Mechanism of Prunella vulgaris L. and luteolin in restoring Tfh/Tfr balance and alleviating oxidative stress in Graves' disease.

BACKGROUND: The pathophysiology of Graves' disease (GD) involves imbalances between follicular helper T (Tfh) and follicular regulatory T (Tfr) cells, as well as oxidative stress (OS). Prunella vulgaris L. (Xia Ku Cao, XKC) and its primary bioactive compound, luteolin, are recognized for their potential in treating GD. Yet, the mechanism accounting for the immune-modulatory and antioxidant effects of XKC remains elusive. PURPOSE: This study aims to evaluate the pharmacological effects and elucidate the underlying mechanism of XKC and luteolin in a GD mouse model induced by recombinant adenovirus of TSH receptor A subunit (Ad-hTSHR-289). METHODS: High-Performance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry (HPLC-QTOF MS) was used to detect the constituents of XKC. The GD model was established through inducing female BALB/c mice with three intramuscular injections of Ad-TSHR-289. Thyroid function, autoantibody and OS parameters were measured by ELISA. Changes of Tfh cells and Tfr cells were detected by flow cytometry. RT-qPCR, Western Blotting, immunohistochemistry were used to explore the related molecular mechanisms. RESULTS: A total of 37 chemical components from XKC were identified by HPLC-QTOF MS, represented by flavonoids, steroids, terpenoids, and luteolin. XKC and luteolin reduced T4, TRAb levels and facilitated the recovery from thyroid damage in GD mice. Meanwhile, XKC and luteolin effectively alleviated OS by decreasing the levels of MDA, NOX2, 4-HNE, 8-OHdG, while increasing GSH level. Flow cytometry showed that XKC and luteolin restored the abnormal proportions of Tfh/Tfr and Tfh/Treg, and the mRNA levels of IL-21, Bcl-6 and Foxp3 in GD mice. In addition, XKC and luteolin inhibited PI3K, Akt, p-PI3K and p-Akt, but activated Nrf2 and HO-1. CONCLUSION: XKC and luteolin could inhibit the development of GD in vivo by rebalancing Tfh/Tfr cells and alleviating OS. This therapeutic mechanism may involve the Nrf2/HO-1 and PI3K/Akt signaling pathways. Luteolin is the main efficacy material basis of XKC in countering GD. For the first time, we revealed the mechanism of XKC and luteolin in the treatment of GD from the perspective of autoimmune and OS.

E4bp4-Cyp3a11 axis in high-fat diet-induced obese mice with weight fluctuation.

OBJECTIVE: Weight regain after weight loss is a challenge in obesity management. The metabolic changes and underlying mechanisms in obese people with weight fluctuation remain to be elucidated. In the present study, we aimed to profile the features and clinical significance of liver transcriptome in obese mice with weight regain after weight loss. METHODS: The male C57BL/6J mice were fed with standard chow diet or high-fat diet (HFD). After 9 weeks, the HFD-induced obese mice were randomly divided into weight gain (WG), weight loss (WL) and weight regain (WR) group. After 10 weeks of dietary intervention, body weight, fasting blood glucose (FBG), intraperitoneal glucose tolerance, triglycerides (TG), total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) were measured. Morphological structure and lipid droplet accumulation in the liver were observed by H&E staining and oil red O staining, respectively. The liver transcriptome was detected by RNA sequencing. Protein expressions of liver cytochrome P450 3a11 (Cyp3a11) and E4 promoter-binding protein 4 (E4bp4) were determined by Western blot. RESULTS: After 10 weeks of dietary intervention, the body weight, FBG, glucose area under the curve, T-CHO and LDL-C in WL group were significantly lower than those in WG group (P < 0.05). At 4 weeks of HFD re-feeding, the mice in WR group presented body weight and T-CHO significantly lower than those in WG group, whereas higher than those in WL group (P < 0.05). Hepatic vacuolar degeneration and lipid droplet accumulation in the liver were significantly alleviated in WL group and WR group, compared to those in WG group. The liver transcriptome associated with lipid metabolism was significantly altered during weight fluctuation in obese mice. Compared with those in WG group, Cyp3a11 in the liver was significantly upregulated, and E4bp4 was significantly downregulated in WL and WR groups. CONCLUSION: Obese mice experience weight regain after weight loss by HFD re-feeding, but their glucose and lipid metabolism disorders are milder than those induced by the persistence of obesity. Downregulated E4bp4 and upregulated Cyp3a11 are detected in obese mice after weight loss, suggesting that the E4bp4-Cyp3a11 axis may involved in metabolic mechanisms underlying weight regulation.

Design, Synthesis and Biological Evaluation of Novel Phenyl-Substituted Naphthoic Acid Ethyl Ester Derivatives as Strigolactone Receptor Inhibitor.

Strigolactones (SLs) are plant hormones that regulate several key agronomic traits, including shoot branching, leaf senescence, and stress tolerance. The artificial regulation of SL biosynthesis and signaling has been considered as a potent strategy in regulating plant architecture and combatting the infection of parasitic weeds to help improve crop yield. DL1b is a previously reported SL receptor inhibitor molecule that significantly promotes shoot branching. Here, we synthesized 18 novel compounds based on the structure of DL1b. We performed rice tillering activity assay and selected a novel small molecule, C6, as a candidate SL receptor inhibitor. In vitro bioassays demonstrated that C6 possesses various regulatory functions as an SL inhibitor, including inhibiting germination of the root parasitic seeds Phelipanche aegyptiaca, delaying leaf senescence and promoting hypocotyl elongation of Arabidopsis. ITC analysis and molecular docking experiments further confirmed that C6 can interact with SL receptor proteins, thereby interfering with the binding of SL to its receptor. Therefore, C6 is considered a novel SL receptor inhibitor with potential applications in plant architecture control and prevention of root parasitic weed infestation.

Design, Synthesis, and Bioactivities of N-Heterocyclic Ureas as Strigolactone Response Antagonists against Parasitic-Weed Seed Germination.

The pernicious parasitism exhibited by root parasitic weeds such as Orobanche and Striga poses substantial peril to agricultural productivity and global food security. This deleterious phenomenon hinges upon the targeted induction of the signaling molecule strigolactones (SLs). Consequently, the identification of prospective SL antagonists holds significant promise in the realm of mitigating the infection of these pernicious weeds. In this study, we synthesized and characterized D12 based on a potent SL antagonist KK094. In vivo assay results demonstrated that D12 remarkably impedes the germination of Phelipanche aegyptiaca and Striga asiatica seeds, while also alleviating the inhibitory consequence of the SL analogue GR24 on hypocotyl elongation in Arabidopsis thaliana. The docking study and ITC assay indicated that D12 can interact strongly with the SL receptor protein, which may interfere with the binding of SL to the receptor protein as a result. In addition, the results of crop safety assessment tests showed that D12 had no adverse effects on rice seed germination and seedling growth and development. The outcomes obtained from the present study suggested that D12 exhibited promise as a prospective antagonist of SL receptors, thereby displaying substantial efficacy in impeding the seed germination process of root parasitic weeds, providing a promising basis for rational design and development of further Striga-specific herbicides.

Ketogenic diet alleviates ß-cell dedifferentiation but aggravates hepatic lipid accumulation in db/db mice.

OBJECTIVE: The aim of this study was to explore the effect of the ketogenic diet (KD) on ß-cell dedifferentiation and hepatic lipid accumulation in db/db mice. METHODS: After a 3-wk habituation, male db/db mice ages 8 wk were assigned into one of three groups: normal diet (ND), KD, and 75% calorie restriction (CR) group. Free access to a standard diet, a KD, and 75% of a standard diet, respectively, were given to each group. Additionally, sex-matched 8-wk-old C57BL/6 mice were used to construct a control (C) group. After a 4-wk dietary intervention, mouse body weight, fasting blood glucose (FBG), blood lipids, fasting insulin (FINS), glucose tolerance, and ß-hydroxybutyric acid level were measured. The morphologies of the islet and liver were observed by hematoxylin and eosin staining. Positive expressions of ß-cell-specific transcription factors in mouse islets were determined by double immunofluorescence staining. The size and number of lipid droplets in mouse liver were examined by Oil Red O staining. Real-time quantitative reverse transcription polymerase chain reaction detected relative levels of adipogenesis-associated and lipolysis-associated genes in mouse liver. Additionally, expressions of CD36 protein in the mouse liver were determined by immunohistochemical staining and Western blot. RESULTS: After a 4-wk dietary intervention, FBG, FINS, and glucose area under the curve in the KD group became significantly lower than in the ND group (all P < 0.05). Regular morphology of mouse islets was observed in the KD group, with an increased number of islet cells. The KD significantly reversed the decrease in ß-cell number, disarrangement of ß-cells, decline of ß/α-cell ratio, and downregulation of ß-cell-specific transcription factors in db/db mice. Serum levels of triacylglycerol, total cholesterol, and low-density lipoprotein cholesterol were comparable between the ND and KD groups. In contrast, serum triacylglycerol levels were significantly lower in the CR group than in the ND group (P < 0.05). Vacuolar degeneration and lipid accumulation in the liver were more prominent in the KD group than in the ND and CR groups. The mRNA levels of Pparα and Acox1 in the KD group were lower than those in the ND group, although no significant differences were detected. Relative levels of Cd36 and inflammatory genes in the mouse liver were significantly higher in the KD group than in the ND group (all P < 0.05). CONCLUSION: The KD significantly reduced FBG and FINS and improved glucose tolerance in db/db mice by upregulating ß-cell-specific transcription factors and reversing ß-cell dedifferentiation. However, the KD also induced hepatic lipid accumulation and aggravated inflammatory response in the liver of db/db mice.

The efficacy of hydrogel containing zinc oxide-loaded and minocycline serum albumin nanopartical in the treatment of peri-implantitis

Background: We conducted this animal study to assess the efficacy of the novel hydrogel containing zinc oxide-loaded and minocycline serum albumin nanoparticals (Mino-ZnO@Alb NPs) on peri-implantitis in an experimental mouse model. Material and methods: Mino-ZnO@Alb NPs was prepared as previously reported. The peri-implantitis model was successfully established in rats, and the rats were divided into three groups randomly: Mino-ZnO@Alb NPs (Mino-ZnO) group, minocycline group, and untreated group. Four weeks later, clinical and radiographic assessments were performed to evaluate soft tissue inflammation and bone resorption level. Histologic analysis was performed to estimate the amount of remaining supporting bone tissue (SBT) around implants. ELISA tests were used to determine the concentration of inflammation factor interleukin-1-beta (IL-1β) and anti-inflammation factor tumor necrosis factor-alpha (TNF-α) around implants. Results: After one month, the Mino-ZnO group showed better results than the other two groups in regards to the results of bleeding on probing, probing pocket depth, bleeding index and gingival index. X-ray showed that SBT at mesial and distal sites around implants in the other two groups was significantly lower compared with that of Mino-ZnO group. The quantity of osteoclasts in peri-implant tissues of the Mino-ZnO group was less than that in the minocycline and untreated groups. IL-1β in the Mino-ZnO group was lower than that in the other two groups. TNF-α level was the opposite. Conclusions: Mino-ZnO@Alb NPs can effectively treat peri-implantitis and promote soft tissue healing, and may act as a promising product. (AU)

Visuospatial or verbal-spatial codes? The different effect of two secondary tasks on the power-space associations during a semantic categorizing task.

The power-space associations have been extensively studied as a possible way to reveal the nature of concept representations, while the visuospatial and verbal-spatial codes are two primary explanations for the phenomenon. In two experiments, we imposed either a visuospatial or a verbal secondary task during the semantic categorizing of power words to examine their respective roles. The results showed that retaining a letter but not a location concurrently interfered with the power-space association. The results suggested that the verbal-spatial codes might play a more fundamental role than the visuospatial codes in the power-space associations during the semantic categorizing of power words.

A DRL-based online VM scheduler for cost optimization in cloud brokers.

The virtual machine (VM) scheduling problem in cloud brokers that support cloud bursting is fraught with uncertainty due to the on-demand nature of Infrastructure as a Service (IaaS) VMs. Until a VM request is received, the scheduler does not know in advance when it will arrive or what configurations it demands. Even when a VM request is received, the scheduler does not know when the VM's lifecycle expires. Existing studies begin to use deep reinforcement learning (DRL) to solve such scheduling problems. However, they do not address how to guarantee the QoS of user requests. In this paper, we investigate a cost optimization problem for online VM scheduling in cloud brokers for cloud bursting to minimize the cost spent on public clouds while satisfying specified QoS restrictions. We propose DeepBS, a DRL-based online VM scheduler in a cloud broker which learns from experience to adaptively improve scheduling strategies in environments with non-smooth and uncertain user requests. We evaluate the performance of DeepBS under two request arrival patterns which are respectively based on Google and Alibaba cluster traces, and the experiments show that DeepBS has a significant advantage over other benchmark algorithms in terms of cost optimization.

Long-term outcomes of endoscopic papillary large-balloon dilation (12-15 mm) with or without limited sphincterotomy for removal of bile duct stones.

BACKGROUND: Limited endoscopic sphincterotomy with large balloon dilation (ES-LBD) and endoscopic papillary large-balloon dilation (EPLBD) have been proven safe and effective for removal of bile duct stones. However, the long-term outcomes are not clear. The aim of this study was to assess the long-term outcomes of EPLBD (12-15 mm) with or without limited sphincterotomy for removal of common bile duct (CBD) stones. METHODS: Patients with EPLBD or ES-LBD referred for the removal of bile-duct stones between June 2008 and August 2020 were retrospectively reviewed. Complete stone clearance, endoscopic retrograde cholangiopancreatography (ERCP)-related adverse events, and late biliary complications during long-term follow-up were analyzed. RESULTS: Basic patient characteristics were not significantly different between the groups that underwent EPLBD (n = 168) and ES-LBD (n = 57). EPLBD compared with ES-LBD resulted in similar outcomes in terms of overall successful stone removal (99.4% vs. 100%, P = 1.00) and ERCP-related adverse events (7.7% vs. 5.3%, P = 0.77). The mean duration of the follow-up were 113.6 months and 106.7 months for patients with EPLBD and ES-LBD, respectively (P = 0.13). There was no significant difference between EPLBD and ES-LBD in the incidence of stone recurrence [20 (11.9%) vs. 9 (15.8%); P = 0.49]. Multivariate analysis showed that a diameter of CBD ≥ 15 mm (OR = 3.001; 95% CI: 1.357-6.640; P = 0.007) was an independent risk factor for stone recurrence. CONCLUSIONS: The application of a large balloon (12-15 mm) via EPLBD is an effective and safe alternative to ES-LBD for extraction of large CBD stones. Endoscopic sphincterotomy prior to EPLBD may be unnecessary. A diameter of CBD ≥ 15 mm is a risk factor of stone recurrence.

Development of matrix certified reference material for accurate determination of docosahexaenoic acid in milk powder.

A novel matrix certified reference material (CRM) of docosahexaenoic acid in milk powder [GBW (E) 100641] was first developed. The CRM candidates was prepared by adding appropriate levels of docosahexaenoic acid to cow's milk, then powder sprayed, lyophilized, mixed, dispensed and sterilized. An optimized acetylchloride-methanol method was proposed and used for the characterization. The CRM characterization was carried out in six laboratories in accordance with ISO Guide 35 requirements. The certified value of CRM was 0.69 mg/g with an uncertainty of 0.08 mg/g (k = 2). The CRM was sufficiently homogeneous between and within bottles and stable up to 6 month at -20℃ and 7 days below 50 â„ƒ. The uncertainty was evaluated by combing the contributions from characterization, homogeneity and stability. Thus, the CRM can be used for quality control and method validation to ensure the accurate and reliable measurements of docosahexaenoic acid in milk for quality monitoring.

Xiehuo Xiaoying decoction inhibits Tfh cell expansion and promotes Tfr cell amplification to ameliorate Graves' disease.

ETHNOPHARMACOLOGICAL RELEVANCE: Xiehuo Xiaoying decoction (XHXY) has shown great potential in the treatment of GD, but its mechanism remains obscure. Increase of follicular helper T (Tfh) cells and reduction of follicular regulatory T (Tfr) cells contribute to a high thyrotropin receptor antibodies (TRAb) level and possible Graves' disease (GD). Oxidative stress (OS) disrupts T helper cell differentiation and aggravates autoimmunity. AIM OF THE STUDY: This study aimed to investigate whether XHXY decoction can ameliorate autoimmunity in GD via inhibiting OS and regulating Tfh and Tfr cells. MATERIALS AND METHODS: The main XHXY bioactive compounds were identified using high-performance liquid chromatography quadrupole time-of-flight mass spectrometry. GD was induced in the mice through three intramuscular injections of adenovirus expressing the TSH receptor. Then, the mice received oral gavage of XHXY (17 g/kg·d) and 34 g/kg·d) for 4 weeks. OS indicators were assessed. Flow cytometry was used to confirm the proportion of Tfh and Tfr cells in the lymph nodes and spleens of the mice. Cytokine expression levels were determined using enzyme-linked immunosorbent assay. Factors including interleukin-21, B-cell lymphoma-6, and forkhead box P3 (Foxp3) were detected using quantitative polymerase chain reaction. The mRNA and protein expression levels of Kelch-like ECH-associated protein 1 (Keap1), nuclear factor erythroid-2-related factor 2 (Nrf2), and haem oxygenase 1 (HO-1) were detected using quantitative polymerase chain reaction and Western blotting, respectively. RESULTS: Twelve main ingredients of XHXY were identified. XHXY relieved GD by lowering thyroxine (p < 0.01) and TRAb levels (p < 0.01). XHXY ameliorated OS by decreasing the levels of NADPH oxidase 2 (p < 0.05), 4-hydroxynonenal (p < 0.01), and 8-oxo-2'-deoxyguanosine (p < 0.001). It inhibited Tfh cell expansion (p < 0.05), as well as the production of cytokine interleukin -21 (p < 0.01), interleukin -4 (p < 0.01) and transcription factor B-cell lymphoma 6 (p < 0.05). XHXY also induced Tfr cell amplification (p < 0.05), increased the production of interleukin -10 (p < 0.05) and transforming growth factor ß (p < 0.05) and the mRNA levels of Foxp3 (p < 0.05). Finally, the Tfh/Tfr ratio returned to normal. In addition, XHXY activated Nrf2 and HO-1 expression, but inhibited Keap1 activation. CONCLUSIONS: XHXY relieves autoimmunity in GD via inhibiting Tfh cell amplification and Tfr cell reduction, a mechanism which probably involves the Keap1/Nrf2 signaling pathway.

Age-specific serum thyrotropin reference range for the diagnosis of subclinical hypothyroidism and its association with lipid profiles in the elderly population.

The overdiagnosis of subclinical hypothyroidism (SCH) in the elderly has driven researchers to establish age-specific thyroid stimulating hormone (TSH) intervals to precisely evaluate the prevalence of SCH. Moreover, abnormal lipid profiles, an insidious manifestation of SCH, show various impacts on different age groups. This study aimed to establish an age-specific TSH reference range to clarify the spectrum of SCH in the elderly. The prevalence of dyslipidemia and the age-specific association between TSH and lipid profiles were analyzed to elucidate the relationship between SCH and dyslipidemia. This cross-sectional study enrolled 2460 participants aged ≥ 65 years via cluster sampling. All participants received physical, laboratory tests and thyroid ultrasound examination and completed the questionnaire. The chi-square test was used to analyze variations of dyslipidemia prevalence among different groups. The Cochran-Armitage trend test was applied for testing the linear trends of age-specific prevalence of dyslipidemia among different TSH intervals in each age group. After adjusting for confounding factors, the age-specific association between TSH and lipid profiles was identified using multi-variate linear regression analysis. The TSH reference ranges in the 65-70 age group, 71-80 age group and > 80 age group were 0.65-5.51 mIU/L, 0.85-5.89 mIU/L and 0.78-6.70 mIU/L, respectively. Using these age-specific reference ranges, the prevalence of SCH in the whole population was 3.74%, which was significantly lower than the prevalence based on the laboratory reference range (10.28%). In the 65-70 age group, only the prevalence of high total cholesterol (TC) increased significantly with the age-specific TSH intervals, and TSH was positively associated with TC and low-density lipoprotein cholesterol (LDL-C). In the 71-80 and > 80 age groups, the prevalence of high TC, high triglycerides (TGs), and high LDL-C increased significantly with elevated TSH reference ranges. The levels of TC, TGs, and LDL-C were also positively associated with TSH level in 71-80 age group. However, such an association disappeared in > 80 age group. An age-specific reference range for TSH can effectively prevent the overdiagnosis of SCH in the elderly. Aging could somewhat attenuate the impact of TSH on lipid profiles.

Diagnostic performance of six ultrasound-based risk stratification systems in thyroid follicular neoplasm: A retrospective multi-center study.

This study aimed to compare the diagnostic performances of six commonly used ultrasound-based risk stratification systems for distinguishing follicular thyroid adenoma (FTA) from follicular thyroid carcinoma (FTC), including the American Thyroid Association Sonographic Pattern System (ATASPS), ultrasound classification systems proposed by American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinology (AACE/ACE/AME), Korean thyroid imaging reporting and data system (K-TIRADS), European Thyroid Association for the imaging reporting and data system (EU-TIRADS), American College of Radiology for the imaging reporting and data system (ACR-TIRADS), and 2020 Chinese Guidelines for Ultrasound Malignancy Risk Stratification of Thyroid Nodules (C-TIRADS). A total of 225 FTA or FTC patients were retrospectively analyzed, involving 251 thyroid nodules diagnosed by postoperative pathological examinations in three centers from January 2013 to October 2021. The diagnostic performances of six ultrasound-based risk stratification systems for distinguishing FTA from FTC were assessed by plotting the receiver operating characteristic (ROC) curves and compared at different cut-off values. A total of 205 (81.67%) cases of FTA and 46 (18.33%) cases of FTC were involved in the present study. Compared with those of FTA, FTC presented more typical ultrasound features of solid component, hypoechoic, irregular margin and sonographic halo (all P<0.001). There were no significant differences in ultrasound features of calcification, shape and comet-tail artifacts between cases of FTA and FTC. There was a significant difference in the category of thyroid nodules assessed by the six ultrasound-based risk stratification systems (P<0.001). The areas under the curve (AUCs) of ATASPS, AACE/ACE/AME, K-TIRADS, EU-TIRADS, ACR-TIRADS and C-TIRADS in distinguishing FTA from FTC were 0.645, 0.729, 0.766, 0.635, 0.783 and 0.798, respectively. Our study demonstrated that all the six ultrasound-based risk stratification systems present potential in the differential diagnosis of FTA and FTC. Specifically, C-TIRADS exerts the best diagnostic performance among the Chinese patients. ATASPS possesses a high sensitivity, while K-TIRADS possesses a high specificity in distinguishing FTA from FTC.

Immune System Acts on Orthodontic Tooth Movement: Cellular and Molecular Mechanisms.

Orthodontic tooth movement (OTM) is a tissue remodeling process based on orthodontic force loading. Compressed periodontal tissues have a complicated aseptic inflammatory cascade, which are considered the initial factor of alveolar bone remodeling. Since skeletal and immune systems shared a wide variety of molecules, osteoimmunology has been generally accepted as an interdisciplinary field to investigate their interactions. Unsurprisingly, OTM is considered a good mirror of osteoimmunology since it involves immune reaction and bone remolding. In fact, besides bone remodeling, OTM involves cementum resorption, soft tissue remodeling, orthodontic pain, and relapse, all correlated with immune cells and/or immunologically active substance. The aim of this paper is to review the interaction of immune system with orthodontic tooth movement, which helps gain insights into mechanisms of OTM and search novel method to short treatment period and control complications.

Efficacy and safety of ultrasound-guided microwave ablation versus surgical resection for Bethesda category IV thyroid nodules: A retrospective comparative study.

Objective: The objective of this study was to assess the efficacy and safety of ultrasound-guided microwave ablation (MWA) for Bethesda IV thyroid nodules and to compare the outcomes, complications, and costs of MWA and thyroidectomy. Methods: A total of 130 patients with Bethesda IV nodules were retrospectively reviewed, involving 46 in the MWA group and 84 in the surgery group. The local institutional review board approved this study. Patients in the MWA group were followed up at 1, 3, 6, and 12 months after the intervention. Postoperative complications, treatment time, and cost in the two groups were compared. Results: Among 84 patients with 85 Bethesda IV nodules in the surgery group, postoperative pathology was benign lesions, borderline tumors, papillary thyroid carcinoma, follicular variant papillary thyroid carcinoma, follicular thyroid carcinoma, and medullary carcinoma in 44, 4, 27, 6, 3, and 1 cases, respectively. Malignant thyroid nodules were more prone to solid echostructure (86.11% vs. 72.72%), hypoechogenicity (55.56% vs. 13.63%), and irregular margin (47.22% vs. 13.63%) than benign lesions. The nodule volume reduction rate of patients at 12 months after MWA was 85.01% ± 10.86%. Recurrence and lymphatic and distant metastases were not reported during the follow-up period. The incidence of complications, treatment time, hospitalization time, incision length, and cost were significantly lower in the MWA group than in the surgery group (all p < 0.001). Conclusions: MWA significantly reduces the volume of Bethesda IV nodules with high safety and is recommended for those with surgical contraindications or those who refuse surgical resection. Patients with suspicious ultrasound features for malignancy should be actively treated with surgery.

Optimal design of model predictive controller based on transient search optimization applied to robotic manipulators.

Due to nonlinearity and uncertainty of the robotic manipulator, the design of the robot controller has a crucial impact on its performance of motion and trajectory tracking. In this paper, the linear parameter varying (LPV) - model predictive controller (MPC) of a two-link robot manipulator is established and then the controller's optimal parameters are determined via a newly developed meta-heuristic algorithm, transient search optimization (TSO). The proposed control method is verified by set point and nonlinear trajectory tracking. In the test of set-point tracking, the LPV-MPC scheme optimized by TSO has better performance compared to the computed torque controller (CTC) schemes tuned by TSO or other metaheuristic algorithms. In addition, good performances can also be observed in the tests of nonlinear trajectory tracking via the LPV-MPC scheme by TSO. Moreover, the robustness of the method to structural uncertainty is verified by setting a large system parameter deviation. Results reveal that we achieved some improvements in the optimization of MPC of the robot manipulator by employing the proposed method.

Cadmium inhibits signal transducer and activator of transcription 6 leading to pancreatic ß cell apoptosis.

The toxic heavy metal cadmium has been proven to cause pancreatic dysfunction and lead to the development of DM. However, the underlying mechanisms have not been completely elucidated. Here, we investigated the effects of cadmium on the pancreatic ß cell line MIN6 and explored the underlying mechanisms. The Cell Counting Kit-8 (CCK8) assay and flow cytometry were used to determine cell viability and apoptosis in MIN6 cells. The expression levels of signal transducer and activator of transcription 6 (STAT6) were assessed by western blotting. We further assessed the effects of cadmium on the function of pancreatic ß cells under high glucose levels using enzyme-linked immunosorbent assay (ELISA) and western blotting. Insulin secretion and expression were decreased by cadmium in MIN6 cells. In addition, cadmium suppressed cell viability and promoted apoptosis of MIN6 cells, downregulated insulin secretion and genesis of MIN6 cells under high glucose conditions, while inhibiting STAT6. Furthermore, after treatment with IL-4, the activator of STAT6, the MIN6 cell viability suppression and apoptosis promotion effect caused by cadmium were blocked. In conclusion, cadmium inhibits pancreatic ß cell MIN6 growth by regulating the activation of STAT6. Our findings reveal a new mechanism of cadmium toxicity in pancreatic ß cells.

Serum Copper and Zinc Levels and Colorectal Cancer in Adults: Findings from the National Health and Nutrition Examination 2011-2016.

Several studies have indicated an association between serum copper and zinc levels and colorectal cancer, but results were controversial. This study assessed the association of serum copper, zinc, and copper/zinc ratio with colorectal cancer in US adults aged 20 years and older through the use of National Health and Nutrition Examination Survey (NHANES) 2011-2016 data. Serum concentrations of copper and zinc were measured using inductively coupled plasma dynamic reaction cell mass spectrometry (ICP-DRC-MS). Odds ratios with 95% confidence intervals (ORs with CIs) were calculated for serum copper, zinc, and copper/zinc ratio by multivariate logistic regression. A total of 4663 participants (2320 males and 2343 females) with 24 colorectal cancer patients were included in the analyses. We did not observe a statistically significant association between serum copper level and colorectal cancer (top vs bottom quartile multivariate OR 1.71; 95% CI, 0.37-7.88; P for trend = 0.429). In addition, serum zinc level was also not significantly associated with colorectal cancer (top vs bottom quartile multivariate OR 0.72; 95% CI, 0.12-4.27; P for trend = 0.346). While in the age- and gender-adjusted model, there seemed to be a trend that participants with higher copper/zinc ratio level had higher odds of colorectal cancer than participants with lower copper/zinc ratio level; no statistically significant association was observed in multivariate-adjusted models. Our findings did not support a significant association between serum copper and zinc level and colorectal cancer risk in the general US population. Furthermore, large longitudinal studies should be needed to confirm these findings.