Effects of dietary supplementation of glycerol monolaurate on laying performance, egg quality, antioxidant capacity, intestinal morphology and immune function in late-phase laying hens.

The objective of this study was to evaluate the effects of different levels of glycerol monolaurate (GML) on laying performance, egg quality, antioxidant capacity, intestinal morphology and immune function in late-phase laying hens. A total of 480 Hy-Line Variety Brown hens (age 54 wk) were randomly assigned to 5 treatments: the control group (basal diet) and 4 GML groups (basal diet supplemented with 100, 200, 300, and 400 mg/kg GML). Each treatment consisted of 8 replicates with 12 hens each and the trial lasted for 8 wk. The results showed that dietary inclusion of GML increased the ADFI in the entire experimental period and the average egg weight in wk 5 to 8 and wk 1 to 8 of the experiment (linear, P < 0.05). Dietary GML addition linearly increased albumen height, Haugh unit and yolk color, and quadratically increased eggshell thickness (P < 0.05). The serum SOD activity, T-AOC and IgG concentrations in the 200 mg/kg GML group, and GSH-Px activity in 200 and 300 mg/kg GML groups were increased, while the MDA concentration in 200 and 300 mg/kg GML groups was decreased than those in the control group (P < 0.05). The jejunal villus height and villus height: crypt depth in 300 mg/kg GML group were higher than that in the control group (P < 0.05). The mRNA expression of TLR4, IL-1ß and TNF-α in spleen and jejunum decreased with the increase of dietary GML concentration (linear, P < 0.05). In conclusion, dietary GML supplementation could improve egg quality, antioxidant capacity, intestinal morphology and immune function in late-phase laying hens, and dietary 300 mg/kg GML inclusion is suggested.

miR-206a-3p suppresses the proliferation and differentiation of chicken chondrocytes in tibial dyschondroplasia by targeting BMP6.

The poultry skeletal system serves multiple functions, not only providing structural integrity but also maintaining the balance of essential minerals such as calcium and phosphorus. However, in recent years, the consideration of skeletal traits has been overlooked in the selective breeding of broilers, resulting in an inadequate adaptation of the skeletal system to cope with the rapid increase in body weight. Consequently, this leads to lameness and bone diseases such as tibial dyschondroplasia (TD), which significantly impact the production performance of broilers. Accumulating evidence has shown that microRNAs (miRNA) play a crucial role in the differentiation, formation, and disease of cartilage. However, the miRNA-mediated molecular mechanism underlying chicken TD formation is still poorly understood. The objective of this study was to investigate the biological function and regulatory mechanism of miRNA in chicken TD formation. Based on transcriptome sequencing of tibial cartilage in the healthy group and TD group, miR-206a-3p was found to be highly expressed in TD cartilage. The function of miR-206a-3p was explored through the transfection test of miR-206a-3p mimics and miR-206a-3p inhibitor. In this study, we utilized qRT-PCR, CCK-8, EdU, western blot, and flow cytometry to detect the proliferation, differentiation, and apoptosis of chondrocytes. The results revealed that miR-206a-3p suppressed the proliferation and differentiation of TD chondrocytes while promoting their programmed cell death. Furthermore, through biosynthesis and dual luciferase assays, it was determined that BMP6 was the direct target gene of miR-206a-3p. This finding was further supported by rescue experiments which confirmed the involvement of BMP6 in the regulatory pathway governed by miR-206a-3p. Our results suggest that miR-206a-3p can inhibits the proliferation and differentiation promote apoptosis through the target gene BMP-6 and suppressing the Smad2/3 signaling pathway in chicken TD chondrocytes.

The relationship between gut microbiota and insomnia: a bi-directional two-sample Mendelian randomization research.

Introduction: Insomnia is the second most common mental health issue, also is a social and financial burden. Insomnia affects the balance between sleep, the immune system, and the central nervous system, which may raise the risk of different systemic disorders. The gut microbiota, referred to as the "second genome," has the ability to control host homeostasis. It has been discovered that disruption of the gut-brain axis is linked to insomnia. Methods: In this study, we conducted MR analysis between large-scale GWAS data of GMs and insomnia to uncover potential associations. Results: Ten GM taxa were detected to have causal associations with insomnia. Among them, class Negativicutes, genus Clostridiuminnocuumgroup, genus Dorea, genus Lachnoclostridium, genus Prevotella7, and order Selenomonadalesare were linked to a higher risk of insomnia. In reverse MR analysis, we discovered a causal link between insomnia and six other GM taxa. Conclusion: It suggested that the relationship between insomnia and intestinal flora was convoluted. Our findings may offer beneficial biomarkers for disease development and prospective candidate treatment targets for insomnia.

Role of iron in host-microbiota interaction and its effects on intestinal mucosal growth and immune plasticity in a piglet model.

Iron is an essential trace element for both the host and resident microbes in the gut. In this study, iron was administered orally and parenterally to anemic piglets to investigate the role of iron in host-microbiota interaction and its effects on intestinal mucosal growth and immune plasticity. We found that oral iron administration easily increased the abundance of Proteobacteria and Escherichia-Shigella, and decreased the abundance of Lactobacillus in the ileum. Furthermore, similar bacterial changes, namely an increase in Proteobacteria, Escherichia-Shigella, and Fusobacterium and a reduction in the Christensenellaceae_R-7_group, were observed in the colon of both iron-supplemented groups. Spearman's correlation analysis indicated that the changed Fusobacterium, Fusobacteria and Proteobacteria in the colon were positively correlated with hemoglobin, colon and spleen iron levels. Nevertheless, it was found that activated mTOR1 signaling, improved villous height and crypt depth in the ileum, enhanced immune communication, and increased protein expression of IL-22 and IL-10 in the colon of both iron-supplemented groups. In conclusion, the benefits of improved host iron outweigh the risks of altered gut microbiota for intestinal mucosal growth and immune regulation in treating iron deficiency anemia.

Garlic essential oil supplementation modulates colonic microbiota compositions and regulates immune response in weaned piglets.

The objective of this study was to investigate the colonic microbiome compositions and immune response and reveal their correlations in weaned piglets fed with garlic essential oil (GEO). Twelve 21-day-old crossbred piglets with the same parity and similar weight (BW = 7.07 ± 0.37 Kg) were randomly divided into control and experimental groups based on BW and sex, which fed either a basal diet (CON group), or a basal diet supplemented with 1.5 g/kg GEO (GEO group). UHPLC-QE-MS showed the main component of GEO were belonged to carbohydrates, organic acid, flavonoids, phenylpropanoids and terpenoids. GEO decreased serum IL-1ß, IL-8 content and the down-regulated mRNA expression of IFN-γ, TLR2 in jejunal mucosa but increased serum IgG, IL-4 content and up-regulated the mRNA expression of IL-4, IL-1ß, TNF-α in ileal mucosa. What's more, the metagenomic analysis demonstrated that GEO increased the abundance of Bacteroidetes, Euryarchaeota and Spirochaetes, while decreased the abundance of Firmicutes and Actinobacteria at Phylum level and Selenomonas_boris, Selenomonadaceae_bacterium_DSM_108025, Clostridiales_bacterium and Phascolarctobacterium_succinatutens at species level. Notably, the main function pathway of virulence factor (VFDB) enriched in GEO group were Fibronection-binding protein, Zn++ metallophrotease and Capsular polysaccharide, while the main function pathway of VFDB enriched in CON group were heme biosynthesis, Lap and FeoAB. Spearman correlation analysis indicated the Spirochaetes had a positive association with IL-6 and IL-4. Acinobacteria was positively correlated with IL-1ß, while negative with the IL-6; In addition, Euryarchaeota had a positive correlation with IL-4, but a negative correlation with IL-1ß; Tenericutes was negative with IL-8; Phascolarcolarctobacterium_succinatutens and was negative with IL-6; Ruminococcaceae_bacterium was negative with TNF-α. While Selenomonadaceae_bacterium_DSM_108025 had a positive correlation with IL-8. In conclusion, our results uncovered that immune regulation effects of GEO may be associated with the microbiome compositions in response to GEO.

A DNA-Gated and Self-Protected Bioorthogonal Catalyst for Nanozyme-Assisted Safe Cancer Therapy.

Transition metal catalysts (TMCs) mediated bioorthogonal uncaging catalysis has sparked increasing interest in prodrug activation. However, due to their "always-on" catalytic activity as well as the complex and catalytic-detrimental intracellular environment, the biosafety and therapeutic efficiency of TMCs are unsatisfactory. Herein, a DNA-gated and self-protected bioorthogonal catalyst has been designed by modifying nanozyme-Pd0 with highly programmable nucleic acid (DNA) molecules to achieve efficient intracellular drug synthesis for cancer therapy. Monolayer DNA molecules could endow the catalyst with targeting and perform as a gatekeeper to achieve selective prodrug activation within cancer cells. Meanwhile, the prepared graphitic nitrogen-doped carbon nanozyme with glutathione peroxidase (GPx) and catalase (CAT)-like activities could improve the catalytic-detrimental intracellular environment to prevent the catalyst from being inactivated and sensitize the subsequent chemotherapy. Overall, we believe that our work will promote the development of secure and efficient bioorthogonal catalytic systems and provide new insights into novel antineoplastic platforms.

Nanozyme-Based Supramolecular Self-Assembly As an Artificial Host Defense System For Treatment of Bacterial Infections.

The proper functioning of host defense system (HDS) is the key to combating bacterial infection in biological organisms. However, the delicate HDS may be dysfunctional or dysregulated, resulting in persistent infection, tissue damage, or delayed wound healing. Herein, a powerful artificial "host defense system" (aHDS) is designed and constructed for treatment of bacterial infections. First, the aHDS can quickly trap the bacteria by electrostatic interactions. Next, the system can be stimulated to produce large amounts of cytotoxic reactive oxygen species (ROS) and exert strong antibacterial effects, which can further regulate the immune microenvironment, leading to macrophage polarization from M0 to pro-inflammatory phenotype (M1) for synergistic bacteria killing. At the later stages, the system can exhibit excellent antioxidant enzyme-like activities to reprogram the M1 macrophage to anti-inflammatory phenotype (M2) for accelerating wound healing. This powerful aHDS can effectively combat the bacteria and avoid excessive inflammatory responses for the treatment of bacteria-infected wounds.

COF-based artificial probiotic for modulation of gut microbiota and immune microenvironment in inflammatory bowel disease.

Conventional strategies for treating inflammatory bowel disease merely relieve inflammation and excessive immune response, but fail to solve the underlying causes of IBD, such as disrupted gut microbiota and intestinal barrier. Recently, natural probiotics have shown tremendous potential for the treatment of IBD. However, probiotics are not recommended for IBD patients, as they may cause bacteremia or sepsis. Herein, for the first time, we constructed artificial probiotics (Aprobiotics) based on artificial enzyme-dispersed covalent organic frameworks (COFs) as the "organelle" and a yeast shell as the membrane of the Aprobiotics to manage IBD. The COF-based artificial probiotics, with the function of natural probiotics, could markedly relieve IBD by modulating the gut microbiota, suppressing intestinal inflammation, protecting the intestinal epithelial cells, and regulating immunity. This nature-inspired approach may aid in the design of more artificial systems for the treatment of various incurable diseases, such as multidrug-resistant bacterial infection, cancer, and others.

[A case of Congenital disorder of glycosylation due to SSR4 gene deletion].

OBJECTIVE: To explore the clinical and molecular characteristics of a child with Congenital disorders of glycosylation (CDG). METHODS: A 4-month-old boy who had presented at the Children's Hospital Affiliated to Zhejiang University Medical School on December 31, 2019 due to feeding difficulties after birth was selected as the study subject. High-throughput sequencing was carried out for the patient, and real-time qPCR was used for validating the suspected deletion fragments and the carrier status of other members of his family. RESULTS: High-throughput sequencing revealed that the child had lost the capture signal for chrX: 153 045 645-153 095 809 (approximately 50 kb), which has involved 4 OMIM genes including SRPK3, IDH3G, SSR4 and PDZD4. qPCR verified that the copy number in this region was zero, while that of his elder brother and parents was all normal. CONCLUSION: The deletion of the fragment containing the SSR4 gene in the Xq28 region probably underlay the SSR4-CDG in this child.

Liquid Metal as Bioinspired and Unusual Modulator in Bioorthogonal Catalysis for Tumor Inhibition Therapy.

Bioorthogonal catalysis mediated by Pd-based transition metal catalysts has sparked increasing interest in combating diseases. However, the catalytic and therapeutic efficiency of current Pd0 catalysts is unsatisfactory. Herein, inspired by the concept that ligands around metal sites could enable enzymes to catalyze astonishing reactions by changing their electronic environment, a LM-Pd catalyst with liquid metal (LM) as an unusual modulator has been designed to realize efficient bioorthogonal catalysis for tumor inhibition. The LM matrix can serve as a "ligand" to afford an electron-rich environment to stabilize the active Pd0 and promote nucleophilic turnover of the π-allylpalladium species to accelerate the uncaging process. Besides, the photothermal properties of LM can lead to the enhanced removal of tumor cells by photo-enhanced catalysis and photothermal effect. We believe that our work will broaden the application of LM and motivate the design of bioinspired bioorthogonal catalysts.

Epidermal nevus syndrome with the mutation of PTCH1 gene and cerebral infarction: a case report and review of the literature.

BACKGROUND: Epidermal nevus syndrome is a group of congenital neuroectodermal and/or mesodermal disorders characterized by the epidermal nevi in common association with cerebral, eye, skeletal, cardiovascular, and renal abnormalities. Epidermal nevus syndrome is a rare syndrome, and epidermal nevus syndrome with the mutation of PTCH1 gene and cerebral infarction is even rarer and has not been reported to the best of our knowledge. CASE PRESENTATION: We report the case of a 10-month-old Chinese female patient who presented to our pediatric neurologic department, University of Wenzhou medical teaching Hospital, Hangzhou. She has mobility disorders on the right limbs and recurrent seizures. She had congenital disorder accompanied by brownish-black and verrucose plaques on the right side of the face as well as extensive brownish-black plaques and brown nevi on the right side of the trunk and the right arm. Epidermal nevus syndrome was diagnosed on the basis of her symptoms. Somatic sebaceous nevi and hypoplastic defects of skin, cerebra, eyes, skeleton, and cardiovascular and renal system were observed. However, in addition to the typical clinical characteristics, the patient also has a mutation (c.109G > T) in PTCH1 gene and cerebral infarction. We present a novel case report and literature review. CONCLUSION: To our knowledge, epidermal nevus syndrome with a mutation of PTCH1 gene and cerebral infarction has not been reported previously. This case report may contribute to characterizing the phenotype of epidermal nevus syndrome, help clinicians be aware of the association of this condition with PTCH1 gene and cerebral infarction, raise clinical suspicion, and improve early therapy.

Magnetoelectrically ignited nanozyme-eel for combating bacterial biofilms.

A magnetoelectrically ignited nanozyme-eel was developed, which could generate abundant surface charges upon the ignition of an alternating magnetic field, leading to a controllable electron transport burst between the nanozyme-eel and bacteria for the eradication of bacterial biofilms.

DNA-based platform for efficient and precisely targeted bioorthogonal catalysis in living systems.

As one of the typical bioorthogonal reactions, copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction holds great potential in organic synthesis, bioconjugation, and surface functionalization. However, the toxicity of Cu(I), inefficient catalytic activity, and the lack of cell specific targeting of the existing catalysts hampered their practical applications in living systems. Herein, we design and construct a DNA-based platform as a biocompatible, highly efficient, and precisely targeted bioorthogonal nanocatalyst. The nanocatalyst presents excellent catalytic efficiency in vitro, which is one order of magnitude higher than the commonly used catalyst CuSO4/sodium ascorbate. The theoretical calculation further supports the contribution of DNA structure and its interaction with substrates to the superior catalytic activity. More importantly, the system can achieve efficient prodrug activation in cancer cells through cell type-specific recognition and produce a 40-fold enhancement of transformation compared to the non-targeting nanocatalyst, resulting in enhanced antitumor efficacy and reduced adverse effects. In vivo tumor therapy demonstrates the safety and efficacy of the system in mammals.

A Metabolic Multistage Glutathione Depletion Used for Tumor-Specific Chemodynamic Therapy.

The high glutathione (GSH) content in tumor cells strongly affects the efficiency of chemodynamic therapy (CDT). Despite devoted efforts, it still remains a formidable challenge for manufacturing a tumor-specific CDT with rapid and thorough depletion of GSH. Herein, a multistage GSH-consuming and tumor-specific CDT is presented. By consuming the reserved GSH and inhibiting both the raw materials and energy supply of GSH synthesis in cancer cells, it achieves highly potent GSH exhaustion. Our used glycolysis inhibitor cuts off the specific glycolysis of tumor cells to increase the sensitivity to CDT. Furthermore, the starvation effect of glycolysis inhibitor can stimulate the protective mode of normal cells. Since the glycolysis inhibitor and nanocarrier are responsive to tumor microenvironment, this makes CDT more selective to tumor cells. Our work not only fabricates nanomedicine with GSH exhausted function for highly potent CDT but also uses metabolic differences to achieve tumor-specific therapy.

Remodeling Macrophages by an Iron Nanotrap for Tumor Growth Suppression.

Tumor-associated macrophages (TAMs) that infiltrate in most tumor tissues are closely correlated with proliferation and metastasis of tumor cells. Immunomodulation of TAMs from pro-tumorigenic M2 phenotype to anti-tumorigenic M1 phenotype is crucial for oncotherapy. Herein, an iron nanotrap was utilized to remodel TAMs for tumor growth inhibition. In the formulation, the ultrasmall nanotrap could capture and targetedly transport endogenous iron into TAMs even inside the tumor. Upon exposing to the lysosomal acidic conditions and intracellular H2O2, iron was released from the nanotrap and produced the generation of oxidative stress, which could reprogram TAMs. The activated M1 macrophages could induce immune responses and suppress tumor growth ultimately. Meanwhile, this metal-free nanotrap with degradability by H2O2 possessed favorable biocompatibility. Our work would present potential opportunities of utilizing endogenous substances for secure treatment of various diseases.

Machine Learning Algorithms for Predicting Fatty Liver Disease.

BACKGROUND: Fatty liver disease (FLD) has become a rampant condition. It is associated with a high rate of morbidity and mortality in a population. The condition is commonly referred as FLD. Early prediction of FLD would allow patients to take necessary preventive, diagnosis, and treatment. The main objective of this research is to develop a machine learning (ML) model to predict FLD that can help medics to classify individuals at high risk of FLD, make novel diagnosis, management, and prevention for FLD. METHODS: Total of 3,419 subjects were recruited with 845 having been screened for FLD. Classification models were used in the detection of the disease. These models include logistic regression (LR), random forest (RF), artificial neural networks (ANNs), k-nearest neighbors (KNNs), extreme gradient boosting (XGBoost), and linear discriminant analysis (LDA). Predictive accuracy was assessed by area under curve (AUC), sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS: We demonstrated that ML models give more accurate predictions, the best accuracy reached to 0.9415 in the XGBoost model. Feature importance analysis not only confirmed some well-known FLD risk factors, but also demonstrated several novel features for predicting the risk of FLD, such as hemoglobin. CONCLUSION: By implementing the XGBoost model, physicians can efficiently identify FLD in general patients; this would help in prevention, early treatment, and management of FLD.

Biological Mediator-Propelled Nanosweeper for Nonpharmaceutical Thrombus Therapy.

Traditional thrombolytic drugs offer limited outcomes due to short circulation half-life and low utilization. Herein, we have designed and constructed a biological mediator-propelled nanosweeper for highly efficient nonpharmaceutical thrombolysis and prevention of thrombus recurrence. Under the near-infrared light irradiation, the nanosweepers were activated to trigger nitric oxide (NO) release, which propelled the nanosweepers to penetrate deeply into the thrombus and resulted in enhanced site-pecific mechanical and photothermal thrombolysis. The experimental evidence confirmed that the ingenious nanosweeper displayed excellent site-specific thrombolytic efficacy even when compared with the clinical thrombolytic drug. In the meantime, as a biological mediator, the release of NO could effectively prevent thrombus recurrence in vivo. Overall, we anticipated that the nanosweeper would provide a promising strategy for the treatment of thrombi.

Elimination of macrophage-entrapped antibiotic-resistant bacteria by a targeted metal-organic framework-based nanoplatform.

A novel metal-organic framework-based platform was designed and constructed for photosensitizer delivery for the elimination of intracellular antibiotic-resistant bacteria. With the merit of targeting and internalizing ability, the system could kill the stealthy bacteria efficiently under light irradiation.

Effects of dietary iron level on growth performance, hematological status, and intestinal function in growing-finishing pigs.

This study investigated the different addition levels of iron (Fe) in growing-finishing pigs and the effect of different Fe levels on growth performance, hematological status, intestinal barrier function, and intestinal digestion. A total of 1,200 barrows and gilts ([Large White × Landrace] × Duroc) with average initial body weight (BW; 27.74 ± 0.28 kg) were housed in 40 pens of 30 pigs per pen (gilts and barrows in half), blocked by BW and gender, and fed five experimental diets (eight replicate pens per diet). The five experimental diets were control diet (basal diet with no FeSO4 supplementation), and the basal diet being supplemented with 150, 300, 450, or 600 mg/kg Fe as FeSO4 diets. The trial lasted for 100 d and was divided into the growing phase (27 to 60 kg of BW) for the first 50 d and the finishing phase (61 to 100 kg of BW) for the last 50 d. The basal diet was formulated with an Fe-free trace mineral premix and contained 203.36 mg/kg total dietary Fe in the growing phase and 216.71 mg/kg in the finishing phase based on ingredient contributions. And at the end of the experiment, eight pigs (four barrows and four gilts) were randomly selected from each treatment (selected one pig per pen) for digesta, blood, and intestinal samples collection. The results showed that the average daily feed intake (P = 0.025), average daily gain (P = 0.020), and BW (P = 0.019) increased linearly in the finishing phase of pigs fed with the diets containing Fe. On the other hand, supplementation with different Fe levels in the diet significantly increased serum iron and transferrin saturation concentrations (P < 0.05), goblet cell numbers of duodenal villous (P < 0.001), and MUC4 mRNA expression (P < 0.05). The apparent ileal digestibility (AID) of amino acids (AA) for pigs in the 450 and 600 mg/kg Fe groups was greater (P < 0.05) than for pigs in the control group. In conclusion, dietary supplementation with 450 to 600 mg/kg Fe improved the growth performance of pigs by changing hematological status and by enhancing intestinal goblet cell differentiation and AID of AA.