Grape seed-derived procyanidins decreases neuropathic pain and nerve regeneration by suppression of toll-like receptor 4-myeloid differentiation factor-88 signaling.

Background: Recent studies have shown that peripheral nerve regeneration process is closely related to neuropathic pain. Toll-like receptor 4 (TLR4) signaling was involved in different types of pain and nerve regeneration. TLR4 induced the recruitment of myeloid differentiation factor-88 adaptor protein (MyD88) and NF-κB-depended transcriptional process in sensory neurons and glial cells, which produced multiple cytokines and promoted the induction and persistence of pain. Our study aimed to investigate procyanidins's effect on pain and nerve regeneration via TLR4-Myd88 signaling. Methods: Spinal nerve ligation (SNL) model was established to measure the analgesic effect of procyanidins. Anatomical measurement of peripheral nerve regeneration was measured by microscopy and growth associated protein 43 (GAP43) staining. Western blotting and/or immunofluorescent staining were utilized to detect TLR4, myeloid differentiation factor-88 adaptor protein (MyD88), ionized calcium-binding adapter molecule 1 (IBA1) and nuclear factor kappa-B-p65 (NF-κB-p65) expression, as well as the activation of astrocyte and microglia. The antagonist of TLR4 (LPS-RS-Ultra, LRU) were intrathecally administrated to assess the behavioral effects of blocking TLR4 signaling on pain and nerve regeneration. Result: Procyanidins reduced mechanical allodynia, thermal hyperalgesia and significantly suppressed the number of nerve fibers regenerated and the degree of myelination in SNL model. Compared with sham group, TLR4, MyD88, IBA1 and phosphorylation of NF-κB-p65 were upregulated in SNL rats which were reversed by procyanidins administration. Additionally, procyanidins also suppressed activation of spinal astrocytes and glial cells. Conclusion: Suppression of TLR4-MyD88 signaling contributes to the alleviation of neuropathic pain and reduction of nerve regeneration by procyanidins.

Washed microbiota transplantation improves symptoms and intestinal barrier function in patients with functional bowel disorders: a propensity-score matching analysis.

BACKGROUND: Alterations in the intestinal microbiota may play a role in the pathogenesis of functional bowel disorders (FBDs). Probiotics are widely used to improve intestinal dysbacteriosis in FBDs. In the context of FBDs, washed microbiota transplantation (WMT) appear to be a promising therapeutic option. We aimed to compare probiotics with WMT by using a propensity-score matching analysis (PSMA). METHODS: We conducted a retrospective investigation of 103 patients with FBDs, including irritable bowel syndrome (IBS), functional constipation (FC), functional diarrhea (FDr), functional abdominal bloating (FAB). Patients were divided into the WMT group or probiotics group (taking probiotics capsules). Data on the following parameters were matched for PSMA: age; sex; disease course; body mass index; anxiety; insomnia; tobacco smoking; alcohol consumption; and levels of D-lactate, diamine oxidase, and lipopolysaccharide. Intestinal barrier function (IBF) and symptoms were evaluated both before and after treatment initiation. Prognostic factors were assessed by Cox proportional hazards regression analysis. RESULTS: PSMA identified in 34 matched pairs (11 IBS, 12 FC, 7 FDr, and 4 FAB in the probiotics group and 14 IBS, 13 FC, 5 FDr, and 2 FAB in the WMT group. Improvement of FBD symptoms was greater with WMT than probiotics (P = 0.002). The WMT group had significantly fewer patients with intestinal barrier damage than the probiotics group (38.2% vs. 67.6%, P = 0.041). This improvement of FBD with WMT was further reflected as a reduction in D-lactate levels (P = 0.031). Increased D-lactate levels which were identified as a prognostic factor for FBDs (HR = 0.248, 95%CI 0.093-0.666, P = 0.006) in multivariate Cox regression analysis. CONCLUSION: WMT could improve symptoms and IBF in patients with FBDs. Increased D-lactate levels in patients with FBDs may predict a favorable response to WMT treatment.

Type 17 mucosal-associated invariant T cells contribute to neutrophilic inflammation in patients with nasal polyps.

BACKGROUND: Immune regulation in chronic rhinosinusitis with nasal polyps (CRSwNP) with a neutrophilic endotype remains unclear. Mucosal-associated invariant T (MAIT) cells are tissue-resident innate T lymphocytes that respond quickly to pathogens and promote chronic mucosal inflammation. OBJECTIVE: We aimed to investigate the roles of MAIT cells in neutrophilic CRSwNP. METHODS: Nasal tissues were obtained from 113 patients with CRSwNP and 29 control subjects. Peripheral and tissue MAIT cells and their subsets were analyzed by flow cytometry. Polyp-derived MAIT cells were analyzed by RNA sequencing to study their effects on neutrophils. RESULTS: Endotypes of CRSwNP were classified as paucigranulocytic (n = 21), eosinophilic (n = 29), neutrophilic (n = 39), and mixed granulocytic (n = 24). Frequencies of MAIT cells were significantly higher in neutrophilic (3.62%) and mixed granulocytic (3.60%) polyps than in control mucosa (1.78%). MAIT cell percentages positively correlated with local neutrophil counts. MAIT cells were more enriched in tissues than in matched PBMCs. The frequencies of MAIT1 subset or IFN-γ+ MAIT cells were comparable among control tissues and CRSwNP subtypes. The proportions of MAIT17 subset or IL-17A+ MAIT cells were significantly increased in neutrophilic or mixed granulocytic polyps compared with controls. RNA sequencing revealed type 17 and pro-neutrophil profiles in neutrophilic polyp-derived MAIT cells. In patients with neutrophilic CRSwNP, the proportions of MAIT and MAIT17 cells were positively correlated with local proinflammatory cytokines and symptom severity. In vitro experiments demonstrated that neutrophilic polyp-derived MAIT cells promoted neutrophil migration, survival, and activation. CONCLUSIONS: MAIT cells from neutrophilic CRSwNP demonstrate type 17 functional properties and promote neutrophil infiltration in nasal mucosa.

AMIGO2 attenuates innate cisplatin sensitivity by suppression of GSDME-conferred pyroptosis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer. Cisplatin is commonly used in the treatment of many malignant tumours including NSCLC. The innate drug sensitivity greatly affects the clinical efficacy of cisplatin-based chemotherapy. As a plasma membrane adhesion molecule, amphoterin-induced gene and ORF-2 (AMIGO2) initially identified as a neurite outgrowth factor has been recently found to play a crucial role in cancer occurrence and progression. However, it is still unclear whether AMIGO2 is involved in innate cisplatin sensitivity. In the present study, we provided the in vitro and in vivo evidences indicating that the alteration of AMIGO2 expression triggered changes of innate cisplatin sensitivity as well as cisplatin-induced pyroptosis in NSCLC. Further results revealed that AMIGO2 might inhibit cisplatin-induced activation of (caspase-8 and caspase-9)/caspase-3 via stimulating PDK1/Akt (T308) signalling axis, resulting in suppression of GSDME cleavage and the subsequent cell pyroptosis, thereby decreasing the sensitivity of NSCLC cells to cisplatin treatment. The results provided a new insight that AMIGO2 regulated the innate cisplatin sensitivity of NSCLC through GSDME-mediated pyroptosis.

Efficacy of washed microbiota transplantation for therapeutic targets of refractory functional constipation and the influencing factors: a single-center, retrospective, 24-week follow-up study.

BACKGROUND: The efficacy of washed microbiota transplantation (WMT) in terms of refractory functional constipation (FC)-related therapeutic targets and influencing factors have not been elucidated. This study aimed to assess the efficacy and influencing factors of WMT in treating refractory FC-related therapeutic targets. METHODS: The clinical data of patients diagnosed with refractory FC and received with WMT were retrospectively collected. The therapeutic targets included straining, hard stools, incomplete evacuation, a sense of anorectal obstruction, manual maneuvers, and decreased stool frequency. Each target was recorded as 1 (yes) or 0 (no). All patients were followed up for approximately 24 weeks from the end of the first course of WMT. The primary outcomes were the improvement rates for the individual therapeutic targets and the overall response in respect of the therapeutic targets decreased by 2 at weeks 4, 8, and 24. The secondary outcomes were the clinical remission rate (i.e., the proportion of patients with an average of 3 or more spontaneous complete bowel movements per week), clinical improvement rate (i.e., the proportion of patients with an average increase of 1 or more SCBMs/week or patients with remission), stool frequency, Wexner constipation score, Bristol Stool Form Scale (BSFS) score, and adverse events. The factors influencing the efficacy were also analyzed. RESULTS: Overall, 63 patients with 112 WMT courses were enrolled. The improvement rates at weeks 8 and 24 were 45.6% and 35.0%, 42.9% and 38.6%, 45.0% and 35.7%, 55.6% and 44.4%, and 60.9% and 50.0%, respectively, for straining, hard stools, incomplete evacuation, a sense of anorectal obstruction, and decreased stool frequency. The overall response rates were 49.2%, 50.8%, and 42.9%, respectively, at weeks 4, 8, and 24. The rates of clinical remission and clinical improvement were 54.0% and 68.3%, respectively, at weeks 4. The stool frequency, BSFS score, and Wexner constipation score tended to improve post-WMT. Only 22 mild adverse events were observed during the 112 WMT courses and the follow-up. The number of WMT courses was identified to be the independent factor influencing the efficacy. CONCLUSIONS: WMT is efficacious in improving refractory FC-related therapeutic targets. The effectiveness of WMT in the management of FC is enhanced with the administration of multiple courses.

Presence of Tertiary Lymphoid Organ in Nasal Inverted Papilloma Is Correlated with Eosinophil Infiltration and Local Immunoglobulin Production.

INTRODUCTION: Nasal inverted papilloma (NIP) is a benign tumour with multiple inflammatory cell infiltration. Tertiary lymphoid organs (TLOs) support local antibody production and play important roles in airway inflammation. However, the evidence of TLOs and local immunoglobulins in NIP has not been reported yet. We investigated the presence of TLOs and immunoglobulins in NIP tissues and their association with the clinical-pathological characteristics of NIPs. METHODS: We analyzed the occurrence and composition of TLOs and local immunoglobulins by immunohistochemistry and evaluated the lymph organogenesis associated genes and cytokines by quantitative qPCR and Luminex assays, respectively, in papilloma tissues from 84 NIP cases. RESULTS: TLOs were present in 54% (45/84) of the NIP patients but not in control subjects. TLOs were composed of T cells, B cells, follicular dendritic cells, macrophages, and natural killer cells. Compared to NIP tissues without TLOs, tissues with TLOs showed significantly higher eosinophil infiltration levels (3.5-fold), elevation of lymphorganogenic genes (CXCL12, CXCL13, CCL20, CCL21, CD21L, and lymphotoxin alpha and beta), and increased Th17 (IL-21, IL-22, and GM-CSF) and Th2 (IL-5 and IL-13) cytokine production. Moreover, NIP with TLOs demonstrated a higher number of follicular T helper cells and immunoglobulin-producing plasma cells (CD138+ IgA+, CD138+ IgM+, CD138+ IgE+, and CD138+ IgG+) than those without TLOs, and these antibody-producing cells were positively correlated with the eosinophil number. CONCLUSION: The high frequency of TLOs and excess local immunoglobulin production are associated with an eosinophilic and Th2 skew microenvironment in the NIP mucosa, which would contribute to an important immunopathogenic response during NIP pathogenesis.

Local IL-17 positive T cells are functionally associated with neutrophil infiltration and their development is regulated by mucosal microenvironment in nasal polyps.

OBJECTIVE AND DESIGN: IL-17 plays essential roles in neutrophilic inflammation in the lower respiratory tract, however, the characteristics of local IL-17+ T cells in nasal inflammatory mucosa are not fully understood. We investigated the roles of IL-17+ T cells in regulating neutrophil infiltration and the effect of the mucosal microenvironment in modulating IL-17+ T cell differentiation in CRSwNP tissues. SUBJECTS: 47 polyp tissues from chronic rhinosinusitis with nasal polyps (CRSwNP) patients without corticosteroid therapy and 26 tissues from healthy mucosa were obtained. METHODS: Immunohistochemistry and flow cytometry were used to analyze the neutrophil infiltration, local IL-17+ T cell subsets, as well as cytokine producing profiles of IL-17+ T cell; tissue homogenates were used to study neutrophil migration and IL-17+ T cell differentiation. RESULTS: Increase of IL-17+ cells and IL-17+ T cell subsets was significant in polyp tissues versus controls, IL-17+ cell number was positively correlated with neutrophil infiltration; while homogenates from polyp tissues with high IL-17 promoted neutrophil migration in vitro. IL-17 response was found in polyp-derived T cells upon Staphylococcus aureus infection. IL-17+ T cells were also down-regulated in polyps from patients treated with glucocorticoid steroids, and exhibited poly-functionality patterns in polyp tissues. Finally, IL-17+ T cell differentiation could be induced by IL-23, and homogenates from polyps could enhance IL-17+ T cell development. CONCLUSIONS: This study determined a functional association of IL-17+ T cells with neutrophils in CRSwNP, and revealed that polyp microenvironment could promote IL-17+ T cell differentiation, suggesting a potential feedback role for IL-17+ T cell development and local neutrophilic inflammation.

[Effect of pranlukast on neonatal rats with periventricular leukomalacia].

OBJECTIVE: To study the effect of pranlukast (Pran) on neonatal rats with periventricular leukomalacia (PVL). METHODS: The rats, aged 3 days, were randomly divided into a sham-operation group, a PVL group, and a Pran group. A rat model of PVL was prepared by right common carotid artery ligation and postoperative hypoxia. The rats in the sham-operation group were given isolation of the right common carotid artery without ligation or hypoxic treatment. The rats in the Pran group were given intraperitoneal injection of Pran (0.1 mg/kg) once every 12 hours, for 3 consecutive days, and those in the sham-operation group and the PVL group were given intraperitoneal injection of an equal volume of normal saline. On day 14 after modeling, hematoxylin-eosin (HE) staining was used to observe the pathological changes of brain tissue; immunofluorescent staining was used to measure the expression of myelin basic protein (MBP) in brain tissue (n=8); Western blot was used to measure the expression of cyclic nucleotide phosphodiesterase (CNPase), MBP, and G protein-coupled receptor 17 (GPR17) (n=8). On day 21 after modeling, Morris water maze test was used to evaluate the learning and memory abilities of rats in each group (n=8). RESULTS: The results of HE staining showed that the PVL group had greater pathological changes of white matter than the sham-operation group, and compared with the PVL group, the Pran group had a significant improvement in such pathological changes. The results of immunofluorescence assay showed that the PVL group had a lower mean fluorescence intensity of MBP than the sham-operation group (P<0.05), and the Pran group had a higher mean fluorescence intensity of MBP than the PVL group (P<0.05). Western blot showed that compared with the sham-operation group, the PVL group had significantly lower relative expression of MBP and CNPase (P<0.05) and significantly higher relative expression of GPR17 (P<0.05), and compared with the PVL group, the Pran group had significantly higher relative expression of MBP and CNPase (P<0.05) and significantly lower relative expression of GPR17 (P<0.05). Morris water maze test showed that compared with the sham-operation group, the PVL group had a significant increase in escape latency and a significant reduction in the number of platform crossings, and compared with the PVL group, the Pran group had a significant reduction in escape latency and a significant increase in the number of platform crossings (P<0.05). CONCLUSIONS: Pran can alleviate brain damage, promote myelination, and improve long-term learning and memory abilities in neonatal rats with PVL, possibly by reducing the expression of GPR17.

The Phenylethanol Glycoside Liposome Inhibits PDGF-Induced HSC Activation via Regulation of the FAK/PI3K/Akt Signaling Pathway.

Cistanche tubulosa is a traditional Chinese herbal medicine that is widely used to regulate immunity, and phenylethanol glycosides (CPhGs) are among the primary components responsible for this activity. However, the application of CPhGs is negatively affected by their poor absorption and low oral utilization. Targeted drug delivery is an important development direction for pharmaceutics. Previous studies have indicated that CPhGs could block the conduction of the signaling pathways in TGF-ß1/smad and inhibit the activation of hepatic stellate cells (HSCs). The aim of this study was to evaluate the anti-hepatic fibrosis effect of CPhG liposomes by inhibiting HSC activation, promoting apoptosis, blocking the cell cycle, suppressing the conduction of signaling pathways in focal adhesion kinase(FAK)/phosphatidylinositol-3-kinase(PI3K)/protein kinase B(Akt), and determining their in vitro hepatoprotective activity. In vitro release studies demonstrated that CPhG liposomes have a sustained release effect compared to drug CPhGs. HSC proliferation was inhibited after treatment with the CPhG liposomes (29.45, 14.72, 7.36 µg/mL), with IC50 values of 42.54 µg/mL in the MTT assay. Different concentrations of the CPhG liposomes could inhibit HSC proliferation, promote apoptosis, and block the cell cycle. The MTT method showed an obvious inhibition of HSC proliferation after CPhG liposome and Recombinant Rat Platelet-derived growth factor-BB(rrPDGF-BB) treatment. The levels of collagen-1, metallopeptidase inhibitor 1 (TIMP-1), α smooth muscle actin (α-SMA), and phosphorylated PI3K/Akt were downregulated, and matrix metalloproteinase-1 (MMP-1) was upregulated, by pretreatment with different concentrations of CPhG liposomes. Moreover, 29.45 µg/mL of CPhG liposomes could decrease the expression of the FAK protein and the phosphorylated PI3K and Akt protein downstream of FAK by overexpression of the FAK gene. This experiment suggests that CPhG liposomes may inhibit the activation of HSCs by inhibiting FAK and then reducing the expression of phosphorylated Akt/PI3K, thereby providing new insights into the application of CPhGs for liver fibrosis.

CCR5 expression in inflammatory bowel disease and its correlation with inflammatory cells and ß-arrestin2 expression.

OBJECTIVE: To elucidate the correlation of expression of CC chemokine receptor 5 (CCR5) with degrees of inflammatory cells infiltration and expression of ß-arrestin2 in biopsic intestinal mucosa of the patients with inflammatory bowel disease (IBD). METHODS: Paraffin sections were derived from 53 patients with active IBD, 26 patients with remissive IBD and 30 healthy people. Immunohistochemical envision two-step method was used to test the expression of CCR5 and ß-arrestin2 in biopsic intestinal mucosa. HE and toluidine blue staining were used to detect the pathological cytological analysis and classification in lamina propria of colonic mucosa. RESULTS: The positive rate, strong positive rate and immunohistochemical score of CCR5 expression in active IBD were significantly higher than that in normal controls and remissive IBD (p < .05). CCR5 expression had no obvious correlation with clinical severity, lesion distribution and endoscopic classification of active IBD. Neutrophils, eosinophils and lymphocytes in active IBD were significantly higher than that in normal controls and remissive IBD (p < .05), while the lymphocyte grade had a positive correlation with CCR5 expression (p = .042, r = .286). Mastocytes in active IBD, remissive IBD and normal controls had no obvious difference (p > .05). ß-arrestin2 expression was significantly lower in active IBD than that in remissive IBD and normal controls, and it had a negative correlation with CCR5 expression (p = .01, r = -.247). CONCLUSIONS: CCR5 is highly expressed in active IBD, and it has positive correlation with lymphocyte grade and negative correlation with expression of ß-arrestin2.

The benefits of an offline to online cognitive behavioral stress management regarding anxiety, depression, spiritual well-being, and quality of life in postoperative intrahepatic cholangiocarcinoma patients.

AIM: Cognitive behavioral stress management (CBSM) has been introduced for the postoperative cancer management, but its application in intrahepatic cholangiocarcinoma (ICC) is rare. This current study constructed an offline to online CBSM (OO-CBSM) program and applying multiple assessing scales, aiming at exploring the benefits of OO-CBSM regarding anxiety, depression, spiritual well-being, and quality of life (QoL) in postoperative ICC patients. METHODS: The study randomly assigned 68 postoperative ICC patients into OO-CBSM (N = 34) and normal care (NC) (N = 34) groups to undergo 10-week interventions. Hospital anxiety-and-depression scale (HADS), Zung's self-reporting anxiety scale (SAS), and depression scale (SDS), functional-assessment of chronic-illness therapy-spiritual well-being scale (FACIT-Sp), European quality-of-life-5 dimensions (EQ-5D), and quality-of-life questionnaire-core30 (QLQ-C30) were assessed within 6 months (M). RESULTS: HADS-anxiety scores at M3 (P = 0.049) and M6 (P = 0.009), SAS score at M6 (P = 0.028), HADS-depression score at M3 (P = 0.043), and SDS scores at M3 (P = 0.044) and M6 (P = 0.028), were lower in the OO-CBSM group versus the NC group. Meanwhile, FACIT-Sp scores at M1 (P = 0.042) and M6 (P = 0.003) were higher in the OO-CBSM group over the NC group. Besides, EQ-5D scores at M3 (P = 0.067) and M6 (P = 0.087) disclosed trends to be lower in the OO-CBSM group versus the NC group, but not statistically significant. QLQ-C30-global-health scores at M3 (P = 0.049) and M6 (P = 0.033), and QLQ-C30-function score at M6 (P = 0.046), were higher in OO-CBSM group over NC group; but QLQ-C30-symptom score was not significantly different at any timepoints between them. CONCLUSION: OO-CBSM attenuates anxiety and depression, and advances spiritual well-being and QoL in postoperative ICC patients, indicating its potency for the ICC postoperative management.

Related Factors Mining of Diabetes Complications Based on Manifold-Constrained Multi-Label Feature Selection.

The primary cause of mortality among individuals with diabetes stems from complications. Identifying related factors for these complications holds immense potential for early prevention. Previous research predominantly employed traditional machine-learning techniques to establish prediction models utilizing medical indicators for related factor selection. However, uncovering the intricate correlations among complication labels and identifying similar characteristics among medical indicators has been challenging. We propose a novel embedded multi-label feature selection approach called LCFSM(Label Cosine and Feature Similar Manifold) to address the issue. LCFSM introduces manifold constraints into the objective function to uncover risk factors associated with diabetes complications. Label cosine similarity is set to optimize feature weights, forming label manifold constraints. Similarly, feature manifold constraints are established to utilize feature kernel similarity in optimizing feature weights. LCFSM formulates an objective function based on the l2,1 regularized Least Squares and previous manifolds constraints, employing the Sylvester equation for convergence assurance. The experimental evaluation compares LCFSM against eight baselines, demonstrating superior performance in top-10 feature selection and feature stacking.LCFSM is applied to identify primary risk factors for diabetes complications. Related factors involve Electromyogram, Urine Routine Protein Positive, etc, offering valuable insights for early treatment.

Digital therapeutics-based lifestyle intervention for gestational diabetes mellitus prevention of high-risk pregnant women: a study protocol for a non-randomised controlled trial.

INTRODUCTION: Digital therapeutics have been approved as a treatment aid for various medical conditions and are increasingly prevalent. Despite numerous studies on the potential of digital therapeutic interventions in preventing gestational diabetes mellitus (GDM), there is a critical need for more high-quality, large-scale studies to validate their effectiveness. This need arises from the inconsistencies in results and variations in the quality of previous research. METHODS AND ANALYSIS: We propose a non-randomised controlled trial involving 800 high-risk pregnant women in 6 maternity and child health hospitals in Fujian, China. This study aims to investigate the role and effectiveness of digital therapeutics-based lifestyle intervention in managing the health of pregnant women at high risk for GDM. The study will compare the differences in GDM prevalence, pregnancy weight management and other pregnancy-related health outcomes between pregnant women who received digital therapeutics-based lifestyle intervention and those in the control group. The intervention includes dietary guidance, a personalised physical activity programme and lifestyle improvement strategies delivered through a smartphone app. Primary outcomes include the incidence of GDM at 24-28 weeks gestation and gestational weight gain (GWG). Secondary outcomes comprise improvements in individual lifestyle and risk factors, nutritional issues, implementation outcomes and other pregnancy-related outcomes. ETHICS AND DISSEMINATION SECTION: The trial was approved by the Ethics Committee of Fujian Maternity and Child Health Hospital (approval number: 2023KY046), Jianyang Maternity and Child Health Hospital (approval number: A202401), Fuqing Maternity and Child Health Hospital (approval number: FY2024003), Changting Maternity and Child Health Hospital (approval number: 202401), Datian Maternity and Child Health Hospital (approval number: dtfy202401) and Quanzhou Maternity and Child Health Hospital (approval number: 2024(50)). We will disseminate our findings by publishing articles in leading peer-reviewed journals. TRIAL REGISTRATION NUMBER: ChiCTR2300071496.

Human apical-out nasal organoids reveal an essential role of matrix metalloproteinases in airway epithelial differentiation.

Extracellular matrix (ECM) assembly/disassembly is a critical regulator for airway epithelial development and remodeling. Airway organoid is widely used in respiratory research, yet there is limited study to indicate the roles and mechanisms of ECM organization in epithelial growth and differentiation by using in vitro organoid system. Moreover, most of current Matrigel-based airway organoids are in basal-out orientation where accessing the apical surface is challenging. We present a human apical-out airway organoid using a biochemically defined hybrid hydrogel system. During human nasal epithelial progenitor cells (hNEPCs) differentiation, the gel gradually degrade, leading to the organoid apical surfaces facing outward. The expression and activity of ECM-degrading enzymes, matrix metalloproteinases (MMP7, MMP9, MMP10 and MMP13) increases during organoid differentiation, where inhibition of MMPs significantly suppresses the normal ciliation, resulting in increased goblet cell proportion. Moreover, a decrease of MMPs is found in goblet cell hyperplastic epithelium in inflammatory mucosa. This system reveals essential roles of epithelial-derived MMPs on epithelial cell fate determination, and provides an applicable platform enabling further study for ECM in regulating airway development in health and diseases.

Anti-obesity and hypolipidemic effects of Fuzhuan brick tea water extract in high-fat diet-induced obese rats.

BACKGROUND: Fuzhuan brick tea is a kind of microbial fermented tea, which has received increasing attention in recent years owing to its benefits for human health. In this study, the anti-obesity and hypolipidemic effects of Fuzhuan brick tea water extracts (FTEs) were investigated. RESULTS: FTEs consisted of 204.07 ± 3.38 mg g(-1) polyphenol, 109.20 ± 1.36 mg g(-1) flavonoids, and others. The FTEs significantly suppressed the increase of body weight and accumulation of adipose tissue, and reduced the level of serum triacylglycerol, total cholesterol and low-density lipoprotein (LDL) cholesterol in obese rats fed a high-fat diet. Moreover, FTEs attenuated the gene expression of sterol regulatory element binding protein-1c, fatty acid synthase and CCAAT/enhancer binding protein α, which is related to lipogenic metabolism. In contrast, the gene expressions of enzymes involved in energy expenditure and lipodieresis including hepatic peroxisome proliferator-activated receptor α, carnitine palmitoyltransferase 1a and LDL receptor gene expression were increased by FTE treatment. CONCLUSIONS: Our study demonstrates that FTEs have anti-obesity and hypolipidemic functions, suggesting that it might be effective for treatment of obesity and hyperlipemia.

[The influence of microcystin-LR on monocytes and lymphocytes of mice].

OBJECTIVE: To investigate the influence of microcystin-LR (MC-LR) on monocytes and lymphocytes in blood of mice and to find a sensitive index of toxic effects. METHODS: Specific pathogen free Kunming male mice, aging 1 month-old,were randomly divided into 5 groups by weights, 7 mice for each group. The mice in 5 groups were exposed to MC-LR through intraperitoneal injection at 0, 3.125,6.250, 12.500 and 25.000 µg/kg respectively for 7 days. Then cytokine levels in the serum were measured by radioimmunoassay, DNA-protein crosslinks (DPC) was measured by the SDS/KCl precipitation technique, and the phagocytosis and ROS of leukocytes were detected by flow cytometry. RESULTS: The levels of interleukin 6 in the 6.250, 12.500 and 25.000 µg·kg(-1)·d(-1) dose groups were (346.837 ± 25.536), (360.847 ± 37.886) and (434.245 ± 35.858)pg/ml respectively, which were significantly higher than those in the control group which the value was (232.775 ± 32.816) pg/ml (t values were -7.258, -6.760 and -10.966 respectively, P values were all < 0.05).While the level of tumor necrosis factor-alpha was(10.782 ± 0.966) fmol/ml in 25 µg·kg(-1)·d(-1) dose group was statistically lower than it in the control group which the value was (16.878 ± 3.378) fmol/ml (t value was 4.591, P < 0.05). The DPC levels of lymphocytes in 6.250, 12.500 µg·kg(-1)·d(-1) dose group were (242.576 ± 7.545),(241.472 ± 2.793) ng/ml,higher than it in the control group while the value was (228.657 ± 4.130) ng/ml (t value was -4.282, -6.801, P values were all <0.05). The fluorescence intensity of DCF in lymphocytes in the 4 treated groups were separately 3299.37 ± 120.54, 3281.38 ± 58.34, 3308.06 ± 136.12 and 3346.92 ± 108.69, all significantly lower than 3770.81 ± 131.39 in the control group (t values were 6.995, 9.007, 6.472 and 6.577 respectively, and P values were all <0.05). The fluorescence intensity of DCF in monocytes in the 4 treated groups (3271.51 ± 140.79, 3270.05 ± 117.92, 3326.90 ± 114.39 and 3292.49 ± 145.97 respectively) were also significantly lower than the value in the control group was 3841.72 ± 130.92 (t values were 7.847, 8.584, 7.835 and 7.411 respectively, P values were all <0.05). There was no significant difference in other index among the four experiment groups and the control group. CONCLUSION: The MC-LR administered via intraperitoneal injection to mice induced the alterations of some cytokines of monocytes and lymphocytes in blood. By comparison, the ROS of leukocyte was the most sensitive index.

The scaling and dynamics of a projectile obliquely impacting a granular medium.

In this paper, the dynamics of a spherical projectile obliquely impacting into a two-dimensional granular bed is numerically investigated using the discrete element method. The influences of projectile's initial velocities and impacting angles are mainly considered. Numerical results show that the relationship between the final penetration depth and the initial impact velocity is very similar to that in the vertical-impact case. However, the dependence of the stopping time on the impact velocity of the projectile exhibits critical characteristics at different impact angles: the stopping time approximately increases linearly with the impact velocity for small impact angles but decreases in an exponential form for larger impact angles, which demonstrates the existence of two different regimes at low and high impact angles. When the impact angle is regarded as a parametric variable, a phenomenological force model at large impact angles is eventually proposed based on the simulation results, which can accurately describe the nature of the resistance force exerted on the projectile by the granular medium at different impact angels during the whole oblique-impact process. The degenerate model agrees well with the existing experimental results in the vertical-impact cases.

[The establishment and application of the method with virus concentration and detection in drinking water].

OBJECTIVE: This study aimed to construct an effective method to concentrate and detect virus in drinking water, and human adenovirus pollution status in actual water samples was monitored by constructed method. METHODS: The concentration efficient of NanoCeram filter for the first concentration with source water and drinking water and the concentration efficient of the different concentrations of PEG 8000 for the second concentration were assessed by spiking f2 bacteriophage into water samples. The standard of human adenovirus for real-time PCR was constructed by T-A clone. The plasmid obtained was identified through sequence analyzing and consistency check comparing to target gene fragment was conducted by using blast algorithm. Then, real-time PCR was constructed to quantify the concentration of human adenovirus using the plasmid as standard. Water samples were concentrated by using NanoCeram filter on the spot and then concentrated for the second time by PEG/NaCl in 2011. The DNA of concentrated samples were extracted for the quantification of human adenovirus in real-time PCR subsequently to monitor the pollution of human adenovirus in water. RESULTS: For the first concentration by NanoCeram filter, the recovery rates were (51.63 ± 26.60)% in source water and (50.27 ± 14.35)% in treated water, respectively. For the second concentration, the highest recovery rate was reached to (90.09 ± 10.50)% at the concentration of 0.13 kg/L of PEG 8000. The sequence identity score of standard of adenovirus for real time PCR and adenovirus gene was 99%, implying that it can be successfully used to quantification with human adenovirus. The levels of human adenovirus in the water samples sampled in 2011 ranged from 4.13×10³ to 2.20×106 copies/L in source water, while range from 5.57×10² to 7.52×105 copies/L in treated water and the removal efficiency range was (75.49 ± 11.71)%. CONCLUSION: NanoCeram filers combined with PEG/NaCl was an effective method to concentrate virus in aquatic environment. There was a large number of human adenovirus in source water, and it is not sufficient to remove them thoroughly through conventional water treatment processes.

Combined Multi-Atlas and Multi-Layer Perception for Alzheimer's Disease Classification.

Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disease. To distinguish the stage of the disease, AD classification technology challenge has been proposed in Pattern Recognition and Computer Vision 2021 (PRCV 2021) which provides the gray volume and average cortical thickness data extracted in multiple atlases from magnetic resonance imaging (MRI). Traditional methods either train with convolutional neural network (CNN) by MRI data to adapt the spatial features of images or train with recurrent neural network (RNN) by temporal features to predict the next stage. However, the morphological features from the challenge have been extracted into discrete values. We present a multi-atlases multi-layer perceptron (MAMLP) approach to deal with the relationship between morphological features and the stage of the disease. The model consists of multiple multi-layer perceptron (MLP) modules, and morphological features extracted from different atlases will be classified by different MLP modules. The final vote of all classification results obtains the predicted disease stage. Firstly, to preserve the diversity of brain features, the most representative atlases are chosen from groups of similar atlases, and one atlas is selected in each group. Secondly, each atlas is fed into one MLP to fetch the score of the classification. Thirdly, to obtain more stable results, scores from different atlases are combined to vote the result of the classification. Based on this approach, we rank 10th among 373 teams in the challenge. The results of the experiment indicate as follows: (1) Group selection of atlas reduces the number of features required without reducing the accuracy of the model; (2) The MLP architecture achieves better performance than CNN and RNN networks in morphological features; and (3) Compared with other networks, the combination of multiple MLP networks has faster convergence of about 40% and makes the classification more stable.

Treatment of hyponatremia in children with acute bacterial meningitis.

Purpose: Few studies have evaluated hyponatremia management in children with bacterial meningitis (BM). Thus, we aimed to describe variations in clinical practice, the effectiveness of sodium management, and adverse outcomes in children with BM and hyponatremia. Methods: This retrospective cross-sectional study conducted at a tertiary institution analyzed participants' demographic, clinical, and sodium-altering treatment data. The sodium trigger for treatment was defined as pretreatment sodium level, with response and overcorrection defined as increments of ≥5 and >10 mmol/L after 24 h, respectively. Results: This study enrolled 364 children with BM (age: <16 years; 215 boys). Hyponatremia occurred in 62.1% of patients, among whom 25.7% received sodium-altering therapies; 91.4% of those individuals had moderate/severe hyponatremia. Monotherapy was the most common initial hyponatremia treatment. After 24 h of treatment initiation, 82.4% of the patients responded. Logistic regression analyses revealed that ΔNa24 <5 mmol/L [odds ratio (OR) 15.52, 95% CI 1.71-141.06, p = 0.015] and minimum Glasgow Coma Scale (GCS) score ≤ 8 (OR 11.09, 95% CI 1.16-105.73, p = 0.036) predicted dysnatremia at 48 h after treatment initiation. Although rare, persistent moderate/severe hyponatremia or hypernatremia at 48 h after treatment initiation was associated with a high mortality rate (57.1%). Conclusion: This study found that most cases of hyponatremia responded well to various treatments. It is important to identify and institute appropriate treatment early for moderate or severe hyponatremia or hypernatremia in children with BM. This study was limited by its non-randomized nature.