibited typical iPS cell characteristics, and it can be used as a model to investigate the pathogenic mechanisms underlying USH2A-associated retinal degeneration and sensorineural hearing loss.

Electroplating is a common process of converting zinc ion in electrolyte as a micro level zinc layer on electroplating pieces. After electroplating, the remaining electrolyte on the surface of the pieces is washed with water, and accordingly, Zn-containing electroplating wastewater is generated. Hazardous Zn-containing wastewater is generated during the washing of electroplating pieces and plating tank. Herein, Zn was enriched from wastewater by commercial flocculant and then recycled as highly purified zinc phosphate via coupled acid extraction and hydrothermal treatment. Firstly, 98.4% Zn was recovered as sludge from wastewater by adding 0.2 g/L of flocculant. Then, the sludge was dissolved into an acid solution to produce a leachate with 31.2/10.8/19.3 g/L of Fe/Al/Zn and then hydrothermally treated to remove Fe/Al. The Fe removal rate was only 54.2% without phosphate and glucose but was increased to 98.6% after the addition of 0.5 g of glucose with Al/Zn loss

Zn2+ is a heavy metal ion, and hazardous sludge from the electroplating and alloy industry is rich in Zn and impure Al and Ca. Such sludge is commonly recycled by dissolution in strong acid and then selective extraction to recycle Zn2+ by a special extraction reagent. In this process, impurity Al3+ is dissolved and then participates in the extraction of Zn2+, so Al3+ should be removed first. Here, a new strategy was reported for the effective removal of Al3+ and recovery of Zn2+ from a simulated Al/Zn-bearing sludge via an improved acid solution–precipitation route. The sludge was simulated by coagulating Zn-bearing waste water (290 mg/L Zn2+) with 600 mg/L polyaluminium chloride. The sludge was dissolved in sulphuric acid and nitric acid to form an acidic solution with Al3+ and Zn2+ concentrations of 3.2 g/L and 5.7 g/L, respectively. The solution was treated directly by hydrothermal method at 270 °C, in which 55% Al3+ was precipitated as boehmite and Al hydroxide. After the addition of 0.2 mL of ethylene glycol, the removal rate of Al3+ dramatically increased to 99.8%, with Zn2+ loss of 1.5%. The residual Zn2+ was 5620 mg/L in the treated solution and further directly precipitated by adjusting the pH of the solution to pH 7.5 with NaOH. The precipitated Zn2+ was in the form of simonkolleite with ZnO content of 63.1%, with Al content of only 0.8%. In the hydrothermal precipitation, the removal rate of Al3+ increased with the temperature and extension of reaction time. Al3+ was hydrolysed and precipitated as aluminium oxonium sulphate hydroxide and then recrystallised in boehmite form. Then, H+ was generated and consumed in the redox reaction of nitrate and ethylene glycol, accelerating the Al3+ precipitation. This method provides a way to efficiently separate Al3+ from a Zn-bearing solution and can be applied in the recycling of Al/Zn-bearing sludge.

The visualization of drugs in living systems has become key techniques in modern therapeutics. Recent advancements in optical imaging technologies and molecular design strategies have revolutionized drug visualization. At the subcellular level, super-resolution microscopy has allowed exploration of the molecular landscape within individual cells and the cellular response to drugs. Moving beyond subcellular imaging, researchers have integrated multiple modes, like optical near-infrared II imaging, to study the complex spatiotemporal interactions between drugs and their surroundings. By combining these visualization approaches, researchers gain supplementary information on physiological parameters, metabolic activity, and tissue composition, leading to a comprehensive understanding of drug behavior. This review focuses on cutting-edge technologies in drug visualization, particularly fluorescence imaging, and the main types of fluorescent molecules used. Additionally, we discuss current challenges and prospects in targeted drug research, emphasizing the importance of multidisciplinary cooperation in advancing drug visualization. With the integration of advanced imaging technology and molecular design, drug visualization has the potential to redefine our understanding of pharmacology, enabling the analysis of drug micro-dynamics in subcellular environments from new perspectives and deepening pharmacological research to the levels of the cell and organelles.

Background: The variations in non-coding RNA alterations and the host immune response between patients with bacterial and non-bacterial sepsis, along with their clinical characteristics, are largely unknown. Methods: The landscape of long non-coding RNA (lncRNA) and mRNA in whole blood cells from pediatric patients with bacterial sepsis or non-bacterial sepsis were characterized using an Arraystar human LncRNA microarray. Weighted correlation network analysis (WGCNA) were conducted to identify immune-related LncRNA-mRNA signatures. Least absolute shrinkage and selection operator (Lasso) regression and Ridge regression analysis were employed to develop a specific LncRNA-mRNA signature, serving as a discriminant classifier for bacterial and non-bacterial sepsis in children. Results: A total of 33 differentially expressed lncRNAs and 52 mRNAs were identified in pediatric patients with either bacterial sepsis or non-bacterial sepsis. Among these, 69 lncRNAs and mRNAs were pinpointed using WGCNA and found to be significantly correlated with clinical parameters. Further intersection analysis identified 12 lncRNAs and 16 mRNAs as immune-related signature for discerning bacterial infections in children with sepsis. Additionaly, the lncRNA-mRNA co-expression network highlighted the key lncRNAs (AC090159.1 and AC080129.2) and mRNAs (S100A8 and TCF7L2) as an infection score model. Lasso regression analysis revealed that this infection score model achieved an area under the received operating curve (AUROC) of 0.96 in the training set and 0.86 in the validation set. Ultimately, the expression levels of these 4 key lncRNAs and mRNAs showed significant correlation with CRP or PCT levels. Conclusion: The machine learning model, developed utilizing key lncRNAs (AC090159.1 and AC080129.2) and mRNAs (S100A8 and TCF7L2), demonstrates robust discrimination and calibration capabilities for distinguishing between bacterial and non-bacterial sepsis in children.

BP has shown good potential for promoting bone regeneration. However, the understanding of the mechanisms of BP-enhanced bone regeneration is still limited. This review first summarizes the recent advances in applications of BP in bone regeneration. We further highlight the possibility that BP enhances bone regeneration by regulating the behavior of mesenchymal stem cells (MSCs), osteoblasts, vascular endothelial cells (VECs), and macrophages, mainly through the regulation of cytoskeletal remodeling, energy metabolism, oxidation resistance and surface adsorption properties, etc. In addition, moderating the physicochemical properties of BP (i.e., shape, size, and surface charge) can alter the effects of BP on bone regeneration. This review reveals the underlying mechanisms of BP-enhanced bone regeneration and provides strategies for further material design of BP-based materials for bone regeneration.

Background: Isolated acquired clotting factor deficiencies (ACFDs) are mainly caused by the existence of anti-factor antibodies or adsorption of clotting factors onto substances such as amyloid. Besides acquired factor (F)VIII deficiency (acquired hemophilia A), the remaining factor deficiencies are rare and diverse, posing challenges in both diagnosis and management. Objectives: To describe different features of isolated ACFDs to improve our understanding of these diseases and provide practical recommendations for their management. Methods: Clinical characteristics of patients with isolated acquired FII, FV, FIX, FX, FXI, FXII, FXIII, and von Willebrand factor deficiencies were collected from a single center between July 1997 and December 2021 and analyzed retrospectively. Results: A total of 54 rare isolated ACFD patients were enrolled in our study, mainly including 20 acquired FV deficiency patients and 16 acquired FX deficiency patients. The median age at diagnosis of all rare isolated ACFD patients was 55 years. The median time to diagnose all rare isolated ACFD patients was 60 days. Ten (18.5%) rare isolated ACFD patients had no bleeding and 2 (3.7%) rare isolated ACFD patients showed venous thromboembolism. Hemostatic treatment was applied to 41 (41/54; 75.9%) rare isolated ACFD patients. Thirty-seven (68.5%) rare isolated ACFD patients received immunosuppressive therapy, and 10 (18.5%) rare isolated ACFD patients received chemotherapy targeting primary diseases. Twenty-two (61.9%) rare isolated ACFD patients achieved complete remission, and 9 (21.4%) rare isolated ACFD patients died. Conclusion: Rare isolated ACFDs are underestimated, associated with delayed diagnosis, and lack effective therapy. Clinicians should raise awareness for recognizing and managing rare isolated ACFD patients to avoid morbidity and mortality.

Liquid-liquid phase separation (LLPS) of intracellular proteins has emerged as a hot research topic in recent years. Membrane-less and liquid-like condensates provide dense spaces that ensure cells to high efficiently regulate genes transcription and rapidly respond to burst changes from the environment. The fomation and activity of LLPS are not only modulated by the cytosol conditions including but not limited to salt concentration and temperture. Interestingly, recent studies have shown that phase separation is also regulated by various post-translational modifications (PTMs) through modulating proteins multivalency, such as solubility and charge interactions. The regulation mechanism is crucial for normal functioning of cells, as aberrant protein aggregates are often closely related with the occurrence and development of human diseases including cancer and nurodegenerative diseases. Therefore, studying phase separation in the perspective of protein PTMs has long-term significance for human health. In this review, we summarized the properties and cellular physiological functions of LLPS, particularly its relationships with PTMs in human diseases according to recent researches.

Extensive research has established the benefits of incorporating low carbohydrate diets (LCDs) for managing obesity, diabetes, and metabolic syndrome (Mets). Recent findings indicate that LCDs could additionally impact cancer development and progression by creating an unfavorable metabolic micro-environment that promotes reprogrammed metabolism in cancer cells. This has led to LCDs being considered as a possible complementary treatment for cancer. Our review specifically examines the association between cancer risk, consumption of dietary carbohydrate, glycemic index (GI), and glycemic load (GL), with a focus on prostate, breast, and colorectal cancer. We also explore relevant mechanism underlying the potential anti-tumor effects of LCD diets, especially in gut microbiota modulation. However, findings in this area remain controversial, and further research is needed to evaluate their application in clinical practice. On the other hand, resistant starch (RS) has gained attention as a healthy and high-quality component of carbohydrate diets. It not only serves as a dietary fiber but also acts as a valuable source of prebiotics due to its ability to influence gut microbial composition, leading to improved metabolic control. This has positioned RS as a potential means for preventing and treating cancer. In this review, we also summarized the RS-gut microbiota-cancer risk axis to enhance our understanding of the health effects of RS consumption. From a clinical perspective, RS supplementation shows promise as a strategy for preventing diseases and managing cancer. It is evident that simply assessing the quantity of dietary carbohydrate intake may not be enough to determine cancer risk; the quality of carbohydrates should also be considered to draw definitive conclusions which will help clinician and nutritionist make a reasonable choice in management cancer.

Boreal peatlands are “hotspots” of net methylmercury (MeHg) production and may become drier in the future due to climate change. This study investigates a critical gap by analyzing the nuanced relationship between soil moisture content and the release of MeHg, inorganic mercury (IHg), sulfate (SO42-), and dissolved organic matter (DOM) in a laboratory incubation of boreal peat soils. Dried peat soils exhibited heightened releases of IHg, MeHg, and SO42- during re-wetting events. Both dried and saturated peat soils released more DOM than moist peat soils during re-wetting events, and DOM released from dried soils had higher bioaccessibility than that from the saturated soils (p

Cisplatin-based chemotherapy is the current standard care for lung cancer patients; however, drug resistance frequently develops during treatment, thereby limiting therapeutic efficacy.The molecular mechanisms underlying cisplatin resistance remain elusive. In this study, we conducted an analysis of microarray data from the Gene Expression Omnibus (GEO) database under the accession numbers GSE21656, which encompassed expression profiling of cisplatin-resistant H460 (DDP-H460)and the parental cells (H460). Subsequently, we calculated the differentially expressed genes (DEGs) between DDP-H460 and H460. Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of DEGs demonstrated significant impact on the Rap1, PI3K/AKT and MAPK signaling pathways. Moreover, protein and protein interaction (PPI) network analysis identified PRKCA, DET1, and UBE2N as hub genes that potentially contribute predominantly to cisplatin resistance. Ultimately, PRKCA was selected for validation due to its significant prognostic effect, which predicts unfavorable overall survival and disease-free survival in patients with lung cancer. Network analysis conducted on The Cancer Genome Atlas (TCGA) database revealed a strong gene-level correlation between PRKCA and TP53, CDKN2A, BYR2, TTN, KRAS, and PIK3CA; whereas at the protein level, it exhibited a high correlation with EGFR, Lck, Bcl2, and Syk. The in vitro experiments revealed that PRKCA was upregulated in the cisplatin-resistant A549 cells (DDP-A549), while knockdown of PRKCA increased DDP-A549 apoptosis upon cisplatin treatment. Moreover, we observed that PRKCA knockdown attenuated DDP-A549 proliferation, migration and invasion ability. Western blot analysis demonstrated that PRKCA knockdown downregulated phosphorylation of PI3K expression while upregulated the genes involved in ferroptosis signaling. In summary, our results elucidate the role of PRKCA in acquiring resistance to cisplatin and underscore its potential as a therapeutic target for cisplatin-resistant lung cancer.

Chronic obstructive pulmonary disease (COPD) is characterized by dyspnea caused by airflow limitation. Further development may lead to decreased lung function and other lung diseases. Pyroptosis is a type of programmed cell death that involves multiple pathways. For example, the pathway induced by the NLR family pyrin domain containing 3 (NLRP3) inflammasome is closely associated with COPD exacerbation. Therefore, in this study, various machine learning algorithms were applied to screen for diagnostically relevant pyroptosis-related genes from the GEO dataset, and the results were verified using external datasets. The results showed that deep neural networks and logistic regression algorithms had the highest AUC of 0.91 and 0.74 in the internal and external test sets, respectively. Here, we explored the immune landscape of COPD using diagnosis-related genes. We found that the infiltrating abundance of dendritic cells significantly differed between the COPD and control groups. Finally, the communication patterns of each cell type were explored based on scRNA-seq data. The critical role of significant pathways involved in communication between DCS and other cell populations in the occurrence and progression of COPD was identified.

Summary: Biological age could be reflective of an individual’s health status and aging degree. Limited estimations of biological aging based on physical examination data in the Chinese population have been developed to quantify the rate of aging. We developed and validated a novel aging measure (Balanced-AGE) based on readily available physical health examination data. In this study, a repeated sub-sampling approach was applied to address the data imbalance issue, and this approach significantly improved the performance of biological age (Balanced-AGE) in predicting all-cause mortality with a 10-year time-dependent AUC of 0.908 for all-cause mortality. This mortality prediction tool was found to be effective across different subgroups by age, sex, smoking, and alcohol consumption status. Additionally, this study revealed that individuals who were underweight, smokers, or drinkers had a higher extent of age acceleration. The Balanced-AGE may serve as an effective and generally applicable tool for health assessment and management among the elderly population.

Subpixel localization techniques for estimating the positions of point-like images captured by pixelated image sensors have been widely used in diverse optical measurement fields. With unavoidable imaging noise, there is a precision limit (PL) when estimating the target positions on image sensors, which depends on the detected photon count, noise, point spread function (PSF) radius, and PSF’s intra-pixel position. Previous studies have clearly reported the effects of the first three parameters on the PL but have neglected the intra-pixel position information. Here, we develop a localization PL analysis framework for revealing the effect of the intra-pixel position of small PSFs. To accurately estimate the PL in practical applications, we provide effective PSF (ePSF) modeling approaches and apply the Cramér–Rao lower bound. Based on the characteristics of small PSFs, we first derive simplified equations for finding the best PL and the best intra-pixel region for an arbitrary small PSF; we then verify these equations on real PSFs. Next, we use the typical Gaussian PSF to perform a further analysis and find that the final optimum of the PL is achieved at the pixel boundaries when the Gaussian radius is as small as possible, indicating that the optimum is ultimately limited by light diffraction. Finally, we apply the maximum likelihood method. Its combination with ePSF modeling allows us to successfully reach the PL in experiments, making the above theoretical analysis effective. This work provides a new perspective on combining image sensor position control with PSF engineering to make full use of information theory, thereby paving the way for thoroughly understanding and achieving the final optimum of the PL in optical localization.

Background: Multiparous women are at a higher risk of gestational diabetes mellitus (GDM) than primiparas. Physical activity during pregnancy has been shown to be beneficial for GDM, but there is little evidence on the association between physical activity and glycemic control among women with GDM, whether primiparas or multiparas. Thus, the objective of the present study was to examine the association between physical activity and glycemic control in women with GDM and to determine what, if any, effects result from number of parous events. Methods: A prospective cohort of 1162 women with GDM was recruited, with 604 multiparas (51.98%). The general linear model was used to calculate the risk difference and its 95% confidence interval (95%CI) to quantify the impact of parous events on glycemic control in pregnancy as well as the association between physical activity time and glycemic control. Results: Among 1162 women with GDM, the median daily activity time was 65 min (interquartile range (IQR): 45–90 min), and the abnormal plasma glucose (PG) percentage, calculated as number of abnormal PG tests divided by the total number of PG tests, was 40.00% (IQR: 22.22%–66.67%). The percentage of abnormal PG was stabilized and statistically lower with daily physical activity time exceeding 60 min among primiparas (IQR: 30.89%–44.43%) and exceeding 90 min among multiparas (ranged from 27.76% to 38.82%). After adjusting for potential confounders, primiparas tended to have a lower percentage of abnormal PG than do multiparas (rate difference = –0.39, 95%CI: –3.61 to 2.84). The same amount of physical activity time was significantly less effective for multiparas than for primiparas (trend p-value < 0.01). Conclusion: In women with GDM, being multiparous is associated with less effective glycemic control through physical activity, such that multiparas need more physical activity to achieve glycemic control at a similar level to primiparas.

Exploratory innovation is critical to the breakthrough of core technologies in the integrated circuit (IC) industry, and cooperative innovation is a promising form of IC industry development. According to the viewpoint of social network, this paper constructs intercity networks of the IC industry by using a data set of cooperation patents from 2011 to 2020 in China. We uncover the evolution characteristics of the innovation networks, explore the relationship between network centrality and exploratory innovation in a city, and consider universities and development zones, named support organizations, as moderating variables. The results of the social network analysis (SNA) and dynamic panel system generalized method of moments model (System-GMM) are given as follows: Cities are increasingly inclined to collaborate with counterparts over time for innovation, but the overall network scale remains small. Beijing occupies core position in the networks. A cooperative innovation model driven by peripheral cities has been formed as the number of the peripheral cities has gradually increased. The network centrality of a city has a positive effect on its exploratory innovation. Both universities and development zones positively moderate the effect of network centrality on exploratory innovation. Based on the characteristics of the network, our study reveals the importance of taking the internal structure of the network and the node support environment into the same framework, which provides guidance for the innovative development of the world IC industry.

Objectives: Vascular hyperpermeability by loss of endothelial barrier integrity is a hallmark of sepsis. Vimentin is involved in the regulation of the endothelial function and inflammatory response. However, the serum level of vimentin and its clinical relevance in pediatric severe sepsis (PSS) remain unknown. Methods: We conducted a prospective study of PSS cases who were admitted to the pediatric intensive care unit (PICU) from January 2018 to December 2020. Results: A total of 108 patients with PSS with a median age of 19.5 month were enrolled. The hospital mortality rate was 19.44% (21/108). Comparing with healthy controls, serum vimentin levels on PICU admission were significantly higher in patients with PSS (P < 0.001). The area under the ROC curve for vimentin to predict the hospital mortality was 0.712 (95% CI: 0.578–846) with a sensitivity of 71.43% and a specificity of 70.11%. Moreover, hospital mortality was significantly higher in patients with vimentin level over the cutoff value of 24.53 ng/ml than in patients with vimentin level below 24.53 ng/ml (P < 0.001). Conclusions: Serum vimentin level as an indicator of endothelial injury is associated with the prognosis of PSS, and serum vimentin level ≥24.53 ng/ml on PICU admission predicts high risk for hospital mortality in PSS.

Background: Insomnia is a common problem among patients with major depressive disorder (MDD). According to previous studies, the development and severity of Insomnia are influenced by childhood trauma experience. Furthermore, negative life events and dysfunctional attitudes may also mediate the impact. So, this study aimed to examine the association between childhood trauma, negative life events, dysfunctional attitudes and insomnia and investigate how negative life events and dysfunctional attitudes mediate the relationship between childhood trauma and insomnia in MDD. Method: This cross-sectional study recruited 621 college students with MDD. The Childhood Trauma Questionnaire (CTQ), Life Event Scale (LES), Dysfunctional Attitude Scale (DAS), Insomnia Severity Index (ISI), and Hamilton Depression Scale-17 (HAMD-17) were used to assess participants' psychosocial factors. Descriptive analysis, Chi-square test, t-test, Pearson correlations, and serial mediation analyses were used in data analysis. In order to eliminate the influence of the severity of depression symptoms, severity of depression symptoms was used as a control variable in this study. Results: There were 166 (26.7%) participants having clinical insomnia (ISI score > 14). After controlling for the effect of severity of depression symptoms, results of serial mediation analyses determined that childhood trauma has a direct (Estimate = 0.109, 95%CI: 0.023,0.190) and indirect (Estimate = 0.090, 95%CI: 0.054,0.137) impact to insomnia. The indirect impact of childhood trauma on insomnia through the pathways of negative life events alone (Estimate = 0.050, 95%CI: 0.024,0.093), dysfunctional attitudes alone (Estimate = 0.027, 95%CI: 0.008,0.050), and negative life events to dysfunctional attitudes (Estimate = 0.013, 95%CI: 0.006,0.024) were significant. Conclusions: This study demonstrates that screening for childhood trauma should be considered when treating insomnia in college students with MDD. Managing negative life events and dysfunctional attitudes may mitigate the negative impact of childhood trauma on insomnia in college students with MDD.

To overcome poor pharmacokinetics and toxicity of triptolide (TPL), a natural compound that exhibits potent anticancer activities, we developed a novel antibody-drug conjugate (ADC) to specifically deliver TPL to epidermal growth factor receptor (EGFR)-overexpressing non-small cell lung cancer (NSCLC) and others. The ADC (Cet-TPL) is made by conjugation of TPL to lysine residues of cetuximab (Cet), a clinically available anti-EGFR monoclonal antibody. Studies of antitumor efficacy demonstrated that Cet-TPL drastically suppressed in vitro proliferation and in vivo growth of these EGFR-overexpressing cancers, including NSCLC A549 and H1299 cells and two patient-derived xenografts, and head and neck squamous carcinoma UM-SCC6 cell, while it did not inhibit the proliferation and growth of NSCLC H520 that rarely expresses EGFR. Furthermore, immunofluorescence analysis revealed that Cet-TPL was effectively internalized and transported into lysosomes of EGFR-overexpressing cells. Cet-TPL effectively led to degradation of RNA polymerase II (Pol II) and demethylation of histone H3 lysines, and significantly induced apoptosis in these EGFR-overexpressing cancers. Compared with TPL, Cet, or their combination, Cet-TPL displayed higher target-specific cytotoxicity against EGFR-expressing cancers and much lower in vivo toxicity. In addition, Cet-TPL efficiently suppressed the activated EGFR pathway in UM-SCC6 cancer cells. Taken together, Cet-TPL represents a potent targeting therapeutic agent against EGFR-overexpressing NSCLC and others.

Background: Nowadays, increasing evidence has found transdiagnostic neuroimaging biomarkers across major psychiatric disorders (MPDs). However, it remains to be known whether this transdiagnostic pattern of abnormalities could also be seen in individuals at familial high-risk for MPDs (FHR). We aimed to examine shared neuroanatomical endophenotypes and protective biomarkers for MPDs. Methods: This study examined brain grey matter volume (GMV) of individuals by voxel-based morphometry method. A total of 287 individuals were included, involving 100 first-episode medication-naive MPDs, 87 FHR, and 110 healthy controls (HC). They all underwent high-resolution structural magnetic resonance imaging (MRI). Results: At the group level, we found MPDs were characterized by decreased GMV in the right fusiform gyrus, the right inferior occipital gyrus, and the left anterior and middle cingulate gyri compared to HC and FHR. Of note, the GMV of the left superior temporal gyrus was increased in FHR relative to MPDs and HC. At the subgroup level, the comparisons within the FHR group did not return any significant difference, and we found GMV difference among subgroups within the MPDs group only in the opercular part of the right inferior frontal gyrus. Conclusion: Together, our findings uncover common structural disturbances across MPDs and substantial changes in grey matter that may relate to high hereditary risk across FHR, potentially underscoring the importance of a transdiagnostic way to explore the neurobiological mechanisms of major psychiatric disorders.

Summary: The recent years have witnessed the emergence of high-throughput phenotyping techniques. In particular, these techniques can characterize a comprehensive landscape of physiological traits of plants responding to dynamic changes in the environment. These innovations, along with the next-generation genomic technologies, have brought plant science into the big-data era. However, a general framework that links multifaceted physiological traits to DNA variants is still lacking. Here, we developed a general framework that integrates functional physiological phenotyping (FPP) with functional mapping (FM). This integration, implemented with high-dimensional statistical reasoning, can aid in our understanding of how genotype is translated toward phenotype. As a demonstration of method, we implemented the transpiration and soil-plant-atmosphere measurements of a tomato introgression line population into the FPP-FM framework, facilitating the identification of quantitative trait loci (QTLs) that mediate the spatiotemporal change of transpiration rate and the test of how these QTLs control, through their interaction networks, phenotypic plasticity under drought stress.

Cancer is still a leading of cause of death worldwide. Among the bio-therapy strategies for cancer, vaccinia virus (VV) has been widely used as an expression vector because of its potent oncolytic activities in addition to its large capacity for insertion of foreign genes and excellent safety records. In the present study, a novel recombinant VV, VV-HBD2-lacZ, expressing human β-defensin 2 (HBD2), an anti-microbial peptide of the innate immune system, was constructed. First, the chemotaxis characteristics of HBD2 expressed on VV-HBD2-lacZ-infected cells toward dendritic cells (DCs) in vitro and in vivo were demonstrated. The anti-tumor effects of VV-HBD2-lacZ in vitro and in vivo in a mouse melanoma cancer model were then investigated. It was found that VV-HBD2-lacZ was able to inhibit tumor growth and metastasis significantly. It was further demonstrated that VV-HBD2-lacZ induced potent cytotoxic activity by increasing the tumor-infiltrating CD4+ and CD8+ T cells. These results indicate that HBD2-expressing VV recruited plasmacytoid DCs (pDCs) to the tumor location, leading to cytotoxic T cell response against the tumor, and thus inhibited tumor growth in vitro and in vivo. In conclusion, oncolytic HBD2-expressing VV provides an effective treatment for tumors by triggering innate and adaptive immunity. Keywords: vaccinia virus, human β-defensin 2, tumor vaccine, cancer immunity therapy

Organic pollutants in industrial and agricultural sewage are a serious threat to the environment and human health. Achieving continuous photocatalytic degradation of organic pollutants under light and dark conditions would have exciting implications for practical sewage treatment. In this paper, CuS/g-C3N4 composite catalysts with CuS nanoparticles anchored on g-C3N4 sheets were successfully fabricated via a simple solvothermal reaction. The morphology, structure, optical absorption characteristics, electron–hole recombination rate, and degradation performance of the as-prepared CuS/g-C3N4 catalysts were investigated in detail. The results confirmed that the as-fabricated CuS/g-C3N4 catalysts exhibited high Fenton-like catalytic degradation efficiencies in the dark, and rapid concerted Fenton-like catalytic, direct H2O2 photocatalytic and CuS/g-C3N4 photocatalytic degradation activities under visible light. Thus, the as-fabricated CuS/g-C3N4 catalysts can degrade organic pollutants continuously during both day and night. These degradation properties, along with the simple catalyst fabrication process, will facilitate the practical application of this system in the continuous removal of organic pollutants. Keywords: CuS/g-C3N4 composites, Fenton-like catalysis, Photocatalysis, Round-the-clock photocatalyst

Objective: Mycoplasma pneumoniae (MP) is the only pathogen in the Mycoplasma family that can cause respiratory symptoms, including acute upper respiratory tract infection and bronchitis, which are often attributed to Mycoplasma pneumoniae pneumonia (MPP). MPP is one of the diseases that commonly affects the pediatric respiratory system, but its pathogenesis is unclear. This study investigated the therapeutic effects and mechanisms of Qingxuan Tongluo formula and its main component, curcumin, on MPP. Methods: A mouse model of MPP was obtained by nasal drip of the MP strain. The effects of Qingxuan Tongluo formula and curcumin on the treatment of MPP were studied. The proteomic profiles of the alveolar lavage fluid of mice in the model group, Qingxuan Tongluo formula group and curcumin group were evaluated by LC–MS/MS. ELISA and immunohistochemistry were used to verify the possible presence of MP infection biomarkers and drug target proteins. Results: Compared with the mice in the model group, the MPP mice in the Qingxuan Tongluo formula group had significantly reduced fever and cough and prolonged the cough incubation period. Moreover, the pulmonary pathology of the MPP mice was significantly improved, and the lung histopathological score was decreased. After treatment with Qingxuan Tongluo formula and curcumin, the functional and pathway abnormalities caused by MP were mainly inhibited. Levels of HSP90AA1, GRP94, ENO1 and PLG expression were verified by ELISA and immunohistochemistry. Conclusion: Qingxuan Tongluo formula significantly reduced fevers and cough and prolonged the cough incubation period of MPP mice. Qingxuan Tongluo formula and curcumin significantly improved the pathological changes in lung tissue caused by MP infection. Proteomics analyses indicated that Qingxuan Tongluo formula and curcumin may have therapeutic effects on MPP by regulating energy metabolism, relieving oxidative stress and activating the fibrinolytic system. ENO1 and PLG were found to be potential drug targets.

Background: With the diffusion of SARS-CoV-2 around the world, human health is being threatened. As there is no effective vaccine yet, the development of the vaccine is urgently in progress. Materials and methods: Immunoinformatics methods were applied to predict epitopes from the Spike protein through mining literature associated with B- and T-cell epitopes prediction published or preprinted since the outbreak of the virus till June 1, 2020. 3D structure of the Spike protein were obtained (PDB ID: 6VSB) for prediction of discontinuous B-cell epitopes and localization of epitopes in the hotspot regions. Results: Methods provided by the Immune Epitope Database (IEDB) server were the most frequently used to predict epitopes. Sequence alignment of the epitopes extracted from literature with the Spike protein demonstrated that the epitopes in different studies converged to multiple short hotspot regions. There were three hotspot regions found in RBD of the Spike protein harboring B-cell linear epitopes (‘RQIAPGQTGKIADYNYKLPD’, ‘SYGFQPTNGVGYQ’ and ‘YAWNRKRISNCVA’) predicted to have high antigenicity score. Two T-cell epitopes (‘KPFERDISTEIYQ’ and ‘NYNYLYRLFR’) predicted to be highly antigenic in the original studies were discovered in the hotspot region. Toxicity and allergenicity analysis confirmed all the five epitopes are of non-toxin, and four of them are of non-allergen. The five epitopes identified in hotspot regions of RBD were found fully exposed based on the 3D structure of the Spike protein. Conclusion: The five epitopes we discovered from literature mining may be potential candidates for diagnostics and vaccine development against SARS-CoV-2.

B lymphocyte-induced maturation protein-1 (Blimp1) is a key regulator that promotes the terminal differentiation of mature B lymphocytes into plasma cells, and is essential for the survival of Multiple myeloma (MM)cells. However, the expression of Blimp1 in MM and its effect on the signaling pathway remain unknown. Studies have found that during long-term endoplasmic reticulum (ER) stress, activated ATF4 may also stimulate the CCAAT-enhancer-binding protein homologous protein (CHOP) gene, triggering the unfolded protein response (UPR) terminal apoptotic pathway in plasma cells. Moreover Aspirin can induce MM cell apoptosis through mitochondria and death receptor pathway. Therefore, we aim to explore whether Aspirin could induce AFT4/CHOP apoptosis pathway in MM by inhibiting Blimp1 expression, thereby promoting MM cell apoptosis and exerting anti-tumor effects.

Myostatin (MSTN) gene negatively controls skeletal muscle development and growth, variations of which play an important role in the regulation of skeletal muscle growth in mammals. However, study on genetic polymorphism ofMSTN gene in donkey is limited. In this study, we screened the single nucleotide polymorphsims (SNPs) ofMSTN gene in 13 Chinese donkey breeds. Four novel SNPs (g.229T>C, g.872A>G, g.2014G>A, and g.2395C>G) were detected and genotyped by sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methods. Six haplotypes (H1-H6) were analyzed, which indicated abundant haplotype diversities in Chinese donkeys. The haplotype H1 was the most dominant and ancient in all breeds. Xinjiang donkey displayed the highest haplotype diversity. The Neighbour-Joining (NJ) tree ofMSTN gene among different species was constructed. The clustering result of nine species was consistent with the fact of species differentiation. Our results will provide a reliable theoretical basis for the preservation, exploration and utilization of Chinese donkey genetic resources.

Objective: Diabetes mellitus is associated with gut microbiota disturbance and intestinal mucosal injuries. This study investigated the influence of propolis on the gut microbiota and intestinal mucosa in rats with diabetes. Methods: Sprague-Dawley (SD) rats were randomly assigned to the control group, model group, and three propolis groups (supplemented with 80, 160, and 240 mg/kg·bw propolis, respectively). A high-fat diet combined with a streptozotocin (STZ) abdominal injection were used to induce diabetes in the rats. After 4 weeks, the intestinal histopathological analysis of the ileum was observed by transmission electron microscopy. The fasting blood glucose (FBG), plasma insulin, glucose tolerance (OGTT) and glycosylated hemoglobin (HbA1c) levels were measured. The expression of tight junction (TJ) proteins in the ileum was measured using western blotting. The molecular ecology of the fecal gut microbiota was analyzed by 16S rDNA high-throughput sequencing. The contents of the short-chain fatty acids (SCFAs) in feces were measured using high-performance liquid chromatography (HPLC). Results: After propolis treatment, compared to the model group, FBG and HbA1c levels declined, while the glucose tolerance and insulin sensitivity index (ISI) increased. The levels of TJ proteins in the ileum increased in the propolis groups. The tight junctions and gap junctions of the intestinal epithelium were also improved in the propolis groups. The contents of the feces acetic acid, propionic acid and butyrate were increased in the propolis groups. 16S rDNA high-throughput sequencing revealed that the composition of the gut microbiota of rats in the propolis supplement group was significantly improved. Conclusions: Compared to the model group, propolis exerted hypoglycemic effects in diabetic rats, and it repaired intestinal mucosal damage, benefited the communities of the gut microbiota and increased SCFA levels in diabetic rats.

N6-methyladenosine (m6A), the most abundant internal modification of RNA in eukaryotic cells, has gained increasing attention in recent years. The m6A modification affects multiple aspects of RNA metabolism, ranging from RNA processing, nuclear export, RNA translation to decay. Emerging evidence suggests that m6A methylation plays a critical role in cancer through various mechanisms. Moreover, m6A methylation has provided more possibilities for the early diagnosis and treatment of cancers. In this review, we focus on m6A-associated mechanisms and functions in several major malignancies and summarize the dual role of m6A methylation as well as its prospects in cancer.

With the increasing prevalence of obesity, childhood type 2 diabetes (T2D) is a growing concern in Taiwan. Unlike its adult counterpart, T2D in children exhibits a more aggressive nature and earlier onset of complications. Metformin represents the first line of drug, but if blood sugar levels do not improve, other drugs are used. This retrospective cohort study endeavors to scrutinize and assess the pattern of treatment modification and associate factors among 79 young people with T2D in Taiwan.The study categorized participants into three distinct groups based on their treatment trajectory and outcomes: (1) those maintaining metformin (n = 34); (2) cases achieving remission (n = 7); and (3) individuals experiencing escalation through oral drugs or insulin (n = 38). The average follow-up period spanned 3.48 years. Findings from univariate analysis using a Cox proportional hazards model and propensity score weighting revealed that HbA1c and weight gain correlated with elevated risk of treatment escalation. Conversely, factors such as hypertension, high weight or body mass index (BMI) SDS, leptin levels, c-peptide concentrations, peak c-peptide values during glucagon stimulation test and LDL-cholesterol levels were associated with reduced risk of escalation. However, in multivariate analyses employing stepwise selection, the sole predictive factor for treatment escalation emerged as weight gain one year post-therapy (HR: 1.06, p

Background: The ZnT8 autoantibody is used to independently diagnose type 1 diabetes (T1D) and as a prediction factor in high-risk populations. This is the first report in Taiwan on the prevalence, diagnostic utility, and clinical characteristics of zinc transporter 8 autoantibody (ZnT8A) in children with T1D. Methods: We performed a retrospective analysis of 268 children (130 boys, 138 girls) newly diagnosed with T1D at three hospitals in North Taiwan from February 1994 to August 2021. Results: ZnT8A was detected in 117 patients (43.7 %). The combined diagnostic rate of the four antibodies, including glutamic acid decarboxylase autoantibody (GADA), islet antigen 2 autoantibody (IA2A), insulin autoantibody (IAA), and ZnT8A, can reach 86.19 % while that of the original three antibodies is 84.3 %. IA2A (64.9 %) showed the highest positive rate, followed by GADA (64.2 %), ZnT8A (43.7 %), and IAA (22.0 %). Of the 268 patients, five (1.9 %) were only ZnT8A+. All antibodies were positive in 19 (7.1 %) people, whereas 37 others (13.8 %) had all antibodies negative. ZnT8A has the strongest relationship with IA2A. 5 patients had ZnT8A positive only. 5/(37 + 5) (about 12 %) T1D patients were diagnosed by ZnT8A testing. Conclusions: ZnT8A testing can diagnose up to 12 % more patients with T1D along with three other antibodies. Furthermore, since the ZnT8A titer decreased over time, it should be tested within six months of onset in Taiwanese patients with T1D.

Ischemic heart disease (IHD) is a significant global health concern, resulting in high rates of mortality and disability among patients. Although coronary blood flow reperfusion is a key treatment for IHD, it often leads to acute myocardial ischemia-reperfusion injury (IRI). Current intervention strategies have limitations in providing adequate protection for the ischemic myocardium. DJ-1, originally known as a Parkinson's disease related protein, is a highly conserved cytoprotective protein. It is involved in enhancing mitochondrial function, scavenging reactive oxygen species (ROS), regulating autophagy, inhibiting apoptosis, modulating anaerobic metabolism, and exerting anti-inflammatory effects. DJ-1 is also required for protective strategies, such as ischemic preconditioning, ischemic postconditioning, remote ischemic preconditioning and pharmacological conditioning. Therefore, DJ-1 emerges as a potential target for the treatment of myocardial IRI. Our comprehensive review delves into its protective mechanisms in myocardial IRI and the structural foundations underlying its functions.

Background: Septic shock is the progression of sepsis, defined as cardiovascular dysfunction during systemic infection, and it has a mortality rate of 40 %–80 %. Loss of vascular tone is an important pathophysiological feature of septic shock. Diastolic blood pressure (DBP) was reported to be associated with vascular tone. This study aimed to identify the associations of several hemodynamic indices, especially DBP, with outcome in pediatric septic shock to allow for timely interventions. Methods: Children with persistent catecholamine-resistant shock had a pulse index continuous cardiac output (PiCCO®) system implanted for invasive hemodynamic monitoring and were enrolled in the current study. Serial cardiac index, systemic vascular resistance index (SVRI), systolic blood pressure (SBP), mean arterial pressure (MAP), and DBP were recorded during the first 24 h following PiCCO® initiation. All hemodynamic parameters associated with 28-day mortality were further analyzed using receiver operating characteristic curve analysis. Results: Thirty-three children with persistent catecholamine-resistant shock were enrolled. The median age was 12 years and the youngest children were 5 years old. Univariate analysis noted that SVRI, SBP, MAP, and DBP were significantly higher, and shock index was significant lower, in survivors compared with non-survivors (p 0.75, indicating a good prediction for mortality. Conclusions: DBP correlated well with SVRI and it can serve as a predictor for mortality in pediatric septic shock. Furthermore, DBP was a superior discriminator of mortality when compared with SBP and MAP. A lower DBP was an independent hemodynamic factor associated with 28-day mortality.

Objective: The POSEIDON criteria stratified patients with poor ovarian response into four subgroups with exclusive characteristics and assisted reproductive technology success rates. However, limited studies focused on miscarriage in the POSEIDON population. This study aimed to explore whether the miscarriage rate different among low prognosis patients according to POSEIDON criteria. Materials and methods: This is a retrospective observational study. All clinical pregnancies achieved after in vitro fertilization or intracytoplasmic sperm injection treatment between January 1998 and April 2021 were analyzed. The primary outcome was miscarriage, defined as the pregnancy loss before 20 weeks of gestation age. Miscarriage rate was estimated per clinical pregnancy and gestational sac. Results: A total of 1222 clinical pregnancies from 1088 POSEIDON patients met the inclusion criteria. The miscarriage rates per clinical pregnancy in each POSEIDON subgroup were as follows: Group 1: 11.7 %, Group 2: 26.5 %, Group 3: 20.9 %, and Group 4: 37.5 %. The miscarriage rate per gestational sac showed a similar trend as the clinical miscarriage rate. Multivariate regression analysis showed that advanced maternal age is an independent factor for miscarriage (Group 2 vs. 1: OR 2.476; Group 4 vs. 3: OR 2.252). Patients with diminished ovarian reserve (DOR) have higher miscarriage risks but without significance (Group 3 vs. 1: OR 1.322; Group 4 vs. 2: OR 1.202). Conclusion: Miscarriage rates differed among low prognosis patients according to the POSEIDON criteria. Age remains a determined risk for miscarriage. DOR might be a potential factor for miscarriage, but it didn't account for a significant impact in POSEIDON patients.

Objective: While many studies agree that the fetal birth weight is higher after frozen embryo transfer (FET), few studies have explored the difference in fetal weight change during such pregnancies. This cohort study was to identify the difference in fetal birth weight and gestational age at birth between singletons born following fresh ET and those born following FET. Materials and methods: This was a hospital-based cohort study using clinical data from the Kaohsiung Chang Gung Memorial Hospital Obstetric and Neonatal Database from January 1, 2007, to December 1, 2018. A sample of 784 eligible women who had singleton pregnancies and live-born deliveries after 428 fresh ET or 356 FET between January 2007 and December 2018. Results: Compared with those in the fresh ET group, singletons in the FET group had higher birth weight (3137 g [2880–3441 g] vs. 3060 g [2710–3340 g], p

Background: The presence of only morphologically poor embryos (MPEs) on day3 is common in autologous in vitro fertilization (IVF), particularly among p Tel: 886-7-7317123 Ext. 8916. Fax: 886-7-7322915.atients who have advanced maternal age or are poor responders. However, there are limited data regarding the disposition of embryos from patients who only produced MPEs on day3. The present study was designed to investigate the possible benefits of extended culturing MPEs. Try to detect whether the extended culture (day4 or day5 culture) can improve the live birth rate per cycle? Methods: This retrospective, observational, single-center, cohort study examined 224 IVF/intracytoplasmic sperm injection (ICSI) cycles between January 2010 and June 2015, in which women only produced MPEs on day3. A total of 544 MPEs were analyzed. The defines a day3 embryo as an MPE if it fails to develop to eight cells, blastomeres of equal size, and less than 20% cytoplasmic fragments. Of the 224 cycles, 89 (39.7%) underwent fresh embryo transfer on day3, and 135 (60.3%) underwent extended culture. Of the 135 extended cultures, 54 cycles (40.0%) experienced day4, or day5 embryo transfer, 16 cycles (11.9%) had all embryos frozen, and 65 cycles (48.1%) had total embryo arrest. Results: Analysis of patient baseline demographic data, cycle characteristics, and cycle outcomes for day3 transfer group and extended culture group indicated that a higher body mass index in the day3 transfer group was the only significant difference (p = 0.006). Both fresh transfer groups had low live birth rates (LBRs) (4.5% vs. 7.4% p = 0.46). After extended culture, 65 cycles (48.1%) were cancelled because the embryos exhibited developmental arrest and 70 cycles (51.9%) grew to day4 or day5. Thirteen frozen embryo transfer (FET) cycles and 22 frozen blastocysts derived from MPEs were thawed. There were more high-quality embryos (p

Background: Previous studies have demonstrated that high levels of estradiol (E2) impair blastocyst implantation through effects on the endometrium; however, whether high E2 directly affects blastocysts is not well established. The present study sought to clarify the direct impacts of high E2 levels on blastocysts in vitro. Methods: ICR virgin albino mice were used. Using an in-vitro 8-day blastocyst culture model, immunofluorescence staining for the estrogen receptor (ER), blastocyst outgrowth assays, differential staining and TUNEL assays of blastocysts, and embryo transfer, we investigated the main outcomes of exposure to different E2 concentrations (10−7 to 10−4 M) in vitro and in vivo. Results: ERα and ERβ expression were detected in pre-implantation stage embryos. In vitro exposure of blastocysts to 10−4 M E2 for 24 h followed by 7 days culture in the absence of E2 caused severe inhibition of implantation and post-implantation development. The late adverse effects of E2 on post-implantation development still occurred at concentrations of 10−7 to 10−5 M. In addition, blastocyst proliferation was reduced and apoptotic cells were increased following exposure to 10−4 M E2. Using an in vivo embryo-transfer model, we also showed that treatment with high E2 resulted in fewer implantation sites (38% vs. 72% in control) and greater resorption of implanted blastocysts (81% vs. 38% in control). Conclusion: Exposure to high E2 concentrations in vitro is deleterious to blastocyst implantation and early post-implantation development, mainly owing to direct impacts of E2 on implanting blastocysts. In clinical assisted reproductive technique (ART), high serum E2 concentrations not only affects the endometrium, but also affects blastocysts directly at the period of implantation.

Background: This study aims to investigate the antimicrobial ability and mechanism analysis of Lactobacillus species against carbapenemase-producing Enterobacteriaceae (CPE). Methods: Five Lactobacillus spp. strains and 18 CPE clinical isolates were collected. Their anti-CPE effects were assessed by agar well diffusion and broth microdilution assay, as well as time-kill test. Finally, the specific anti-CPE mechanism, especially for the effect of organic acids was determined using broth microdilution method. Results: All of five Lactobacilli isolates displayed the potent activity against most CPE isolates with mean zones of inhibition ranging 10.2–21.1 mm. The anti-CPE activity was not affected by heating, catalase, and proteinase treatment. Under the concentration of 50% LUC0180 cell-free supernatant (CFS), lactic acid, and mix acid could totally inhibit the growth of carbapenem-resistant Klebsiella pneumoniae (CPE0011), and acetic acid could inhibit 67.8%. In contrast, succinic acid and citric acid could not inhibit the growth of CPE0011. While we decreased the concentration to 25%, only lactic acid and mix acid displayed 100% inhibition. In contrast, succinic acid, citric acid and acetic acid did not show any inhibitory effect. Conclusions: Lactobacillus strains exhibit potent anti-CPE activity, and lactic acid produced by Lactobacillus strains is the major antimicrobial mechanism.