FNICM: A New Methodology To Identify Core Metabolites Based on Significantly Perturbed Metabolic Subnetworks.

Metabolomics has emerged as a powerful tool in biomedical research to understand the pathophysiological processes and metabolic biomarkers of diseases. Nevertheless, it is a significant challenge in metabolomics to identify the reliable core metabolites that are closely associated with the occurrence or progression of diseases. Here, we proposed a new research framework by integrating detection-based metabolomics with computational network biology for function-guided and network-based identification of core metabolites, namely, FNICM. The proposed FNICM methodology is successfully utilized to uncover ulcerative colitis (UC)-related core metabolites based on the significantly perturbed metabolic subnetwork. First, seed metabolites were screened out using prior biological knowledge and targeted metabolomics. Second, by leveraging network topology, the perturbations of the detected seed metabolites were propagated to other undetected ones. Ultimately, 35 core metabolites were identified by controllability analysis and were further hierarchized into six levels based on confidence level and their potential significance. The specificity and generalizability of the discovered core metabolites, used as UC's diagnostic markers, were further validated using published data sets of UC patients. More importantly, we demonstrated the broad applicability and practicality of the FNICM framework in different contexts by applying it to multiple clinical data sets, including inflammatory bowel disease, colorectal cancer, and acute coronary syndrome. In addition, FNICM was also demonstrated as a practicality methodology to identify core metabolites correlated with the therapeutic effects of Clematis saponins. Overall, the FNICM methodology is a new framework for identifying reliable core metabolites for disease diagnosis and drug treatment from a systemic and a holistic perspective.

Comparison of Semen Aesculi species from different geographical origins and horse chestnut based on metabolomics and chemometrics analysis.

BACKGROUND: Semen Aesculi, a traditional Chinese herbal medicine, has a long history of use for treating chest and abdominal pain with distension. In addition, the horse chestnut (Aesculus hippocastanum L.) is another species of Aesculus in Europe and has notable clinical significance in alleviating chronic venous insufficiency, hemorrhoids, and postoperative edema. Thus, highlighting the comparative study of Semen Aesculi and horse chestnut may broaden clinical applications. OBJECTIVES: To conduct a comprehensive comparative analysis on the chemical profiling of these two varieties and determine whether they have equivalent clinical efficacy by integrating plant metabolomics and multivariate statistical methods. METHODS: Initially, a comprehensive characterisation was performed using ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS/MS) platform, and in total 44 active ingredients were identified. Then, untargeted metabolomics combined with principal component analysis (PCA) and partial least squares-discriminant analysis (PLS-DA) was applied for the discrimination of a German species and three official Chinese species. Next, 24 marker compounds responsible for the discrimination of different species were screened out and used to predict the species of unknown samples by genetic algorithm-optimised support vector machine (GA-SVM) with a high prediction accuracy. Finally, a heatmap visualisation was employed for clarifying the distribution of the identified active ingredients. RESULTS: The three species of Chinese Semen Aesculi showed distinct separation from each other, while European horse chestnut and Aesculus chinensis Bunge were similar in chemical composition. CONCLUSIONS: This work provided experimental evidence for further expanding the clinical application of Chinese Semen Aesculi and promoted the species identification and quality control of Semen Aesculi.

[Plasma components of Danzhi Xiaoyao Formula and its mechanism of action in treating perimenopausal depression based on UPLC-Q-TOF-MS~E integrated with network pharmacology].

In this study, ultra-performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS~E) was used to analyze the plasma components of Danzhi Xiaoyao Formula after oral administration. Forty-nine plasma components were found in the serum of rats by comparing the compound extract, drug-containing serum, and blank serum. Components, such as 6-hydroxycoumarin, poricoic acid F, deoxoglabrolide, 30-norhederagenin, kanzonol R, 3',6'-di-O-galloylpaeoniflorin, 16α-hydroxytrametenolic acid, 16-deoxyporicoic acid B, 3-O-acetyl-16α-hydroxytrametenolic acid, and 16α,25-dihydroxydehydroeburiconic acid, were first found in rat serum. Behavioral tests, including the tail suspension test, novel object recognition test, and novelty-suppressed feeding test, were conducted for behavioral analysis. It was confirmed that this formula had therapeutic effects on perimenopausal depression. Furthermore, in combination with the network pharmacology method, 53 core targets including MAPK1, HRAS, AKT1, EGFR, and ESR1 were screened, and these targets participated in 165 signaling pathways, including PI3K-AKT, AMPK, VEGFA, MAPK, and HIF-1. In summary, the potential effects of Danzhi Xiaoyao Formula in treating perimenopausal depression are associated with mechanisms in accelerating inflammation repair, improving neuroplasticity, affecting neurotransmitters, regulating estrogen levels, and promoting new blood vessel formation.

Patient-reported outcome measure for obstructive sleep apnea: Symptoms, Tiredness, Alertness, Mood and Psychosocial questionnaire: Preliminary results.

Obstructive sleep apnea (OSA) is a common chronic condition that has a significant impact on the biopsychosocial aspects of the patient's life. There is currently no psychometrically validated patient-reported outcome measure to assess the impact of this condition on the health-related quality of life. We designed a novel instrument based on common patient statements, prioritized by patient preference. Sixty-three patients with OSA and 33 participants with no symptoms of sleep-disordered breathing were asked to complete a 20-item initial questionnaire. The acceptability, reliability and validity of the instrument were assessed using known psychometric techniques. The instrument had strong acceptability and was completed within 180 s with no missing data. Five items were removed as they had a high ceiling factor. A further three items were removed as they did not represent the central construct uniquely. The final 12-item instrument had high internal consistency (Cronbach's alpha 0.91), strong test-retest reliability (p = .83) and high discriminant validity when comparing mean total scores of controls (6.88; 95% confidence interval [CI], 4.67-9.08) and those with OSA (31.39; 95% CI, 27.94-34.84) (p < .001). Further studies are planned to help validate this instrument for clinical use.

A comparison of psychometric properties of two common measures of caregiving burden: the family burden interview schedule (FBIS-24) and the Zarit caregiver burden interview (ZBI-22).

PURPOSE: The Family Burden Interview Schedule (FBIS-24) and the Zarit Caregiver Burden Interview (ZBI-22) are among the most widely used measures for assessing caregiving burden, but their psychometric performances have not been compared in the same study of caregivers of people living with schizophrenia (PLS). This is important because the measures assess overlapping constructs- the FBIS-24 assesses objective burden (e.g., completion of manual tasks) and the ZBI-22 assesses subjective burden (e.g., perceived distress, stigma). This study seeks to fill this gap by comparing the reliability and validity of the FBIS-24 and the ZBI-22 in a Chinese community sample of caregivers of PLS. METHODS: A Cross-sectional stud was conducted in a community-based mental health service program in Central South part of China. A total of 327 primary family caregivers of PLS completed face-to-face interviews of the FBIS-24, the ZBI-22, the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder Scale (GAD-7), and the Family Adaptation, Partnership, Growth, Affection and Resolve Index scale (APGAR), and PLS were assessed using the Global Assessment of Function scale (GAF). RESULTS: Our findings show that both the FBIS-24 and ZBI-22 have comparable psychometric performance in terms of the internal consistency, convergent validity and known group's validity. CONCLUSION: Both the FBIS-24 and the ZBI-22 are psychometrically sound measures of caregiving burden but the choice of which measure to use will depend on the research question.

Development and validation of an ultrasound-based nomogram to improve the diagnostic accuracy for malignant thyroid nodules.

OBJECTIVES: The aim of this study was to develop an ultrasound-based nomogram to improve the diagnostic accuracy of the identification of malignant thyroid nodules. METHODS: A total of 1675 histologically proven thyroid nodules (1169 benign, 506 malignant) were included in this study. The nodules were grouped into the training dataset (n = 700), internal validation dataset (n = 479), or external validation dataset (n = 496). The grayscale ultrasound features included the nodule size, shape, aspect ratio, echogenicity, margins, and calcification pattern. We applied least absolute shrinkage and selection operator (lasso) regression to select the strongest features for the nomogram. Nomogram discrimination (area under the receiver operating characteristic curve, AUC) and calibration were assessed. The nomogram was subjected to bootstrapping validation (1000 bootstrap resamples) to calculate a mean AUC and 95% confidence interval (CI). RESULTS: The nomogram showed good discrimination in the training dataset, with an AUC of 0.936 (95% CI: 0.918-0.953) and good calibration. Application of the nomogram to the internal validation dataset also resulted in good discrimination (AUC: 0.935; 95% CI, 0.915-0.954) and good calibration. The model tested in an external validation dataset demonstrated a lower AUC of 0.782 (95% CI: 0.776-0.789). CONCLUSIONS: This ultrasound-based nomogram can be used to quantify the probability of malignant thyroid nodules. KEY POINTS: • Ultrasound examination is helpful in the differential diagnosis of malignant and benign thyroid nodules. • However, ultrasound accuracy relies heavily on examiner experience. • A less subjective diagnostic model is desired, and the developed nomogram for thyroid nodules showed good discrimination and good calibration.

Determining a cutoff score for the family burden interview schedule using three statistical methods.

BACKGROUND: While it is widely acknowledged that family burden can be ameliorated with effective psycho-social interventions, how to measure family burden and define a valid cutoff to identify family caregivers in need of such interventions remains a key question. The purpose of the present study was to determine a statistically valid cutoff score for the Family Burden Interview Schedule (FBIS), using the cutoff scores of the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder Scale (GAD-7) as the reference. METHODS: The FBIS, PHQ-9, and GAD-7 were administered to a representative community sample of 327 family caregivers of schizophrenia patients. A FBIS cutoff score was determined using three different statistical methods: tree-based modeling, K-means clustering technique and linear regression. Contingency analysis was conducted to compare the FBIS cutoff with depression and anxiety scale scores. RESULTS: Findings proposed a cutoff score of 23 for the FBIS, with sensitivity being 76% for PHQ-9 and 74% for GAD-7, specificity being 68% for PHQ-9 and 67% for GAD-7. CONCLUSION: This cutoff score would enable health care providers to assess family caregivers at risk and provide necessary interventions to improve their quality of life.

Cutoff of the Zarit Burden Interview in predicting depression and anxiety.

BACKGROUND: The purpose of the present study was to determine a statistically valid cutoff score for the Zarit Burden Interview (ZBI) in order to identify family caregivers at risk for depression and anxiety to guide for further assessment and future intervention. METHODS: The ZBI, the Patient Health Questionnaire (PHQ), and the Generalized Anxiety Disorder Scale (GAD) were administered to a representative community sample of 327 family caregivers of schizophrenia individuals. A ZBI cutoff score was determined using three different statistical methods: tree-based modeling, K-means clustering technique and linear regression, followed by contingency analysis and receiver operating characteristic (ROC) curve to compare between depression and anxiety scale scores with the ZBI cutoff. RESULTS: Findings suggest that a cutoff score of 48 in ZBI has significant predictive validity for identifying caregivers at risk for both depression and anxiety. A ZBI cutoff of 48 showed sensitivity of 73% for PHQ and 70% for GAD, specificity of 80% for PHQ and 79% for GAD, PPV (positive predictive value) of 75% for PHQ and 73% for GAD, NPV (negative predictive value) of 78% for PHQ and 76% for GAD. CONCLUSIONS: This cutoff score would enable health care providers to assess family caregivers at risk and provide necessary interventions to improve their quality of life in this important role.

Who cares for the schizophrenia individuals in rural China - A profile of primary family caregivers.

OBJECTIVE: The present study aims to provide a comprehensive profile of the primary family caregivers of schizophrenia individuals in rural China. METHOD: A cross-sectional study was conducted with a sample of 327 primary family caregivers of schizophrenia individuals recruited through a one-stage cluster sampling in Ningxiang County of Hunan province, China. The social demographic and psychological profiles of primary caregivers were measured using standard scales and self-designed scales. RESULTS: The typical caregiver profile consists of a 58-year old married first degree relative (mostly parents or spouses) with a low socio-economic position. Most of them have been caregiving for over 10 years (74.3%) and have some physical illness (67.0%). The major caregiving activities were medicine management (71.6%) and hospital visit (69.4%), yet there is still 17.1% primary caregivers involved with neither of the care. Most (84%) of caregivers reported some kind of burden, with anxiety in 45.9% of caregivers and depression in 45.4%. Family caregivers also reported positive aspects of caregiving including a well-functional family (51.0%) and rewarding feelings (58.3%). CONCLUSION: The findings of the present study have brought attention to a special group of family caregivers for schizophrenia, with implications for intervention on them in the future.

Modest Oxygen-Defective Amorphous Manganese-Based Nanoparticle Mullite with Superior Overall Electrocatalytic Performance for Oxygen Reduction Reaction.

Manganese-based oxides have exhibited high promise as noncoinage alternatives to Pt/C for catalyzing oxygen reduction reaction (ORR) in basic solution and a mix of Mn3+/4+ valence is believed to be vital in achieving optimum ORR performance. Here, it is proposed that, distinct from the most studied perovskites and spinels, Mn-based mullites with equivalent molar ratio of Mn3+ and Mn4+ provide a unique platform to maximize the role of Mn valence in facile ORR kinetics by introducing modest content of oxygen deficiency, which is also beneficial to enhanced catalytic activity. Accordingly, amorphous mullite SmMn2 O5-δ nanoparticles with finely tuned concentration of oxygen vacancies are synthesized via a versatile top-down approach and the modest oxygen-defective sample with an Mn3+ /Mn4+ ratio of 1.78, i.e., Mn valence of 3.36 gives rise to a superior overall ORR activity among the highest reported for the family of Mn-based oxides, comparable to that of Pt/C. Altogether, this study opens up great opportunities for mullite-based catalysts to be a cost-effective alternative to Pt/C in diverse electrochemical energy storage and conversion systems.

A retrospective study of ultrasound and FNA cytology investigation of thyroid nodules: working towards combined risk stratification.

The British Thyroid Association recommended in new guidelines on thyroid cancer treatment [Kwak et al. (Korean J Radiol 14:110-117, 2013)] that ultrasound grading of thyroid nodules should be incorporated into MDT management. A retrospective study was carried out to determine that the impact of US grading has had on MDT decision making in practice. The design used in the study is a retrospective review of case notes. The study was carried out in the hub hospital for thyroid cancer in the North west London Cancer network. We included consecutive patients referred to the regional thyroid multidisciplinary meeting between August 2014 and May 2015 for investigation of thyroid nodules. Data were collected on patient demographics, co-morbidity, thy grading, ultrasound grading, surgery, post-operative histology, and radioactive iodine treatment details. Accuracy of cytology and ultrasound in diagnosing malignancy was correlated to definitive histology. 99 patients with thyroid nodules were included in the study. 97% of patients had at least one fine needle aspiration and 75% had ultrasound grading. Thy3f (Bethesda IV) nodules were more likely to be carcinoma if associated with a U4 grade rather than U3 (67 vs 18%, p = 0.028). Ultrasound grading has recently been introduced to the standard practice in investigation of thyroid nodules. Further assessment of the accuracy of ultrasound grading in clinical practice may allow us to risk-stratify thy3a/thy3f (Bethesda III/IV) lesions and personalise treatment.

Recognition of depression, anxiety, and alcohol abuse in a Chinese rural sample: a cross-sectional study.

BACKGROUND: Under-utilization of mental health services is a global health issue. Recognition of mental disorders, as the first step to seeking help from professional sources, has been well studied in developed countries, yet little is known about the situation in rural areas of developing countries like China. The purpose of the study is to understand the recognition of depression, anxiety, and alcohol abuse and its predictive factors in a Chinese rural sample METHODS: Face-to-face interviews were conducted on a representative rural adult sample in a cross-sectional study in China (N = 2052). Respondents were presented with three vignettes depicting depression, anxiety and alcohol abuse and asked to label the disorder and its cause to assess their recognition of the three mental disorders. They also completed the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder Scale (GAD-7), and the Alcohol Use Disorders Identification Test (AUDIT) to assess their current mental health status. RESULTS: The alcohol abuse vignette was more frequently attributed as a mental problem than the depression vignette and anxiety vignette. The correct labeling rate was 16.1 % in the depression vignette, 15.5 % in the anxiety vignette, and 58.2 % in the alcohol vignette. Higher education is the common and also strongest factor positively predicting the recognition of all three vignettes. Beyond that, being female is an independent predictor of correct recognition of alcohol abuse, while recognition of depression and anxiety were positively predicted by younger age. CONCLUSIONS: Lower recognition of depression and anxiety as compared to alcohol abuse confirms the importance and need to increase the public's awareness and knowledge about common mental disorders. Recognition of common mental disorders could be improved through general public campaign and education, while paying attention to the unique predictive factors for each specific disorder and implement targeted intervention.

Thyroid surgery for Graves' disease and Graves' ophthalmopathy.

BACKGROUND: Graves' disease is an autoimmune disease caused by the production of auto-antibodies against the thyroid-stimulating hormone receptor, which stimulates follicular cell production of thyroid hormone. It is the commonest cause of hyperthyroidism and may cause considerable morbidity with increased risk of cardiovascular and respiratory adverse events. Five per cent of people with Graves' disease develop moderate to severe Graves' ophthalmopathy. Thyroid surgery for Graves' disease commonly falls into one of three categories: 1) total thyroidectomy, which aims to achieve complete macroscopic removal of thyroid tissue; 2) bilateral subtotal thyroidectomy, in which bilateral thyroid remnants are left; and 3) unilateral total and contralateral subtotal thyroidectomy, or the Dunhill procedure. Recent American Thyroid Association guidelines on treatment of Graves' hyperthyroidism emphasised the role of surgery as one of the first-line treatments. Total thyroidectomy removes target tissue for the thyroid-stimulating hormone receptor antibody. It controls hyperthyroidism at the cost of lifelong thyroxine replacement. Subtotal thyroidectomy leaves a thyroid remnant and may be less likely to lead to complications, however a higher rate of recurrent hyperthyroidism is expected and revision surgery would be challenging. The choice of the thyroidectomy technique is currently largely a matter of surgeon preference, and a systematic review of the evidence base is required to determine which option offers the best outcomes for patients. OBJECTIVES: To assess the optimal surgical technique for Graves' disease and Graves' ophthalmopathy. SEARCH METHODS: We searched the Cochrane Library, MEDLINE and PubMed, EMBASE, ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). The date of the last search was June 2015 for all databases. We did not apply any language restrictions. SELECTION CRITERIA: Only randomised controlled trials (RCTs) involving participants with a diagnosis of Graves' disease based on clinical features and biochemical findings of hyperthyroidism were eligible for inclusion. Trials had to directly compare at least two surgical techniques of thyroidectomy. There was no age limit to study inclusion. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted and cross-checked the data for analysis, evaluation of risk of bias and establishment of 'Summary of findings' tables using the GRADE instrument. The senior review authors reviewed the data and reconciled disagreements. MAIN RESULTS: We included five RCTs with a total of 886 participants; 172 were randomised to total thyroidectomy, 383 were randomised to bilateral subtotal thyroidectomy, 309 were randomised to the Dunhill procedure and 22 were randomised to either bilateral subtotal thyroidectomy or the Dunhill procedure. Follow-up ranged between six months and six years. One trial had three comparison arms. All five trials were conducted in university hospitals or tertiary referral centres for thyroid disease. All thyroidectomies were performed by experienced surgeons. The overall quality of the evidence ranged from low to moderate. In all trials, blinding procedures were insufficiently described. Outcome assessment for objective outcomes was blinded in one trial. Surgeons were not blinded in any of the trials. One trial blinded participants. Attrition bias was a substantial problem in one trial, with 35% losses to follow-up. In one trial the analysis was not carried out on an intention-to-treat basis.Total thyroidectomy was more effective than subtotal thyroidectomy techniques (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in 0/150 versus 11/200 participants (OR 0.14 (95% CI 0.04 to 0.46); P = 0.001; 2 trials; moderate quality evidence). Total thyroidectomy was also more effective than bilateral subtotal thyroidectomy at preventing recurrent hyperthyroidism in 0/150 versus 10/150 participants (odds ratio (OR) 0.13 (95% confidence interval (CI) 0.04 to 0.44); P = 0.001; 2 trials; moderate quality evidence). Compared to bilateral subtotal thyroidectomy, the Dunhill procedure was more likely to prevent recurrent hyperthyroidism in 20/283 versus 8/309 participants (OR 2.73 (95% CI 1.28 to 5.85); P = 0.01; 3 trials; low quality evidence). Total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism in 8/172 versus 3/221 participants (OR 4.79 (95% CI 1.36 to 16.83); P = 0.01; 3 trials; low quality evidence). Effects of the various surgical techniques on permanent recurrent laryngeal nerve palsy and regression of Graves' ophthalmopathy were neutral. One death was reported in one study in year three of follow-up. No study investigated health-related quality of life or socioeconomic effects. AUTHORS' CONCLUSIONS: Total thyroidectomy is more effective than subtotal thyroidectomy (both bilateral subtotal thyroidectomy and the Dunhill procedure) at preventing recurrent hyperthyroidism in Graves' disease. The type of surgery performed does not affect regression of Graves' ophthalmopathy. There was some evidence that total thyroidectomy compared with subtotal thyroidectomy conferred a greater risk of permanent hypocalcaemia/hypoparathyroidism, which however, was not seen in comparison with bilateral subtotal thyroidectomy. Permanent recurrent laryngeal nerve palsy did not seem to be affected by type of thyroidectomy. Health-related quality of life as a patient-important outcome measure should form a core determinant of any future trial on the effects of thyroid surgery for Graves' disease.

Effect of enzymatic de-esterification and RG-I degradation of high methoxyl pectin (HMP) on sugar-acid gel properties.

The influence of RG-I domains on high methoxyl pectin (HMP) sugar-acid gel properties has rarely been reported. In our work, HMP was modified by enzymatic de-esterification and degradation of RG-I domains to compare and analyze the relationship between the structure and final sugar-acid gel properties. The results showed that the degree of esterification (DE) of REP (pectin degraded by rhamnosidase) and GEP (pectin debranched by galactosidase) was the same as that of untreated HMP, whereas the DE of PMEP (pectin de-esterified by pectin methyl esterase) decreased from 59.63 % to 54.69 %. The monosaccharide composition suggested no significant changes in the HG and RG-I structural domains of PMEP. In contrast, the percentage of RG-I structural domains of REP and GEP dropped from 37 % to about 28 %, accompanied by a reduction in the proportion of the RG-I backbones and side chains. The rheological characterization of sugar-acid gels demonstrated an enhanced gel grade for PMEP and a weakened one for REP and GEP. Moreover, we constructed a correlation relationship between the fine structure of pectin and the properties of the sugar-acid gels, confirming the critical contribution of the RG-I region (especially the neutral sugar side chains) to the HMP sugar-acid gels.

High expression levels of centromere protein O participates in cell proliferation of human ovarian cancer.

Ovarian cancer is a common malignant tumor in women, with a high mortality rate ranking first among gynecological tumors. Currently, there is insufficient understanding of the causes, pathogenesis, recurrence and metastasis of ovarian cancer, and early diagnosis and treatment still face great challenges. The sensitivity and specificity of existing ovarian cancer screening methods are still unsatisfactory. Centromere protein O (CENP-O) is a recently discovered structural centromere protein that is involved in cell death and is essential for spindle assembly, chromosome separation, and checkpoint signaling during mitosis. The abnormal high expression of CENP-O was detected in various tumors such as bladder cancer and gastric cancer, and it participates in the regulation of tumor cell proliferation. In this study, we detect the expression abundance of CENP-O mRNA in different ovarian cancer cells ( ES-2, A2780, Caov-3, OVCAR-3 and SK-OV-3). The biological function changes of cell proliferation and apoptosis were detected and the role of CENP-O in ovarian cancer cell proliferation and apoptosis was explored by knocking down the expression of CENP-O gene. The results showed that CENP-O gene was significantly expressed in 5 types of ovarian cancer cell lines. After knocking down the CENP-O gene, the proliferation and cloning ability of ovarian cancer cells decreased, and the apoptosis increased. This study indicates that CENP-O has the potential to be a molecular therapeutic target, and downregulating the expression of CENP-O gene can break the unlimited proliferation ability of cancer cells and promote their apoptosis, providing a foundation and new ideas for subsequent molecular mechanism research and targeted therapy.

Zuo Gui Wan Promotes Osteogenesis via PI3K/AKT Signaling Pathway: Network Pharmacology Analysis and Experimental Validation.

OBJECTIVE: Osteogenesis is vitally important for bone defect repair, and Zuo Gui Wan (ZGW) is a classic prescription in traditional Chinese medicine (TCM) for strengthening bones. However, the specific mechanism by which ZGW regulates osteogenesis is still unclear. The current study is based on a network pharmacology analysis to explore the potential mechanism of ZGW in promoting osteogenesis. METHODS: A network pharmacology analysis followed by experimental validation was applied to explore the potential mechanisms of ZGW in promoting the osteogenesis of bone marrow mesenchymal stem cells (BMSCs). RESULTS: In total, 487 no-repeat targets corresponding to the bioactive components of ZGW were screened, and 175 target genes in the intersection of ZGW and osteogenesis were obtained. And 28 core target genes were then obtained from a PPI network analysis. A GO functional enrichment analysis showed that the relevant biological processes mainly involve the cellular response to chemical stress, metal ions, and lipopolysaccharide. Additionally, KEGG pathway enrichment analysis revealed that multiple signaling pathways, including the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway, were associated with ZGW-promoted osteogensis. Further experimental validation showed that ZGW could increase alkaline phosphatase (ALP) activity as well as the mRNA and protein levels of ALP, osteocalcin (OCN), and runt related transcription factor 2 (Runx 2). What's more, Western blot analysis results showed that ZGW significantly increased the protein levels of p-PI3K and p-AKT, and the increases of these protein levels significantly receded after the addition of the PI3K inhibitor LY294002. Finally, the upregulated osteogenic-related indicators were also suppressed by the addition of LY294002. CONCLUSION: ZGW promotes the osteogenesis of BMSCs via PI3K/AKT signaling pathway.

Preoperative and postoperative optimisation of patients undergoing thyroid surgery: a multicentre quality improvement project at Barts Health NHS Trust.

Hypocalcaemia following thyroid surgery can occur in up to 38% of patients. With over 7100 thyroid surgeries performed in 2018 in the UK, this is a common postoperative complication. Undertreated hypocalcaemia can result in cardiac arrhythmias and death. Preventing adverse events from hypocalcaemia requires preoperative identification and treatment of at-risk patients with vitamin D deficiency, timely recognition of postoperative hypocalcaemia and prompt appropriate treatment with calcium supplementation. This project aimed to design and implement a perioperative protocol for prevention, detection and management of post-thyroidectomy hypocalcaemia. A retrospective audit of thyroid surgeries (n=67; October 2017 to June 2018) was undertaken to establish baseline practice of (1) preoperative vitamin D levels assessment, (2) postoperative calcium checks and incidence of postoperative hypocalcaemia and (3) management of postoperative hypocalcaemia. A multidisciplinary team approach following quality improvement principles was then used to design a perioperative management protocol with all relevant stakeholders involved. After dissemination and implementation, the above measures were reassessed prospectively (n=23; April-July 2019). The percentage of patients having their preoperative vitamin D measured increased from 40.3% to 65.2%. Postoperative day-of-surgery calcium checks increased from 76.1% to 87.0%. Hypocalcaemia was detected in 26.8% of patients before and 30.43% of patients after protocol implementation. The postoperative component of the protocol was followed in 78.3% of patients. Limitations include low number of patients which precluded from analysis of the impact of the protocol on length of stay. Our protocol provides a foundation for preoperative risk stratification and prevention, early detection and subsequent management of hypocalcaemia in thyroidectomy patients. This aligns with enhanced recovery protocols. Moreover, we offer suggestions for others to build on this quality improvement project with the aim to further advance the perioperative care of thyroidectomy patients.

The Impact of Team Learning Climate on Innovation Performance - Mediating role of knowledge integration capability.

To address the fierce competition for corporate innovation in the digital economy, this study introduces knowledge integration capability as a mediating variable in light of social information processing theory, and explores the mechanism of team learning climate on innovation performance. Data were collected from a sample of 184 team members for statistical analysis, and Statistical methods such as descriptive statistical analysis, correlation analysis, and regression analysis were used to verify the study hypotheses through SPSS and Amos software, and the results showed that: (1) Team learning climate has a significant positive effect on knowledge integration capability. (2) Team learning climate has a significant positive effect on innovation performance. (3) Knowledge integration capability has a significant positive effect on innovation performance. (4) Knowledge integration capability partially mediates the role between team learning climate and innovation performance. The results proved the perspective of knowledge integration capability for the mechanism of team learning climate on innovation performance from the perspective of knowledge integration capability, and provided theoretical references for creating a learning climate in companies to promote members' knowledge learning and enhance innovation performance.

Structure-guided engineering of a flavin-containing monooxygenase for the efficient production of indirubin.

Indirubin is a bisindole compound for the treatment of chronic myelocytic leukemia. Here, we presented a structure-guided method to improve the activity of a flavin-containing monooxygenase (bFMO) for the efficient production of indirubin in Escherichia coli. A flexible loop interlocked with the active pocket through a helix and the substrate tunnel rather than the active pocket in bFMO were identified to be two reconfigurable structures to improve its activity, resulting in K223R and N291T mutants with enhanced catalytic activity by 2.5- and 2.0-fold, respectively. A combined modification at the two regions (K223R/D317S) achieved a 6.6-fold improvement in catalytic efficiency (kcat/Km) due to enhancing π-π stacking interactions stabilization. Finally, an engineered E. coli strain was constructed by metabolic engineering, which could produce 860.7 mg/L (18 mg/L/h) indirubin, the highest yield ever reported. This work provides new insight into the redesign of FMOs to boost their activities and an efficient approach to produce indirubin.

Test of the stress process model of family caregivers of people living with schizophrenia in China.

Across the world, people living with schizophrenia (PLS) are often cared for by family caregivers. This is especially true in China where community-based systems of care for PLS are underdeveloped. Thus, family caregivers of PLS may experience emotional distress and burden in the absence of community-based services. Pearlin (1990) proposed a highly influential model for understanding the stress process and its relationship to health and wellbeing. Although the model has been examined worldwide, it has yet to be studied in China for caregivers of PLS. In the present study, we use Pearlin's stress process model to examine the mediating effect of perceived caregiver burden, family functioning, and caregivers' positive feelings about caregiving on PLS global functioning and caregiver depressive symptoms. We also examine whether the model differs for parent and spouse caregivers. A total of 327 primary family caregivers of PLS in Hunan province, China, were assessed cross-sectionally using culturally-validated measures. Bootstrap methods with Hayes's PROCESS Macro were used to test multiple mediation models of global functioning scores of PLS and caregiver depressive symptoms. In this first study of the stress process model of family caregivers of PLS in China, the results generally support the model. Caregiver perceived burden, family functioning, and positive caregiver feelings about caregiving all mediate the relationship between PLS global functioning and caregiver depression, with perceived caregiver burden having the strongest indirect effect. Analyses also show that the stress process differs between parent and spouse caregivers, with perceived caregiver burden a mediator for both groups but family functioning only a mediator for parent depressive symptoms. We discuss implications of these findings for extending the stress process model cross-culturally; suggest hypotheses for future research to examine parent and spouse differences; and discuss fruitful directions for intervention.