Copper(II)-Based Nano-Regulator Correlates Cuproptosis Burst and Sequential Immunogenic Cell Death for Synergistic Cancer Immunotherapy.

Immunogenic cell death (ICD) of tumor cells serves as a crucial initial signal in the activation of anti-tumor immune responses, holding marked promise in the field of tumor immunotherapy. However, low immunogenicity tumors pose challenges in achieving complete induction of ICD, thereby limiting the response rates of immunotherapy in clinical patients. The emergence of cuproptosis as a new form of regulated cell death has presented a promising strategy for enhanced immunotherapy of low immunogenic tumors. To trigger cuproptosis, copper-ionophore elesclomol (ES) had to be employed for the copper-transporting-mediated process. Herein, we proposed a copper(II)-based metal-organic framework nanoplatform (Cu-MOF) to facilitate a cooperative delivery of encapsulated ES and copper (ES-Cu-MOF) to induce cuproptosis burst and enhance ICD of fibrosarcoma. Our results showed that the ES-Cu-MOF nano-regulator could effectively release Cu2+ and ES in response to the intracellular environment, resulting in elevated mitochondrial ROS generation and initiated cuproptosis of tumor cells. Furthermore, sequential ICDs were significantly triggered via the ES-Cu-MOF nano-regulator to activate the anti-tumor immune response. The results of tumor inhibition experiment indicated that the nano-regulator of ES-Cu-MOF obviously accumulated in the tumor site, inducing ICD for dendritic cell activation. This enabled an increased infiltration of cytotoxic CD8+ T cells and consequently enhanced antitumor immune responses for successfully suppressing fibrosarcoma growth. Thus, the copper(II)-based metal-organic framework nano-regulator offered a promising approach for inducing cuproptosis and cuproptosis-stimulated ICD for cancer immunotherapy.

Independent and Joint Effects of Prenatal Incense-Burning Smoke Exposure and Children's Early Outdoor Activity on Preschoolers' Obesity.

Incense burning is a significant source of indoor air pollution in many Asian regions. There is emerging evidence that maternal prenatal exposure to incense-burning smoke may be a risk factor for childhood obesity. We aimed to extend this new line of research by investigating the independent and joint effect of incense-burning smoke exposure, and children's outdoor activity in early life, on preschoolers' obesity. A total of 69,637 mother-child dyads were recruited from all kindergartens in the Longhua District of Shenzhen, China. Information on sociodemographic characteristics, maternal exposure to incense-burning smoke (IBS) during pregnancy, and frequency and duration of outdoor activity at the age of 1-3 years was collected by a self-administered questionnaire. In addition, the heights and weights of the children were measured by the research team. Logistic regression models and cross-over analyses were conducted to investigate the independent and combined effects of maternal exposure to incense-burning smoke during pregnancy and children's early outdoor activity on obesity in preschoolers. We found that prenatal exposure to incense-burning smoke increased the risk of the presence of obesity in preschoolers' (AOR = 1.13, 95% CI = 1.03-1.23). Additionally, lower frequencies (<3 times/week) or shorter durations (<60 min/time) of outdoor activity from the age of 1-3 years were significantly associated with the presence of obesity, with AORs of 1.24 (95% CI =1.18-1.32) and 1.11 (95% CI = 1.05-1.17), respectively. Furthermore, the cross-over analysis showed that prenatal exposure to IBS combined with a lower frequency of early outdoor activity (AOR = 1.47, 95% CI = 1.31-1.66) or a shorter duration of outdoor activity during ages of 1-3 years (AOR = 1.22, 95% CI = 1.07-1.39) increased the risk of obesity in preschoolers. Finally, additive interactions between prenatal exposure to IBS and postnatal outdoor activity on obesity were identified. Our study indicates that maternal exposure to incense-burning smoke during pregnancy and early lower postanal outdoor activity may independently and jointly increase the risk of obesity among preschoolers.

In Silico Insights into Micro-Mechanism Understanding of Extracts of Taxus Chinensis Fruits Against Alzheimer's Disease.

BACKGROUND: The taxus chinensis fruit (TCF) shows promises in treatment of aging-related diseases such as Alzheimer's disease (AD). However, its related constituents and targets against AD have not been deciphered. OBJECTIVE: This study was to uncover constituents and targets of TCF extracts against AD. METHODS: An integrated approach including ultrasound extractions and constituent identification of TCF by UPLC-QE-MS/MS, target identification of constituents and AD by R data-mining from Pubchem, Drugbank and GEO databases, network construction, molecular docking and the ROC curve analysis was carried out. RESULTS: We identified 250 compounds in TCF extracts, and obtained 3,231 known constituent targets and 5,326 differential expression genes of AD, and 988 intersection genes. Through the network construction and KEGG pathway analysis, 19 chemicals, 31 targets, and 11 biological pathways were obtained as core compounds, targets and pathways of TCF extracts against AD. Among these constituents, luteolin, oleic acid, gallic acid, baicalein, naringenin, lovastatin and rutin had obvious anti-AD effect. Molecular docking results further confirmed above results. The ROC AUC values of about 87% of these core targets of TCF extracts was greater than 0.5 in the two GEO chips of AD, especially 10 targets with ROC AUC values greater than 0.7, such as BCL2, CASP7, NFKBIA, HMOX1, CDK2, LDLR, RELA, and CCL2, which mainly referred to neuron apoptosis, response to oxidative stress and inflammation, fibroblast proliferation, etc.Conclusions:The TCF extracts have diverse active compounds that can act on the diagnostic genes of AD, which deserve further in-depth study.

Balanced transformer: efficient classification of glioblastoma and primary central nervous system lymphoma.

Objective.Primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM) are malignant primary brain tumors with different biological characteristics. Great differences exist between the treatment strategies of PCNSL and GBM. Thus, accurately distinguishing between PCNSL and GBM before surgery is very important for guiding neurosurgery. At present, the spinal fluid of patients is commonly extracted to find tumor markers for diagnosis. However, this method not only causes secondary injury to patients, but also easily delays treatment. Although diagnosis using radiology images is non-invasive, the morphological features and texture features of the two in magnetic resonance imaging (MRI) are quite similar, making distinction with human eyes and image diagnosis very difficult. In order to solve the problem of insufficient number of samples and sample imbalance, we used data augmentation and balanced sample sampling methods. Conventional Transformer networks use patch segmentation operations to divide images into small patches, but the lack of communication between patches leads to unbalanced data layers.Approach.To address this problem, we propose a balanced patch embedding approach that extracts high-level semantic information by reducing the feature dimensionality and maintaining the geometric variation invariance of the features. This approach balances the interactions between the information and improves the representativeness of the data. To further address the imbalance problem, the balanced patch partition method is proposed to increase the receptive field by sampling the four corners of the sliding window and introducing a linear encoding component without increasing the computational effort, and designed a new balanced loss function.Main results.Benefiting from the overall balance design, we conducted an experiment using Balanced Transformer and obtained an accuracy of 99.89%, sensitivity of 99.74%, specificity of 99.73% and AUC of 99.19%, which is far higher than the previous results (accuracy of 89.6% ∼ 96.8%, sensitivity of 74.3% ∼ 91.3%, specificity of 88.9% ∼ 96.02% and AUC of 87.8% ∼ 94.9%).Significance.This study can accurately distinguish PCNSL and GBM before surgery. Because GBM is a common type of malignant tumor, the 1% improvement in accuracy has saved many patients and reduced treatment times considerably. Thus, it can provide doctors with a good basis for auxiliary diagnosis.

Enhanced TARP-γ8-PSD-95 coupling in excitatory neurons contributes to the rapid antidepressant-like action of ketamine in male mice.

Ketamine produces rapid antidepressant effects at sub-anesthetic dosage through early and sustained activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), however, the exact molecular mechanism still remains unclear. Transmembrane AMPAR regulatory protein-γ8 (TARP-γ8) is identified as one of AMPAR auxiliary subunits, which controls assemblies, surface trafficking and gating of AMPARs. Here, we show that ketamine rescues both depressive-like behaviors and the decreased AMPARs-mediated neurotransmission by recruitment of TARP-γ8 at the postsynaptic sites in the ventral hippocampus of stressed male mice. Furthermore, the rapid antidepressant effects of ketamine are abolished by selective blockade of TARP-γ8-containing AMPAR or uncoupling of TARP-γ8 from PSD-95. Overexpression of TARP-γ8 reverses chronic stress-induced depressive-like behaviors and attenuation of AMPARs-mediated neurotransmission. Conversely, knockdown of TARP-γ8 in excitatory neurons prevents the rapid antidepressant effects of ketamine.

Eye Movement Abnormalities During Different Periods in Patients with Vestibular Migraine.

Purpose: The aim of this study was to assess abnormal eye movement signs during different periods, namely, ictal periods and symptom-free intervals, in patients with vestibular migraine. Patients and Methods: We assessed oculomotor signs using videonystagmography in 90 patients with VM (40 during ictal periods and 50 during symptom-free intervals) according to validated diagnostic criteria. Results: Abnormal saccades, smooth pursuit and optokinetic test results; spontaneous nystagmus; and positional nystagmus were all observed in vestibular migraine patients, and there was no significant difference between different periods. Positional nystagmus was the most common in both the ictal and asymptomatic periods (60% and 36%, respectively). Positional nystagmus was induced in a variety of positions during both periods, and the slow-phase velocity ranged from <2 to 10°/s. The duration of positional nystagmus was over 60s in most cases. Overall, central oculomotor dysfunctions occurred in 27.5% of patients during VM attacks and 4% of patients during symptom-free intervals; this difference was statistically significant (p = 0.002). Conclusion: In patients with VM, abnormal oculomotor signs can be found during both vertigo attacks and asymptomatic intervals. Positional nystagmus is the most common of these abnormalities and can be induced in different positions. The amplitude of these patients' positional nystagmus tends to be low, and the duration tends to be long. Observing changes in eye movements by videonystagmography may be helpful in the diagnosis of VM.

Study on the antioxidant activity of peptides from soybean meal by fermentation based on the chemical method and AAPH-induced oxidative stress.

Preparation and antioxidant activities of soybean peptides using solid fermentation to decrease the content of trypsin inhibitor (TI) and antigen protein were investigated in this study. The results showed the optimal fermentation conditions were as follows: fermentation time 48 h, the ratio of material to solvent 1:2, inoculum size 12%, and the ratio of Lactic acid bacteria and Aspergillus oryzae 2:1. The hydrolysate was were divided into four components of <1, 1-3, 3-5, and >5 kDa by ultrafiltration based on molecular weight, and the <1 kDa peptides expressed the highest antioxidant activities. Meanwhile, the cell antioxidant activity of the <1 kDa soybean peptides was investigated using AAPH-induced erythrocyte hemolysis, which effectively inhibited erythrocyte hemolysis with the inhibit rate of 85.8% through inhibition of the ROS intracellular generation. In addition, soybean peptides could significantly restore the intracellular antioxidant enzymes (SOD, GSH-Px, and CAT) activities, as well as inhibited intracellular MDA generation and depletion of GSH. The intracellular antioxidant detoxifying mechanism of soybean peptides was associated with both non-enzymatic and enzymatic defense systems. According to this study, fermentation could effectively improve the antioxidant activities of soybean peptides.

Excessive iron inhibits insulin secretion via perturbing transcriptional regulation of SYT7 by OGG1.

Although iron overload is closely related to the occurrence of type 2 diabetes mellitus (T2DM), the specific mechanism is unclear. Here, we found that excessive iron inhibited the secretion of insulin (INS) and impaired islet ß cell function through downregulating Synaptotagmin 7 (SYT7) in iron overload model in vivo and in vitro. Our results further demonstrated that 8-oxoguanine DNA glycosylase (OGG1), a key protein in the DNA base excision repair, was an upstream regulator of SYT7. Interestingly, such regulation could be suppressed by excessive iron. Ogg1-null mice, iron overload mice and db/db mice exhibit reduced INS secretion, weakened ß cell function and subsequently impaired glucose tolerance. Notably, SYT7 overexpression could rescue these phenotypes. Our data revealed an intrinsic mechanism by which excessive iron inhibits INS secretion through perturbing the transcriptional regulation of SYT7 by OGG1, which suggested that SYT7 was a potential target in clinical therapy for T2DM.

Short-term outcomes of reduced-port laparoscopic surgery versus conventional laparoscopic surgery for total gastrectomy: a single-institute experience.

BACKGROUND: The efficacy of reduced-port laparoscopic surgery (RLS) for total gastrectomy remains unclear. This study focused on evaluating the short-term outcomes of RLS compared with conventional laparoscopic surgery (CLS) for total gastrectomy. METHODS: One hundred and ten patients who underwent completed laparoscopic total gastrectomy for gastric cancer between September 2018 and June 2022 were retrospectively collected and classified into two groups (65 CLS and 45 RLS) according to different operation approach. Twenty-four RLS cases underwent single-incision plus two ports laparoscopic surgery (SILS + 2) and twenty-one underwent single-incision plus one port laparoscopic surgery (SILS + 1). Surgical outcomes, pain intensity, cosmetic and postoperative morbidity, and mortality were compared between groups. RESULTS: The overall incidence of postoperative complications was similar between the CLS group and the RLS group (16.9% vs. 8.9%, P = 0.270). It was also comparable in the Clavien-Dindo classification (P = 0.774). However, compared with the CLS group, the RLS group had a significantly shorter total length of incision (5.6 ± 1.0 cm vs. 7.1 ± 0.7 cm, P = 0.000); shorter time to first ambulation (24.9 ± 5.9 h vs. 27.6 ± 5.0 h, P = 0.009), flatus (3.0 ± 0.8 d vs. 3.5 ± 1.0 d, P = 0.022) and oral intake (4.0 ± 1.6 d vs. 6.1 ± 5.1 d, P = 0.011); lower white blood cell count on the third day after the operation (9.8 ± 4.0*109/L vs. 11.6 ± 4.7*109/L, P = 0.037); and lower visual analogue scale score on postoperative days 1 and 3(3.0 ± 0.7 vs. 3.3 ± 0.7, P = 0.044 and 0.6 ± 0.7 vs. 1.6 ± 0.6, P = 0.000 respectively). On the other hand, it didn't find any difference in short-term outcomes between the SILS + 2 group and the SILS + 1 group (P > 0.05). But the proximal resection margin was longer in the SILS + 2 group than in the SILS + 1 group (2.6 ± 0.7 cm vs. 1.5 ± 0.9 cm, P = 0.046) in patients with adenocarcinoma of the esophagogastric junction (AEG). CONCLUSIONS: RLS for total gastrectomy is a feasible and safe technique when performed by an experienced laparoscopic surgeon. Moreover, compared with SILS + 1, SILS + 2 might have some advantages in AEG patients.

Efficacy of perinatal pharmacotherapeutic actions for survival of very preterm newborn rabbits at 26-day gestation.

Investigation of the pathophysiology of lung impairment and protection in very preterm neonates at birth requires adequate experimental models. This study aimed to elucidate the efficacy and mechanism of perinatal pharmacotherapeutic action in postnatal survival of very preterm rabbits. Pregnant New Zealand White rabbits on 25-day gestation (term 31 days) were given dexamethasone (D), or sham injection as control (C), and cesarean delivered 24 hours later on day 26. Newborns were anesthetized, intratracheally intubated, randomly received either saline or porcine surfactant (S), allocated to four groups (C, S, D, and DS), and ventilated with low tidal volume. Under the identical protocol, another four groups were added with nitric oxide (N) inhalation (CN, SN, DN, and DSN). Survival length, lung mechanics, histopathology, and pathobiology of lung tissue were measured for benefits and injury patterns. DSN had the longest median survival time (ST50, 10.3 h), whereas C had the shortest (3.5 h), with remaining groups in-between. The survival was mainly benefited by S, when additive effects with D and/or N were discernible, by improved lung mechanics and alveolar aeration, ameliorated lung injury severity and pneumothorax, and augmented lung phospholipid pools, with DSN being the most optimal. Variable mRNA expression profiles of alveolar epithelia-associated cytokines and inflammatory mediators further characterized injury and response patterns as phenotyping conditioned in pharmacotherapeutic actions. In conclusion, the combined regimens of perinatal medications achieved remarkable survival in very preterm rabbits with lung protective ventilation strategy, offering a unique model in investigation of very preterm birth-associated respiratory physiology and morbidities.NEW & NOTEWORTHY By establishing a very preterm rabbit model with 26-day gestation (term 31 days), optimal survival length for 50% of animals in groups was achieved by comparing regimens of combined antenatal glucocorticoids, postnatal surfactant and inhaled nitric oxide, with a low tidal volume ventilation strategy. The efficacies of pharmacotherapeutic action were associated with significantly improved lung mechanics, ameliorated lung injury and pneumothorax, and enhanced surfactant phospholipid metabolism, along with variable mRNA expression profiles characterizing the response patterns.

Efficacy of synthetic surfactant (CHF5633) bolus and/or lavage in meconium-induced lung injury in ventilated newborn rabbits.

BACKGROUND: The pathogenesis of neonatal meconium aspiration syndrome (MAS) involves meconium-induced lung inflammation and surfactant inactivation. Bronchoalveolar lavage (BAL) with diluted surfactant facilitates the removal of meconium. CHF5633, one of the most promising synthetic surfactants, is effective in neonatal respiratory distress syndrome. Here we investigated its efficacy via BAL in an experimental MAS model. METHODS: Experimental MAS was induced at birth in near-term newborn rabbits by intratracheal instillation of reconstituted human meconium. First, undiluted CHF5633 was compared with a porcine-derived surfactant (Poractant alfa) via intratracheal bolus (200 mg/kg). Second, the efficacy of BAL with diluted CHF5633 (5 mg/mL, 20 ml/kg) alone, or followed by undiluted boluses (100 or 300 mg/kg), was investigated. RESULTS: Meconium instillation caused severe lung injury, reduced endogenous surfactant pool, and poor survival. CHF5633 had similar benefits in improving survival and alleviating lung injury as Poractant alfa. CHF5633 BAL plus higher boluses exerted better effects than BAL or bolus alone in lung injury alleviation by reversing phospholipid pools and mitigating proinflammatory cytokine mRNA expression, without fluid retention and function deterioration. CONCLUSIONS: CHF5633 improved survival and alleviated meconium-induced lung injury, the same as Poractant alfa. CHF5633 BAL plus boluses was the optimal modality, which warrants further clinical investigation. IMPACT: To explore the efficacy of a synthetic surfactant, CHF5633, in neonatal lung protection comparing with Poractant alfa in a near-term newborn rabbit model with meconium-induced lung injury. Similar effects on improving survival and alleviating lung injury were found between CHF5633 and Poractant alfa. Optimal therapeutic effects were identified from the diluted CHF5633 bronchoalveolar lavage followed by its undiluted bolus instillation compared to the lavage or bolus alone regimens. Animals with CHF5633 lavage plus bolus regimen exerted neither substantial lung fluid retention nor lung mechanics deterioration but a trend of higher pulmonary surfactant-associated phospholipid pools.

BMI and pelvimetry help to predict the duration of laparoscopic resection for low and middle rectal cancer.

BACKGROUND: In rectal cancer surgery, recent studies have found associations between clinical factors, especially pelvic parameters, and surgical difficulty; however, their findings are inconsistent because the studies use different criteria. This study aimed to evaluate common clinical factors that influence the operative time for the laparoscopic anterior resection of low and middle rectal cancer. METHODS: Patients who underwent laparoscopic radical resection of low and middle rectal cancer from January 2018 to December 2020 were retrospectively analyzed and classified according to the operative time. Preoperative clinical and magnetic resonance imaging (MRI)-related parameters were collected. Logistic regression analysis was used to identify factors for predicting the operative time. RESULTS: In total, 214 patients with a mean age of 60.3 ± 8.9 years were divided into two groups: the long operative time group (n = 105) and the short operative time group (n = 109). Univariate analysis revealed that the male sex, a higher body mass index (BMI, ≥ 24.0 kg/m2), preoperative treatment, a smaller pelvic inlet (< 11.0 cm), a deeper pelvic depth (≥ 10.7 cm) and a shorter intertuberous distance (< 10.1 cm) were significantly correlated with a longer operative time (P < 0.05). However, only BMI (OR 1.893, 95% CI 1.064-3.367, P = 0.030) and pelvic inlet (OR 0.439, 95% CI 0.240-0.804, P = 0.008) were independent predictors of operative time. Moreover, the rate of anastomotic leakage was higher in the long operative time group (P < 0.05). CONCLUSION: Laparoscopic rectal resection is expected to take longer to perform in patients with a higher BMI or smaller pelvic inlet.

Consensus on informed consent for participants in cancer clinical studies (2021 edition).

To fully protect the rights of participants in cancer clinical studies and clarify the key points for the ethics review of the content of informed consent forms and the process of collecting informed consent, the Medical Ethics Professional Committee of the China Anti-Cancer Association engaged in joint discussions with the ethics committees of well-known cancer hospitals in China to formulate this consensus, along with the attached general template for informed consent forms for cancer clinical studies. This work is expected to provide guidance and suggestions for the practice of the sponsors, researchers, and ethics committees.

Investigation into potential mechanisms of metabolic syndrome by integrative analysis of metabolomics and proteomics.

Metabolic syndrome (MetS) is a complex syndrome cluster of metabolic disorders, which greatly increases the risks of diabetic and cardiovascular diseases. Although it has become a significantly worldwide public health burden, its pathogenesis largely remains unknown. In this study, we first performed an integrated analysis of proteomic and metabonomic data of liver tissues of rats between MetS and control groups to reveal possible mechanisms of MetS. A total of 16 significantly perturbed pathways were identified, of which three pathways were shared by patients with MetS and diabetes identified by analysis of serum samples, including alanine, aspartate and glutamate metabolism, valine, leucine and isoleucine biosynthesis, and glycine, serine and threonine metabolism. Additionally, it was found that 18 differential metabolites were closely related with 36 differential proteins, which were considered as significantly discriminant metabolites and proteins between two groups and were mainly involved in metabolic processes of gamma-aminobutyric acid and acetyl-CoA, biosynthetic processes of cholesterol and amino acids. The results of PPI network analysis and topological parameter calculation of four methods revealed that 16 proteins can serve as hub proteins of MetS. Followed by searching the PubMed database and molecular docking of Cyp7a1 and Got1, we concluded that atorvastatin and resveratrol may be potential drugs for MetS.

Comparison of short-term outcomes between single-incision plus one-port laparoscopic surgery and conventional laparoscopic surgery for distal gastric cancer: a randomized controlled trial.

Background: The technical safety and efficacy of single-incision plus one-port laparoscopic surgery (SILS+1) for distal gastric cancer remain unclear. This study was performed to compare the short-term outcomes of patients with distal gastric cancer undergoing SILS+1 versus conventional laparoscopic surgery (CLS). Methods: This randomized controlled trial involved patients with clinical stage cT1b-3N0-2M0 distal gastric cancer. The patients were randomized to the CLS group or SILS+1 group. The surgical and pathologic outcomes, postoperative mortality, and pain intensity were compared between the two groups. Results: From January 2019 to April 2021, 117 patients were enrolled and assigned to either the CLS group (n=59) or SILS+1 group (n=58). The clinical characteristics, including blood loss, tumor diameter, pathologic stage, number of lymph nodes harvested, and postoperative recovery, were similar between the two groups (P>0.05). There were no statistically significant differences in the overall postoperative complication rates between the CLS group and SILS+1 group (10.2% vs. 6.9%, respectively; P=0.743). The Clavien-Dindo classification was also comparable (P=0.435). However, the operating time was significantly longer in the CLS group than SILS+1 group (207.0±41.2 vs. 185.1±40.7 min, respectively; P=0.005), and the total incision length was significantly shorter in the SILS+1 group than CLS group (6.1±0.6 vs. 7.6±0.7 cm, respectively; P=0.000). Moreover, on the third day after surgery, the visual analog scale (VAS) score was significantly higher in the CLS group than SILS+1 group (1.6±0.6 vs. 0.6±0.7, respectively; P=0.000). Conclusions: The results of this study suggest that SILS+1 for distal gastric cancer performed by an experienced surgeon might be a feasible and safe technique with better cosmetic results and less pain in strictly selected patients. Trial Registration: This trial was registered at www.chictr.org.cn (ChiCTR2100051491).

Effect of kaempferol on hedgehog signaling pathway in rats with --chronic atrophic gastritis - Based on network pharmacological screening and experimental verification.

OBJECTIVE: The effect of active ingredients of Chaishaoliujun Decoction (CD) on chronic atrophic gastritis (CAG) was screened by network pharmacological method and verified by preliminary experiment. METHODS: Firstly, the active ingredients and drug targets of CD were retrieved in TCMSP database; CAG-related targets from PharmGkb, OMIM, GeneCards and DrugBank databases were collected as well. Secondly, the drug targets and disease targets were mapped to obtain the intersection targets. PPI network and active ingredient-common target network were constructed for the intersection targets obtained and KEGG enrichment analysis was also carried out. Finally, the core active ingredient (kaempferol), effective targets (IL-1ß、IL-6) and hedgehog signaling pathway were verified by animal experiments. RESULTS: There were 137 active ingredients, 243 potential target so and 48 intersection targets with CAG in CD. 147 KEGG enrichment pathways were obtained, mainly involving JAK/STAT signaling pathway, PI3K/Akt signaling pathway, hedgehog signaling pathway, etc. The results of animal experiments showed: The content of IL-1ß and IL-6 in model group was significantly increased compared with the normal group, while the mRNA and protein expressions of Shh, Ptch1 and Gli1 were also significantly decreased (P < 0.05); compared with model group, the content of IL-1ß and IL-6 in the vitacoenzyme group, the CD group and the kaempferol group were significantly decreased, while the mRNA and protein expressions of Shh, Ptch1 and Gli1 were significantly increased (P < 0.05). CONCLUSION: Kaempferol, the active ingredient of CD, could reduce the levels of IL-6 and IL-1ß by regulating hedgehog signaling pathway so as to play a role in the treatment of CAG. Hence this paper could provide the methodological basis and theoretical basis for further revealing the pharmacological mechanism of CD.

Hyper-Pseudo-Viscoelastic Model and Parameter Identification for Describing Tensile Recovery Stress-Strain Responses of Rubber Components in TBR.

Tires are often in service under dynamic conditions. Realizing the high-precision prediction of the mechanical response of rubber materials under cyclic loading can provide guidance for the design of high-performance tires. In this work, the tensile recovery stress-strain responses of rubber materials in nine different components of a truck and bus radial (TBR) tire were obtained through experiments. Before fitting, an experimental data processing method was proposed to facilitate the parameter identification for a hyper-pseudo-viscoelastic model, that is, the raw experimental data were changed to the adjusted test data. The HyperFit software was used to fit the adjusted test data based on the Yeoh hyperelastic model and the Ogden-Roxburgh pseudoelastic model to obtain the initial material parameters for the two models. In order to describe the permanent set, the Prony series viscoelastic model was introduced. The Isight software was adopted to optimize the parameters. The results showed that the hyper-pseudo-viscoelastic model (i.e., the combination of Yeoh, Ogden-Roxburgh and Prony series models) can describe the tensile recovery mechanical responses (loading curve, unloading curve and permanent set) of nine different rubber components in TBRs. The fitting results are in good agreement with the adjusted data, and all the coefficients of determination (R2) exceed 0.975. Finally, the cyclic deformation simulation of a dumbbell rubber specimen was carried out based on the above constitutive model and fitted parameters. R2 was used to describe the simulation accuracy and its value reached 0.968.

Risk factors related balance disorder for patients with dizziness/vertigo.

BACKGROUND: When dizziness/vertigo patients presented with balance disorder, it will bring severe morbidity. There is currently lack of research to explore risk factor related balance disorder in dizziness patients, especially in those who walk independently. AIM: To investigate risk factors related balance disorder in dizziness/vertigo patients who walk independently. METHODS: Medical data of 1002 dizziness/vertigo patients registered in vertigo/balance disorder registration database were reviewed. The demographic data, medical history, and risk factors for atherosclerosis (AS) were collected. Enrolled dizziness/vertigo patients could walk independently, completed Romberg test, videonystagmography (VNG), and limits of stability (LOS). The subjective imbalance was patient complained of postural symptom when performing Romberg test. Multivariable logistic regression analyzed risk factors related balance disorder. The receiver operating characteristic (ROC) curve evaluated the utility of regression model. RESULTS: Five hundred fifty-three dizziness/vertigo patients who walk independently were included in the final analysis. According to LOS, patients were divided into 334 (60%) normal balance and 219 (40%) balance disorder. Compared with normal balance, patients with balance disorder were older (P = 0.045) and had more risk factors for AS (P<0.0001). The regression showed that risk factors for AS (OR 1.494, 95% CI 1.198-1.863), subjective imbalance (OR 4.835, 95% CI 3.047-7.673), and abnormality of optokinetic nystagmus (OR 8.308, 95% CI 1.576-43.789) were related to balance disorder. The sensitivity and specificity of model were 71 and 63% (P<0.0001). The area under the curve (AUC) was 0.721. CONCLUSIONS: Risk factors for AS, subjective imbalance, and abnormality of optokinetic nystagmus were predictors for balance disorder in patients with dizziness/vertigo who walk independently.

Fast Identification of Adverse Drug Reactions (ADRs) of Digestive and Nervous Systems of Organic Drugs by In Silico Models.

This study aimed to discover concurrences of adverse drug reactions (ADRs) and derive models of the most frequent items of ADRs based on the SIDER database, which included 1430 marketed drugs and 5868 ADRs. First, common ADRs of organic drugs were manually reclassified according to side effects in the human system and followed by an association rule analysis, which found ADRs of digestive and nervous systems often occurred at the same time with a good association rule. Then, three algorithms, linear discriminant analysis (LDA), support vector machine (SVM) and deep learning, were used to derive models of ADRs of digestive and nervous systems based on 497 organic monomer drugs and to identify key structural features in defining these ADRs. The statistical results indicated that these kinds of QSAR models were good tools for screening ADRs of digestive and nervous systems, which gave the ROC AUC values of 81.5%, 98.9%, 91.5%, 69.5%, 78.4% and 78.8%, respectively. Then, these models were applied to investigate ADRs of 1536 organic compounds with four phase and zero rule-of-five (RO5) violations from the ChEMBL database. Based on the consensus ADRs' predictions of models, 58.1% and 42.6% of compounds were predicted to cause these two ADRs, respectively, indicating the significance of initial assessment of ADRs in early drug discovery.

Seasonality and Cardio-Cerebrovascular Risk Factors for Benign Paroxysmal Positional Vertigo.

Background: Benign paroxysmal positional vertigo (BPPV) is the most common cause of vertigo, especially in the elderly. Several studies have revealed a possible seasonality to BPPV. However, whether the seasonality of BPPV also exists in China is unclear. The characteristics of cardio-cerebrovascular risk factors for BPPV in the cold season have not yet been investigated. Objectives: (1) To investigate the seasonality of BPPV; (2) To explore the relationship between cardio-cerebrovascular risk factors and seasonality of BPPV. Methods: A retrospective observational study was performed in Beijing Tiantan Hospital from Jan 2016 to Dec 2018. The study included 1,409 new-onset BPPV patients aged 18-88 years. The demographic data, onset time, and medical history of BPPV were collected. The meteorological data, including temperature, atmospheric pressure, rainfall, and insolation, was obtained from Beijing Meteorological service. The x 2 goodness of fit test was used to evaluate whether BPPV patients' numbers were significantly different among different months of the year. The Spearman correlation was used to detect the correlation between numbers of BPPV patients diagnosed monthly with each climatic parameter. The chi-square test for linear-by-linear association were used to investigate the relationship between cardio-cerebrovascular risk factor and seasonality of BPPV. Results: November to next March is the top 5 months with higher BPPV patient numbers (P < 0.001). The numbers of BPPV diagnosed monthly were conversely correlated with temperature and rainfall (r = -0.736, P = 0.010; r = -0.650, P = 0.022, respectively), positively correlated with atmospheric pressure (r = 0.708, P = 0.010), but no significant correlated with insolation. BPPV in the cold season (including January, February, March, November, and December) had a higher proportion, accounting for 54.2% of all BPPV patients. Among BPPV patients with ≥2, 1, and none cardio-cerebrovascular risk factors, the cold season accounted for 57.0, 56.0, 49.8%, respectively. As the number of cardio-cerebrovascular risk factors increased, the proportion of patients in the cold season of BPPV increased (P = 0.025). Conclusions: BPPV patients are seen more in the months with low temperature, low rainfall, and high atmospheric pressure. Compared with the non-cold season, BPPV patients have more risk factors for cardio-cerebrovascular diseases in the cold season.