Spatiotemporal Changes and Influencing Factors of Hand, Foot, and Mouth Disease in Guangzhou, China, From 2013 to 2022: Retrospective Analysis.

Background: In the past 10 years, the number of hand, foot, and mouth disease (HFMD) cases reported in Guangzhou, China, has averaged about 60,000 per year. It is necessary to conduct an in-depth analysis to understand the epidemiological pattern and related influencing factors of HFMD in this region. Objective: This study aims to describe the epidemiological characteristics and spatiotemporal distribution of HFMD cases in Guangzhou from 2013 to 2022 and explore the relationship between sociodemographic factors and HFMD incidence. Methods: The data of HFMD cases in Guangzhou come from the Infectious Disease Information Management System of the Guangzhou Center for Disease Control and Prevention. Spatial analysis and space-time scan statistics were used to visualize the spatiotemporal distribution of HFMD cases. Multifactor ordinary minimum regression model, geographically weighted regression, and geographically and temporally weighted regression were used to analyze the influencing factors, including population, economy, education, and medical care. Results: From 2013 to 2022, a total of 599,353 HFMD cases were reported in Guangzhou, with an average annual incidence rate of 403.62/100,000. Children aged 5 years and younger accounted for 93.64% (561,218/599,353) of all cases. HFMD cases showed obvious bimodal distribution characteristics, with the peak period from May to July and the secondary peak period from August to October. HFMDs in Guangzhou exhibited a spatial aggregation trend, with the central urban area showing a pattern of low-low aggregation and the peripheral urban area demonstrating high-high aggregation. High-risk areas showed a dynamic trend of shifting from the west to the east of peripheral urban areas, with coverage first increasing and then decreasing. The geographically and temporally weighted regression model results indicated that population density (ß=-0.016) and average annual income of employees (ß=-0.007) were protective factors for HFMD incidence, while the average number of students in each primary school (ß=1.416) and kindergarten (ß=0.412) was a risk factor. Conclusions: HFMD cases in Guangzhou were mainly infants and young children, and there were obvious differences in time and space. HFMD is highly prevalent in summer and autumn, and peripheral urban areas were identified as high-risk areas. Improving the economic level of peripheral urban areas and reducing the number of students in preschool education institutions are key strategies to controlling HFMD.

The developmental pattern related to fatty acid uptake and oxidation in the yolk sac membrane and jejunum during embryogenesis in Muscovy duck.

This study aimed to investigate the developmental change of body growth and gene expression related to fatty acid uptake and oxidation in the yolk sac membrane (YSM) and jejunum during embryogenesis in Muscovy ducks. The weights of embryos and yolk sac (YS) (5 embryos per replicate, n = 6) were recorded on embryonic days (E)16, E19, E22, E25, E28, E31, and the day of hatch (DOH). The fat and fatty acid contents in YSM, jejunal histology, and gene expression related to fatty acid metabolism in YSM and jejunum were determined in each sampling time. Among the nonlinear models, the maximum growth is estimated at 2.83 (E22.5), 2.67 (E22.1), and 2.60 (E21.3) g/d using logistic, Gompertz, and Von Bertalanffy models, respectively. The weight of YS, and ether extract-free YS as well as the amounts of fat and fatty acids in YS decreased (P < 0.05) linearly, whereas the villus height, crypt depth, villus height/crypt depth, and musculature thickness in jejunum increased (P < 0.05) linearly during embryogenesis. The mRNA expression of CD36, SLC27A4, and FABP1 related to fatty acid uptake as well as the mRNA and protein expressions of PPARα and CPT1 related to fatty acid oxidation increased in a quadratic manner (P < 0.05) in both YS and jejunum, and the maximum values were achieved during E25 to E28. In conclusion, the maximum growth rate of Muscovy duck embryos was estimated at 2.60 to 2.83 g/d on E21.3 to E23.5, while the accumulations of lipid and fatty acid in YS were decreased in association with the increased absorptive area of morphological structures in jejunum. The gene and protein expression involved in fatty acid metabolism displayed a similar enhancement pattern between YSM and jejunum during E25 to E28, suggesting that fatty acid utilization could be strengthened to meet the energy demand for embryonic development.

Feature-Assisted Machine Learning for Predicting Band Gaps of Binary Semiconductors.

The band gap is a key parameter in semiconductor materials that is essential for advancing optoelectronic device development. Accurately predicting band gaps of materials at low cost is a significant challenge in materials science. Although many machine learning (ML) models for band gap prediction already exist, they often suffer from low interpretability and lack theoretical support from a physical perspective. In this study, we address these challenges by using a combination of traditional ML algorithms and the 'white-box' sure independence screening and sparsifying operator (SISSO) approach. Specifically, we enhance the interpretability and accuracy of band gap predictions for binary semiconductors by integrating the importance rankings of support vector regression (SVR), random forests (RF), and gradient boosting decision trees (GBDT) with SISSO models. Our model uses only the intrinsic features of the constituent elements and their band gaps calculated using the Perdew-Burke-Ernzerhof method, significantly reducing computational demands. We have applied our model to predict the band gaps of 1208 theoretically stable binary compounds. Importantly, the model highlights the critical role of electronegativity in determining material band gaps. This insight not only enriches our understanding of the physical principles underlying band gap prediction but also underscores the potential of our approach in guiding the synthesis of new and valuable semiconductor materials.

Design and investigation of a capacitance-coupling pre-ionized sharpening switch.

The sharpening switch is one of the most important elements in the trigger generator, which is used to sharpen the front of the trigger pulse. The breakdown performance of the sharpening switch has an important influence on the output and stability of the trigger generator. In this paper, a novel 200 kV capacitance-coupling pre-ionized sharpening switch, which can realize pre-ionization by dividing voltage through its own structural capacitances, is proposed and investigated. In order to obtain the optimal parameters of the pre-ionized sharpening switch, the influences of the electrode structure, electrode material, main gap distance, and pre-ionized gap distance on the breakdown performance are studied experimentally. The experimental results show that the electrode structure with a circular knife-edged cathode and a plate-shaped anode has the smallest breakdown jitter, followed by the needle-plate structure and the tapered ball-head structure. The stainless steel electrode has the smallest jitter, followed by graphite, aluminum, and brass electrodes. When the gap distances of the main gap and the pre-ionized gap are 13 and 1.5 mm, respectively, the breakdown stability of the pre-ionized sharpening switch is the best. Under an input voltage pulse with a rise time of about one microsecond, the jitter of the capacitance-coupling pre-ionized sharpening switch with the optimal parameters is 6.08 ns, which is about 0.6% of the rise time of the input pulse. The jitter decreases by 44.5% compared to the switch without pre-ionization. The rise time of the output pulse is sharpened to 17 ns, corresponding to a voltage rise rate of more than 11 kV/ns.

Evidence from an Avian Embryo Model that Zinc-Inducible MT4 Expression Protects Mitochondrial Function Against Oxidative Stress.

BACKGROUND: Metallothioneins (MTs) have a strong affinity for zinc (Zn) and remain at a sufficiently high level in mitochondria. As the avian embryo is highly susceptible to oxidative damage and relatively easy to manipulate in a naturally closed chamber, it is an ideal model of the effects of oxidative stress on mitochondrial function. However, the protective roles and molecular mechanisms of Zn-inducible protein expression on mitochondrial function in response to various stressors are poorly understood. OBJECTIVES: The study aimed to investigate the mechanisms by which Zn-induced MT4 expression protects mitochondrial function and energy metabolism subjected to oxidative stress using the avian embryo and embryonic primary hepatocyte models. METHODS: First, we investigated whether MT4 expression alters mitochondrial function. Then, we examined the effects of Zn-induced MT4 overexpression and MT4 silencing on embryonic primary hepatocytes from breeder hens fed a normal Zn diet subjected to a tert-butyl hydroperoxide (BHP) oxidative stress challenge during incubation. In vivo, the avian embryos from hens fed the Zn-deficient and Zn-adequate diets were used to determine the protective roles of Zn-induced MT4 expression on the function of mitochondria exposed to oxidative stress induced by in ovo BHP injection. RESULTS: An in vitro study revealed that Zn-induced MT4 expression reduced reactive oxygen species accumulation in primary hepatocytes. MT4 silencing exacerbated BHP-mediated mitochondrial dysfunction whereas Zn-inducible MT4 overexpression mitigated it. Another in vivo study disclosed that maternal Zn-induced MT4 expression protected mitochondrial function in chick embryo hepatocytes against oxidative stress by inhibiting the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)/peroxisome proliferators-activated receptor-γ (PPAR-γ) pathway. CONCLUSION: This study underscores the potential protective roles of Zn-induced MT4 expression via the downregulation of the PGC-1α/PPAR-γ pathway on mitochondrial function stimulated by the stress challenge in the primary hepatocytes in an avian embryo model. Our findings suggested that Zn-induced MT4 expression could provide a new therapeutic target and preventive strategy for repairing mitochondrial dysfunction in disease.

A deterministic robust control with parameter optimization for uncertain two-wheel driven mobile robot.

The uncertainty in mobile robot greatly affects control accuracy. This makes it difficult to apply to more rigorous high-precision engineering fields. Therefore, the fuzzy set theory is introduced to describe the uncertainty. Based on that, the fuzzy mobile robot system is established. The virtual speed controller using backstepping method is designed. Then, a robust control method is proposed to guarantee the uniform boundedness and uniform ultimate boundedness of the controlled system. Furthermore, the balance optimization problem of the performance and cost of the controlled system is explored. By minimizing the performance index containing fuzzy numbers, the optimal control parameter is obtained. Compared with the linear quadratic regulator algorithm, which is the representative optimal robust controller, the proposed control method and optimization strategy based on fuzzy set theory are verified to be effective. The control accuracy is further improved.

Enhancing Caregiver Empowerment Through the Story Mosaic System: Human-Centered Design Approach for Visualizing Older Adult Life Stories.

Background: Various older adult care settings have embraced the use of the life story approach to enhance the development of comprehensive care plans. However, organizing life stories and extracting useful information is labor-intensive, primarily due to the repetitive, fragmented, and redundant nature of life stories gathered from everyday communication scenarios. Existing life story systems, while available, do not adequately fulfill the requirements of users, especially in the application of care services. Objective: The objective of this study is to design, develop, and evaluate a digital system that provides caregivers with the necessary tools to view and manage the life stories of older adults, enabling expedited access to pertinent information effectively and visually. Methods: This study used a multidisciplinary, user-centered design approach across 4 phases: initial design requirements, prototyping, prototype refinement workshops, and usability testing. During the initial phase, we conducted field research in the Hefei Tianyu Senior Living Service Nursing Home, China, to discover how caregivers currently store and use life stories and their needs, challenges, and obstacles in organizing and retrieving information. Subsequently, we designed a low-fidelity prototype according to the users' requirements. A prototyping workshop involving 6 participants was held to collaboratively design and discuss the prototype's function and interaction. User feedback from the workshops was used to optimize the prototype, leading to the development of the system. We then designed 2 rounds of usability testing with 7 caregivers to evaluate the system's usability and effectiveness. Results: We identified 3 categories of functionalities that are necessary to include in the design of our initial low-fidelity prototype of life story visualizations: life story input, life story organization, and timeline generation. Subsequently, through the workshops, we identified 3 categories for functional optimization: feedback on user interface and usability, optimization suggestions for existing features, and the request for additional functionalities. Next, we designed a medium-fidelity prototype based on human-centered design. The Story Mosaic system underwent usability testing in the Hefei Tianyu Senior Living Service Nursing Home. Overall, 7 users recorded and organized 1123 life stories of 16 older adults. The usability testing results indicated that the system was accessible and easy to use for caregivers. Based on the feedback from the usability testing, we finalized the high-fidelity prototype. Conclusions: We designed, developed, and evaluated the Story Mosaic system to support the visual management of older adults' life stories. This system empowers caregivers through digital technology and innovative design, pioneering personal narrative integration in caregiving. This system can expand to include informal caregivers and family members for continued adaptability and empathy.

Shikimate-Derived Meroterpenoids from the Ascidian-Derived Fungus Amphichorda felina SYSU-MS7908 and Their Anti-Glioma Activity.

Glioma is a clinically heterogeneous type of brain tumor with a poor prognosis. Current treatment approaches have limited effectiveness in treating glioma, highlighting the need for novel drugs. One approach is to explore marine natural products for their therapeutic potential. In this study, we isolated nine shikimate-derived diisoprenyl-cyclohexene/ane-type meroterpenoids (1-9), including four new ones, amphicordins A-D (1-4) from the ascidian-derived fungus Amphichorda felina SYSU-MS7908, and further semisynthesized four derivatives (10-13). Their structures were extensively characterized using 1D and 2D NMR, modified Mosher's method, HR-ESIMS, NMR and ECD calculations, and X-ray crystallography. Notably, amphicordin C (3) possesses a unique benzo[g]chromene (6/6/6) skeleton in this meroterpenoid family. In an anti-glioma assay, oxirapentyn A (7) effectively inhibited the proliferation, migration, and invasion of glioma cells and induced their apoptosis. Furthermore, an in silico analysis suggested that oxirapentyn A has the potential to penetrate the blood-brain barrier. These findings highlight the potential of oxirapentyn A as a candidate for the development of novel anti-glioma drugs.

Predicting response to immunotherapy in gastric cancer via assessing perineural invasion-mediated inflammation in tumor microenvironment.

BACKGROUND: The perineural invasion (PNI)-mediated inflammation of the tumor microenvironment (TME) varies among gastric cancer (GC) patients and exhibits a close relationship with prognosis and immunotherapy. Assessing the neuroinflammation of TME is important in predicting the response to immunotherapy in GC patients. METHODS: Fifteen independent cohorts were enrolled in this study. An inflammatory score was developed and validated in GC. Based on PNI-related prognostic inflammatory signatures, patients were divided into Clusters A and B using unsupervised clustering. The characteristics of clusters and the potential regulatory mechanism of key genes were verified by RT-PCR, western-blot, immunohistochemistry and immunofluorescence in cell and tumor tissue samples.The neuroinflammation infiltration (NII) scoring system was developed based on principal component analysis (PCA) and visualized in a nomogram together with other clinical characteristics. RESULTS: Inflammatory scores were higher in GC patients with PNI compared with those without PNI (P < 0.001). NII.clusterB patients with PNI had abundant immune cell infiltration in the TME but worse prognosis compared with patients in the NII.clusterA patients with PNI and non-PNI subgroups. Higher immune checkpoint expression was noted in NII.clusterB-PNI. VCAM1 is a specific signature of NII.clusterB-PNI, which regulates PD-L1 expression by affecting the phosphorylation of STAT3 in GC cells. Patients with PNI and high NII scores may benefit from immunotherapy. Patients with low nomogram scores had a better prognosis than those with high nomogram scores. CONCLUSIONS: Inflammation mediated by PNI is one of the results of tumor-nerve crosstalk, but its impact on the tumor immune microenvironment is complex. Assessing the inflammation features of PNI is a potential method in predicting the response of immunotherapy effectively.

Anti-inflammatory acetylenic meroterpenoids from the ascidian-derived fungus Amphichorda felina SYSU-MS7908.

A combination strategy of 13C NMR and bioinformatics was established to expedite the discovery of acetylenic meroterpenoids from the ascidian-derived fungus Amphichorda felina SYSU-MS7908. This approach led to the identification of 13 acetylenic meroterpenoids (1-13) and four biogenic analogs (14-17), including five new ones named felinoids A-E (1-4 and 15). Their structures and absolute configurations were elucidated using extensive spectroscopy, ECD quantum chemical calculations, and single-crystal X-ray diffraction analysis. Compound 1 possessed a rare cyclic carbonate in natural acetylenic meroterpenoids. The plausible shikimate-terpenoid biosynthetic pathways of 1-4 were also postulated. Five of these isolates exhibited anti-inflammatory activity by inhibiting NO production in LPS-induced RAW264.7 cells (IC50 = 11.6-19.5 µM). Moreover, oxirapentyn E diacetate showed a dose-dependent inhibition of pro-inflammatory cytokines IL-6 and TNF-α. Structural modification of oxirapentyn B yielded 29 new derivatives, among which seven showed improved activity (IC50 < 3 µM) and higher selectivity index (SI > 22). The structure-activity relationship study indicated that 7, 8-epoxy, and 6-acylation were crucial for the activity. These findings may provide a powerful tool to accelerate the discovery of new fungal acetylenic meroterpenoids for future anti-inflammatory drug development.

Cyclohexenone Derivative and Drimane Sesquiterpenes from the Seagrass-Derived Fungus Aspergillus insuetus.

One new cyclohexenone derivative (1), and two undescribed drimane sesquiterpenes (2 and 3), together with another seven known drimane sesquiterpenes were isolated from a seagrass-derived fungus Aspergillus insuetus SYSU6925. Structures of these metabolites were elucidated by comprehensive spectroscopic analysis, including NMR analysis, mass spectrometry, and ECD calculations. Compounds 1-3, 5 and 7 displayed weak to moderate antifungal activities towards four phytopathogenic fungi, with Minimum inhibition concentration (MIC) values range from 50 to 200 µg/mL. Compound 1, a rare cyclohexenone derivative with n-propyl group exhibited more potent inhibitory activities (MIC, 50 µg/mL) against F. oxysporum than positive control (Triadimefon). Compounds 2 and 3 also exhibit potent anti-inflammatory activities by inhibiting the production of nitric oxide (NO) in RAW264.7 cells with IC50 values of 21.5±1.1 and 32.6±1.16 µM, respectively.

Movie recommendation model based on probabilistic matrix decomposition using hybrid AdaBoost integration.

In recent years, recommendation systems have already played a significant role in major streaming video platforms.The probabilistic matrix factorization (PMF) model has advantages in addressing high-dimension problems and rating data sparsity in the recommendation system. However, in practical application, PMF has poor generalization ability and low prediction accuracy. For this reason, this article proposes the Hybrid AdaBoost Ensemble Method. Firstly, we use the membership function and the cluster center selection in fuzzy clustering to calculate the scoring matrix of the user-items. Secondly, the clustering user items' scoring matrix is trained by the neural network to improve the scoring prediction accuracy further. Finally, with the stability of the model, the AdaBoost integration method is introduced, and the score matrix is used as the base learner; then, the base learner is trained by different neural networks, and finally, the score prediction is obtained by voting results. In this article, we compare and analyze the performance of the proposed model on the MovieLens and FilmTrust datasets. In comparison with the PMF, FCM-PMF, Bagging-BP-PMF, and AdaBoost-SVM-PMF models, several experiments show that the mean absolute error of the proposed model increases by 1.24% and 0.79% compared with Bagging-BP-PMF model on two different datasets, and the root-mean-square error increases by 2.55% and 1.87% respectively. Finally, we introduce the weights of different neural network training based learners to improve the stability of the model's score prediction, which also proves the method's universality.

Maternal zinc alleviates tert-butyl hydroperoxide-induced mitochondrial oxidative stress on embryonic development involving the activation of Nrf2/PGC-1α pathway.

BACKGROUND: Mitochondrial dysfunction induced by excessive mitochondrial reactive oxygen species (ROS) damages embryonic development and leads to growth arrest. OBJECTIVE: The purpose of this study is to elucidate whether maternal zinc (Zn) exert protective effect on oxidative stress targeting mitochondrial function using an avian model. RESULT: In ovo injected tert-butyl hydroperoxide (BHP) increases (P < 0.05) hepatic mitochondrial ROS, malondialdehyde (MDA) and 8-hydroxy-2-deoxyguanosine (8-OHdG), and decreases (P < 0.05) mitochondrial membrane potential (MMP), mitochondrial DNA (mtDNA) copy number and adenosine triphosphate (ATP) content, contributing to mitochondrial dysfunction. In vivo and in vitro studies revealed that Zn addition enhances (P < 0.05) ATP synthesis and metallothionein 4 (MT4) content and expression as well as alleviates (P < 0.05) the BHP-induced mitochondrial ROS generation, oxidative damage and dysfunction, exerting a protective effect on mitochondrial function by enhancing antioxidant capacity and upregulating the mRNA and protein expressions of Nrf2 and PGC-1α. CONCLUSIONS: The present study provides a new way to protect offspring against oxidative damage by maternal Zn supplementation through the process of targeting mitochondria involving the activation of Nrf2/PGC-1α signaling.

Integrated opposite charge grafting induced ionic-junction fiber.

The emergence of ionic-junction devices has attracted growing interests due to the potential of serving as signal transmission and translation media between electronic devices and biological systems using ions. Among them, fiber-shaped iontronics possesses a great advantage in implantable applications owing to the unique one-dimensional geometry. However, fabricating stable ionic-junction on curved surfaces remains a challenge. Here, we developed a polyelectrolyte based ionic-junction fiber via an integrated opposite charge grafting method capable of large-scale continuous fabrication. The ionic-junction fibers can be integrated into functions such as ionic diodes and ionic bipolar junction transistors, where rectification and switching of input signals are implemented. Moreover, synaptic functionality has also been demonstrated by utilizing the fiber memory capacitance. The connection between the ionic-junction fiber and sciatic nerves of the mouse simulating end-to-side anastomosis is further performed to realize effective nerve signal conduction, verifying the capability for next-generation artificial neural pathways in implantable bioelectronics.

Absolute configuration of cyclopropanes and the structural revision of pyrones from Marine-derived fungus Stagonospora sp. SYSU-MS7888.

Two new cyclopropane derivatives (1-2) and seven undescribed α-pyrone derivatives (3-9), along with one known congener (10) were obtained from the marine fungus Stagonospora sp. SYSU-MS7888, which was isolated from the South China Sea. Their planar structures were established through extensive spectroscopic analyses including 1D and 2D NMR and HR-ESIMS. The absolute configurations were identified on basis of the quantum chemical calculations of ECD and NMR, as well as the modified Mosher's method. It's particularly noteworthy that the tetrasubstituted furopyrans, chenopodolans A-F, possessing phytotoxicity and zootoxicity, were structural misassignments. The structures of chenopodolans featuring with furopyran skeleton were revised as common trisubstituted α-pyrones by computational chemistry, NMR spectroscopic method, and empirical rule. Compounds 1, 2, 7, and 9 showed significant anti-inflammatory activity with IC50 values ranging from 3.6 to 22.8 µM, which is better than the positive control indomethacin (IC50 = 26.5 ± 1.13 µM). This discovery holds potential for the development of new anti-inflammatory agents.

Flame Retardancy and Mechanical Properties of Melt-Spun PA66 Fibers Prepared by End-Group Blocking Technology.

Preparing flame-retardant polyamide 66 (PA66) fibers through melt spinning remains one of the biggest challenges nowadays. In this work, dipentaerythritol (Di-PE), an eco-friendly flame retardant, was blended into PA66 to prepare PA66/Di-PE composites and fibers. It was confirmed that Di-PE could significantly improve the flame-retardant properties of PA66 by blocking the terminal carboxyl groups, which was conducive to the formation of a continuous and compact char layer and the reduced production of combustible gas. The combustion results of the composites showed that the limiting oxygen index (LOI) increased from 23.5% to 29.4%, and underwriter laboratories 94 (UL-94) passed the V-0 grade. The peak of heat release rate (PHRR), total heat release (THR), and total smoke production (TSP) decreased by 47.3%, 47.8%, and 44.8%, respectively, for the PA66/6 wt% Di-PE composite compared to those recorded for pure PA66. More importantly, the PA66/Di-PE composites possessed excellent spinnability. The prepared fibers still had good mechanical properties (tensile strength: 5.7 ± 0.2 cN/dtex), while maintaining good flame-retardant properties (LOI: 28.6%). This study provides an outstanding industrial production strategy for fabricating flame-retardant PA66 plastics and fibers.

Developmental changes in lipid and fatty acid metabolism and the inhibition by in ovo feeding oleic acid in Muscovy duck embryogenesis.

Hepatic lipid and fatty acid (FA) metabolism are critical for regulating energetic homeostasis during embryogenesis. At present, it remains unclear how an exogenous FA intervention affects embryonic development in an avian embryo model. In Exp. 1, 30 fertilized eggs were sampled on embryonic days (E) 16, 19, 22, 25, 28, 31 and the day of hatch (DOH) to determine the critical period of lipid metabolism. In Exp. 2, a total of 120 fertilized eggs were divided into two groups (60 eggs/group) for in ovo feeding (IOF) procedures on E25. Eggs were injected into the yolk sac with PBS as the control group and with oleic acid (OA) as the IOF-OA treatment group. Samples were collected on E28 and E31. In Exp. 1, hepatic triacylglycerol (TG) and cholesterol (CHO) contents increased while serum TG content decreased from E16 to DOH (P < 0.05). Both serum and liver displayed an increase in unsaturated FA and a decrease in saturated FA (P < 0.05). There was a quadratic increase in the target gene and protein expression related to hepatic FA de novo synthesis and oxidation (P < 0.05), whose inflection period was between E22 and E28. In Exp. 2, compared with the control embryos, IOF-OA embryos had an increased yolk sac TG content on E28 and E31, and a decreased serum TG and CHO content on E28 (P < 0.05). The IOF-OA embryos had less OA in the yolk sac and liver on E28, and less unsaturated FA in the serum and liver on E31 than did the control embryos (P < 0.05). Hepatic gene mRNA expression related to FA uptake, synthesis, and oxidation on E28 was lower in IOF-OA than in control embryos (P < 0.05), not on E31 (P > 0.05). Maximal metabolic changes in lipid and FA metabolism occurred on E22-E28 in Muscovy duck embryogenesis, along with the altered target gene and protein expression related to lipogenesis and lipolysis. IOF-OA intervention on E25 could inhibit the target gene expression related to FA uptake, synthesis, and oxidation, which may influence the normal FA metabolism on E28 during embryogenesis.

Development of novel hydrazidoarylaminopyrimidine-based BTK/FLT3 dual inhibitors with potent in vivo anti-hematological malignancies effects.

Computer-aided drug design and structure-based drug design techniques were used to find 18 novel hydrazidoarylaminopyrimidine-based BTK/FLT3 dual inhibitors. At 1 µM and 0.05 µM, the majority of the target compounds inhibited BTK and FLT3 by more than 80%, respectively. Among these, compound RSH-7 inhibited BTK and FLT3 most effectively, with IC50 values of 47 and 12 nM, respectively, which were superior to spebrutinib (BTK IC50 = 54 nM) and sorafenib (FLT3 IC50 = 33 nM). RSH-7 effectively inhibited the proliferation of multiple hematological malignancy cells with IC50 values ranging from 3 to 17 nM, which were 81-133 folds lower than spebrutinib. Furthermore, RSH-7 strongly inhibited BTK and FLT3 signaling and induced apoptosis in jeko-1 cells by upregulating pro-apoptotic proteins and downregulating Bcl-2 levels. RSH-7 showed moderate in vitro ADME properties. Importantly, RSH-7 demonstrated highly efficacious and well-tolerated in jeko-1 (50 mg/kg, TGI = 79.78%) and MV4-11 (20 mg/kg, TGI = 94.84%) xenograft models. These findings indicated that RSH-7 may be a promising lead compound for the treatment of hematological malignancies.

A TEMPOL and rapamycin loaded nanofiber-covered stent favors endothelialization and mitigates neointimal hyperplasia and local inflammation.

An increased level of reactive oxygen species (ROS) plays a major role in endothelial dysfunction and vascular smooth muscle cell (VSMC) proliferation during in-stent thrombosis and restenosis after coronary artery stenting. Herein, we report an electrospun core-shell nanofiber coloaded with 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL) and rapamycin (RAPA) that correspondingly serves as an ROS scavenger and VSMC inhibitor. This system has the potential to improve the biocompatibility of current drug-eluting stent (DES) coatings with the long-term and continuous release of TEMPOL and rapamycin. Moreover, the RAPA/TEMPOL-loaded membrane selectively inhibited the proliferation of VSMCs while sparing endothelial cells (ECs). This membrane demonstrated superior ROS-scavenging, anti-inflammatory and antithrombogenic effects in ECs. In addition, the membrane could maintain the contractile phenotype and mitigate platelet-derived growth factor BB (PDGF-BB)-induced proliferation of VSMCs. In vivo results further revealed that the RAPA/TEMPOL-loaded covered stents promoted rapid restoration of vascular endothelium compared with DES and persistently impeded inflammation and neointimal hyperplasia in porcine models.

Targeted Discovery of Sorbicillinoid Pigments with Anti-Inflammatory Activity from the Sponge-Derived Fungus Stagonospora sp. SYSU-MS7888 Using the PMG Strategy.

An effective identification and discovery of fungal pigments is very important to illustrate the role of fungal pigments in the life process and conduce to the discovery of new bioactive and edible pigments. The phenotype combined with metabolomic and genomic (PMG) strategy led to the discovery and characterization of three new sorbicillinoid pigments, stasorbicillinoids A-C (1-3), and five known analogues (4-8) from the sponge-derived fungus Stagonospora sp. SYSU-MS7888. Their structures were elucidated by the application of spectroscopic methods (NMR, MS, UV, IR, and ECD) and modified Mosher's method. Compounds 1 and 2 featured novel naphthone nuclei linked by two alkyl side chains possibly undergoing inter- and intramolecular Michael reactions. Compounds 1-8 exhibited potent anti-inflammatory activity with IC50 values in the range of 3.56-22.8 µM. Furthermore, compound 2 inhibited the production of IL-1ß, IL-6, and TNF-α in a dose-dependent manner. This study provides an effective strategy to accelerate the discovery of new fungal pigments and further exploration of their potential applications in different fields such as medicine and food industries.