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Abstract Background Nerve guide conduits are a promising strategy for reconstructing peripheral nerve defects. Improving the survival rate of seed cells in nerve conduits is still a challenge and microcarriers are an excellent three-dimensional (3D) culture scaffold. Here, we investigate the effect of the 3D culture of microcarriers on the biological characteristics of adipose mesenchymal stem cells (ADSCs) and to evaluate the efficacy of chitosan nerve conduits filled with microcarriers loaded with ADSCs in repairing nerve defects. Methods In vitro, we prepared porous chitosan microspheres by a modified emulsion cross-linking method for loading ADSCs and evaluated the growth status and function of ADSCs. In vivo, ADSCs-loaded microcarriers were injected into chitosan nerve conduits to repair a 12 mm sciatic nerve defect in rats. Results Compared to the conventional two-dimensional (2D) culture, the prepared microcarriers were more conducive to the proliferation, migration, and secretion of trophic factors of ADSCs. In addition, gait analysis, neuro-electrophysiology, and histological evaluation of nerves and muscles showed that the ADSC microcarrier-loaded nerve conduits were more effective in improving nerve regeneration. Conclusions The ADSCs-loaded chitosan porous microcarrier prepared in this study has a high cell engraftment rate and good potential for peripheral nerve repair. Graphical Abstract

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with high pulmonary pressure, which ultimately leads to right heart failure and premature death. Emerging evidence suggests that both hypoxia and epigenetics play a pivotal role in the pathogenesis of PAH development. In this review article, we summarize the current developments in regulation of hypoxia inducible factor (HIF) isoforms in PAH vascular remodeling and the development of suitable animal models for discovery and testing of HIF pathway-targeting PAH therapeutics. In addition, we also discuss the epigenetic regulation of HIF-dependent isoforms in PAH and its therapeutic potential from a new perspective which highlights the importance of HIF isoform-specific targeting as a novel salutary strategy for PAH treatment.

Background and ObjectiveEnhancing therapy choices for varying stages of esophageal cancer and improving patient survival depend on timely and precise diagnosis. Blood metabolites may play a role in either causing or preventing esophageal cancer, but further research is needed to determine whether blood metabolites constitute a genetic risk factor for the disease. In order to tackle these problems, we evaluated the causal association between esophageal cancer and 486 blood metabolites that functioned as genetic proxies using a two-sample Mendelian randomization (MR) study.MethodsWe utilized two-sample MR analyses to evaluate the causal links between blood metabolites and esophageal cancer. For the exposure, we used a genome-wide association study (GWAS) of 486 metabolites, and a GWAS study on esophageal cancer from Sakaue et al. was used for preliminary analyses. Causal analyses employed randomized inverse variance weighted (IVW) as the main method, supplemented by MR-Egger and weighted median (WM) analyses. Sensitivity analyses included the MR-Egger intercept test, Cochran Q test, MR-PRESSO, and leave-one-out analysis. Additionally, independent esophageal cancer GWAS data were utilized for replication and meta-analysis. FDR correction was applied to discern features with causal relationships. For conclusive metabolite identification, we conducted Steiger tests, linkage disequilibrium score regression, and colocalization analyses. Moreover, we utilized the program MetaboAnalyst 5.0 to analyze metabolic pathways.ResultsThis study found an important association between esophageal cancer and three metabolites: 1-linoleoylglycerophosphoethanolamine* [odds ratio (OR) = 3.21, 95% confidence interval (CI): 1.42–7.26, p < 0.01], pyroglutamine* (OR = 1.92, 95% CI: 1.17–3.17, p < 0.01), and laurate (12:0) (OR = 3.06, 95% CI: 1.38–6.78, p < 0.01).ConclusionThis study establishes a causal link between three defined blood metabolites and esophageal cancer, offering fresh insights into its pathogenesis.

N-acetylcysteine (NAC) is a well-established antioxidant that offers exciting opportunities for intestinal health in weaned piglets, while the effects of NAC on muscle and liver has not been fully characterized. Therefore, the present study was performed to investigate the effects of dietary supplementation with NAC on muscle and liver in weaned piglets challenged with lipopolysaccharide (LPS). Twenty-four piglets (24-day-old) were randomly assigned to three treatment groups, the piglets in the control (CTR) and LPS- challenged (LPS) groups were fed the basal diet and those in the LPS+ NAC group was fed the basal diet supplemented with 500 mg/kg NAC. The animal trial lasted for 21 days. At the end of the trial, piglets in the LPS and LPS+ NAC groups were injected intraperitoneally with LPS (100 μg/kg body weight) and piglets in the CTR group were administrated with an equal volume of normal saline. 3 h later, the blood was collected and tissue samples were obtained after 6 h of LPS or normal saline treatment. The results showed that the level of IL-1β, and the mRNA levels of C-X-C motif chemokine receptor 3 (CXCR3) and interferon-γ (IFN-γ) in the liver were up-regulated, and the mRNA levels of insulin-like growth factor 1 (IGF-1), total glutathione (T-GSH), and the ratio of total protein to DNA in the liver were decreased under LPS challenge (P < 0.05). At the same time, LPS increased the level of H2O2 and decreased the content of T-GSH and DNA in the longissimus dorsi and gastrocnemius muscles (P < 0.05). In addition, the percentage of monocytes and the level of epidermal growth factor (EGF) were down-regulated in the LPS treatment (P < 0.05). Interestingly, dietary NAC supplementation reversed the above changes induced by LPS (P < 0.05). Furthermore, NAC might alleviate the muscle and liver injury in LPS-challenged piglets by regulating the expression of genes related to the type I interferon signaling pathway, as well as hypoxia inducible factor 1 (HIF1) and nuclear factor erythroid-2 related factor 2 (Nrf-2). Our findings suggested that dietary supplementation with NAC could benefit the health of muscle and liver in LPS-challenged weaned piglets.

This study aims to elucidate the mechanism underlying the reduced jejunal injury in PEDV-challenged piglets after oral administration of puerarin and poria cocos polysaccharides combination (PR + PCP, PP). Results showed that the PEDV challenge caused damage to the small intestine by injuring the villi and inducing redox imbalance which exacerbated the diarrhea of piglets, while PP administration trended to reduce the PEDV infection-caused diarrhea in piglets by alleviating the jejunal injury and restoring the redox balance. Further proteomics and qPCR results showed that PP could significantly reduce the decline of the protein and mRNA levels of gene SDSL inhibiting cellular autophagy in PEDV-infected jejunum of piglets. The immunofluorescence results showed that the autophagy levels of the jejunum expressing low SDSL caused by PEDV infection in the PEDV group were significantly higher than those of the jejunum expressing higher levels of SDSL caused by PP administration in the PP + PEDV group. These results showed that PEDV infection caused jejunal excessive autophagy in piglets by reducing the expression level of SDSL. However, the restoration of the expression level of SDSL significantly reduced the PEDV infection-caused jejunal excessive autophagy in piglets, leading to a decrease in jejunal injury. Therefore, PP administration can alleviate the excessive autophagy-caused jejunal injury by increasing SDSL levels in PEDV-infected piglets. This result suggests that PP can be used as a potential feed additive to prevent PEDV infection.

Abstract Background and purpose Effective evaluation of rotator cuff tear residual tendon quality is the key to surgical repair. However, until now, the evaluation of rotator cuff tissue by ultrasonic shear wave elasticity (SWE) has been controversial. This prospective study analyzed the association between preoperative SWE and arthroscopic residual tendon quality scores. Methods The shear wave velocity (SWV) of the deltoid muscle, the supraspinatus tendon, and the supraspinatus muscle were measured in full-thickness rotator cuff tear patients. Tendon quality was scored according to tear size, tendon margin, tendon thickness, and footprint coverage during arthroscopy. The arthroscopic scores were used as the gold standard, and the SWV ratio of tendon and muscle (supraspinatus tendon/deltoid and supraspinatus muscle/deltoid) were calculated and correlated with the arthroscopic scores. Result Eighty-nine patients (129 shoulders) were enrolled, including 89 operation shoulders and 40 control shoulders. In the group of operation shoulders, both the SWV ratios of tendon (SWV-RT) and the SWV ratio of muscle (SWV-RM) were negatively correlated with arthroscopic scores (The correlation coefficient (R) ranged from -0.722 to -0.884 and -0.569 to -0.689). The SWV-RT and SWV-RM of the operation shoulders were significantly lower than that of the control shoulders (p

Abstract Although platelet-rich plasma-derived exosomes (PRP-Exos) hold significant repair potential, their efficacy in treating rotator cuff tear (RCT) remains unknown. In light of the potential for clinical translation of fibrin gel and PRP-Exos, we evaluated their combined impact on RCT healing and explored suitable gel implantation techniques. In vitro experiments demonstrated that PRP-Exos effectively enhanced key phenotypes changes in tendon stem/progenitor cells. Multi-modality imaging, including conventional ultrasound, shear wave elastography ultrasound, and micro-computed tomography, and histopathological assessments were performed to collectively evaluate the regenerative effects on RCT. The regenerated tendons exhibited a well-ordered structure, while bone and cartilage regeneration were significantly improved. PRP-Exos participated in the healing process of RCT. In-situ gelation of fibrin gel-encapsulated PRP-Exos at the bone-tendon interface during surgery proved to be a feasible gel implantation method that benefits the healing outcome. Comprehensive multi-modality postoperative evaluations were necessary, providing a reliable foundation for post-injury repair.

ObjectivesTo compare the inter-rectus distance (IRD), rectus abdominis thickness (RAT), and stiffness in women during pregnancy and postpartum and identify the risk and protective factors affecting diastasis recti abdominis (DRA).Materials and methodsA total of 171 pregnant women who volunteered to participate in this study were recruited. Using an ultrasonographic diagnostic instrument with shear wave elastography function, IRD, RAT and the Young’s modulus of the rectus abdominis muscles were measured at 12 weeks, 37 weeks of pregnancy, and 6 weeks postpartum.ResultsThe IRD at 37 weeks was significantly higher than that at 12 weeks and then decreased at 6 weeks postpartum, but it was still higher than that at 12 weeks (p < 0.001). RAT and Young’s modulus decreased significantly at 37 weeks compared with those at 12 weeks and then recovered at 6 weeks postpartum, but they were lower than those at 12 weeks (p < 0.001). IRD at 12 weeks was significantly higher in multiparae than in primiparae (p < 0.001). Moreover, positive correlation between the RAT and Young’s modulus of rectus abdominis muscles at 12 and 37 weeks of gestation and 6 weeks postpartum (p < 0.001) was observed. Multiple linear regression analysis showed that the regression equation was significant (f = 24.856, p < 001).ConclusionOur study identified differences in IRD, thickness and stiffness of the rectus abdominis muscle between early and advanced pregnancy and the postpartum period. The risk and protective factors of DRA may guide pregnant women’s protection and treatment.

Introduction: The escalating pursuit of oil and gas reserves in China has led to increasingly deep and ultra-deep well drilling, encountering extreme temperatures that challenge the heat resistance capabilities of cement slurries. This study addresses the critical need for high-performance cement slurries capable of withstanding ultra-high temperatures during drilling and completion operations.Methods: A novel ultrahigh temperature conventional density (UHTE) cement slurry was formulated by incorporating high-temperature-resistant additives, namely DRF-1S and DRH-2L. An indoor testing framework was established to assess the slurry’s performance across various parameters: Evaluating the slurry’s ability to maintain uniform consistency over time. Measuring the amount of free water separated from the slurry under simulated downhole conditions. Assessing the slurry’s transition from fluid to solid state over time. Determining the compressive strength and other mechanical attributes after curing at elevated temperatures.Results: The experimental findings revealed the following: An optimal silica sand dosage of 50% was found to enhance the overall performance of the UHTE cement slurry. The developed UHTE cement system, fortified with DRF-1S and DRH-2L, demonstrated effective functionality within a temperature range of 180°C to 210°C, representing a significant advancement in high-temperature resistance. The slurry maintained API water loss below 100 mL, ensuring minimal fluid loss during placement. Adjusted thickening time allowed for adequate pumping and placement without premature setting. Settlement stability was maintained below 0.04 g/cm3, indicating excellent homogeneity and stability. Incorporation of the anti-decay material DRB-3S ensured a 28-day compressive strength exceeding 50 MPa at 210°C, signifying robust structural integrity under extreme thermal conditions.Discussion: This research provides a robust foundation for the practical application of UHTE cementing technology in ultra-high temperature environments. The successful development of the UHTE cement slurry system, characterized by its superior temperature resistance, controlled water loss, optimized thickening behavior, and exceptional mechanical properties, paves the way for field trials and further enhancements. Future work will involve testing the effectiveness of the new additive combination under actual downhole conditions and refining the formulation to develop an even more advanced UHTE cementing additive. These advancements will contribute to enhanced wellbore integrity, improved drilling efficiency, and increased safety in deep and ultra-deep oil and gas exploration endeavors in China.

Brain metastasis (BMs) in small cell lung cancer (SCLC) has a very poor prognosis. This study combined WGCNA with the mfuzz algorithm to identify potential biomarkers in the peripheral blood of patients with BMs. By comparing the significantly differentially expressed genes present in BMs samples, we identified ADCY4 as a target for further study. Expression of ADCY4 was used to cluster mfuzz expression pattern, and 28 hub genes for functional enrichment. PPI network analysis were obtained by comparing with differentially expressed genes in BMs. GABRE, NFE4 and LMOD2 are highly expressed in patients with BMs and have a good diagnostic effect. Immunoinfiltration analysis showed that SCLC patients with BMs may be associated with memory B cells, Tregs, NK cell activation, macrophage M0 and dendritic cell activation. prophytic was used to investigate the ADCY4-mediated anti-tumor drug response. In conclusion, ADCY4 can be used as a promising candidate biomarker for predicting BMs, molecular and immune features in SCLC. PCR showed that ADCY4 expression was increased in NCI–H209 and NCI–H526 SCLC cell lines. In vitro experiments confirmed that the expression of ADCY4 was significantly decreased after anti-PD1 antibody treatment, while the expression of energy metabolism factors were significantly different. This study reveals a potential mechanism by which ADCY4 mediates poor prognosis through energy metabolism -related pathways in SCLC.

Porcine epidemic diarrhea virus (PEDV) has caused severe damage to the global pig industry in the past 20 years, creating an urgent demand for the development of associated medications. Flavonoids have emerged as promising candidates for combating coronaviruses. It is believed that certain flavonoids can directly inhibit the 3C-like protease (3CLpro), thus displaying antiviral activity against coronaviruses. In this investigation, we applied a flavonoid library to screen for natural compounds against PEDV 3CLpro. Baicalein and baicalin were found to efficiently inhibit PEDV 3CLproin vitro, with the IC50 value of 9.50 ± 1.02 μM and 65.80 ± 6.57 μM, respectively. A docking analysis supported that baicalein and baicalin might bind to the active site and binding pocket of PEDV 3CLpro. Moreover, both baicalein and baicalin successfully suppressed PEDV replication in Vero and LLC-PK1 cells, as indicated by reductions in viral RNA, protein, and titer. Further investigation revealed that baicalein and baicalin mainly inhibited the early viral replication of the post-entry stage. Furthermore, baicalein showed potential effects on the attachment or invasion step of PEDV. Collectively, our findings provide experimental proof for the inhibitory effects of baicalein and baicalin on PEDV 3CLpro activity and PEDV infection. These discoveries may introduce novel therapeutic strategies for controlling porcine epidemic diarrhea (PED).

BackgroundCoronary slow flow (CSF) has gained significance as a chronic coronary artery disease, but few studies have integrated both biological and anatomical factors for CSF assessment. This study aimed to develop and validate a simple-to-use nomogram for predicting CSF risk by combining biological and anatomical factors.MethodsIn this retrospective case-control study, 1042 patients (614 CSF cases and 428 controls) were randomly assigned to the development and validation cohorts at a 7:3 ratio. Potential predictive factors were identified using least absolute shrinkage and selection operator regression and subsequently utilized in multivariate logistic regression to construct the nomogram. Validation of the nomogram was assessed by discrimination and calibration.ResultsN-terminal pro brain natriuretic peptide, high density lipoprotein cholesterol, hemoglobin, left anterior descending artery diameter, left circumflex artery diameter, and right coronary artery diameter were independent predictors of CSF. The model displayed high discrimination in the development and validation cohorts (C-index 0.771, 95% CI: 0.737-0.805 and 0.805, 95% CI: 0.757-0.853, respectively). The calibration curves for both cohorts showed close alignment between predicted and actual risk estimates, demonstrating improved model calibration. Decision curve analysis suggested high clinical utility for the predictive nomogram.ConclusionThe constructed nomogram accurately and individually predicts the risk of CSF for patients with suspected CSF and may be considered for use in clinical care.

Porcine epidemic diarrhea virus (PEDV) has developed as a global problem for the pig business, resulting in significant financial losses. Black soldier fly extract (BFE) has been proven to improve intestinal growth in pigs after weaning. Consequently, the goal of the present investigation was to explore the effects of BFE supplementation on intestinal function in PEDV-infected piglets. Eighteen piglets were randomly allocated to three groups: control, PEDV, and BFE + PEDV. The piglets in the BFE + PEDV group received 500 mg/kg BW of BFE orally for seven days from day 4 to 10 of the study. On day 9 of the study, six pigs from each group received either clean saline or PEDV solution at a dosage of 106 TCID50 (50% tissue culture infectious dose) per pig. On day 11, samples of blood and intestine were taken for additional investigation. The results indicated a significant decrease in the average daily gain (ADG) of piglets infected with PEDV (p < 0.05). Additionally, PEDV infection led to an alteration of blood indexes and a reduction in plasma D-xylose concentration and villi height in the small intestine, while it increased plasma diamine oxidase activity and small intestinal crypt depth in piglets (p < 0.05). The PEDV infection significantly reduced antioxidant enzyme activity in plasma and the gut, including total superoxide dismutase and catalase, while increasing contents of oxidation-relevant products such as malondialdehyde and hydrogen peroxide in piglets. Moreover, PEDV infection increased the mRNA expression level of antiviral-related genes (p < 0.05). Nutritional supplementation with BFE improved intestinal histomorphological indicators and reduced oxidative stress produced by PEDV infection in piglets. Interestingly, BFE could significantly promote the mRNA expression level of antiviral-related genes in the ileum (p < 0.05). Overall, the preliminary results suggest that dietary BFE could improve intestinal function in piglets after PEDV infection. Currently, the findings put a spotlight on the role of BFE in the prevention and treatment of PED in piglets.

This study is to explore the effects of natural tannin (NBT) on intestinal injury in piglets challenged with enterotoxigenic Escherichia coli (ETEC). Thirty-two 7-day-old piglets were divided into four groups: I) control group, piglets were fed a basic diet without challenge; II) ETEC group, piglets were fed a basic diet and challenged with enterotoxigenic E. coli; III) NBT + ETEC group, piglets were fed a basic diet with supplementation of 2 g/kg NBT and challenged with enterotoxigenic E. coli; and IV) ZnO + ETEC group, piglets were fed a basic diet with supplementation of 3 g/kg ZnO and challenged with enterotoxigenic E. coli. Results showed that diarrhoea rate was significantly increased in ETEC group, whereas it was decreased after NBT supplementation (P < 0.05); NBT supplementation significantly increased the average daily gain of ETEC-infected piglets. ETEC group showed damaged intestinal morphology (as indicated by decreased villus height, surface area and increased crypt depth) and barrier function (as indicated by decreased d-xylose content and increased diamine oxidase activity), induced oxidative stress (as indicated by increased myeloperoxidase activity) while supplementation of NBT had an obvious impact on the recovery of intestinal function and alleviated the oxidative damage. Further analysis showed that NBT could decrease the expression of genes related to intestinal injury (matrix metalloproteinase-3), and specifically upregulate the expression of oxidative stress-related genes (nuclear factor erythroid 2-related factor 2 and hypoxia inducible factor-1). Overall, dietary supplementation of NBT relieved intestinal injury and oxidative stress in piglets challenged with ETEC. NBT could be an alternative to ZnO as a feed additive in piglet diet.

The present study was conducted to decipher the protection effects of ellagic acid (EA) on piglets infected with porcine epidemic diarrhea virus (PEDV). Thirty 7-day-old piglets were randomly assigned to three treatment groups: control, PEDV, and EA + PEDV groups. After a 3-day period of adaption, piglets in the EA + PEDV group were orally administered with 20 mg/kg·BW EA during days 4-11 of the trial. On day 8, piglets were orally administered with PEDV at a dose of 106 TCID50 (50% tissue culture infectious dose) per pig. Additionally, intestinal porcine epithelial (IPEC-1) cells infected with PEDV were used to investigate the anti-PEDV effect of EA in vitro. The results showed that EA at a dose of 10-40 μmol/L increased the viability of PEDV-infected IPEC-1 cells, and EA administration mitigated intestinal edema in piglets challenged with PEDV. Further studies indicated that EA treatment significantly increased the proportion of white blood cells in blood and concentrations of IL-6, IL-1β, and IL-10 in the serum, but decreased the TNF-α content and gene expression of IL-6, IL-1β, TNF-α, and CXCL2 in the jejunum. Moreover, EA intervention considerably elevated the activity of total superoxide dismutase (T-SOD), but decreased the H2O2 concentration in the ileum of piglets. Importantly, EA suppressed the increased expression of antiviral-related genes and proteins (including MXI, ISG15, HSP70, and p-IRF7) induced by PEDV challenge in the jejunum. Furthermore, PEDV infection increased the protein abundance of p-JAK2 and p-STAT3, which were further enhanced by EA supplementation. In conclusion, our results revealed that EA could promote the restoration of intestinal homeostasis by regulating the interferon pathway that was interrelated with the activation of JAK2/STAT3 signaling. These findings provide theoretical basis for the use of EA as a therapy targeting PEDV infection in piglets.

Osteoarthritis (OA) is one of the most common degenerative joint diseases, significantly impacting individuals and society. With the acceleration of global aging, the incidence of OA is increasing. The pathogenesis of osteoarthritis is not fully understood, and there is no effective way to alleviate the progression of osteoarthritis. Therefore, it is necessary to develop new disease models and seek new treatments for OA. Cartilage organoids are three-dimensional tissue masses that can simulate organ structure and physiological function and play an important role in disease modeling, drug screening, and regenerative medicine. This review will briefly analyze the research progress of OA, focusing on the construction and current development of cartilage organoids, and then describe the application of cartilage organoids in OA modeling, drug screening, and regeneration and repair of cartilage and bone defects. Finally, some challenges and prospects in the development of cartilaginous organoids are discussed.

BackgroundEnterotoxigenic Escherichia coli (ETEC), an important intestinal pathogen, poses a significant threat to the intestinal health of piglets. Bacillus coagulans (BC), a potential feed additive, can improve the intestinal function of piglets. However, the effects of BC on growth performance and intestinal function in ETEC-infected piglets are still unclear. In this study, 24 7-day-old piglets were randomly assigned to three treatment groups: control group (fed a basal diet), ETEC group (fed a basal diet and challenged with ETEC K88) and BC+ETEC group (fed a basal diet, orally administered BC, challenged with ETEC K88). During Days 1-6 of the trial, piglets in the BC+ETEC group were orally administered BC (1×108CFU/kg). On Day 5 of the trial, piglets in the ETEC and BC+ETEC groups were orally administered ETEC K88 (5×109CFU/piglet). Blood, intestinal tissue, and content samples were collected from the piglets on Day 7 of the trial.ResultsThe average daily feed intake in the ETEC group was significantly reduced compared to that of the control group. Further research revealed that ETEC infection significantly damaged the structure of the small intestine. Compared to the control group, the villus height and surface area of the jejunum, the ratio of villus height to crypt depth in the duodenum and jejunum, and the activities of catalase and total superoxide dismutase in the jejunum were significantly reduced. Additionally, the levels of myeloperoxidase in the jejunum, malondialdehyde in the plasma and jejunum, and intestinal epithelial apoptosis were significantly increased in the ETEC group. However, BC supplementation had significantly mitigated these negative effects in the BC+ETEC group by Day 7 of the trial. Moreover, BC supplementation improved the gut microbiota imbalance by reversing the decreased numbers of Enterococcus, Clostridium and Lactobacillus in jejunum and Escherichia coli, Bifidobacterium and Lactobacillus in the colon, as well as the increased number of Escherichia coli in the jejunum induced by ETEC K88.ConclusionsOverall, BC supplementation reduced the decline in average daily feed intake in ETEC K88-infected piglets by attenuating intestinal epithelial apoptosis and oxidative stress and regulating the gut microbiota. This suggests that BC may be used to prevent intestinal infections caused by ETEC in piglets.

The aim of this study was to investigate the effects of dietary l-glutamine (Gln) supplementation on the morphology and function of the intestine and the growth of muscle in piglets. In this study, sixteen 21-day-old piglets were randomly divided into two groups: the Control group (fed a basal diet) and the Gln group (fed a basal diet supplemented with 0.81% Gln). Blood, gut, and muscle samples were collected from all piglets on Day 20 of the trial. Compared with the Control group, the supplementation of Gln increased (p < 0.05) the villus height, villus width, villus surface area, and villus height/crypt depth ratio of the small intestine. Furthermore, the supplementation of Gln increased (p < 0.05) total protein, total protein/DNA, and RNA/DNA in both the jejunum and ileum. It also increased (p < 0.05) the concentrations of carnosine and citrulline in the jejunal mucosa, as well as citrulline and cysteine concentrations in the ileum. Conversely, Gln supplementation decreased (p < 0.05) Gln concentrations in both the jejunum and ileum, along with β-aminoisobutyric acid and 1-Methylhistidine concentrations, specifically in the ileum. Subsequent research revealed that Gln supplementation increased (p < 0.05) the mRNA levels for glutathione-S-transferase omega 2 and interferon-β in the duodenum. In addition, Gln supplementation led to an increase (p < 0.05) in the number of Lactobacillus genus in the colon, but a decrease (p < 0.05) in the level of HSP70 in the jejunum and the activity of diamine oxidase in plasma. Also, Gln supplementation reduced (p < 0.05) the mRNA levels of glutathione-S-transferase omega 2 and interferon stimulated genes, such as MX1, OAS1, IFIT1, IFIT2, IFIT3, and IFIT5 in both the jejunum and ileum, and the numbers of Clostridium coccoides, Enterococcus genus, and Enterobacterium family in the colon. Moreover, Gln supplementation enhanced (p < 0.05) the concentrations of total protein, RNA/DNA, and total protein/DNA ratio in the longissimus dorsi muscle, the concentrations of citrulline, ornithine, arginine, and hydroxyproline, and the mRNA level of peptide transporter 1, while reducing the contents of hydrogen peroxide and malondialdehyde and the mRNA level of glutathione-S-transferase omega 2 in the longissimus dorsi muscle. In conclusion, dietary Gln supplementation can improve the intestinal function of piglets and promote the growth of the longissimus dorsi muscle.

IntroductionPheochromocytomas combined with aortic dissections are rare. Treatment of aortic dissection can be complicated by the presence of pheochromocytomas.Case presentationwe present the case of a 48-year-old male who visited the hospital with chest and back pain for 13 h. Enhanced computed tomography (CT) revealed a type B aortic dissection combined with a left adrenal mass (72 mm). Elevated 24-h urinary vanillylmandelic acid levels can aid in the diagnosis of pheochromocytomas. Aortic dissection due to unstable hypertension secondary to pheochromocytoma is rare and complicates the procedure. Thoracic endovascular aortic repair was performed, and antihypertensive treatments were administered after surgery. After hypertension was addressed and the patient was stable, laparoscopic resection of the adrenal mass was performed.Conclusionsdespite its rarity, it is important to consider pheochromocytoma as a differential factor for unstable hypertension when an aortic dissection is found.

This study aimed to investigate the effect of N-acetylcysteine (NAC) on indomethacin (IDMT)-induced intestinal injury in a piglet model and explore the underlying molecular mechanisms. Piglets were randomly divided into 3 treatment groups: (1) control group; (2) IDMT group; (3) NAC+IDMT group. The results showed that NAC administration significantly increased the average daily gain of piglets, attenuated the intestine hyperemia, and restored normal jejunal morphology. Further studies indicated that NAC administration significantly increased plasma citrulline concentration and jejunal villin expression, but decreased the content of proinflammatory cytokines in plasma and jejunum of IDMT-stimulated piglets. NAC administration selectively decreased the proportion of eosinophils but not neutrophils in plasma. Furthermore, NAC administration significantly increased the activities of superoxide dismutase and catalase in plasma but decreased the concentrations of hydrogen peroxide (plasma) and malondialdehyde (plasma and jejunum), as well as the activity of myeloperoxidase (jejunum) when comparing NAC+IDMT group with IDMT group. Gene Ontology analysis showed that the significantly enriched molecular function term was “ubiquitin-like protein ligase binding” for NAC+IDMT versus IDMT differentially regulated genes. In the biological process category, differentially regulated genes of NAC+IDMT versus IDMT were mainly enriched in immune-related terms. The major enrichments for differentially regulated proteins (DRPs) of NAC+IDMT versus IDMT were terms involved in lipid metabolism and immune response. KEGG pathway enrichment analysis showed that “arginine biosynthesis” was a significant enrichment term for the DRPs of NAC+IDMT versus IDMT. Further studies demonstrated that NAC administration up-regulated argininosuccinate synthase 1 mRNA expression and down-regulated arginase mRNA expression in the jejunum of IDMT-stimulated piglets. Moreover, the content of nitric oxide was restored to a normal level with the reduction of nitric oxide synthase activity. NAC administration ameliorated intestinal injury in IDMT-challenged piglets by enhancing antioxidant and anti-inflammatory functions and modulating arginine metabolism in the small intestine.

The mode field distribution at the distal end of a multimode fiber can vary randomly when environmental perturbations introduce changes in the relative phases of different eigenmodes and variations in coupling among modes. Random rotations of the high-order mode-field distribution at the distal end can produce large coupling losses at the multimode waveguide grating coupler (MWGC) in the fiber-chip interface. In this paper, we propose a solution to this problem by using a novel approach based on controlling the relative phases and amplitudes of different modes launched at the proximal end of the fiber. We implemented an integrated mesh of Mach Zehnder Interferometer at the transmitter to demonstrate control of the distal end mode field distribution to ensure low coupling losses in the receiver's MWGC. The MWGC on the silicon-on-insulator (SOI) platform had measured coupling efficiency of (−5.7 dB, −7.1 dB) for (LP01x, LP11ax) modes, without needing any manual adjustment to align the mode orientation with the MWGC. The coherent Mach-Zehnder Interferometer (MZI) network can be dynamically controlled to produce the desired mode pattern at the distal end of the FMF to enable low-loss coupling at the distal end. This enables the practical deployment of mode division multiplexing with MWGC without needing manual control of fiber orientation at the receiver. The proof-of-concept experiment demonstrates that the transmitter mode control is suitable for future deployment of mode division-multiplexing (MDM) data center interconnects.

Background: Osteoarthritis (OA) is a common degenerative joint disease with significant negative impact on the quality of life. It has been reported that abnormal upregulation of β-catenin signaling could lead to OA development; however, the upstream regulatory mechanisms of β-catenin signaling have not been determined. Methods: Primary rat chondrocytes and ATDC5 chondrocyte cell line were stimulated with AKT2 and treated with or without metformin, an adenosine 5′-monophosphate-activated protein kinase (AMPK) activator. Westerrn blot analysis, luciferase reporter assay and immunofluorescent (IF) staining were performed to examine changes in β-cateninS552 phosphorylation and β-catenin nuclear translocation in ATDC5 cells and in primary chondrocytes. Results: We found that metformin inhibited β-cateninS552 phosphorylation in ATDC5 cells and in primary chondrocytes in a time-dependent manner. Metformin inhibited β-catenin nuclear translocation and β-catenin reporter activity. In addition, metformin also attenuated the expression of β-catenin downstream target genes. We also demonstrated that metformin inhibited β-cateninS552 phosphorylation in articular cartilage in mice. Conclusion: These findings suggest that metformin may exert its chondro-protective effect at least in part through the inhibition of β-catenin signaling in chondrocytes. The translational potential of this article: This study demonstrated the interaction between AMPK and β-catenin signaling in chondrocytes and defined novel molecular targets for the treatment of OA disease.

Abstract Background The purpose of this research is to determine the effects of sodium gluconate (SG) on the growth performance and intestinal function in weaned pigs challenged with a recombinant Escherichia coli strain expressing heat-stable type I toxin (STa). Results Pigs (n = 24, 21 days of age) were randomly allocated to three treatments: Control group (pigs were fed basal diet), STa group (pigs were fed basal diet and challenged with a recombinant E. coli strain expressing STa), and SG group (pigs were fed basal diet supplemented with 2500 mg/kg sodium gluconate and challenged with a recombinant E. coli strain expressing STa). The trial period lasted for 15 days. On days 12 and 13, pigs in the STa and SG groups were orally administered with the recombinant Escherichia coli strain, while those in the control group were orally administered with normal saline at the same volume. On day 15, blood, intestinal tissues and colonic contents were collected for further analysis. Results showed that dietary SG supplementation had a tendency to increase average daily gain, and reduced (P

Abstract Background Primary thyroid lymphoma (PTL) and papillary thyroid carcinoma (PTC) are both thyroid malignancies, but their therapeutic methods and prognosis are different. This study aims to explore their sonographic and computed tomography(CT)features, and to improve the early diagnosis rate. Methods The clinical and imaging data of 50 patients with non-diffuse PTL and 100 patients with PTC confirmed by pathology were retrospectively analysed. Results Of the 150 patients, from the perspective of clinical data, between non-diffuse PTL and PTC patients existed significant difference in age, maximum diameter of nodule, asymmetric enlargement and Hashimoto’s thyroiditis (P 0.05). With respect to sonographic feature, non-diffuse PTL patients had a higher proportion than PTC patients in markedly hypoechoic, internal linear echogenic strands, posterior echo enhancement, rich vascularity, lack of calcification and homogeneous enhancement, with statistically significant difference (P

Hepatocellular carcinoma is a common gastrointestinal malignancy with a high mortality rate and limited treatment options. Molecularly targeted drugs combined with immune checkpoint inhibitors have shown unique advantages over single-agent applications, significantly prolonging patient survival. This paper reviews the research progress of molecular-targeted drugs combined with immune checkpoint inhibitors in the treatment of hepatocellular carcinoma and discusses the effectiveness and safety of the combination of the two drugs to provide a reference for the further application of molecular-targeted drugs combined with immune checkpoint inhibitors in clinical practice.

To understand and respond to the common ecological and environmental challenges faced by human beings, this study investigated the relationship between territorial spatial development (TSD), eco-environmental responses, and territorial spatial planning (TSP) from the perspective of human-environment interactions and explores a feasible way to modulate these human-environment interactions by taking China’s TSP practice as an illustrative case. The research results show that (1) the interplay between territorial development, resource utilization, and environmental feedback forms the crux of human-environment interactions. Notably, eco-environment responses, one of which is the spread of germs, coupled with human development and utilization behavior constitute a complete negative feedback loop. Human beings’ adjustment to the unbalanced conditions in these interactions, employing institutions, technology, planning, and other tools, constitutes a positive cycle within human-environment interactions. (2) TSP can regulate the whole process of human-environment interactions through mechanisms such as coordination and control, adaptation and mitigation, and consolidation and restoration. (3) Unreasonable agricultural development and urban expansion have triggered intense negative feedback on the ecological environment. (4) The Chinese government has carried out a top-down TSP reform initiative to establish a unified planning system. This aims to alleviate the adverse ecological and environmental effects caused by TSD and build a more secure territory space pattern. Therefore, nations around the globe should innovate their spatial planning management systems and spatial planning systems, standardize and guide the development and utilization of spatial resources, and coordinate the relationship between humans and the environment.

Abstract Background Synovial sarcoma is a soft tissue sarcoma of temporarily unknown histologic origin with the ability for biphasic differentiation, occurring mostly in the vicinity of large joints of the extremities. Synovial sarcoma that originates in the liver is extremely rare. Only 7 cases have been reported in the domestic and international literature. Case presentation We report an 11-year-old female patient who underwent partial hepatectomy for a liver mass. Microscopically, she was diagnosed with hepatic biphasic synovial sarcoma. Cytogenetic examination revealed the fusion gene SS18-SSX1 (+), which confirmed the diagnosis. Conclusion Synovial sarcoma of the liver is a rare malignancy that is difficult to diagnose. Confirmation of diagnosis is based on histopathological assessment combined with immunohistochemical staining and, if necessary, cytogenetic aids.

BackgroundThe effects of cinnamaldehyde, carvacrol and thymol complex (CCT) on the growth performance and intestinal function of piglets challenged with lipopolysaccharide (LPS) were determined. Colistin sulphate (CS) was as a positive control.MethodPiglets (n = 24, 32 days of age) were allocated to four treatments: Control group (fed basal diet), LPS group (fed basal diet), CS+LPS group (fed basal diet + 50 mg/kg CS), and CCT+LPS group (fed basal diet + 50 mg/kg CCT).ResultsResults showed that diarrhea rates of piglets were significantly reduced by CCT and CS supplementation respectively. Further research showed that CS supplementation tended to improve the intestinal absorption function in LPS-challenged piglets. Moreover, CS supplementation significantly reduced the contents of cortisol in blood and malondialdehyde in the duodenum and the activities of inducible nitric oxide synthase in the duodenum and ileum and total nitric oxide synthase in the ileum in LPS-challenged piglets. CS supplementation significantly increased the activities of sucrase in the ileum and myeloperoxidase in the jejunum in LPS-challenged piglets. CS supplementation significantly alleviated the reduced mRNA levels of immune-related genes (IL-4, IL-6, IL-8, IL-10) in mesenteric lymph nodes and jejunum and mucosal growth-related genes (IGF-1, mTOR, ALP) in LPS-challenged piglets. These results suggested that CS supplementation improved the intestinal function in LPS-challenged piglets by improving intestinal oxidative stress, immune stress, and absorption and repair function. However, although CCT supplementation improved oxidative stress by reducing (p < 0.05) the content of malondialdehyde and the activity of nitric oxide synthase in the duodenum, CCT supplementation tended to aggravate the intestinal absorption dysfunction in LPS-challenged piglets. Furthermore, compared with the control and LPS groups, CCT supplementation remarkably elevated the content of prostaglandin in plasma and the mRNA levels of pro-inflammatory factor IL-6 in mesenteric lymph nodes and jejunum, and reduced the activity of maltase in the ileum in LPS-challenged piglets. These results suggested that CCT supplementation had a negative effect on intestinal function by altering intestinal immune stress response and reducing disaccharidase activity in LPS-challenged piglets.ConclusionsCompared to CS, CCT supplementation exhibited a negative effect on intestinal function, suggesting whether CCT can be as an effective feed additive still needs further study.

This study was to investigate the impact of α-terpineol (α-TPN) and Bacillus coagulans (B. coagulans) on weaned piglets infected with Enterotoxigenic Escherichia coli (ETEC). Thirty-two weaned piglets were assigned into four treatments: Control group (basal diet), STa group (basal diet + 1 × 1010 CFU ETEC), TPN+STa group (basal diet + 0.01% α-TPN + ETEC) and BC+STa group (basal diet + 2 × 106 CFU B. coagulans + ETEC). Result showed that both α-TPN and B. coagulans could alleviate diarrhea (decreased diarrhea rate), intestinal injury (improved intestinal morphology, decreased blood I-FABP concentration, increased protein expression level of Occludin), oxidative stress (increased GSH-Px activity and decreased MDA content) and inflammation (altered concentration of TNF-α, IL-1β in blood) induced by ETEC infection. Mechanism investigation further demonstrated that the beneficial effects of α-TPN and B. coagulans supplementation upon ETEC infection may be achieved by decreasing the protein expression levels of caspase-3, AQP4 and p-NF-κB and decreasing the gene expression levels of INSR and PCK1. Besides, α-TPN supplementation could specifically decreased expression level of gene b0,+AT, and B. coagulans supplementation could specifically decreased expression level of gene AQP10 and protein HSP70 in ETEC-infected weaned piglets. These results suggested that α-TPN and B. coagulans can be used as antibiotic alternatives against ETEC infection in weaned piglets.

Abstract Background Exosomes derived from stem cells have been widely studied for promoting regeneration and reconstruction of multiple tissues as “cell-free” therapies. However, the applications of exosomes have been hindered by limited sources and insufficient therapeutic potency. Results In this study, a stem cell-mediated gene therapy strategy is developed in which mediator mesenchymal stem cells are genetically engineered by bone morphogenetic protein-2 gene to produce exosomes (MSC-BMP2-Exo) with enhanced bone regeneration potency. This effect is attributed to the synergistic effect of the content derived from MSCs and the up-regulated BMP2 gene expression. The MSC-BMP2-Exo also present homing ability to the injured site. The toxic effect of genetical transfection vehicles is borne by mediator MSCs, while the produced exosomes exhibit excellent biocompatibility. In addition, by plasmid tracking, it is interesting to find a portion of plasmid DNA can be encapsulated by exosomes and delivered to recipient cells. Conclusions In this strategy, engineered MSCs function as cellular factories, which effectively produce exosomes with designed and enhanced therapeutic effects. The accelerating effect in bone healing and the good biocompatibility suggest the potential clinical application of this strategy. Graphical Abstract

This study was conducted to investigate the effect of Lactobacillus zeae LB2 on the gut microbiota in piglets infected with enterotoxigenic Escherichia coli (ETEC). Thirty-two healthy 7-day-old piglets were randomly divided into four treatment groups: control group (basal diet), LB2 group (supplemented with 1 × 108 CFU/pig/day L. zeae LB2), ETEC group (infected with 1 × 1010 CFU/pig/day ETEC) and ETEC+LB2 group (LB2 supplementation + ETEC infection). Intestinal contents were collected for DNA extraction and Illumina sequencing. Significant result was observed for alpha diversity in the four intestinal sections, and both ETEC infection and LB2 supplementation showed a higher Chao1 alpha diversity. At the phylum level, Firmicutes and Bacteroidetes were dominant in the healthy piglets, while Proteobacteria were dominant in the ETEC-infected piglets. At the genus level, ETEC infection decreased the abundance of Prevotella, Ruminococcaceae, Lactobacillus, Alloprevotella, Flavobacterium, and Sutterella and increased the abundance of Actinobacillus. The LB2 supplementation reduced the abundance of Ruminococcaceae, Actinobacillus, Porphyromonas, and Alloprevotella, and increased the abundance of Prevotella and Lactobacillus. Both ETEC infection and LB2 supplementation affected several functional pathways associated with cellular processes, environmental information processing, genetic information processing, diseases, metabolism, and organismal systems. In summary, ETEC infection induced dysbiosis of the gut microbiome in piglets, while L. zeae supplementation could positively regulate the gut microbiome during ETEC infection. Therefore, L. zeae LB2 may be an ideal probiotic for the prevention or treatment of ETEC infection.

Objective: Temporomandibular joint (TMJ) osteoarthritis (OA) is a type of TMJ disorders with clinical symptoms of pain, movement limitation, cartilage degeneration and joint dysfunction. This review article is aiming to summarize recent findings on signaling pathways involved in TMJ OA development and progression. Methods: Most recent findings in TMJ OA studies have been reviewed and cited. Results: TMJ OA is caused by inflammation, abnormal mechanical loading and genetic abnormalities. The molecular mechanisms related to TMJ OA have been determined using different genetic mouse models. Recent studies demonstrated that several signaling pathways are involved in TMJ OA pathology, including Wnt/β-catenin, TGF-β and BMP, Indian Hedgehog, FGF, NF-κB, and Notch pathways, which are summarized in this review article. Alterations of these signaling pathways lead to the pathological changes in TMJ tissues, affecting cartilage matrix degradation, catabolic metabolism and chondrocyte apoptosis. Conclusion: Multiple signaling pathways were involved in the pathological process of TMJ OA. New therapeutic strategies, such as stem cell application, gene editing and other techniques may be utilized for TMJ OA treatment. The translational potential of this article: TMJ OA is a most important subtype of TMJ disorders and may lead to substantial joint pain, dysfunction, dental malocclusion, and reduced health-related quality of life. This review article summarized current findings of signaling pathways involved in TMJ OA, including Wnt/β-catenin, TGF-β and BMP, Indian Hedgehog, FGF, NF-κB, and Notch pathways, to better understand the pathological mechanisms of TMJ OA and define the molecular targets for TMJ OA treatment.

Axin1 is a key regulator of canonical Wnt signaling pathway. Roles of Axin1 in skeletal development and in disease occurrence have not been fully defined. Here, we report that Axin1 is essential for lower limb development. Specific deletion of Axin1 in limb mesenchymal cells leads to fibular hemimelia (FH)-like phenotype, associated with tarsal coalition. Further studies demonstrate that FH disease is associated with additional defects in Axin1 knockout (KO) mice, including decreased osteoclast formation and defects in angiogenesis. We then provide in vivo evidence showing that Axin1 controls limb development through both canonical β-catenin and BMP signaling pathways. We demonstrate that inhibition of β-catenin or BMP signaling could significantly reverse the FH phenotype in mice. Together, our findings reveal that integration of β-catenin and BMP signaling by Axin1 is required for lower limb development. Defect in Axin1 signaling could lead to the development of FH disease.

Porcine epidemic diarrhea virus (PEDV) has become a challenging problem in pig industry all over the world, causing significant profit losses. Tannins and organic zinc have been shown to exert protective effects on the intestinal dysfunction caused by endotoxins. However, there is little information on tannic acid-chelated zinc (TAZ) supplementation in the diet of newborn piglets. This study was conducted to determine the effects of TAZ on the intestinal function of piglets infected with PEDV. Thirty-two 7-day-old piglets were randomly allocated to 1 of 4 treatments in a 2 × 2 factorial design consisting of 2 diets (0 or 50 mg/kg BW TAZ) and challenge (saline or PEDV). On day 9 of the trial, 8 pigs per treatment received either sterile saline or PEDV solution at 106 TCID50 (50% tissue culture infectious dose) per pig. Pigs infected with PEDV had greater diarrhea rate and lower average daily gain (ADG) (P < 0.05). PEDV infection decreased plasma D-xylose concentration, most antioxidative enzyme activities in plasma and intestine, as well as the small intestinal villus height (P < 0.05). Plasma diamine oxidase and blood parameters were also affected by PEDV infection. Dietary supplementation with TAZ could ameliorate the PEDV-induced changes in all measured variables (P < 0.05). Moreover, TAZ decreased the concentration of malondialdehyde in plasma, duodenum, jejunum, and colon (P < 0.05). Collectively, our results indicated that dietary TAZ could alleviate PEDV induced damage on intestinal mucosa and antioxidative capacity, and improve the absorptive function and growth in piglets. Therefore, our novel findings also suggest that TAZ, as a new feed additive for neonatal and weaning piglets, has the potential to be an alternative to ZnO.

Antarctica is the coldest, driest, and most windy continent on earth. The major terrestrial vegetation consists of cryptogams (mosses and lichens) and two vascular plant species. However, the molecular mechanism of cold tolerance and relevant regulatory networks were largely unknown in these Antarctic plants. Here, we investigated the global alterations in metabolites and regulatory pathways of an Antarctic moss (Pohlia nutans) under cold stress using an integrated multi-omics approach. We found that proline content and several antioxidant enzyme activities were significantly increased in P. nutans under cold stress, but the contents of chlorophyll and total flavonoids were markedly decreased. A total of 559 metabolites were detected using ultra high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS). We observed 39 and 71 differentially changed metabolites (DCMs) after 24 h and 60 h cold stress, indicating that several major pathways were differentially activated for producing fatty acids, alkaloids, flavonoids, terpenoids, and phenolic acids. In addition, the quantitative transcriptome sequencing was conducted to uncover the global transcriptional profiles of P. nutans under cold stress. The representative differentially expressed genes (DEGs) were identified and summarized to the function including Ca2+ signaling, ABA signaling, jasmonate signaling, fatty acids biosynthesis, flavonoid biosynthesis, and other biological processes. The integrated dataset analyses of metabolome and transcriptome revealed that jasmonate signaling, auxin signaling, very-long-chain fatty acids and flavonoid biosynthesis pathways might contribute to P. nutans acclimating to cold stress. Overall, these observations provide insight into Antarctic moss adaptations to polar habitats and the impact of global climate change on Antarctic plants.

ObjectiveTo establish and verify a nomogram based on multimodal ultrasonography (US) for the assessment of the malignancy risk of thyroid nodules and to explore its value in distinguishing benign from malignant thyroid nodules.MethodsFrom September 2020 to December 2021, the data of 447 individuals with thyroid nodules were retrieved from the multicenter database of medical images of the National Health Commission’s Capacity Building and Continuing Education Center, which includes data from more than 20 hospitals. All patients underwent contrast-enhanced US (CEUS) and elastography before surgery or fine needle aspiration. The training set consisted of three hundred datasets from the multicenter database (excluding Zhejiang Cancer Hospital), and the external validation set consisted of 147 datasets from Zhejiang Cancer Hospital. As per the pathological results, the training set was separated into benign and malignant groups. The characteristics of the lesions in the two groups were analyzed and compared using conventional US, CEUS, and elastography score. Using multivariate logistic regression to screen independent predictive risk indicators, then a nomogram for risk assessment of malignant thyroid nodules was created. The diagnostic performance of the nomogram was assessed utilizing calibration curves and receiver operating characteristic (ROC) from the training and validation cohorts. The nomogram and The American College of Radiology Thyroid Imaging, Reporting and Data System were assessed clinically using decision curve analysis (DCA).ResultsMultivariate regression showed that irregular shape, elastography score (≥ 3), lack of ring enhancement, and unclear margin after enhancement were independent predictors of malignancy. During the training (area under the ROC [AUC]: 0.936; 95% confidence interval [CI]: 0.902–0.961) and validation (AUC: 0.902; 95% CI: 0.842–0.945) sets, the multimodal US nomogram with these four variables demonstrated good calibration and discrimination. The DCA results confirmed the good clinical applicability of the multimodal US nomogram for predicting thyroid cancer.ConclusionsAs a preoperative prediction tool, our multimodal US-based nomogram showed good ability to distinguish benign from malignant thyroid nodules.

The objective of this study was to investigate the effect of puerarin supplementation on the growth performance and intestinal function of piglets challenged with enterotoxigenic Escherichia coli (ETEC) K88. Twenty-four ternary crossbred piglets were randomly assigned to three treatment groups: control group, ETEC group (challenged with ETEC K88 on day 8), and ETEC + Puerarin group (supplemented with 5 mg/kg puerarin and challenged with ETEC K88 on day 8). All piglets were orally administered D-xylose (0.1 g/kg body weight) on day 10, and blood samples were collected after 1 h. Subsequently, piglets were killed and intestinal samples were collected for further analysis. The results showed that puerarin supplementation significantly decreased the adverse effects of ETEC K88-challenged piglets; significantly improved growth performance; increased the number of Bifidobacterium in the colon and Lactobacillus in the jejunum, cecum and colon; decreased the number of Escherichia coli in the jejunum and cecum; reduced the hydrogen peroxide content in the jejunum and myeloperoxidase activity in the jejunum and ileum; and increased the activities of catalase and superoxide dismutase in the jejunum and ileum. In addition, puerarin supplementation alleviated ETEC K88-induced intestinal injury in piglets, significantly downregulated the mRNA level of Interleukin-1β and upregulated the mRNA levels of intercellular cell adhesion molecule-1, myxovirus resistance protein 1, myxovirus resistance protein 2, and guanylate-binding protein-1 in the small intestine of piglets. In conclusion, dietary supplementation with puerarin could attenuate ETEC K88-induced intestinal injury by increasing the antioxidant and anti-inflammatory capacity and the number of beneficial intestinal bacteria in piglets.

The Antarctic continent has extreme natural environment and fragile ecosystem. Mosses are one of the dominant floras in the Antarctic continent. However, their genomic features and adaptation processes to extreme environments remain poorly understood. Here, we assembled the high-quality genome sequence of the Antarctic moss (Pohlia nutans) with 698.20 Mb and 22 chromosomes. We found that the high proportion of repeat sequences and a recent whole-genome duplication (WGD) contribute to the large size genome of P. nutans when compared to other bryophytes. The genome of P. nutans harbors the signatures of massive segmental gene duplications and large expansions of gene families, likely facilitating neofunctionalization. Genomic characteristics that may support the Antarctic lifestyle of this moss comprise expanded gene families involved in phenylpropanoid biosynthesis, unsaturated fatty acid biosynthesis, and plant hormone signal transduction. Additional contributions include the significant expansion and upregulation of several genes encoding DNA photolyase, antioxidant enzymes, flavonoid biosynthesis enzymes, possibly reflecting diverse adaptive strategies. Notably, integrated multi-omic analyses elucidate flavonoid biosynthesis may function as the reactive oxygen species detoxification under UV-B radiation. Our studies provide insight into the unique features of the Antarctic moss genome and their molecular responses to extreme terrestrial environments.

Abstract Background The exact incidence, clinical features and uniform diagnostic criteria of exogenous insulin autoimmune syndrome (EIAS) are still unclear. The purpose of this study is to explore the clinical characteristics of EIAS and to provide a structural approach for clinical diagnosis, treatment and prevention. Methods The literature on EIAS in Chinese and English from 1970 to 2020 was collected for retrospective analysis. Results A total of 122 patients (33 males and 73 females) were included in the study with a median age of 67 years (range 14–86) and a median HbA1c of 7.7%. EIAS mainly occurred in type 2 diabetes mellitus patients using premixed insulin. Symptoms manifested were hypoglycemia in 86.54%, recurrent episodes of symptomatic hypoglycemia in 35.58%, nocturnal hypoglycemia along with daytime hyperglycemia in 21.15% and recurrent hypoglycemia after discontinued insulin in 64.43%. The onset of symptoms occurred at night, in the early morning or during fasting, ranging from a few days to 78 months after the administration of insulin. The mean blood glucose level during the hypoglycemic phase was 2.21 mmol/L (range 1–3.4), and the serum insulin levels were mainly ≥ 100 U/mL and were associated with low C-peptide levels (≤ 10 ng/ml). Insulin autoantibodies (IAAs) were positive in all EIAS patients. The 75-g extended oral glucose tolerance test (OGTT) mainly showed a diabetic curve. Pancreatic imaging was unremarkable. Withdrawal of insulin alone or combination of oral hypoglycemic agents or replacement of insulin formulations or with corticosteroid treatment eliminated hypoglycemia in a few days to 3 months. IAA turned negative in 6 months (median, range 1–12). No hypoglycemia episodes were observed at a median follow-up of 6 months (range 0.5–60). Conclusions EIAS is an autoimmune disease caused by insulin-binding antibodies in susceptible subjects. Insulin antibodies change glucose dynamics and could increase the incidence of hypoglycemic episodes. Detection of insulin antibodies is the diagnostic test. Changing therapeutic modalities reduced the incidence of hypoglycemic episodes.

Abstract Puerarin has been reported to be an excellent antioxidant, anti-inflammatory and antimicrobial agent, but the potential effect of puerarin on porcine epidemic diarrhea virus (PEDV) is unclear. This study aimed to determine whether puerarin could alleviate intestinal injury in piglets infected with PEDV. A PEDV (Yunnan province strain) infection model was applied to 7-day-old piglets at 104.5 TCID50 (50% tissue culture infectious dose). Piglets were orally administered with puerarin at the dosage of 0.5 mg/kg body weight from day 5 to day 9. On day 9 of the trial, piglets were inoculated orally with PEDV. Three days later, jugular vein blood and intestinal samples were collected. Results showed puerarin reduced morbidity of piglets infected with PEDV. In addition, puerarin reduced the activities of aspartate aminotransferase and alkaline phosphatase, the ratio of serum aspartate aminotransferase to serum alanine aminotransferase, the number of white blood cells and neutrophils, and the plasma concentrations of interleukin-6, interleukin-8 and tumor necrosis factor-α, as well as protein abundances of heat shock protein-70 in PEDV-infected piglets. Moreover, puerarin increased D-xylose concentration but decreased intestinal fatty acid-binding protein concentration and diamine oxidase activity in the plasma of piglets infected with PEDV. Puerarin increased the activities of total superoxide dismutase, glutathione peroxidase and catalase, while decreasing the activities of myeloperoxidase and concentration of hydrogen peroxide in both the intestine and plasma of PEDV-infected piglets. Puerarin decreased mRNA levels of glutathione S-transferase omega 2 but increased the levels of nuclear factor erythroid 2-related factor 2. Furthermore, puerarin increased the abundance of total eubacteria (16S rRNA), Enterococcus genus, Lactobacillus genus and Enterobacteriaceae family in the intestine, but reduced the abundance of Clostridium coccoides in the caecum. These data indicate puerarin improved intestinal function in piglets infected by PEDV and may be a promising supplement for the prevention of PEDV infection.

Mono-lactate glyceride (LG) is a short-chain fatty acid ester. It has been shown that short-chain fatty acid esters play an important role in maintaining intestinal structure and function. The aim of this study is to investigate the effects of mono-lactate glyceride on growth performance and intestinal morphology and function in weaned piglets. Sixteen 21-day-old weaned piglets of similar weight were distributed arbitrarily to two treatments: The control group (basal diet) and the LG group (basal diet + 0.6% mono-lactate glyceride). The experiment lasted for 21 days. On day 21 of the trial, piglets were weighed, and blood and intestinal samples were collected for further analysis. Results showed that dietary supplementation with 0.6% mono-lactate glyceride decreased (p < 0.05) the diarrhea rate and the contents of malondialdehyde and hydrogen peroxide in the ileum and jejunum and increased (p < 0.05) the expression of intestinal tight junction protein (Occludin) and the activities of superoxide dismutase and catalase in the ileum and colon. In addition, mono-lactate glyceride supplementation could enhance intestinal mucosal growth by increasing (p < 0.05) the mRNA levels of extracellular regulated protein kinases, promote intestinal mucosal water and nutrient transport and lipid metabolism by increasing (p < 0.05) the mRNA levels of b0,+ amino acid transporter, aquaporin 3, aquaporin 10, gap junction protein alpha 1, intestinal fatty acid-binding protein, and lipoprotein lipase, enhance antiviral and immune function by increasing (p < 0.05) the mRNA levels of nuclear factor kappa-B, interferon-β, mucovirus resistance protein II, 2’-5’-oligoadenylate synthetase-like, interferon-γ, C-C motif chemokine ligand 2, and toll-like receptor 4, and enhance antioxidant capacity by increasing (p < 0.05) the mRNA levels of NF-E2-related factor 2 and glutathione S-transferase omega 2 and decreasing (p < 0.05) the mRNA level of NADPH oxidase 2. These results suggested that dietary supplementation with mono-lactate glyceride could decrease the diarrhea rate by improving intestinal antioxidant capacity, intestinal mucosal barrier, intestinal immune defense function, and intestinal mucosal water and nutrient transport. Collectively, dietary supplementation with 0.6% mono-lactate glyceride improved the intestinal function of weaned piglets.

Abstract β-Conglycinin (β-CG), an anti-nutritional factor, is a major allergen in soybeans to induce intestinal dysfunction and diarrhea in neonatal animals, including piglets and human infants. This study with a piglet model determined the effects of N-acetylcysteine (NAC) on intestinal function and autophagy in response to β-CG challenge. Twenty-four 12-day-old piglets (3.44 ± 0.28 kg), which had been weaned at 7 days of age and adapted for 5 days after weaning, were randomly allocated to the control, β-CG, and β-CG + NAC groups. Piglets in the control group were fed a liquid diet containing 10% casein, whereas those in the β-CG and β-CG + NAC groups were fed the basal liquid diets containing 9.5% casein and 0.5% β-CG for 2 days. Thereafter, pigs in the β-CG + NAC group were orally administrated with 50 mg (kg BW)−1 NAC for 3 days, while pigs in the other two groups were orally administrated with the same volume of sterile saline. NAC numerically reduced diarrhea incidence (− 46.2%) and the concentrations of hydrogen peroxide and malondialdehyde, but increased claudin-1 and intestinal fatty-acid binding protein (iFABP) protein abundances and activities of catalase and glutathione peroxidase in the jejunum of β-CG-challenged piglets. Although β-CG challenge decreased the villus height, villus height/crypt depth ratio, and mRNA levels of claudin-1 and occludin, no significant differences were observed in these indices between the control and β-CG + NAC groups, suggesting the positive effects of NAC supplementation on intestinal mucosal barrier function. Moreover, NAC increased the concentrations of citrulline and D-xylose in the plasma, as well as the expression of genes for aquaporin (AQP) 3, AQP4, peptide transporter 1 (PepT1), sodium/glucose co-transporter-1 (SGLT-1), potassium inwardly-rectifying channel, subfamily J, member 13 (KCNJ13), and solute carrier family 1 member 1 (SLC1A1) in the jejunum, demonstrating that NAC augmented intestinal metabolic activity and absorptive function. Remarkably, NAC decreased Atg5 protein abundance and the LC3II/LC3I ratio (an indicator of autophagy) in the jejunum of β-CG-challenged piglets. Taken together, NAC supplementation improved intestinal function and attenuated intestinal autophagy in β-CG-challenged piglets.

Objective Cold stress induces oxidative damage and impairs energy status of broilers. N-acetylcysteine (NAC) exhibits antioxidant properties and modulates energy metabolism of animals. This study was conducted to investigate the effects of NAC on energy status and antioxidant capacity of heart and liver in the cold-stressed broilers. Methods The experiment consisted of 4 treatments in a 2×2 factorial arrangement with two diets (basal diet or plus 0.1% NAC) and two ambient temperatures (thermoneutral [conventional ambient temperature] or cold stress [10°C±1°C during days 15 to 42]). Results No ascites were seen in cold-stressed broilers. NAC did not attenuate the impaired growth performance of stressed birds. However, NAC decreased plasma asparagine but increased aspartate levels in cold-stressed birds (p

Glycerol-lactate esters are energy supplements for exercise, but effects of trilactic glyceride (TLG) on intestinal function and hepatic metabolism are unknown. We found that dietary supplementation with 0.5% TLG to weanling piglets decreased plasma concentrations of low-density lipoprotein and gamma-glutamyl transferase but increased those of D-xylose and high-density lipoprotein. TLG supplementation enhanced mRNA levels for fatty acid synthase (FASN) and SLC27A2 in white adipose tissue; insulin receptor in duodenum; aquaporin-8 in ileum, jejunum and colon; aquaporin-10 in duodenum and ileum; nuclear factor like-2 in jejunum and colon; glutathione S-transferase and phosphoenolpyruvate carboxykinase-1 in intestines; and abundances of claudin-1 and occludin proteins. TLG supplementation decreased mRNA levels for: hepatic hormone-sensitive lipase E, lipoprotein lipase, FASN, insulin-like growth factor-binding protein-3, and SLC27A2; and intestinal lipoprotein lipase, FASN and NADPH oxidase. Furthermore, TLG supplementation enhanced abundances of genus Bifidobacterium, while reducing abundances of family Enterobacteriaceae in ileum, colon and cecum; jejunal caspase-3 protein and diarrhea rate. In conclusion, dietary supplementation with TLG modulated lipid metabolism and alleviated diarrhea by improving intestinal function and regulating intestinal microflora in piglets.

Abstract BMP signaling deficiency is evident in the lungs of patients with pulmonary arterial hypertension. We demonstrated that PHD2 deficiency suppresses BMP signaling in the lung endothelial cells, suggesting the novel mechanisms of dysregulated BMP signaling in the development of pulmonary arterial hypertension.

Porcine epidemic diarrhea virus (PEDV) has reemerged as the main pathogen of piglets due to its high mutation feature. Monolaurin (ML) is a natural compound with a wide range of antibacterial and antiviral activities. However, the role of ML in PEDV infection is still unknown. This study aimed to evaluate the effect of ML on the growth performance, intestinal function, virus replication and cytokine response in piglets infected with PEDV, and to reveal the mechanism through proteomics analysis. Piglets were orally administrated with ML at a dose of 100 mg/kg·BW for 7 days before PEDV infection. Results showed that although there was no significant effect on the growth performance of piglets, ML administration alleviated the diarrhea caused by PEDV infection. ML administration promoted the recovery of intestinal villi, thereby improving intestinal function. Meanwhile, PEDV replication was significantly inhibited, and PEDV-induced expression of IL-6 and IL-8 were decreased with ML administration. Proteomics analyses showed that 38 proteins were differentially expressed between PEDV and ML+PEDV groups and were significantly enriched in the interferon-related pathways. This suggests ML could promote the restoration of homeostasis by regulating the interferon pathway. Overall, the present study demonstrated ML could confer a protective effect against PEDV infection in piglets and may be developed as a drug or feed additive to prevent and control PEDV disease.

Our previous study reported that N-acetylcysteine (NAC) administration improved the function of intestinal absorption in piglets infected with porcine epidemic diarrhea virus (PEDV). However, the effects of NAC administration on the functions of other tissues and organs in PEDV-infected piglets have not been reported. In this study, the effects of NAC on the liver, spleen, lung, lymph node, and gastrocnemius muscle in PEDV-infected piglets were investigated. Thirty-two 7-day-old piglets with similar body weights were randomly divided into one of four groups: Control group, NAC group, PEDV group, and PEDV+NAC group (eight replicates per group and one pig per replicate). The trial had a 2 × 2 factorial design consisting of oral administration of 0 or 25 mg/kg body weight NAC and oral administration of 0 or 1.0 × 104.5 TCID50 PEDV. The trial lasted 12 days. All piglets were fed a milk replacer. On days 5–9 of the trial, piglets in the NAC and PEDV + NAC groups were orally administered NAC once a day; piglets in the control and PEDV groups were orally administered the same volume of saline. On day 9 of trial, piglets in the PEDV and PEDV+NAC groups were orally administrated 1.0 × 104.5 TCID50 PEDV, and the piglets in the control and NAC groups were orally administrated the same volume of saline. On day 12 of trial, samples, including of the liver, spleen, lung, lymph node, and gastrocnemius muscle, were collected. PEDV infection significantly increased catalase activity but significantly decreased the mRNA levels of Keap1, Nrf2, HMOX2, IFN-α, MX1, IL-10, TNF-α, S100A12, MMP3, MMP13, TGF-β, and GJA1 in the spleens of piglets. NAC administration ameliorated abnormal changes in measured variables in the spleens of PEDV-infected piglets. In addition, NAC administration also enhanced the antioxidant capacity of the mesenteric lymph nodes and gastrocnemius muscles in PEDV-infected piglets. Collectively, these novel results revealed that NAC administration improved the redox and functional gene expression levels in the spleen, mesenteric lymph nodes, and gastrocnemius muscle in PEDV-infected piglets.

SUMMARY: Oleum cinnamomi (OCM, cinnamon oil), which is produced by aromatic cinnamon plants, is increasingly used as a feed additive to animal diets. OCM is a natural product rich in polyphenolic compounds that exhibit strong antioxidative property. However, the direct addition of OCM to the feed is questionable due to several limiting physical–chemical factors such as the high hydrophobicity, volatility, odor, fast decomposition, and poor availability in the lower gastrointestinal tract of animals. Therefore, the coated form of OCM (cOCM) is one of the ways to solve these concerns. We have demonstrated that dietary cOCM supplementation did not improve the growth performance of broiler chickens, but it showed beneficial effects on immunity and intestinal integrity. In the current study, we further investigated the intestinal cinnamaldehyde release and antioxidative capacity of chickens fed cOCM-supplemented diets. As cinnamaldehyde is a major constituent of OCM, we evaluated the release of cOCM in the intestine of birds by determining the contents of cinnamaldehyde in the digesta of small intestine and cecum. The increased availability of OCM in the lower intestine supplied a foundation for exerting its antioxidative effects. The activities of antioxidative enzymes were increased and superoxide levels were decreased in the plasma and intestinal mucosa of birds fed cOCM-supplemented diets. The improvement of antioxidative capacity was achieved by modulating the gene expression of nuclear factor erythroid 2-related factor 2 and downstream antioxidative enzymes.