Perinatal complications and neonatal outcomes in in vitro fertilization/intracytoplasmic sperm injection: a propensity score matching cohort study.

Background: The utilization of in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) has witnessed a significant increase in recent years. However, the comparative perinatal and neonatal outcomes compared to natural pregnancies are unclear. This study aims to compare the outcomes of pregnancies from IVF and ICSI with natural pregnancies. Methods: This retrospective, propensity score-matched cohort study was conducted at the First People's Hospital of Shangqiu and The First Affiliated Hospital of Xinjiang Medical University, involving 5,628 patients from February 2019 to December 2022. It compared pregnancies achieved through IVF/ICSI with those conceived naturally. The primary outcomes assessed were perinatal complications and neonatal health parameters. Propensity score matching and multivariate logistic regression analysis were employed to adjust for potential confounders and identify independent associations. Results: After propensity score matching, the IVF/ICSI group demonstrated significantly higher rates of placental adherence (12.1% vs. 7.4%, p < 0.001) and postpartum hemorrhage (11.1% vs. 7.6%, p = 0.002) compared to the NP group. Neonates in the IVF/ICSI group had a lower gestational age (38.21 ± 2.12 weeks vs. 38.63 ± 2.29 weeks, p < 0.001), reduced birth weight (3159.42 ± 722.75 g vs. 3211.31 ± 624.42 g, p = 0.032), and an increased preterm delivery rate (11.2% vs. 8.9%, p = 0.017). Multivariate analysis further confirmed these findings, highlighting the independent associations between IVF/ICSI and these adverse outcomes. Conclusion: This study suggests a potential correlation between the use of IVF/ICSI and unfavorable perinatal and neonatal outcomes. These findings underscore the critical need for ongoing monitoring and research efforts to enhance the safety and effectiveness of these reproductive technologies.

Distinct maturation, glucose metabolism, and inflammatory function of human monocytes-derived IDECs mediated by anti-IgE and Pam3CSK4 alone or in combination.

Background: Cell energy metabolism controls the activation and function of dendritic cells (DCs). Inflammatory dendritic epidermal cells (IDECs) in skin lesions of atopic dermatitis (AD) express high-affinity IgE receptor (FcϵRI) and toll-like receptor 2 (TLR2), which mediate the generation and maintenance of inflammation. However, cellular energy metabolism and effector function of IDECs mediated by FcϵRI and TLR2 have not been fully elucidated. Methods: IDECs in vitro were treated with TLR2 agonist Pam3CSK4 and anti-IgE alone or in combination for 24 h. Further, we analyzed the expression of cell surface activation markers, production of inflammatory factors, and cellular energy metabolism profiles of IDECs by using flow cytometry, multiplex assay, RNA sequencing, targeted energy metabolism, and seahorse assays. Results: Compared to the unstimulated or anti-IgE groups, Pam3CSK4 alone or combined with anti-IgE groups significantly increased the expression of CD80, CD83, and CD86 on IDECs, but did not affect the expression of the above markers in the anti-IgE group. The release of inflammatory cytokines increased in the Pam3CSK4 alone or combined with anti-IgE groups, while there was a weak increasing trend in the anti-IgE group. The glycolysis/gluconeogenesis pathway of carbon metabolism was affected in all treatment groups. Furthermore, compared to the control group, we found a decrease in pyruvic acid, upregulation of PFKM, downregulation of FBP1, and increase in extracellular lactate, glycolysis rate, and glycolysis capacity after all treatments, while there was no difference between each treatment group. However, there was no difference in glycolytic reserve and mitochondrial basic and maximum respiration among all groups. Conclusion: Our results indicate that glycolysis of IDECs may be activated through FcϵRI and TLR2 to upregulate inflammatory factors, suggesting that danger signals from bacteria or allergens might evoke an inflammatory response from AD through the glycolysis pathway.

Photo-induced decarboxylative C-S bond formation to access sterically hindered unsymmetric S-alkyl thiosulfonates and SS-alkyl thiosulfonates.

Due to the high reactivity and versatility of benzenesulfonothioates, significant advancements have been made in constructing C-S bonds. However, there are certain limitations in the synthesis of S-thiosulfonates and SS-thiosulfonates, especially when dealing with substantial steric hindrance, which poses a significant challenge. Herein, we present an innovative approach for assembling unsymmetric S-thiosulfonates and unsymmetric SS-thiosulfonates through the integration of dual copper/photoredox catalysis. Moreover, we also realized the one-pot strategy by directly using carboxylic acids as raw materials by in-situ activation of them to access S-thiosulfonates and SS-thiosulfonates without further purification and presynthesis of NHPI esters. The envisaged synthesis and utilization of these reagents are poised to pioneer an innovative pathway for fabricating a versatile spectrum of mono-, di-, and polysulfide compounds. Furthermore, they introduce a class of potent sulfenylating reagents, empowering the synthesis of intricate unsymmetrical disulfides that were previously challenging to access.

Evolutionary Sparsity Regularisation-based Feature Selection for Binary Classification.

In classification, feature selection is an essential pre-processing step that selects a small subset of features to improve classification performance. Existing feature selection approaches can be divided into three main approaches: wrapper approaches, filter approaches, and embedded approaches. In comparison with two other approaches, embedded approaches usually have better trade-off between classification performance and computation time. One of the most well-known embedded approaches is sparsity regularisation-based feature selection which generates sparse solutions for feature selection. Despite its good performance, sparsity regularisation-based feature selection outputs only a feature ranking which requires the number of selected features to be predefined. More importantly, the ranking mechanism introduces a risk of ignoring feature interactions which leads to the fact that many top-ranked but redundant features are selected. This work addresses the above problems by proposing a new representation that considers the interactions between features and can automatically determine an appropriate number of selected features. The proposed representation is used in a differential evolutionary (DE) algorithm to optimise the feature subset. In addition, a novel initialisation mechanism is proposed to let DE consider various numbers of selected features at the beginning. The proposed algorithm is examined on both synthetic and real-world datasets. The results on the synthetic dataset show that the proposed algorithm can select complementary features while existing sparsity regularisation-based feature selection algorithms are at risk of selecting redundant features. The results on real-world datasets show that the proposed algorithm achieves better classification performance than well-known wrapper, filter, and embedded approaches. The algorithm is also as efficient as filter feature selection approaches.

Atavistic strategy for the treatment of hyperuricemia via ionizable liposomal mRNA.

Hyperuricemia is associated with an increased risk of gout, hypertension, diabetes, and cardiovascular diseases. Most mammals maintain normal serum uric acid (SUA) via urate oxidase (Uox), an enzyme that metabolizes poorly-soluble UA to highly-soluble allantoin. In contrast, Uox became a pseudogene in humans and apes over the long course of evolution. Here we demonstrate an atavistic strategy for treating hyperuricemia based on endogenous expression of Uox in hepatocytes mediated by mRNA (mUox) loaded with an ionizable lipid nanoparticle termed iLAND. mUox@iLAND allows effective transfection and protein expression in vitro. A single dose of mUox@iLAND lowers SUA levels for several weeks in two female murine models, including a novel long-lasting model, which is also confirmed by metabolomics analysis. Together with the excellent safety profiles observed in vivo, the proposed mRNA agent demonstrates substantial potential for hyperuricemia therapy and the prevention of associated conditions.

Application of a newly constructed NGS panel with 45 X-linked microhaplotypes demonstrates the unique value of X-MH for kinship testing and mixture analysis.

X-linked microhaplotypes (X-MHs) have the potential to be a valuable supplementary tool in complex kinship identification or the resolution of DNA mixtures, because they bring together the distinctive genetic pattern of X chromosomal markers and the benefits of microhaplotypes (MHs). In this study, we used the 1000 Genome database to screen and select 63 X-MHs; 18 MHs were filtered out though a batch sequencing assessment of the DNA samples collected from 112 unrelated Chinese Han individuals. The resulting 45-plex panel performed well in comprehensive assessments including repeatability, sensitivity, species specificity, resistance to PCR inhibitors or degradation, mutation rate, and accuracy in detecting DNA mixture samples. The minimum amount of DNA template that can be tested with this panel is 0.5 ng. Additionally, the alleles of the minor contributor can be accurately detected when the mixture rate is larger than 1:9 in female-male mixture or 1:19 in male-male mixture. Then, we calculated population parameters on each MH based on the allele frequency data obtained from the sequence results of the aforementioned 112 unrelated samples. Combining these parameters on each MH, it can be calculated that TDPm, TDPf, CPET, CPEDFM, CPEDFF and CNCEP3 of the 45-plex system were 1-8.99×10-13, 1-1.62×10-19, 0.9999999995, 0.9999981, 0.9955, 0.9999971 and 0.99940, respectively, indicating that the panel is capable in personal identification and parentage testing. To reveal the unique advantage of X-MHs in the analyses of complex kinship and male DNA mixture, further assessments were made. For complex kinship identification, 22 types of individual pairs with different second-degree kinship were simulated and different types of likelihood ratios (LR) were calculated for each. The results revealed that the panel can achieve accuracy of approximately 70 %∼80 % when dividing each of the three types of second-degree kinships into three or four groups. Theoretically, such sub-division cannot be done by using independent autosomal markers. For male DNA mixture analysis without suspects, the maximum likelihood ratio strategy was derived and employed in the estimation of the number of male contributors (NOMC). Simulations were conducted to verify the efficacy of the 45-plex panel in the field and to compare it with autosomal markers by assuming the 45 MHs as autosomal ones. The results showed that X-MHs can achieve higher accuracy in the estimation of NOMC than autosomal ones when the mixed males were unrelated. The results highlighted the unique value of X-linked MHs in complex kinship and male mixture analyses.

Dual-Responsive Epigenetic Inhibitor Nanoprodrug Combined with Oncolytic Virus Synergistically Boost Cancer Immunotherapy by Igniting Gasdermin E-Mediated Pyroptosis.

Cancer immunotherapy has emerged as a promising approach for the treatment of various cancers. However, the immunosuppressive tumor microenvironment (TME) limits the efficacy of current immunotherapies. In this study, we designed a dual-responsive DNA methyltransferase inhibitor nanoprodrug ACNPs for combination therapy with oncolytic herpes simplex virus (oHSV). We found that the epigenetic inhibitor 5-Azacytidine (5-Aza) upregulated gasdermin E (GSDME) expression at the gene level, whereas the oHSV decreased the ubiquitination and degradation of GSDME to elevate its levels. Based on these observations, we further discovered that ACNPs and oHSV synergistically enhanced GSDME-mediated pyroptosis. Additionally, the combination therapy of ACNPs and oHSV effectively inhibited tumor growth, remodeled the immunosuppressive TME, and improved the efficacy of immune checkpoint blockade (ICB) therapy. These results demonstrate the potential to overcome immunosuppression through synergistic combinations, offering a promising approach for cancer immunotherapy.

Dysregulated Wnt/ß-catenin signaling confers resistance to cuproptosis in cancer cells.

Cuproptosis is characterized by the aggregation of lipoylated enzymes of the tricarboxylic acid cycle and subsequent loss of iron-sulfur cluster proteins as a unique copper-dependent form of regulated cell death. As dysregulation of copper homeostasis can induce cuproptosis, there is emerging interest in exploiting cuproptosis for cancer therapy. However, the molecular drivers of cancer cell evasion of cuproptosis were previously undefined. Here, we found that cuproptosis activates the Wnt/ß-catenin pathway. Mechanistically, copper binds PDK1 and promotes its interaction with AKT, resulting in activation of the Wnt/ß-catenin pathway and cancer stem cell (CSC) properties. Notably, aberrant activation of Wnt/ß-catenin signaling conferred resistance of CSCs to cuproptosis. Further studies showed the ß-catenin/TCF4 transcriptional complex directly binds the ATP7B promoter, inducing its expression. ATP7B effluxes copper ions, reducing intracellular copper and inhibiting cuproptosis. Knockdown of TCF4 or pharmacological Wnt/ß-catenin blockade increased the sensitivity of CSCs to elesclomol-Cu-induced cuproptosis. These findings reveal a link between copper homeostasis regulated by the Wnt/ß-catenin pathway and cuproptosis sensitivity, and suggest a precision medicine strategy for cancer treatment through selective cuproptosis induction.

Manure enriched with nitrogen derived from high-protein food waste in a large dining facility.

Food waste (FW) from large dining facility has been a pressing environmental challenge in China recently. This study developed an innovative species-specific feeding strategy for producing pigeon meat and excellent manure from FW. Adding FW to the feed of pigeons significantly increased their feed intake and promoted their growth although the pigeons showed a strong aversion to the FW. We produced a "super manure" with exceptionally high nitrogen (N) content (mean = 10.77 % on a dry basis, 8.04-12.57 %, n = 264) by feeding slowly-growing pigeon species (Columba livia vs. and Caoge Huzhou 11) with protein-high commercial feed and FW. A significant negative relationship between the N and carbon (C) contents in the pigeon manure was found, with C depletion higher than N depletion. Furthermore, the N content in the anaerobic composting (AnC) manure was 29.16 % higher than that in the FW. Fourier transform infrared (FT-IR) analysis and stable isotopes δ13C and δ15N in the manure clearly identified the transformations of nutrients during pigeon feeding and the AnC process. This study opens a path for producing N-high manure using protein-high food waste.

Ferroptosis: A novel therapeutic target of natural products against doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX), a commonly used chemotherapy drug, is hindered due to its tendency to induce cardiotoxicity (DIC). Ferroptosis, a novel mode of programmed cell death, has received substantial attention for its involvement in DIC. Recently, natural product-derived ferroptosis regulator emerged as a potential strategy for treating DIC. In this review, a comprehensive search was conducted across PubMed, Web of Science, Google Scholar, and ScienceDirect databases to gather relevant articles on the use of natural products for treating DIC in relation to ferroptosis. The available papers were carefully reviewed to summarize the therapeutic effects and underlying mechanisms of natural products in modulating ferroptosis for DIC treatment. It was found that ferroptosis plays an important role in DIC pathogenesis, with dysregulated expression of ferroptosis-related proteins strongly implicated in the condition. Natural products, such as flavonoids, polyphenols, terpenoids, and quinones can act as GPX4 activators, Nrf2 agonists, and lipid peroxidation inhibitors, thereby enhancing cell viability, attenuating myocardial fibrosis, improving cardiac function, and suppressing ferroptosis in both in vitro and in vivo models of DIC. This review demonstrates a strong correlation between DOX-induced cardiac ferroptosis and key proteins, such as GPX4, Keap1, Nrf2, AMPK, and HMOX1. Natural products are likely to exert therapeutic effects against DIC by modulating the activity of these proteins.

Recent Advances of Neoadjuvant Immunotherapy for Urothelial Bladder Cancer.

Urothelial bladder cancer is one of the most common malignant tumors of the urinary system, which accounts for 90~95% of urothelial carcinoma. Despite the current standard neoadjuvant management for localized urothelial MIBC (T2-4cN0M0) is cisplatin-based chemotherapy before radical cystectomy, there still had poor performances and less overall survival benefits in patients with localized urothelial MIBC. Moreover, nearly half of MIBC patients were ineligible for receiving cisplatin because of chronic kidney disease and performance status. Although immunotherapy, immune checkpoint inhibitors (ICIs) has been identified as first or second-line treatments for localized and metastasis bladder cancer based on less adverse reactions and favorable outcomes, neoadjuvant immunotherapy had rarely used for the treatment of these patients because of less large-scale clinical randomized studies and limited outcomes. Therefore, we reviewed the advances of efficacy and safety with neoadjuvant immunotherapy for urothelial bladder cancer depended on published articles and clinical studies, which could provide more theoretical evidences and promising strategy for clinical therapeutic development.

Soft tissue inflammation around upper third molar cause limited mouth opening: common but overlooked.

OBJECTIVES: The aim of this study was to explore inflammation of soft tissue around the upper third molar as a prevalent cause of limited mouth opening, identify the clinical and radiographic features, and summarize the therapeutic effectiveness of tooth extraction. MATERIALS AND METHODS: A retrospective analysis of data from 264 patients with limited mouth opening over the last five years was performed. RESULTS: Among the 264 patients, 24 (9.1%) had inflammation of the soft tissue around the upper third molar, which was the second most common cause of limited mouth opening. Twenty-one of the twenty-four affected patients, with an average mouth opening of 19.1 ± 7.6 mm, underwent upper third molar extraction. Gingival tenderness around the upper third molar or maxillary tuberosity mucosa was a characteristic clinical manifestation (p < 0.05). The characteristic features on maxillofacial CT included soft tissue swelling around the upper third molar and gap narrowing between the maxillary nodules and the mandibular ascending branch. Post extraction, the average mouth opening increased to 31.4 ± 4.9 mm (p < 0.05), and follow-up CT demonstrated regression of the inflammatory soft tissue around the upper third molar. CONCLUSIONS: Inflammation of soft tissue around the upper third molar is a common cause of limited mouth opening. Symptoms of pain associated with the upper third molar and distinctive findings on enhanced maxillofacial CT scans are crucial for diagnosis. Upper third molar extraction yields favorable therapeutic outcomes. CLINICAL RELEVANCE: Inflammation of the soft tissue around the maxillary third molar commonly causes limited mouth opening, but this phenomenon has long been overlooked. Clarifying this etiology can reduce the number of misdiagnosed patients with restricted mouth opening and enable more efficient treatment for patients.

Identification of Angiogenesis-Related Genes and Molecular Subtypes for Psoriasis Based on Random Forest Algorithm.

Psoriasis is a chronic immune-mediated recurrent skin disease causing systemic damage. Increased angiogenesis has been reported to participate in the progression of psoriasis. However, angiogenesis-related genes (ARGs) in psoriasis have not been systematically elucidated. Therefore, we aim to identify potential biomarkers and subtypes using two algorithms. Transcriptome sequencing data of patients with psoriasis were obtained, in which differentially expressed genes were assessed by principal component analysis (PCA). A diagnostic model was developed using random forest algorithm (ntree=400) and validated by ROC curves. Subsequently, we performed consensus clustering to calculate angiogenesis-associated molecular subtypes of psoriasis. Additionally, a correlation analysis was conducted between ARGs and immune cell infiltration. Finally, validation of potential ARG genes was performed by qRT-PCR. We identified 29 differentially expressed ARGs, including 13 increased and 16 decreased. Ten ARGs, CXCL8, ANG, EGF, HTATIP2, ANGPTL4, TNFSF12, RHOB, PML, FOXO4, and EMCN were subsequently sifted by the diagnostic model based on a random forest algorithm. Analysis of the ROC curve (area under the curve [AUC] = 1.0) indicated high diagnostic performance in internal validation. The correlation analysis suggested that CXCL8 has a high positive correlation with neutrophil (R =0.8, P<0.0001) and interleukins pathway (R=0.79, P<0.0001). Furtherer, two ARG-mediated subtypes were obtained, indicating potential heterogeneity. Finally, the qRT-PCR demonstrated that the mRNA expression levels of CXCL8 and ANGPTL4 were elevated in psoriasis patients, with a reduced expression of EMCN observed. The current paper indicated potential ARG-related biomarkers of psoriasis, including CXCL8, ANGPTL4, and EMCN, with two molecular subtypes.

Visible Light [2 + 2] Cycloadditions of Thermoresponsive Dendronized Styryltriazines To Exhibit Tunable Microconfinement.

Visible light-triggered photochemical reactions in aqueous media are highly valuable to tailor molecular structures and properties in an ecofriendly manner. Here we report visible light-induced catalyst-free [2 + 2] cycloadditions of thermoresponsive dendronized styryltriazines, which show tunable microconfinement to guest dyes in aqueous media. These dendronized styryltriazines are constituted of conjugated mono- or tristyryltriazines, which carry hydrophilic dendritic oligoethylene glycol (OEG) pendants. They underwent efficient [2 + 2] cycloadditions to form dendronized cyclobutane dimers or oligomers in water through irradiation with visible light of 400 nm, and their cycloaddition behavior was dominated by dendritic architectures and solvent conditions. Dendronization with dendritic OEGs also afforded them characteristic thermoresponsive properties with tunable phase transition temperatures in the range 36-65 °C, which can be further modulated through photocycloaddition of styryltriazine chromophores. Importantly, dendronized styryltriazines can form tunable microenvironments in aqueous media, which encapsulate hydrophobic solvatochromic Nile red to exhibit variable photophysical properties. The encapsulated guest dye can be simultaneously released through noninvasive visible light-induced [2 + 2] cycloaddition reactions.

Retracing from Outcomes to Causes: NRF2-Driven GSTA4 Transcriptional Regulation Controls Chronic Inflammation and Oxidative Stress in Atopic Dermatitis Recurrence.

Atopic dermatitis (AD), a chronic and recurrent inflammatory skin disorder, presents a high incidence and imposes a substantial economic burden. Preventing its recurrence remains a significant challenge in dermatological therapy owing to poorly understood underlying mechanisms. In our study, we adopted a strategy of tracing the mechanisms of recurrence from clinical outcomes. We developed a mouse model of recurrent AD and applied clinically validated treatment regimens. Transcriptomic analyses revealed a pronounced enrichment in the glutathione metabolic pathway in the treated group. Through integrated bioinformatics and in vivo validation, we identified glutathione S-transferase alpha 4 (GSTA4) as a pivotal mediator in AD recurrence. Immunohistochemical analysis demonstrated decreased GSTA4 expression in lesions from patients with AD. Functionally, in vitro overexpression of GSTA4 significantly curtailed AD-like inflammatory responses and ROS production. Moreover, we discovered that NRF2 transcriptional activity regulates GSTA4 expression and function. Our treatment notably augmented NRF2-mediated GSTA4 transcription, yielding pronounced anti-inflammatory and ROS-neutralizing effects. Conclusively, our findings implicate GSTA4 as a critical factor in the recurrence of AD, particularly in the context of oxidative stress and chronic inflammation. Targeting the NRF2-GSTA4 axis emerges as a promising anti-inflammatory and antioxidative strategy for preventing AD recurrence.

Regulation of metabolism by circadian rhythms: Support from time-restricted eating, intestinal microbiota & omics analysis.

Circadian oscillatory system plays a key role in coordinating the metabolism of most organisms. Perturbation of genetic effects and misalignment of circadian rhythms result in circadian dysfunction and signs of metabolic disorders. The eating-fasting cycle can act on the peripheral circadian clocks, bypassing the photoperiod. Therefore, time-restricted eating (TRE) can improve metabolic health by adjusting eating rhythms, a process achieved through reprogramming of circadian genomes and metabolic programs at different tissue levels or remodeling of the intestinal microbiota, with omics technology allowing visualization of the regulatory processes. Here, we review recent advances in circadian regulation of metabolism, focus on the potential application of TRE for rescuing circadian dysfunction and metabolic disorders with the contribution of intestinal microbiota in between, and summarize the significance of omics technology.

Genome-wide identification of bZIP transcription factors in 12 Rosaceae species and modeling of novel mechanisms of EjbZIPs response to salt stress.

In plantae, basic leucine zipper (bZIP) transcription factors (TFs) are widespread and regulate a variety of biological processes under abiotic stress. However, it has not been extensively studied in Rosaceae, and the functional effects of bZIP on Eriobotrya japonica under salt stress are still unknown. Therefore, in this study, the bZIP TF family of 12 species of Rosaceae was analyzed by bioinformatics method, and the expression profile and quantitative real-time polymerase chain reaction of E. japonica under salt stress were analyzed. The results showed that a total of 869 bZIP TFs were identified in 12 species of Rosaceae and divided into nine subfamilies. Differences in promoter cis-elements between subfamilies vary depending on their role. Species belonging to the same subfamily have a similar number of chromosomes and the number of genes contained on each chromosome. Gene duplication analysis has found segmental duplication to be a prime force in the evolution of Rosaceae species. In addition, nine EjbZIPs were significantly different, including seven up-regulated and two down-regulated in E. japonica under salt stress. Especially, EjbZIP13 was involved in the expression of SA-responsive proteins by binding to the NPR1 gene. EjbZIP27, EjbZIP30, and EjbZIP38 were highly expressed in E. japonica under salt stress, thus improving the salt tolerance capacity of the plants. These results can provide a theoretical basis for exploring the characteristics and functions of the bZIP TF family in more species and breeding salt-tolerant E. japonica varieties. It also provides a reference for resolving the response mechanism of bZIP TF in 12 Rosaceae species under salt stress.

Voxel Design of Grayscale DLP 3D-Printed Soft Robots.

Grayscale digital light processing (DLP) printing is a simple yet effective way to realize the variation of material properties by tuning the grayscale value. However, there is a lack of available design methods for grayscale DLP 3D-printed structures due to the complexities arising from the voxel-level grayscale distribution, nonlinear material properties, and intricate structures. Inspired by the dexterous motions of natural organisms, a design and fabrication framework for grayscale DLP-printed soft robots is developed by combining a grayscale-dependent hyperelastic constitutive model and a voxel-based finite-element model. The constitutive model establishes the relationship between the projected grayscale value and the nonlinear mechanical properties, while the voxel-based finite-element model enables fast and efficient calculation of the mechanical performances with arbitrarily distributed material properties. A multiphysics modeling and experimental method is developed to validate the homogenization assumption of the degree of conversion (DoC) variation in a single voxel. The design framework is used to design structures with reduced stress concentration and programmable multimodal motions. This work paves the way for integrated design and fabrication of functional structures using grayscale DLP 3D printing.

Biological function molecular pathways and druggability of DNMT2/TRDMT1.

5-methylcytosine (m5C) is among the most common epigenetic modification in DNA and RNA molecules, and plays an important role in the animal development and disease pathogenesis. Interestingly, unlike other m5C DNA methyltransferases (DNMTs), DNMT2/TRDMT1 has the double-substrate specificity and adopts a DNMT-similar catalytic mechanism to methylate RNA. Moreover, it is widely involved in a variety of physiological regulatory processes, such as the gene expression, precise protein synthesis, immune response, and disease occurrence. Thus, comprehending the epigenetic mechanism and function of DNMT2/TRDMT1 will probably provide new strategies to treat some refractory diseases. Here, we discuss recent studies on the spatiotemporal expression pattern and post-translational modifications of DNMT2/TRDMT1, and summarize the research advances in substrate characteristics, catalytic recognition mechanism, DNMT2/TRDMT1-related genes or proteins, pharmacological application, and inhibitor development. This review will shed light on the pharmacological design by targeting DNMT2/TRDMT1 to treat parasitic, viral and oncologic diseases.

ß-Sitosterol Reduces the Content of Triglyceride and Cholesterol in a High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease Zebrafish (Danio rerio) Model.

OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is strongly associated with hyperlipidemia, which is closely related to high levels of sugar and fat. ß-sitosterol is a natural product with significant hypolipidemic and cholesterol-lowering effects. However, the underlying mechanism of its action on aquatic products is not completely understood. METHODS: A high-fat diet (HFD)-induced NAFLD zebrafish model was successfully established, and the anti-hyperlipidemic effect and potential mechanism of ß-sitosterol were studied using oil red O staining, filipin staining, and lipid metabolomics. RESULTS: ß-sitosterol significantly reduced the accumulation of triglyceride, glucose, and cholesterol in the zebrafish model. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that differential lipid molecules in ß-sitosterol mainly regulated the lipid metabolism and signal transduction function of the zebrafish model. ß-sitosterol mainly affected steroid biosynthesis and steroid hormone biosynthesis in the zebrafish model. Compared with the HFD group, the addition of 500 mg/100 g of ß-sitosterol significantly inhibited the expression of Ppar-γ and Rxr-α in the zebrafish model by at least 50% and 25%, respectively. CONCLUSIONS: ß-sitosterol can reduce lipid accumulation in the zebrafish model of NAFLD by regulating lipid metabolism and signal transduction and inhibiting adipogenesis and lipid storage.