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Abstract Background It is now realized that peripheral inflammation and abnormal immune responses, especially T cells, contribute to the development of Alzheimer’s disease (AD). Gasdermin D (GSDMD) -mediated pyroptosis has been associated with several neuroinflammatory diseases, but whether GSDMD is involved in the peripheral inflammation and T cell immunity during AD remains unclear. Methods We dynamically investigated GSDMD activation in the peripheral and central nervous system of 5×FAD mouse model and dissected the role of myeloid GSDMD using genetic knockout mice, especially its influence on peripheral T cell responses and AD inflammation. RNA sequencing and in vitro coculture were used to elucidate the underlying immune mechanisms involved. Targeted inhibitor experiments and clinical correlation analysis were used to further verify the function of GSDMD in AD. Results In the present study, caspase activated GSDMD in the spleen of 5×FAD mice earlier than in the brain during disease progression. Loss of myeloid cell GSDMD was shown to impair early-stage effector T cell activation in the periphery and prevent T cell infiltration into the brain, with an overall reduction in neuroinflammation. Furthermore, myeloid cell GSDMD induced T cell PD-1 expression through the IL-1β/NF-κB pathway, restricting regulatory T cells. The administration of a GSDMD inhibitor combined with an anti-PD-1 antibody was found to mitigate the development of AD-associated inflammation. In some AD patients, plasma sPD-1 is positively correlated with IL-Iβ and clinical features. Conclusions Our study systematically identified a role for GSDMD in the AD-related peripheral inflammation and early-stage T cell immunity. These findings also suggest the therapeutic potential of targeting GSDMD for the early intervention in AD.

Abstract The properties of rockfalls, such as the volume and geometry of the detached rock mass as well as the number and diameter of rock fragments, greatly affect their propagated behavior, and different strategies are required to mitigate rockfall hazards. Landquakes generated by rockfalls are regarded as good proxies for those properties. To explore the free‐fall impact dynamics of rockfalls, a series of free‐fall experiments on granular masses were designed and conducted with the characteristics of the generated landquakes versus initial variables being analyzed. The results show that the particle diameter is a dominant factor affecting landquakes, with the most significant effect on the mean frequency. The impact area is another key factor, with which both the maximum seismic amplitude and radiated seismic energy have strong positive correlations, while the mean frequency of landquakes shows a weak negative correlation. The maximum seismic amplitude appears to have a poor correlation with the numbers of layers of the free‐falling granular masses, and it was proven that the maximum seismic amplitude is determined by only the lower part of the granular masses. Quantitative relationships between the number of particles and seismic signal characteristics indicate that disintegration needs to be accounted for when landquakes are used to investigate the characteristics of a rockfall. Moreover, the frequency of landquakes decreases with a decrease in the vertical velocity and increase in the horizontal velocity during granular mass collapse.

Abstract Tamoxifen (TAM) is the frontline therapy for estrogen receptor-positive (ER+) breast cancer in premenopausal women that interrupts ER signaling. As tumors with elevated heterogeneity, amounts of ER-negative (ER−) cells are present in ER+ breast cancer that cannot be directly killed by TAM. Despite complete remissions have been achieved in clinical practice, the mechanism underlying the elimination of ER− cells during TAM treatment remains an open issue. Herein, we deciphered the elimination of ER− cells in TAM treatment from the perspective of the bystander effect. Markable reductions were observed in tumorigenesis of ER− breast cancer cells by applying both supernatants from TAM-treated ER+ cells and a transwell co-culture system, validating the presence of a TAM-induced bystander effect. The major antitumor protein derived from ER+ cells, peptidyl-prolyl cis-trans isomerase B (PPIB), is the mediator of the TAM-induced bystander effect identified by quantitative proteomics. The attenuation of ER− cells was attributed to activated BiP/eIF2α/CHOP axis and promoted endoplasmic reticulum stress (ERS)-induced apoptosis, which can also be triggered by PPIB independently. Altogether, our study revealed a novel TAM-induced bystander effect in TAM treatment of ER+ breast cancer, raising the possibility of developing PPIB as a synergistic antitumor agent or even substitute endocrine therapy.

Typhoons' rapid variation makes effective hazard prevention difficult, which remains a challenging research topic requiring novel observation technology and analysis methodology. We developed an automatic methodology for mining the information on the rapid variation of typhoon cloud-top motion from high-spatial-temporal-resolution satellite cloud images, which has steps of estimating and decomposing the typhoon cloud-top motion, locating the typhoon cloud-top center, and analyzing the motion and center position variations. The Gaofen-4 satellite acquired 50-m-1-min-resolution cloud images of Typhoon Megi's (2016) landfall over mountainous Taiwan Island. The data provide an excellent chance to explore what such high-spatial-temporal-resolution successive observations can tell about the cloud-top motion variation of a typhoon landfall using the methodology. Before its landfall, Typhoon Megi's cloud-top center dramatically increased the northwestward migration speed from ∼22 to ∼58 km/h in only ∼2.5 h. It also presented small-scale oscillation along its migration path with a 1.6-to-2.4-km amplitude, a 31-to-33-km spatial period, and a 1.46-to-1.48-h temporal period. We averaged the motion speeds (velocity magnitudes) in each motion field to assess the field strength. The so-calculated cloud-top average rotation speed of Typhoon Megi decreased quickly during landfall. Meanwhile, its average divergence speed increased dramatically by ∼30% in a short period of ∼2.5 h, reaching ∼2 times the rotation speed. This result means that Megi's cloud-top motion rapidly changed from a typical rotation motion-dominated status to a divergence motion-dominated status. This rapid transformation from typical rotation motion dominance to divergence motion dominance implies intense upward warm and moist airflows that cause severe precipitation.

Abstract Background Triple-negative breast cancer is a complex breast malignancy subtype characterized by poor prognosis. The pursuit of effective therapeutic approaches for this subtype is considerably challenging. Notably, recent research has illuminated the key role of the tricarboxylic acid cycle in cancer metabolism and the complex landscape of tumor development. Concurrently, an emerging body of evidence underscores the noteworthy role that long non-coding RNAs play in the trajectory of breast cancer development. Despite this growing recognition, the exploration of whether long non-coding RNAs can influence breast cancer progression by modulating the tricarboxylic acid cycle has been limited. Moreover, the underlying mechanisms orchestrating these interactions have not been identified. Methods The expression levels of LINC00571 and IDH2 were determined through the analysis of the public TCGA dataset, transcriptome sequencing, qRT‒PCR, and Western blotting. The distribution of LINC00571 was assessed using RNA fluorescence in situ hybridization. Alterations in biological effects were evaluated using CCK-8, colony formation, EdU, cell cycle, and apoptosis assays and a tumor xenograft model. To elucidate the interaction between LINC00571, HNRNPK, and ILF2, RNA pull-down, mass spectrometry, coimmunoprecipitation, and RNA immunoprecipitation assays were performed. The impacts of LINC00571 and IDH2 on tricarboxylic acid cycle metabolites were investigated through measurements of the oxygen consumption rate and metabolite levels. Results This study revealed the complex interactions between a novel long non-coding RNA (LINC00571) and tricarboxylic acid cycle metabolism. We validated the tumor-promoting role of LINC00571. Mechanistically, LINC00571 facilitated the interaction between HNRNPK and ILF2, leading to reduced ubiquitination and degradation of ILF2, thereby stabilizing its expression. Furthermore, ILF2 acted as a transcription factor to enhance the expression of its downstream target gene IDH2. Conclusions Our study revealed that the LINC00571/HNRNPK/ILF2/IDH2 axis promoted the progression of triple-negative breast cancer by regulating tricarboxylic acid cycle metabolites. This discovery provides a novel theoretical foundation and new potential targets for the clinical treatment of triple-negative breast cancer.

PurposeThe incidence of thyroid cancer is growing fast and surgery is the most significant treatment of it. For patients with unilateral cN0 papillary thyroid cancer whether to dissect contralateral central lymph node is still under debating. Here, we aim to provide a machine learning based prediction model of contralateral central lymph node metastasis using demographic and clinical data.Methods2225 patients with unilateral cN0 papillary thyroid cancer from Wuhan Union Hospital were retrospectively studied. Clinical and pathological features were compared between patients with contralateral central lymph node metastasis and without. Six machine learning models were constructed based on these patients and compared using accuracy, sensitivity, specificity, area under the receiver operating characteristic and decision curve analysis. The selected models were then verified using data from Differentiated Thyroid Cancer in China study. All statistical analysis and model construction were performed by R software.ResultsMale, maximum diameter larger than 1cm, multifocality, ipsilateral central lymph node metastasis and younger than 50 years were independent risk factors of contralateral central lymph node metastasis. Random forest model performed better than others, and were verified in external validation cohort. A web calculator was constructed.ConclusionsGender, maximum diameter, multifocality, ipsilateral central lymph node metastasis and age should be considered for contralateral central lymph node dissection. The web calculator based on random forest model may be helpful in clinical decision.

Oxaliplatin (OXA)-based chemotherapy is one of the first-line treatments for advanced gastric cancer. However, the potential risk for chemotherapy-induced hepatic injury can hinder its effectiveness. Polyene phosphatidylcholine (PPC) is often used as a hepatoprotective agent to counter OXA-induced hepatic injury; however, its impact on the antitumour effectiveness of OXA remains uncertain. Our retrospective study examined 98 patients with stage IV gastric cancer to assess the impact of PPC on progression-free survival (PFS) and disease control rate (DCR). Furthermore, in vitro and in vivo assays were conducted to elucidate the combined biological effects of OXA and PPC (OXA+PPC) on gastric cancer. RNA sequencing, luciferase reporter assays, live/dead cell assays, immunofluorescence, and western blotting were used to identify the activated signalling pathways and downstream factors post OXA+PPC treatment. The findings indicated that PPC served as an independent prognostic factor, correlating with prolonged PFS and improved DCR in patients with gastric cancer. The combination of OXA and PPC significantly inhibited tumour cell growth both in vitro and in vivo. RNA sequencing revealed that OXA+PPC treatment amplified reactive oxygen species and ferroptosis signalling pathways. Mechanistically, OXA+PPC upregulated the expression of haem oxygenase-1 by promoting the nuclear migration of nuclear factor erythroid 2-related factor (Nrf2), thereby enhancing its transcriptional activity. Drug-molecule docking analysis demonstrated that PPC competitively bound to the peptide structural domains of both Nrf2 and Kelch-like ECH-associated protein 1 (KEAP1), accounting for the increased translocation of Nrf2. In conclusion, our study reveals the synergistic antitumour potential of PPC and OXA while protecting patients against hepatic injury. This suggests a promising combined treatment approach for patients with advanced gastric cancer.

Abstract Background To compare glycemic control in Chinese patients with type 2 diabetes mellitus (T2DM) whose blood glucose levels were inadequately controlled with oral antidiabetic drugs after beinaglutide alone or combined with insulin glargine (IGlar). Methods In this 16‐week multicenter, randomized clinical trial, 68 participants randomly received beinaglutide or IGlar for 8 weeks, then the two drugs in combination for 8 weeks. The primary outcomes were the proportion of individuals achieving their glycemic target and the change in glucose variability as measured with a continuous glucose monitoring system from baseline to 8 and 16 weeks. Results Both the beinaglutide and IGlar groups showed increased proportions achieving their glycemic target at 8 weeks, and the combination augmented the proportion reaching the glycated hemoglobin target from 25.42% at 8 weeks to 40.68% at 16 weeks. The beinaglutide group showed a significant reduction in body weight, body mass index, waist circumference, and systolic blood pressure. Beinaglutide elevated high‐density lipoprotein cholesterol by 0.08 mmol/L (95% confidence interval [CI], 0.00–0.16), and diminished low‐density lipoprotein cholesterol by 0.21 mmol/L (95% CI, 0.05–0.48), whereas IGlar showed no effect. Though IGlar was more efficient in lowering fasting plasma glucose than beinaglutide at comparable efficacies (to −1.57 mmol/L [95% CI, −2.60 to −0.54]), this difference was abolished in patients whose fasting C‐peptide was ≥0.9 ng/mL. Conclusion Beinaglutide exhibited a favorable hypoglycemic effect on patients with T2DM, and in combination with IGlar, glucose level was further decreased. Low fasting C‐peptide in patients may reduce the glycemic response to beinaglutide therapy. We recommend that C‐peptide levels be evaluated when using or switching to the novel glucagon‐like peptide‐1 receptor agonists beinaglutide. Trial Registration ClinicalTrials.gov: NCT03829891.

Background: Recurrence remains the primary cause of death in patients with breast cancer. Although machine learning can efficiently predict the prognosis of breast cancer patients, the black-box nature of the model may result in a lack of evidence for clinicians when making critical decisions. Methods: In this study, our main objective was twofold: (1) to develop a clinical decision support tool for predicting the prognosis of breast cancer and (2) to identify and explore the key factors that influence breast cancer recurrence. To achieve this, we employed an explainable ensemble learning method called Shapley additive explanation (SHAP), which leverages cooperative game theory. Using real-world data from 1629 breast cancer patients, we analyzed and uncovered the key factors associated with breast cancer recurrence. Subsequently, we used these identified factors to create a recurrence prediction model and establish a decision mechanism for the tool. The proposed method not only provides accurate recurrence predictions but also offers transparent explanations for these predictions. Results: By utilizing four key factors, namely, tumor size, clinical stage III, number of lymph node metastases, and age, our decision support tool for predicting breast cancer recurrence achieved significant improvements. The extra-tree model exhibited an increased area under the receiver operating characteristic curve (AUC) of 0.97, while the Random Forest model demonstrated an improved AUC of 0.96. We also offer a decision mechanism for a recurrence prediction model based on the identified key factors. This transparent and interpretable decision-making process facilitated by our explainable ensemble learning model enhances trust and promotes its applicability in clinical settings. Conclusions: The proposed explainable ensemble learning method shows promising results in predicting breast cancer recurrence, outperforming existing methods with high accuracy and transparency. This advancement has the potential to significantly improve clinical decision-making and patient outcomes in breast cancer treatment.

Abstract Long noncoding RNAs (lncRNAs) play crucial regulatory roles in the progression of various cancers. However, the functional roles of lncRNAs in breast cancer remain unclear. In this study, we investigated the functional role of a novel long noncoding RNA SEMA3B-AS1 (lncRNA SEAS1) in breast cancer progression and the underlying mechanisms. SEAS1 was downregulated in the triple-negative breast cancer (TNBC) tissues compared with the para-carcinoma tissues, which was associated with poor prognosis of TNBC patients. We demonstrated that SEAS1 knockdown significantly increased the proliferation, migration, and invasion of TNBC cell lines, whereas SEAS1 overexpression reversed these effects. Bioinformatics analysis demonstrated that microRNA (miR)-3940-3p was a potential target of SEAS1. Mechanistically, RNA immunoprecipitation (RIP) and luciferase reporter assays confirmed that lncRNA SEMA3B-AS1 acted as sponge for miR-3940-3p, preventing the degradation of its target gene KLLN, which acts as a tumor-inhibiter in TNBC. Moreover, RNA pulldown, mass spectrometry, ChIP, and luciferase reporter assays confirmed that SMAD3 directly interacted with the promoter of SEAS1 and suppressed its transcription, thereby promoting TNBC progression. The clinical samples of TNBC confirmed SEAS1 was correlated inversely with lymphatic and distant metastasis. In conclusion, our findings reveal a novel pathway for TNBC progression via SMAD3/lncRNA SEAS1/miR-3940-3p/KLLN axis, and suggest that SEAS1 may serve as a potential biomarker and therapeutic target for TNBC.

Abstract This study analyzes microphysical signatures relevant to the short‐cycle lightning activity in the inner core of Typhoon Hato (2017) before landfall in China. Observations reveal that the lightning bursts were accompanied by enhanced inner‐core convection with a behavior cycle of about 3 hr. The coupling between wavenumber‐2 vortex Rossby waves (VRWs) and shear‐forced convective asymmetries resulted in a local updraft enhancement. Furthermore, supercooled liquid water droplets invigorated a striking enhancement of graupel via riming immediately above the freezing level, further enhancing charge separation and lightning generation outside the eyewall. Furthermore, when similar phase‐locking was associated with other propagating VRWs, graupel and updraft volumes were significantly boosted, leading to short‐cycle lightning outbreaks in the inner core.

Online large-group teaching (OLGT), employed to reach a large group of learners in separate physical locations, allows asynchronous learning and facilitates social distancing. While online large-groups can be a powerful and resource-lean means of health professions education, it has challenges and potential pitfalls that may affect the learning process and outcomes. Through a sociomateriality framework, this article describes strategies for effective online large-group teaching in health professions education in three key strands. Firstly, to optimize learning, OLGT sessions should match learning needs with appropriate OLGT platforms, incorporate strategies to sustain learner attention, and accommodate learners of different abilities. Secondly, to develop a learning culture, OLGT must not only focus on cognitive aspects of learning but also build a community of practice, nurture digital professionalism and professional identity. Thirdly, we discuss the avoidance of pitfalls such as cognitive overload of both tutors and learners, technical issues and security risks, mitigating inequities in access to online learning, and the use of program evaluation to plan for sustained improvements. We conclude with a case vignette that discusses the challenges of OLGT and the application of the above strategies in a teaching scenario.

Abstract Purpose Metabolic syndrome (Mets) is a pathological condition that includes many abnormal metabolic components and requires a simple detection method for rapid use in a large population. The aim of the study was to develop a diagnostic model for Mets in a Chinese population with noninvasive anthropometric and demographic predictors. Patients and methods Least absolute shrinkage and selection operator (LASSO) regression was used to screen predictors. A large sample from the China National Diabetes and Metabolic Disorders Survey (CNDMDS) was used to develop the model with logistic regression, and internal, internal-external and external validation were conducted to evaluate the model performance. A score calculator was developed to display the final model. Results We evaluated the discrimination and calibration of the model by receiver operator characteristic (ROC) curves and calibration curve analysis. The area under the ROC curves (AUCs) and the Brier score of the original model were 0.88 and 0.122, respectively. The mean AUCs and the mean Brier score of 10-fold cross validation were 0.879 and 0.122, respectively. The mean AUCs and the mean Brier score of internal–external validation were 0.878 and 0.121, respectively. The AUCs and Brier score of external validation were 0.862 and 0.133, respectively. Conclusions The model developed in this study has good discrimination and calibration performance. Its stability was proved by internal validation, external validation and internal-external validation. Then, this model has been displayed by a calculator which can exhibit the specific predictive probability for easy use in Chinese population.

The convection initiation (CI) mechanisms of severe storms have received increasing attention because severe storms have been occurring more frequently around the globe in recent years. In this work, the CI mechanisms of severe convective weather associated with a gust front (GF) which occurred on 9 July 2016, near the Korla at the northern edge of the Tarim Basin, Xinjiang, is investigated using observational data including Doppler weather radar data and automatic weather stations data, and high-resolution numerical simulation data. The results showed that, during the eastward movement of the GF, a number of convective cells were successively triggered in the vicinity of the GF, which developed rapidly and continuously merged with the convective system from behind, resulting in the further development and maintenance of this convective system. According to the diagnostic analysis of vertical acceleration which can be decomposed into dynamic acceleration (ad) and buoyant acceleration (ab), it was found that both ad (up to ~4 × 10−3 m s−2) and ab (up to ~7 × 10−3 m s−2) made positive contributions to the CI. Further analyses based on the decompositions of the ad and ab revealed that the extension term was the main contributor for the ad, while the warming of the dry air due to the release of latent heat from the precipitation condensate made the major contribution to the ab. The extension term indicates the elevated convergence jointly induced by the airflow of mid-level horizontal convective rolls (MHCRs) and updraft flow near the leading edge of the GF. The jointly induced elevated convergent updraft can be considered to be an important contributor for the CI mechanisms.

Using a three-chamber vicarious social defeat stress model in mice, Qi et al. show that chronic emotional stress (CES) induced anxiety-like behavior and transient social interaction changes. Bidirectional modulation of NAc-VTA circuit mimics or reverses the CES-induced anxiety-like behavior.

Abstract Background To assess the gaps between the initial management of patients with differentiated thyroid cancer (DTC) in real clinical practice and the recommendations of the 2012 Chinese DTC guidelines. Methods This multicenter, prospective study was conducted at nine tertiary hospitals across China. Eligible patients were those having intermediate or high-risk DTC after first-time thyroidectomy. During 1 year of follow-up, comprehensive medical records were collected and summarized using descriptive statistics. Results Of 2013 patients, 1874 (93.1%) underwent standard surgery according to the guidelines (including total lobectomy plus isthmusectomy and total/near total thyroidectomy), and 1993 (99.0%) underwent lymph node dissection; only 56 (2.8%) had postoperative complications. Overall, 982/2013 patients (48.8%) received radioactive iodine (RAI) therapy after thyroidectomy. Of all enrolled patients, 61.4% achieved the target serum thyroid-stimulating hormone level, with a median time to target of 234.0 days (95% CI: 222.0–252.0). At 1 year of follow-up, proportions of patients with excellent response, incomplete structural response, biochemical incomplete response, and indeterminate response were 34.6, 11.2, 6.6, and 47.5%, respectively; recurrence or metastasis occurred in 27 patients (1.3%). During the overall study period, 209 patients (10.4%) had at least one adverse event: 65.1% of cases were mild, 24.9% moderate, and 10.1% severe. Conclusions This was the first large-scale prospective study of how patients with DTC in China are treated in actual practice. Initial DTC management is generally safe and adheres to the 2012 Chinese guidelines but could be improved, and the level of guideline adherence did not produce the anticipated treatment response at 1 year of follow-up.

BackgroundDiabetic nephropathy (DN) is a chronic microvascular complication in patients with diabetes mellitus, which is the leading cause of end-stage renal disease. However, the role of copper-related genes (CRGs) in DN development remains unclear.Materials and methodsCRGs were acquired from the GeneCards and NCBI databases. Based on the GSE96804 and GSE111154 datasets from the GEO repository, we identified hub CRGs for DN progression by taking the intersection of differentially expressed CRGs (DECRGs) and genes in the key module from Weighted Gene Co-expression Network Analysis. The Maximal Clique Centrality algorithm was used to identify the key CRGs from hub CRGs. Transcriptional factors (TFs) and microRNAs (miRNAs) targeting hub CRGs were acquired from publicly available databases. The CIBERSORT algorithm was used to perform comparative immune cell infiltration analysis between normal and DN samples.ResultsEighty-two DECRGs were identified between normal and DN samples, as were 10 hub CRGs, namely PTGS2, DUSP1, JUN, FOS, S100A8, S100A12, NAIP, CLEC4E, CXCR1, and CXCR2. Thirty-nine TFs and 165 miRNAs potentially targeted these 10 hub CRGs. PTGS2 was identified as the key CRG and FOS as the most significant gene among all of DECRGs. RELA was identified as the hub TF interacting with PTGS2 by taking the intersection of potential TFs from the ChEA and JASPAR public databases. let-7b-5p was identified as the hub miRNA targeting PTGS2 by taking the intersection of miRNAs from the miRwalk, RNA22, RNAInter, TargetMiner, miRTarBase, and ENCORI databases. Similarly, CREB1, E2F1, and RELA were revealed as hub TFs for FOS, and miR-338-3p as the hub miRNA. Finally, compared with those in healthy samples, there are more infiltrating memory B cells, M1 macrophages, M2 macrophages, and resting mast cells and fewer infiltrating activated mast cells and neutrophils in DN samples (all p< 0.05).ConclusionThe 10 identified hub copper-related genes provide insight into the mechanisms of DN development. It is beneficial to examine and understand the interaction between hub CRGs and potential regulatory molecules in DN. This knowledge may provide a novel theoretical foundation for the development of diagnostic biomarkers and copper-related therapy targets in DN.

Abstract Background Berberine and Bifidobacterium have been reported to improve glucose tolerance in people with hyperglycemia or other metabolic disorders. This study aimed to assess the hypoglycemic effect and the regulation of the gut microbiota caused by berberine and Bifidobacterium and the possible additive benefits of their combination. Methods This was an 18-week, multi-center, randomized, double-blind, parallel-controlled study of patients newly diagnosed with hyperglycemia. After a 2-week run-in period, 300 participants were randomly assigned to the following four groups for 16 weeks of treatment: berberine (Be), Bifidobacterium (Bi), berberine and Bifidobacterium (BB), and placebo group. The primary efficacy endpoint was the absolute value of fasting plasma glucose (FPG) compared with baseline after 16 weeks of treatment. Results Between October 2015 and April 2018, a total of 297 participants were included in the primary analysis. Significant reductions of FPG were observed in the Be and BB groups compared with the placebo group, with a least square (LS) mean difference of − 0.50, 95% CI [− 0.85, − 0.15] mmol/L, and − 0.55, 95% CI [− 0.91, − 0.20] mmol/L, respectively. The Be and BB groups also showed significant reductions in 2-h postprandial plasma glucose. A pronounced decrease in HbA1c occurred in the BB group compared to the placebo group. Moreover, compared with the Bi and placebo groups, the Be and BB groups had more changes in the gut microbiota from the baseline. Conclusions Berberine could regulate the structure and function of the human gut microbiota, and Bifidobacterium has the potential to enhance the hypoglycemic effect of berberine. These findings provide new insights into the hypoglycemic potential of berberine and Bifidobacterium. Trial registration ClinicalTrials.gov , NCT03330184. Retrospectively registered on 18 October 2017

A previously published study showed that stress may interfere with associative aversive learning and facilitate mood-related disorders. However, whether emotional stress alone affects aversive learning is unknown. Using three chamber-vicarious social defeat stress (3C-VSDS) model mice, we investigated the effect of emotional stress on aversive learning. An important origin of dopamine (DA) neurons, the zona incerta (ZI), is expected to be a novel target for the modulation of aversive learning. However, less is known about the circuit mechanism of ZIDA neurons in aversive learning. Here, we subjected mice to a fear-conditioning system (FCS) and observed an increased calcium activity of ZI TH+ neurons in aversive expectation during the conditioning phase, especially during the late stage of the conditional stimulus (CS) when CS and unconditional stimulus (US) pairings were used. Optogenetic inhibition of ZI TH+ neurons at the late stage of CS disrupted conditioned fear learning in mice. We further identified a TH+ projection from the ZI to the basomedial amygdala (BMA) and found that optogenetic inhibition of the ZI-BMA circuit could also block aversive learning. Finally, we used 3C-VSDS mice as a model of emotional stress. We found that the 3C-VSDS model mice demonstrated reduced aversive expectation associated with ZI TH+ neurons in the late stage of CS and impaired aversive learning in FCS. Optogenetic activation of ZI-BMA TH+ projections in the late stage of CS significantly reversed the aversive FCS learning disability of 3C-VSDS model mice. These data suggest that a TH+ circuit from the ZI to the BMA is required for aversive expectation, both at baseline and in 3C-VSDS-induced aversive learning deficits and that this circuit is a potential target for the modulation of aversive learning. Low activity of ZI-BMA TH+ projections is one reason for 3C-VSDS-induced aversive learning deficits.

This work studies the characteristics of high winds in the Tianshan Grand Canyon (TGC), Northwest China by using surface wind observations at six automatic weather stations during 2017–2018. Three high wind indices are examined, namely, high wind hour (HWH), station high wind event (SHWE) and regional high wind event (RHWE). SHWE denotes persistent high winds of more than 3 h at an individual station while RHWE is defined for the southern TGC as a whole. High winds are mainly northwesterly/westerly, occurring predominantly in southern TGC. HWHs most often occur in spring and summer, while winter and spring HWHs possess the strongest intensity. The occurrence of HWHs exhibits an apparent diurnal variation, most frequent in the afternoon and evening while least from mid-night to early morning. SHWEs and RHWEs are prone to take place in spring, possessing relatively long lifetime and strong intensity. According to composite analysis of the 0.25° FNL reanalysis, favorable synoptic conditions are obtained for the persistent high winds in spring. Of great importance is the mid-tropospheric trough in the mid-high latitudes located to the north (i.e., upstream) of the TGC. The cold advection behind the trough cools and stabilizes the mid-lower troposphere, while the post-trough sinking motion causes a surface high that accelerates the low-level northwesterly wind. The synoptic thermal and dynamical forcing help set an upstream flow of moderate Froude number such that the mesoscale orographic flow traversing the TGC is in the nonlinear high-drag regime. Large-amplitude gravity waves are excited, with the isentropes descending abruptly over the lee slope which resembles internal hydraulic jump. Downslope windstorms are produced at the expense of flow potential energy as the subcritical upstream flow is transitioned to supercritical at the TGC peak. These findings have important implications on the formation and prediction of high winds in the TGC.

Abstract We evaluated the risk of developing diabetes in Chinese individuals with normal weight obesity (NWO). This 9-year population-based cohort study was based on the China National Diabetes and Metabolic Disorders Survey. A total of 1128 subjects without diabetes were included. Body fat percentage (BF%) was assessed by electrical bioimpedance. NWO was defined as subjects with a normal BMI (

In this paper, an Archimedean spiral antenna has been developed to flexibly radiate orbital angular momentum (OAM) wave with tunable modes. The operation mechanism for generation of the OAM wave is elaborated in terms of phases of the currents flowing on the spiral arm of the Archimedean structure. Two pairs of feeding probes are introduced to excite the Archimedean spiral antenna. With the signals with different phase differences fed into the spiral antenna, the OAM waves with the modes of $l=\pm 1$ , $l=\pm 2$ , and their all mixed modes are radiated, respectively. Simulated and measured results are given to demonstrate that the proposed Archimedean spiral antenna radiates the tunable OAM waves from the sole mode to the mixed four modes in an overlapped band of 5~6 GHz.

BackgroundEndoscopic thyroidectomy is widely accepted for its advantages. However, implant metastasis remains a significant complication of endoscopic thyroidectomy.MethodsThis is the first report of breast implantation diagnosed with poorly differentiated thyroid carcinoma following endoscopic thyroidectomy.ResultsWe present a case of a 35-year-old woman who was initially diagnosed with a 3.0 cm conventional papillary thyroid carcinoma after endoscopic thyroidectomy via total areola. Two years later, she was reported to have recurring poorly differentiated thyroid carcinoma in the right areola. Implantation after endoscopic thyroidectomy is rare, and even rarer is dedifferentiated papillary thyroid carcinoma around the implant site.ConclusionsStringently evaluated endoscopic surgery indications, appropriate preoperative evaluation, meticulous surgical technique, and adequate protective measures can significantly reduce the incidence of local implantation or recurrence.

BackgroundAs the indication for immunotherapy is rapidly expanding, it is crucial to accurately identify patients who are likely to respond. Infiltration of B cells into many tumor types correlates with a good response to immune checkpoint inhibitor (ICI) therapy. However, B cells’ roles in the anti-tumor response are far from clear.MethodsBased on single-cell transcriptomic data for ICI-treated patients, we identified a B-cell cluster [BIR (ICI-Responsive B) cells] and described the phenotype, cell–cell communication, biological processes, gene signature, and prognosis value of BIR cells through bioinformatic analysis, tissue immunofluorescence, and animal experiments. Surgery samples from 12 non-small cell lung carcinoma (NSCLC) patients with adjuvant checkpoint blockade were evaluated as external validation.ResultsBIR cells were identified as a subset of CD20+CD22+ADAM28+ B cells with a memory phenotype. Bioinformatic analysis revealed that BIR cells had enhanced cell viability and epigenetic regulation, and that ALOX5AP, MIF, and PTPRC/CD45 expressed by myeloid cells may be critical coordinators of diverse biological processes of BIR cells. Immunofluorescence confirmed the presence of BIR cells in tertiary lymphoid structures (TLSs) in skin SCC, RCC, CRC, and breast cancer. BIR-associated gene signatures correlate with positive outcomes in patients with melanoma, glioblastoma, NSCLC, HNSCC, or RCC treated with ICI therapy, and BIR-cell density predicted NSCLC patients’ response to checkpoint immunotherapy. In line with this, melanoma-bearing mice depleted of BIR cells were resistant to ICIs.ConclusionsCD20+CD22+ADAM28+ BIR cells were present in cancer-associated TLS and promoted the response to ICI therapy.

N7-Methylguanosine (m7G) and long non-coding RNAs (lncRNAs) have been widely reported to play an important role in cancer. However, there is little known about the relationship between m7G-related lncRNAs and clear cell renal cell carcinoma (ccRCC). To find new potential biomarkers and construct an m7G-related lncRNA prognostic signature for ccRCC, we retrieved transcriptome data and clinical data from The Cancer Genome Atlas (TCGA), and divided the entire set into train set and test set with the ratio of 1:1 randomly. The m7G-related lncRNAs were identified by Pearson correlation analysis (|coefficients| > 0.4, and p < 0.001). Then we performed the univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to construct a 12 m7G-related lncRNA prognostic signature. Next, principal component analysis (PCA), the Kaplan–Meier method, time-dependent receiver operating characteristics (ROC) were made to verify and evaluate the risk signature. A nomogram based on the risk signature and clinical parameters was developed and showed high accuracy and reliability for predicting the overall survival (OS). Functional enrichment analysis (GO, KEGG and GSEA) was used to investigate the potential biological pathways. We also performed the analysis of tumor mutation burden (TMB), immunological analysis including immune scores, immune cell infiltration (ICI), immune function, tumor immune escape (TIE) and immunotherapeutic drug in our study. In conclusion, using the 12 m7G-related lncRNA risk signature as a prognostic indicator may offer us insight into the oncogenesis and treatment response prediction of ccRCC.

Abstract Aims/Introduction There are substantial differences in genes, diet, culture and environment between the northern and southern Chinese populations, which might influence treatment strategy and screening policy. We studied the differences in type 2 diabetes and diabetic complications between northern and southern China. Materials and Methods We carried out a cross‐sectional survey using data from the China Cardiometabolic Registries on blood pressure, blood lipids and blood glucose in 25,398 Chinese type 2 diabetes patients. Macrovascular, microvascular and other complications were collected by self‐report or medical records, and then divided into the northern and southern groups by the boundary of the Yangtze River. Results Northern patients were younger, and had heavier weight, greater body mass index and waist circumference, higher blood pressure, higher total cholesterol, higher low‐density lipoprotein cholesterol, and higher hemoglobin A1C. The prevalence of cardiovascular, cerebrovascular and macrovascular complications were 1.76‐fold, 1.24‐fold and 1.47‐fold more in northern than that in southern Chinese patients. In addition, the prevalence of diabetic nephropathy, retinopathy, neuropathy and microvascular complications in northern Chinese patients also increased. When stratified by age, the difference in both cardiovascular disease and ischemic stroke morbidity became significant, even in the 35–44 years age group. Conclusions More macrovascular and microvascular complications were found in northern compared with southern patients, and the largest difference also appeared in the younger age groups

Endocrine therapy is a systemic therapy and has become the main treatment strategy for patients with estrogen receptor (ER)-positive breast cancer. However, tamoxifen resistance has become an insurmountable clinical challenge, and the underlying mechanisms are still poorly understood. In this study, we explored the roles of CXC chemokine receptor type 4 (CXCR4) in tamoxifen-treated breast cancer and tamoxifen resistance. Based on the Gene Expression Omnibus (GEO) database, high expression of CXCR4 was found to be associated with worse overall survival (hazard ratio [HR] = 4.646, p < 0.001) and cancer-specific survival (HR = 4.480, p < 0.001) in tamoxifen-treated breast cancer. CXCR4 was also positively correlated with the level of AKT phosphorylation and the resistance to tamoxifen in breast cancer. AMD3100 is a CXCR4 antagonist and was found to decrease phosphorylated (p)-AKT levels of tamoxifen-resistant cells. The reversal effect of AMD3100 on tamoxifen resistance was also confirmed in vitro and in vivo. Taken together, our study demonstrated that CXCR4 could be a potential prognostic biomarker for tamoxifen-treated breast cancer, and the combination of AMD3100 with tamoxifen could be a more efficacious therapeutic strategy for the treatment of tamoxifen resistance.

Abstract Aims/Introduction To develop a new non‐invasive risk score for undiagnosed diabetes in Chinese people, and to evaluate the incident diabetes risk in those with high‐risk scores, but no diabetes on initial testing. Materials and Methods A total of 2,609 participants with no known diabetes (aged 25–74 years) who underwent oral glucose tolerance tests in Hong Kong (HK) were investigated for independent risk factors of diabetes to develop a categorization point scoring system, the Non‐invasive Diabetes Score (NDS). This NDS was validated in a cross‐sectional study of 2,746 participants in Shaanxi, China. HK participants tested to not have diabetes at baseline were assessed for subsequent incident diabetes rates. Results In the HK cohort, hypertension, age and body mass index were the key independent risk factors selected to develop the NDS, with ≥28 out of 50 NDS points considered as high risk. The area under the receiver operating characteristic curve for undiagnosed diabetes was 0.818 and 0.720 for the HK and Shaanxi cohort, respectively. The negative predictive value was 97.4% (HK) and 95.8% (Shaanxi); the number needed to screen to identify one case of diabetes was five (HK) and 11 (Shaanxi), respectively. Among those that tested non‐diabetes at baseline, individuals with NDS ≥28 had a threefold risk of incident diabetes during the subsequent 20.9 years, compared with those with NDS

In this paper, a water antenna has been designed to generate tunable orbital angular momentum (OAM) vortex wave. With a revisiting theoretical analysis about radiation characteristic of the shorted ring patch fed by two probes, a frequency dependent single shorted ring water antenna is designed. With the increase of the operating frequency, the single-ring water antenna can radiate the OAM waves with the changeable modes. Furthermore, a dual shorted ring water antenna is proposed. With a tunable feeding network, the OAM waves with the reconfigurable modes including the l = 1, l = 2 and mixed modes can be radiated by adjusting ON/OFF states of the PIN diode. The prototype of the dual-ring water antenna is fabricated and measured. Good agreement between the simulation and the measurement demonstrates that the overlapped bandwidth for three states covers 2.35~2.55 GHz with a good mode purity.

BackgroundMetaplastic breast cancer (MBC) is a rare tumor with aggressive biological behavior. This study aimed to evaluate the efficacy of post-mastectomy radiotherapy (PMRT) on patients with low-risk (T1N0M0), intermediate-risk (T1-2N1M0 and T3N0M0), and high-risk (T1-4N2-3M0 and T4N0-1M0) MBC via propensity-score matching (PSM).MethodsWe analyzed information from the Surveillance, Epidemiology, and End Results (SEER) public-use database from 1975 to 2016 for MBC incidence trends and compared overall survival (OS) and breast cancer-specific survival (BCSS) between groups of MBC women diagnosed from 2001 to 2016 using Kaplan–Meier analysis and the multivariate Cox proportional model. PSM was used to make 1:1 case–control matching.ResultsJoinpoint analyses identified 1984 and 2003 as the inflection points among 4,672 patients. 1,588 (42.4%) of the 3,748 patients diagnosed with MBC between 2001 and 2016 received PMRT. According to multivariate analyses, PMRT provided better OS (p < 0.001) and BCSS (p < 0.001) before PSM, and better prognosis after PSM (n = 2528) for patients receiving PMRT (n = 1264) compared to those without PMRT (OS, p < 0.001 and BCSS, p < 0.001). When stratifying the case–control matching patients into low-risk, intermediate-risk, and high-risk groups, PMRT could improve BCSS compared with that in non-PMRT patients in the high-risk groups; it also improved OS in both the intermediate- and high-risk groups.ConclusionsPer findings of the PSM analysis, PMRT could provide better BCSS in high-risk groups, and better OS in intermediate- and high-risk groups.

IntroductionAfter the publication of the 2015 American Thyroid Association (ATA) guidelines, the indication for total thyroidectomy (TT) was reported to be underestimated before surgery, which may lead to a substantial rate of secondary completion thyroidectomy (CTx).Methods and MaterialsWe retrospectively analyzed differentiated thyroid cancer patients from Wuhan Union Hospital (WHUH). Univariate analysis was performed to evaluate all preoperative and intraoperative factors. New models were picked out by comminating and arranging all significant factors and were compared with ATA and National Comprehensive Cancer Network (NCCN) guidelines in the multicenter prospective Differentiated Thyroid Cancer in China (DTCC) cohort.ResultsA total of 5,331 patients from WHUH were included. Pre- and intraoperative criteria individually identified 906 (17.0%) and 213 (4.0%) patients eligible for TT. Among all factors, age 4 cm” with “age 4 cm” and “age

Abstract Aims/Introduction Metabolic unhealth can be defined by the components of metabolic syndrome, which is closely connected to insulin resistance. We aimed to determine a simple index to identify metabolic unhealth in the Chinese adult population. Materials and Methods A total of 30,291 individuals were screened from the China National Diabetes and Metabolic Disorders Study carried out from June 2007 to May 2008. Metabolic unhealth was defined using components of metabolic syndrome, except waist circumference. We compared the three surrogate indices of insulin resistance: the product of fasting triglycerides and glucose (TyG), triglycerides divided by high‐density lipoprotein cholesterol and the metabolic score for insulin resistance for the evaluation of metabolic status. Results All indices had high sensitivity and specificity for the identification of metabolic unhealth, especially the TyG index with an area under the curve of 0.863 for men and 0.867 for women. Participants were divided into subgroups for further analysis. The TyG index also showed high diagnostic values, especially for younger individuals and men with normal waist circumference. Sex‐specific cut‐offs for three indices were also used to define metabolic unhealth. The TyG index showed the highest agreement with κ values of 0.603 and 0.605 for men and women between the components of metabolic syndrome and three indices. Conclusions We propose that the TyG index, just read in one blood laboratory test report, is simpler and more suitable for the identification of metabolically unhealthy individuals as well as who have high risk of cardiometabolic diseases of the Chinese adult population.

Depression and transient ischaemic attacks are tightly regulated but the neural circuits underlying depression-modulated ischaemic injury are not known. Here, the authors show that the locus coeruleus-CA1 pathway is involved in depression-associated ischaemia susceptibility.

Abstract Background To investigate the potential barriers to optimal diabetes control by evaluating the different perspectives of physicians and patients on such matters in China. Methods This multi-center survey was conducted from December 2015 to March 2016. A multi-stage stratified random sampling method was used to sample representative diabetes physicians and patients in 18 hospitals in Shaanxi province, China. A self-designed questionnaire was used. The questionnaire mainly consisted of 2 questions for physicians and 1 question for patients of which the participants were required to rank in priority of 3 (for physicians) and 2 (for patients) choices from a list of barriers. The strategies to improve diabetes control were only in the questionnaire for physicians. Results A total of 85 physicians and 584 patients completed the questionnaire. Physicians and patients differed regarding the patients’ awareness of the risk of diabetes: over 70% of the physicians believed that the patients had no sufficient understanding of the harm and risk of diabetes, whereas the patients believed otherwise. Both physicians and patients considered self-monitoring of blood glucose to be an important link of glucose control; unfortunately, most of the patients failed to do so in practice. In addition, physicians considered “improving health insurance coverage for diabetes” as the first important measure and “providing more and easy-to-use diabetes brochures or educational materials for patients” as the second important measure to improve diabetes control. Conclusion The survey revealed differences between the perspectives of physicians and patients on the potential barriers to optimal diabetes control. The main potential barriers to optimal diabetes control were patient’s poor lifestyle interventions, limited understanding of the danger of diabetes, and poor self-monitoring of blood glucose. From the physicians’ perspective, China’s primary focus about diabetes control in the future should still be put on diabetes education, particular the importance of lifestyle interventions.

Background: Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast. However, the effect of molecular subtype on treatment and prognosis of MBC remains unclear. Patients and methods: The Surveillance, Epidemiology, and End Results database was used to analyze patients with MBC between 2010 and 2016. Molecular subtype was stratified to TN group (ER and PR-/HER2-), HER2 group (ER and PR-/HER2+, ER/PR+ and HER2+), and HR group (ER/PR+ and HER2-). The breast cancer-specific survival (BCSS) differences were estimated using multivariate Cox regression model and Kaplan-Meier curves. Results: We included 1665 patients with median follow-up time of 27 months (range 0–83 months). 1154 (69.3%), 65 (3.9%), and 446 (26.8%) patients presented in TN group, HER2 group, and HR group, respectively. On multivariate Cox analysis, the prognosis was related to age, tumor size, regional node metastasis, and surgery. Molecular subtype remained no impact on BCSS. Radiotherapy (RT) was associated with better prognosis. Patients cannot benefit from chemotherapy. In Kaplan-Meier curve, triple-negative (P = 0.047) and HR-positive (P = 0.006) patients receiving RT had a superior BCSS than that not RT. HER2-positive patients cannot benefit from RT. However, adjusted Kaplan-Meier survival model showed that triple-negative (P = 0.019) but not HER2-positive (P = 0.575) or HR-positive (P = 0.574) patients receiving RT had a superior BCSS than that not RT. Conclusions: Molecular subtype is not associated with the better prognosis of MBC. Patients could benefit from RT. However, triple-negative but not HR-positive or HER2-positive patients have superior survival after receiving RT.

BackgroundMetaplastic breast cancer (MBC) is a rare and aggressive subtype of the breast. To understand the characteristics and prognosis of single hormone receptor-positive (HR+) MBC (estrogen receptor-positive [ER+]/progesterone receptor-negative [PR-] and ER-/PR+), we compared these tumors to double HR+ tumors as well as HR- tumors.Patients and MethodsThe Surveillance, Epidemiology, and End Results database was used to analyze MBC between 1975 and 2016. The effect of HR status was evaluated using a multivariate Cox regression model.ResultsWe included 3369 patients with a median follow-up time of 42 months (range 0-322 months). In this study, 280 (8.3%) cases were double HR+ tumors, 2597 (77.1%) were double HR- tumors, and 492 (14.6%) cases were single HR+ tumors, of which 159 (4.7%) cases were ER-/PR+ tumors and 333 (9.9%) were ER+/PR- tumors. On multivariate Cox analysis, the prognosis was related to age, race/ethnicity, tumor grade, TNM stage, and surgery. HR status remained no impact on breast cancer-specific survival (BCSS). In the Kaplan-Meier curve, HR status was not associated with better BCSS or overall survival (OS). In patients without HER2 overexpression, the BCSS and OS of ER+/PR- and ER-/PR+ tumors were not significantly different from that of ER-/PR- and ER+/PR+ tumors. The difference remains no significant in patients with HER2 overexpression.ConclusionsIn comparison with both ER-/PR- and ER+/PR+ tumors, we have identified clinically and biologically distinct features of single HR+ tumors. In patients with or without HER2 overexpression, the prognosis of single HR+ tumors was similar to ER-/PR- and ER+/PR+ tumors.

ObjectiveMounting evidence has suggested a link between gut microbiome characteristics and type 2 diabetes (T2D). To determine whether these alterations occur before the impairment of glucose regulation, we characterize gut microbiota in normoglycemic individuals who go on to develop T2D.MethodsWe designed a nested case-control study, and enrolled individuals with a similar living environment. A total of 341 normoglycemic individuals were followed for 4 years, including 30 who developed T2D, 33 who developed prediabetes, and their matched controls. Fecal samples (developed T2D, developed prediabetes and controls: n=30, 33, and 63, respectively) collected at baseline underwent metagenomics sequencing.ResultsCompared with matched controls, individuals who went on to develop T2D had lower abundances of Bifidobacterium longum, Coprobacillus unclassified, and Veillonella dispar and higher abundances of Roseburia hominis, Porphyromonas bennonis, and Paraprevotella unclassified. The abundance of Bifidobacterium longum was negatively correlated with follow-up blood glucose levels. Moreover, the microbial Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of carbohydrate metabolism, methane metabolism, amino acid metabolism, fatty acid metabolism, and membrane transport were changed between the two groups.ConclusionsWe found that fecal microbiota of healthy individuals who go on to develop T2D had already changed when they still were normoglycemic. These alterations of fecal microbiota might provide insights into the development of T2D and a new perspective for identifying individuals at risk of developing T2D.

RANKL and RANK are expressed in different cell types and tissues throughout the body. They were originally described for their essential roles in bone remodeling and the immune system but have subsequently been shown to provide essential signals from regulating mammary gland homeostasis during pregnancy to modulating tumorigenesis. The success of RANKL/RANK research serves as a paragon for translational research from the laboratory to the bedside. The case in point has been the development of Denosumab, a RANKL-blocking monoclonal antibody which has already helped millions of patients suffering from post-menopausal osteoporosis and skeletal related events in cancer. Here we will provide an overview of the pathway from its origins to its clinical relevance in disease, with a special focus on emerging evidence demonstrating the therapeutic value of targeting the RANKL/RANK/OPG axis not only in breast cancer but also as an addition to the cancer immunotherapy arsenal.

Long non-coding RNA NBR2 is a transcript of the neighbor of BRCA1 gene 2 and can regulate tumor development. However, there is little information on the role of NBR2 in the progression of thyroid cancers (TC). Here, we show that NBR2 expression is down-regulated in TC tissues and associated with histologic subtypes of TC. NBR2 expression was variably reduced in different TC cells. While NBR2 silencing significantly enhanced the malignancy of BCPAP cells by increasing cell proliferation, clonogenicity, wound healing, and invasion as well as tumor growth in vivo, and decreasing spontaneous apoptosis, NBR2 over-expression had opposite effects in BHT101 cells. Furthermore, treatment with A-769662 (a specific AMPK activator), like NBR2 over-expression, significantly attenuated the malignancy of BHT101 cells while treatment with Compound C (a specific AMPK inhibitor) significantly rescued that NBR2-reduced malignancy of BHT101 cells. In comparison with non-tumor thyroid epithelial Nthy-ori 3-1 cells, obviously increased GLUT-1 expression, but decreased AMPK and ACC phosphorylation were detected in TC cells. While NBR2 silencing further enhanced GLUT-1 expression and reduced AMPK and ACC phosphorylation as well as the EMT process in BCPAP cells. NBR2 over-expression also had opposite effects in BHT101 cells. Similar patterns of GLUT-1 expression and AMPK and ACC phosphorylation were detected in the different types of xenograft TC tumors in vivo. Therefore, such data indicated that NBR2 acted as a tumor suppressor of thyroid cancers associated with enhancing the AMPK signaling and NBR2 may be a potential biomarker and therapeutic target for thyroid cancers.

Purpose: Patients' complaints can be predictors of patient care quality and safety. Understanding patients' complaints could help healthcare organizations target the areas for improvements. The purpose of this study is to use a mixed method analysis to a) examine the characteristics and categories of patients' complaints, b) explore the relationships of patients' complaints with professions and units, and c) propose theory-based strategies to improve care quality. Methods: This is a descriptive mixed method study. Data examined are patients' complaints filed at a university-affiliated hospital in China from January 2016 to December 2017. A qualitative content analysis was conducted to categorize complaints. A TwoStep cluster analysis was performed to provide an overall profile of patients' complaints. Chi-Square tests were conducted to investigate the relationships among complaints, professions, and units. Results: 838 complaints were filed, with 821 valid cases for analysis. Six categories surfaced from the qualitative analysis: uncaring attitudes, unsatisfactory quality of treatment or competence, communication problems, the process of care, fees and billing issues, and other miscellaneous causes. Physicians received most of the complaints (56.6%). The unit receiving the most complaints were outpatient clinics and medical support units (52.7%). The cluster analysis indicated four distinct clusters. Significant relationships existed between complaints and professions (χ2 (20) = 178.82, P

Abstract Background Berberine is one of the most important examples of a Chinese traditional medicine that has hypoglycemic effects but there have been no randomized controlled trials of the drug in a larger sample. In addition, the use of probiotic biotherapy to maintain an appropriate intestinal flora may represent an effective early intervention for hyperglycemia. Unfortunately, there has been a shortage of relevant research on this possibility at the population level. This study was designed to determine the hypoglycemic effect and safety of both bifidobacteria and berberine administration to newly diagnosed patients with pre-diabetes or diabetes mellitus. Methods/design This is a multicenter, double-blind, randomized, and parallel-controlled study that includes a run-in period of 2 weeks and a treatment period of 16 weeks, which will be conducted between June 2015 and October 2018. The 300 randomized patients will be assigned to the following four groups for 16 weeks’ treatment: Bifidobacterium, berberine, Bifidobacterium combined berberine, and placebo control groups. The primary outcome is the absolute value of fasting plasma glucose compared with baseline after 16 weeks of treatment. Discussion This is the first randomized controlled trial to determine the hypoglycemic effect and safety of both bifidobacteria and berberine administration to newly diagnosed patients with pre-diabetes or diabetes mellitus. It may provide support for the use of berberine and bifidobacteria in the treatment of diabetes. Trial registration ClinicalTrials.gov, ID: NCT03330184. Retrospectively registered on 18 October 2017.

Malaysia's previously hegemonic Barisan Nasional (BN) government was unexpectedly defeated in the 2018 general election despite a fragmented opposition and widespread three-corner fights that theory states should inhibit turnover. Why? We argue that the opposition-split hypothesis rests on three core assumptions: third parties split only the anti-incumbent vote; coalition/party support is relatively uniform across the country; and opposition parties are not “elite splits” in disguise. The Malaysian context challenges all three of these assumptions. Counterfactual election simulations ultimately suggest that the opposition split neither dramatically helped nor hurt the BN. While this does not upend conventional wisdom on opposition coordination, it does demonstrate that the theory manifests only when its assumptions accord with local realities. More substantively, our analysis also provides insights into why the new opposition will likely seek to increase the salience of ethno-religious issues in a bid to recapture electoral ground.

Based on 40 years of daily precipitation, 272 extreme precipitation days in the Northern Xinjiang region are defined. Using the daily precipitation data on these days, four precipitation spatial patterns were obtained through principal component analysis. Then, daily-averaged reanalysis data were used to analyze the variations of synoptic systems on extreme precipitation days and the two days before and after. The rainfall centers shifted with the influential systems at 500 hPa. Water vapor of the western Tianshan type (Type WT) and the north of Northern Xinjiang type (Type NN) comes from the west, while vapor of the Central Tianshan type (Type CT) mainly comes from the east. In the east of Northern Xinjiang type (Type EN), water vapor converges from both sides. The centers of the upper-level jets are located west of 80° E in Type WT and CT. However, they are to the east of 80° E in the other types. This article summarizes the variations of the systems at 500 hPa, the South Asia High, the westerly jet, and the water vapor transport between the surface and 500 hPa in four types of patterns, and builds the conceptual model for each type. The models built can be applied to the heavy rainfall forecast of Northern Xinjiang.

The mechanism of convection initiation (CI) occurring in the Southwest Xinjiang, Northwest China is investigated using quantitative budget analysis of vertical momentum for the first time. The Weather Research and Forecasting (WRF) model is used to reproduce and analyze the CI events. The observations showed that many CIs occurred continuously, with an intense mesoscale convective system eventually forming. The overall features of the CIs were well captured by the simulation. Lagrangian vertical momentum budgets, in which the vertical acceleration was decomposed into dynamic and buoyant components, were performed along the backward trajectories of air parcels within two convective cells. The results showed that the buoyant acceleration is the major contributor in both the slow and rapid lifting period of the CI, while the dynamic acceleration also showed a considerably positive effect only during the rapid lifting period. The buoyant acceleration during the slow lifting period was due to the warm advection generated by the radiative heating near the mountainous area on the south side of Tarim Basin in the afternoon. The buoyant acceleration during the rapid lifting period was from the latent heat release within the convective cell. Further decomposition of the dynamic acceleration showed that the vertical twisting related to the vertical shear of horizontal wind almost completely dominated the dynamic acceleration, while the horizontal curvature and extension showed very weak contribution. These findings provide some new insights into the roles of buoyant and dynamic forcing in the mechanism of CI in Southwest Xinjiang.