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Neuro-inflammation involves distinct alterations of microglial phenotypes, containing nocuous pro-inflammatory M1-phenotype and neuroprotective anti-inflammatory M-phenotype. Currently, there is no effective treatment for modulating such alterations. M1/M2 marker of primary microglia influenced by Melatonin were detected via qPCR. Functional activities were explored by western blotting, luciferase activity, EMSA, and ChIP assay. Structure interaction was assessed by molecular docking and LIGPLOT analysis. ER-stress detection was examined by ultrastructure TEM, calapin activity, and ERSE assay. The functional neurobehavioral evaluations were used for investigation of Melatonin on the neuroinflammation in vivo. Melatonin had targeted on Peroxisome Proliferator Activated Receptor Delta (PPARδ) activity, boosted LPS-stimulated alterations in polarization from the M1 to the M2 phenotype, and thereby inhibited NFκB–IKKβ activation in primary microglia. The PPARδ agonist L-165,041 or over-expression of PPARδ plasmid (ov-PPARδ) showed similar results. Molecular docking screening, dynamic simulation approaches, and biological studies of Melatonin showed that the activated site was located at PPARδ (phospho-Thr256-PPARδ). Activated microglia had lowered PPARδ activity as well as the downstream SIRT1 formation via enhancing ER-stress. Melatonin, PPARδ agonist and ov-PPARδ all effectively reversed the above-mentioned effects. Melatonin blocked ER-stress by regulating calapin activity and expression in LPS-activated microglia. Additionally, Melatonin or L-165,041 ameliorated the neurobehavioral deficits in LPS-aggravated neuroinflammatory mice through blocking microglia activities, and also promoted phenotype changes to M2-predominant microglia. Melatonin suppressed neuro-inflammation in vitro and in vivo by tuning microglial activation through the ER-stress-dependent PPARδ/SIRT1 signaling cascade. This treatment strategy is an encouraging pharmacological approach for the remedy of neuro-inflammation associated disorders. Schematic of Proposed Mechanism for the role of Melatonin in Activated Microglia and neuro-inflammation Effects. LPS-induced ER Stress and Regulated PPARδ Expression, NFκB Phosphorylation, Subsequently Reduces SIRT1 Expression and then Triggers the Microglia Activation and Brain Damage. In the Present Study, we Provide the Evidence to Demonstrate that Melatonin Plays a Potential Protective role in Neuroprotective Effects through PPARδ/SIRT1 Pathway. In Addition, PPARδ Pharmacological Agonists L165041 also Possessed Similar Effects. These Results Suggest that the Activation of PPARδ/SIRT1 by Melatonin could Counteract the Detrimental Effect of LPS. Also, the Results Suggest Melatonin may Exert a Therapeutic Effect for Neuroinflammatory Disorders [ABSTRACT FROM AUTHOR]

Introduction: CCN1 is an immediate-early gene product pivotal for arthritis progression. We have previously shown that sirtuin 6 (SIRT6) inhibited hypoxia-induced CCN1 expression in osteoblasts. Herein we examined the contribution of cyclic AMP-responsive element binding protein (CREB)/CRE to this suppressive action and the influence of CCN1 on cyclooxygenase (COX) 2 synthesis. Materials and methods: MC3T3-E1 murine osteoblasts were cultured under normoxia (21% oxygen) or hypoxia (2% oxygen). Expressions of CCN1, phospho-CREB (Ser133), COX2 and relevant kinases were assessed by Western blot. SIRT6 was overexpressed in cultured osteoblasts and arthritic joints by a lentiviral-based technique. Activities of CCN1 gene promoter constructs were examined by luciferase reporter assay. Interaction between CREB and CCN1 promoter was assessed by chromatin immunoprecipitation (ChIP). Collagen-induced arthritis (CIA) was established in 20 rats to evaluate the effects of SIRT6 therapy on osteoblastic expressions of phospho-CREB, CCN1 and COX2. Results: SIRT6 suppressed hypoxia-enhanced CCN1 expression and CREB phosphorylation. Attenuation of calcium/calmodulin-dependent protein kinase II (CaMKII) may be responsible for SIRT6-induced CREB inhibition. CRE at − 286 bp upstream of the ATG start codon was essential for CCN1 expression under hypoxia and SIRT6 reduced hypoxia-stimulated CREB/CRE interaction. Forced expression of CREB rescued SIRT6-suppressed CCN1 synthesis. CCN1 induced COX2 expression in osteoblasts. In rat CIA, the therapeutic effect of SIRT6 was accompanied by decreases in osteoblastic expressions of phospho-CREB, CCN1 and COX2. Conclusion: Our study indicated that the benefits of SIRT6 to inflammatory arthritis and bone resorption are at least partially derived from its modulation of CREB/CCN1/COX2 pathway in osteoblasts. [ABSTRACT FROM AUTHOR]

Background and purpose: Histone deacetylase (HDAC) inhibitors (HDIs) can modulate the epithelial-mesenchymal transition (EMT) progression and inhibit the migration and invasion of cancer cells. Emerging as a novel class of anti-cancer drugs, HDIs are attracted much attention in the field of drug discovery. This study aimed to discern the underlying mechanisms of Honokiol in preventing the metastatic dissemination of gastric cancer cells by inhibiting HDAC3 activity/expression. Experimental approach: Clinical pathological analysis was performed to determine the relationship between HDAC3 and tumor progression. The effects of Honokiol on pharmacological characterization, functional, transcriptional activities, organelle structure changes, and molecular signaling were analyzed using binding assays, differential scanning calorimetry, luciferase reporter assay, HDAC3 activity, ER stress response element activity, transmission electron microscopy, immune-blotting, and Wnt/β-catenin activity assays. The in vivo effects of Honokiol on peritoneal dissemination were determined by a mouse model and detected by PET/CT tomography. Key results: HDAC3 over-expression was correlated with poor prognosis. Honokiol significantly abolished HDAC3 activity (Y298) via inhibition of NFκBp65/CEBPβ signaling, which could be reversed by the over-expression of plasmids of NFκBp65/CEBPβ. Treatments with 4-phenylbutyric acid (a chemical chaperone) and calpain-2 gene silencing inhibited Honokiol-inhibited NFκBp65/CEBPβ activation. Honokiol increased ER stress markers and inhibited EMT-associated epithelial markers, but decreased Wnt/β-catenin activity. Suppression of HDAC3 by both Honokiol and HDAC3 gene silencing decreased cell migration and invasion in vitro and metastasis in vivo. Conclusions and implications: Honokiol acts by suppressing HDAC3-mediated EMT and metastatic signaling. By prohibiting HDAC3, metastatic dissemination of gastric cancer may be blocked. Conceptual model showing the working hypothesis on the interaction among Honokiol, HDAC3, and ER stress in the peritoneal dissemination of gastric cancer. Honokiol targeting HDAC3 by ER stress cascade and mitigating the peritoneal spread of gastric cancer. Honokiol-induced ER stress–activated calpain activity targeted HDAC3 and blocked Tyr298 phosphorylation, subsequently blocked cooperating with EMT transcription factors and cancer progression. The present study provides evidence to demonstrate that HDAC3 is a positive regulator of EMT and metastatic growth of gastric cancer cells. The findings here imply that overexpressed HDAC3 is a potential therapeutic target for honokiol to reverse EMT and prevent gastric cancer migration, invasion, and metastatic dissemination. • Honokiol significantly abolished HDAC3 activity on catalytic tyrosine 298 residue site. In addition, Honokiol-induced ER stress markedly inhibited HDAC3 expression via inhibition of NFκBp65/CEBPβ signaling. • HDAC3, which is a positive regulator of metastatic gastric cancer cell growth, can be significantly inhibited by Honokiol. • Opportunities for HDAC3 inhibition may be a potential therapeutic target for preventing gastric cancer metastatic dissemination. [ABSTRACT FROM AUTHOR]

In current era, the intelligent development of traditional Chinese medicine (TCM) has attracted more and more attention. As the main carrier of clinical medication, formulas use synergies of active substances to enhance efficacy and reduce side effects. Related studies show that there is a nonlinear relationship between the efficacy of formulas and herbs. Deep learning is an effective technique for fitting nonlinear relationships. However, it is not good for using deep learning model directly due to ignoring the characteristics of formulas. In this paper, we propose a detached feature extraction approach (TCM2Vec) based on deep learning for better feature extraction and efficacy prediction. We build two detached encoders, one of it uses cross-feature-based unsupervised pre-training model (FMh2v) to extract the relationship features of herbal medicines for initializing, while the other one simulates multi-dimensional characteristics of medicines by normal distribution. Then we integrate relationships and medicinal characteristics for deep feature extraction. We processed 31,114 unlabeled formulas for pre-training and two classification tasks in-domain for predicting and fine-tuning. One of tasks is multi-classed with 1036 formulas, other one is multi-labelled with 1,723 formulas. For labelled formulas, different feature extraction models based on detached encoder are trained to predict efficacy. Compared with the no pre-training, CBOW and BERT baseline models, FMh2v leads to performance gains. Moreover, the detached encoder offers large positive effects in different models which for efficacy prediction, where ACC increased by 5.80% on average and F1 increased by 12.06% on average. Overall, the proposed feature extraction is an effective method for obtaining characteristic representation of TCM formulas, and provides reference for the adaptability of artificial intelligence technology in the domain of TCM. [ABSTRACT FROM AUTHOR]

Exposure to air pollution during pregnancy has been linked to birth defects. But the directions of studies on the associations between air pollutants exposure and effect on the incidence of congenital heart disease (CHDs) were inconsistent. To date, few studies were concentrated on the effects of both particulate matter and gaseous air pollutant exposure on CHDs across the full gestational week simultaneously. Our study aimed to investigate the critical exposure windows for each air pollutant throughout 40 gestational weeks. Data on CHDs, air pollution, and meteorological factors from 2013 to 2019 were collected in Lanzhou, China. A distributed lag nonlinear model combined with a quasi-Poisson regression model was applied to evaluate the weekly exposure–lag–response association between air pollutants levels and CHDs, and the subgroup analyses were conducted by gender (baby boy and baby girl). The study included 1607 mother–infant pairs. The results demonstrated that exposure of pregnant women to particulate matter ≤ 5 μm (PM2.5) at lag 1–4 weeks was significantly associated with the risk of CHDs, and the strongest effects were observed in the lag 1 week (1.150, 95%CI 1.059–1.248). For exposure to particulate matter ≤ 10 μm (PM10) at lag 1–3 weeks, the strongest effects were observed in the lag 1 week (1.075, 95% CI 1.026–1.128). For exposure to sulfur dioxide (SO2) at lag 1–4 weeks, the strongest effects were observed in the lag 1 week (1.154, 95% CI 1.025–1.299). For exposure to carbon monoxide (CO) at lag 1–3 weeks, the strongest effects were observed in the lag 1 week (1.089, 95% CI 1.002–1.183). For exposure to ozone (O3) concentration at lag 9–15 weeks, the strongest effects were observed in the lag 15 weeks (1.628, 95% CI 1.001–2.649). The cumulative effects of PM2.5, PM10, SO2, and CO along weeks with a maximum of 1.609 (95%CI 1.000–2.589), 1.286 (95%CI 1.007–1.641), 1.648 (95%CI 1.018–2.668), and 1.368 (95%CI 1.003, 1.865), respectively. The effects were obvious in the initial gestational weeks too. Through the gender stratification analysis, the air pollutants with significant effects were PM2.5 for baby boys and PM2.5, PM10, SO2, CO, NO2, and O3 for baby girl. For the relationship between CHDs and air pollution in Lanzhou, PM2.5, PM10, SO2, CO, and O3 played an important role in the initial gestational weeks, especially for baby girl. [ABSTRACT FROM AUTHOR]

Current post-earthquake assessment relies on manual inspections to assess the safety conditions of existing buildings. Such field inspection in a building-to-building manner remains challenging as it is labor-intensive and relatively inefficient, which may affect the associated post-earthquake management plan and the economic loss. A simulation-based rapid performance evaluation of buildings is, therefore, needed. This study proposes a seismic performance evaluation framework for the frame structures with the aid of local ground-motion measurements, prior-event field testing, and time-history analysis. The linear behavior of the SDOF model is calibrated by the dynamic properties determined from dynamic tests under ambient vibration. When an earthquake happens, the peak spectral displacement of the building is estimated using the calibrated SDOF model via a time-history analysis. The feasibility and accuracy of the proposed method are validated using the data and inspection results collected from the Van Nuys hotel under Whitter, Landers, BigBear, and Northridge earthquakes. Results reveal that the proposed method can estimate the peak displacement with a favorable agreement. The proposed method is further applied to assess the conditions of thirty-five frame structures under earthquakes those happened from January 2019 to April 2022, in Gongxian city, Sichuan province. [ABSTRACT FROM AUTHOR]

Few studies have evaluated the association between air pollutants and neural tube defects (NTDs). Moreover, the existing research ignores the lag effect of air pollution on health and provides inconsistent epidemiological evidence. We aim to estimate the association between air pollution and NTDs during the first trimester of pregnancy and identify specific susceptible windows. Birth data was collected from the Birth Defects Surveillance Network in Lanzhou from September 1, 2014, to December 31, 2019. Air quality and meteorological data were collected from ambient air monitoring stations and China Meteorological Data Network. The log connection function of the Poisson distribution function is used to establish a DLNM model to estimate the exposure–effect relationship and exposure–lag relationship association between air pollutants levels and NTDs. There were 320,787 perinatal infants in Lanzhou from September 1, 2014, to December 31, 2019, and 486 cases of NTDs (1.5‰). The result indicates that exposure to inhalable particles (PM10) at lag 2–4 weeks was significantly associated with the risk of NTDs, with the most significant impact at the lag 2 week (RR=1.048, 95%CI, 1.015–1.084). Exposure to fine particulate matter (PM2.5) at the lag 2 week was significantly associated with the risk of NTDs, with the most significant impact at the lag 2 week (RR=1.077, 95%CI, 1.004–1.155). Exposure to sulfur dioxide (SO2) and nitrogen dioxide (NO2) at lag 3–6weeks was significantly associated with the risk of NTDs, with the most significant impact at the lag 4 week (RR=1.220, 95%CI, 1.105–1.348; RR=1.143, 95%CI, 1.048–1.245). This study provides further evidence that exposure to air pollutants in the first trimester of pregnancy significantly increases the risk of neural tube defects. [ABSTRACT FROM AUTHOR]

Objective: Modeling methods for busulfan-induced oligoasthenozoospermia are controversial. We aimed to systematically review the modeling method of busulfan-induced oligospermia and asthenozoospermia, and analyze changes in various evaluation indicators at different busulfan doses over time. Methods: We searched the Cochrane Library, PubMed databases, Web of Science, the Chinese National Knowledge Infrastructure, and the Chinese Biomedical Literature Service System until April 9, 2022. Animal experiments of busulfan-induced spermatogenesis dysfunction were included and screened. The model mortality and parameters of the evaluation indicators were subjected to meta-analysis. Results: Twenty-nine animal studies were included (control/model: 669/1829). The mortality of mice increased with busulfan dose. Significant spermatogenesis impairment occurred within 5 weeks, regardless of busulfan dose (10–40 mg/kg). Testicular weight (weighted mean difference [WMD]: − 0.04, 95% CI: − 0.05, − 0.03), testicular index (WMD: − 2.10, 95% CI: − 2.43, − 1.76), and Johnsen score (WMD: − 4.67, 95% CI: − 5.99, − 3.35) were significantly decreased. The pooled sperm counts of the model group were reduced by 32.8 × 106/ml (WMD: − 32.8, 95% CI: − 44.34, − 21.28), and sperm motility decreased by 37% (WMD: − 0.37, 95% CI: − 0.47, − 0.27). Sperm counts decreased slightly (WMD: − 3.03, 95% CI: − 3.42, − 2.64) in an intratesticular injection of low-dose busulfan (4 − 6 mg/kg), and the model almost returned to normal after one seminiferous cycle. Conclusion: The model using low-dose busulfan (10 − 20 mg/kg) returned to normal after 10 − 15 weeks. However, in some spermatogenesis cycles, testicular weight reduction and testicular spermatogenic function damage were not proportional to busulfan dose. Sperm counts and motility results in different studies had significant heterogeneity. Standard protocols for sperm assessment in animal models were needed to reduce heterogeneity between studies. [ABSTRACT FROM AUTHOR]

Current studies on air pollutant exposure during pregnancy and orofacial clefts (OFCs) have inconsistent results, and few studies have investigated refined susceptible windows for OFCs. We aim to estimate association between air pollution and OFCs during the first trimester of pregnancy and identify specific susceptible windows. Birth data was obtained from Birth Defects Surveillance Network in Lanzhou from 2014 to 2019. Air pollution data and temperature data were obtained from ambient air monitoring stations and China Meteorological Data Network, respectively. A distribution lag nonlinear model (DLNM) was applied to estimate weekly-exposure-lag-response association between air pollutant levels and OFCs. The study included 320,787 perinatal infants from 2014 to 2019, of which 685 (2.14‰) were OFCs. The results demonstrated that exposure of pregnant women to aerodynamic diameter ≤ 10 μm (PM10) at lag 4–5 weeks was significantly associated with the risk of OFCs, with the greatest impact at the lag 4 week (RR = 1.029, 95% CI = 1.001–1.057). Exposure to sulfur dioxide (SO2) at lag 2–4 weeks was significantly associated with the risk of OFCs, with the greatest impact at the lag 3 week (RR = 1.096, 95% CI = 1.041–1.177). This study provides further evidence that exposure to air pollution increases the risk of OFCs in the first trimester of pregnancy. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a progressively neurodegenerative disease following dopamine neuron loss and motor dysfunction. Selective monoamine oxidase B (MAO-B) inhibitors are regarded as the potential candidates for the treatment of PD. 2-Pyrazoline structure, an important pharmacodynamic parent nucleus of MAO inhibitors, was introduced into the lead compound 2,3-dibromo-4,5-dihydroxylbenzophenone (LM48), thirty-two triphenylpyrazoline ketone chlorophenols were therefore synthesized, and their protective activities against 6-hydroxydopamine damaged SH-SY5Y cells were further evaluated. Seven chlorophenols 9d, 11d, 28d, 29d, 30d, 31d, and 32d exhibited the significant protective activity with the EC50 values in the range of 0.3–1.2 μM, superior to LM48 (EC50 > 20 μM) and Rasagiline (EC50 = 1.1 ± 0.6 μM). Moreover, they could obviously reduce ROS level. Their MAO-A and MAO-B inhibitory activities in vitro were further compared. MAO-A inhibitory activity was not found at 50 μM, but sixteen compounds were discovered showing selective MAO-B inhibitory activity. Of which, compound 6d presented the optimal activity (IC50 = 12.2 ± 2.3 μM). Compared with Rasagiline (an irreversible MAO-B inhibitor), the combination of 6d and MAO-B was reversible displaying the higher selectivity and safety. These findings suggest that triphenylpyrazoline ketone chlorophenols could potentially be promising candidates for the treatment of PD. [ABSTRACT FROM AUTHOR]

Excessive displacement responses of monopiles affect the serviceability of offshore structures. Related to complicated pile—seabed—wave interactions, the actual behavior of monopiles in silty seabed under periodic wave action remains unclear, and relevant studies in the literature are limited. A series of experiments were conducted in a wave flume containing single piles in silty seabed with relative density of 0.77 subjected to regular waves. Two stages of wave loading were applied successively, accompanied by data recording which included pore water pressure, water surface elevation, pile head displacement, and pile strain. Development of pile-head displacement and pore pressure in silty seabed was the main focus, but the effects of pile diameter, pile type, and pile stiffness were also investigated. The experimental results indicate that, in silty seabed, piles of large diameter or with fins accelerate soil liquefaction, resulting in strengthened soil which allows a higher upper boundary of pore pressure. Using fins at deeper locations led to a quick failure of the piles, but the opposite result was observed with an increase in fin dimensions. Once pile-head displacement entered its rapid development period, the wave load calculated via the pile moment was an overestimation, especially for the piles of large diameter. [ABSTRACT FROM AUTHOR]

The label flipping attack is a special poisoning attack in the adversarial environment. The research designed a novel label noise processing framework, the core of which is the semi-supervised learning label correction algorithm based on AdaBoost (AdaSSL). It can effectively improve the label quality of training data and improve the classification performance of the model. Based on five real UCI datasets, this study chose six classic machine learning algorithms (NB, LR, SVM, DT, KNN and MLP) as the base classifiers to classify them. With a noise level of 0 ∼ 20%, we evaluated the classification effect of these classifiers on UCI datasets based on the entropy label flipping attack and the AdaSSL defense algorithm. The experimental results show that the AdaSSL algorithm can effectively improve the robustness of the classifier against label flipping attack. Compared with the most advanced semi-supervised defense algorithm in the literature, the algorithm does not need to use additional datasets. At a noise ratio of 10%, the AdaSSL algorithm is significantly better than state-of-the-art label noise defense technology. [ABSTRACT FROM AUTHOR]

The comb-type breakwater (CTB) has been proposed and investigated in recent years due to its advantages in terms of deep-water adaptability, material saving and water exchanges. All existing empirical formulae for CTBs have been so far restricted to the water level above the bottom of the superstructure, which mainly occurs under the high tides or storm tides. However, based on recent engineering applications and experimental observations, the most severe conditions for CTBs are more likely to occur under a medium water level, because impulsive wave pressure may occur due to interactions between waves and the special chamber in CTBs. Meanwhile, during the most of construction and operation periods, the CTBs are mainly working under the medium water levels, i.e., water levels below the bottom of the superstructure. In this study, the effects of main influence parameters on the horizontal wave force coefficient and wave transmission coefficient for open CTBs (with partially immersed side plates) under medium water levels were investigated based on a 3D numerical wave flume and corresponding empirical formulae were proposed. It is indicated that the location of the side plate related to the main caisson has significant influence on the hydrodynamic performance of CTBs. In engineering applications, the location of the side plate can be designed at b/L ⩽ 0.15 or b/L ⩾ 0.3 (where b is the distance between the side plate and the front face of the main caisson and L is the incident wave length) for efficiently lowering the horizontal wave force and wave transmission. The flow mechanism of impulsive wave force on CTBs was revealed based on synchronous analyses of flow fields and pressure distribution. Through appropriate design of the height of the superstructure according to H/hD ⩽ 1.0 or H/hD ⩾ 1.5 (where H is the incident wave height and hD is the distance between the still water level and the bottom of the superstructure), the likely impulsive wave pressure on the side plate can also be diminished. [ABSTRACT FROM AUTHOR]

Background: Constant DNA damage occurs in cells, and the cells are programmed to respond constitutively. This study explored the roles of ataxia-telangiectasia mutated interactor (ATMIN), one of the impaired pathways involving the DNA damage response (DDR) in mismatch repair-deficient [microsatellite instability (MSI)-high] colorectal carcinoma (CRC). Methods: Expression of ATMIN messenger RNA (mRNA) was detected in CRC specimens with microsatellite instability (MSI) characteristics. The effects of ectopic ATMIN expression and ATMIN knockdown on invasion abilities were evaluated in MSI-high cell lines, and liver metastasis ability was investigated in vivo. Protein-protein interactions were assessed by coimmunoprecipitation analyses in vitro. Results: Decreased ATMIN expression was positively correlated with advanced stage of disease (P < 0.05), lymph node metastases (P < 0.05), and deeper invasion (P < 0.05) in MSI-high tumors. Transient or stable ATMIN knockdown significantly increased cell motility. Moreover, in the high-throughput microarray and gene set enrichment analysis, ATMIN was shown to act on the Wnt-signaling pathway via PARP1. This cascade influences β-catenin/transcription factor 4 (TCF4) binding affinity in MSI-high tumors, and PARP1 inhibition significantly decreased the number of metastases from ATMIN knockdown cancer cells. Conclusions: The results not only indicated the critical role of ATMIN, but also shed new light on PARP1 inhibitors, providing a basis for further clinical trials of MSI-high CRC. [ABSTRACT FROM AUTHOR]

Tumor organoids offer new opportunities for translational cancer research, but unlike animal models, their broader use is hindered by the lack of clinically relevant imaging endpoints. Here, we present a positron-emission microscopy method for imaging clinical radiotracers in patient-derived tumor organoids with spatial resolution 100-fold better than clinical positron emission tomography (PET). Using this method, we quantify 18F-fluorodeoxyglucose influx to show that patient-derived tumor organoids recapitulate the glycolytic activity of the tumor of origin, and thus, could be used to predict therapeutic response in vitro. Similarly, we measure sodium-iodine symporter activity using 99mTc- pertechnetate and find that the iodine uptake pathway is functionally conserved in organoids derived from thyroid carcinomas. In conclusion, organoids can be imaged using clinical radiotracers, which opens new possibilities for identifying promising drug candidates and radiotracers, personalizing treatment regimens, and incorporating clinical imaging biomarkers in organoid-based co-clinical trials. Positron emission tomography (PET) radiotracers measure the metabolic activity in cancer cells in patients. Here, the authors develop a microscopy method to image organoids using clinical radiotracers, which allows a direct comparison to PET imaging in patients. [ABSTRACT FROM AUTHOR]

In late 2019, the first case of COVID-19 was reported in Wuhan, China. Soon after, cases began to spread globally. This study aimed to examine the psychological impact of the COVID-19 pandemic on the adult population in the United States. We conducted an exploratory cross-sectional study using an anonymous online survey methodology distributed to participants across 13 states. The data collected included demographical information and outcomes from validated mental health screeners (GAD-7, PHQ-9, and IES-R) to assess levels of anxiety, depression, and stress. A total of 1356 participants completed the survey. GAD-7, PHQ-9, and IES-R levels differed significantly (p < 0.05) according to age, gender, and educational level. There was also significant difference between GAD-7 level as well as IES-R level between healthcare and non-healthcare workers (p = 0.02 and p = 0.028). Overall, this study has helped to garner a better understanding of COVID-19's impact on mental health outcomes. [ABSTRACT FROM AUTHOR]

Purpose: Tumor metastasis is the main cause of death from breast cancer patients and cell migration plays a critical role in cancer metastasis. Recent studies have shown long non-coding RNAs (lncRNAs) play an essential role in the initiation and progression of cancer. In the present study, the role of an LncRNA, Rho GTPase Activating Protein 5- Antisense 1 (ARHGAP5-AS1) in breast cancer was investigated. Methods: RNA sequencing was performed to find out dysregulated LncRNAs in MDA-MB-231-LM2 cells. Transwell migration assays and F-actin staining were utilized to estimate cell migration ability. RNA pulldown assays and RNA immunoprecipitation were used to prove the interaction between ARHGAP5-AS1 and SMAD7. Western blot and immunofluorescence imaging were used to examine the protein levels. Dual luciferase reporter assays were performed to evaluate the activation of TGF-β signaling. Results: We analyzed the RNA-seq data of MDA-MB-231 and its highly metastatic derivative MDA-MB-231-LM2 cell lines (referred to as LM2) and identified a novel lncRNA (NR_027263) named as ARHGAP5-AS1, which expression was significantly downregulated in LM2 cells. Further functional investigation showed ARHGAP5-AS1 could inhibit cell migration via suppression of stress fibers in breast cancer cell lines. Afterwards, SMAD7 was further identified to interact with ARHGAP5-AS1 by its PY motif and thus its ubiquitination and degradation was blocked due to reduced interaction with E3 ligase SMURF1 and SMURF2. Moreover, ARHGAP5-AS1 could inhibit TGF-β signaling pathway due to its inhibitory role on SMAD7. Conclusion: ARHGAP5-AS1 inhibits breast cancer cell migration via stabilization of SMAD7 protein and could serve as a novel biomarker and a potential target for breast cancer in the future. [ABSTRACT FROM AUTHOR]

Label flipping attack is a poisoning attack that flips the labels of training samples to reduce the classification performance of the model. Robustness is used to measure the applicability of machine learning algorithms to adversarial attack. Naive Bayes (NB) algorithm is a anti-noise and robust machine learning technique. It shows good robustness when dealing with issues such as document classification and spam filtering. Here we propose two novel label flipping attacks to evaluate the robustness of NB under label noise. For the three datasets of Spambase, TREC 2006c and TREC 2007 in the spam classification domain, our attack goal is to increase the false negative rate of NB under the influence of label noise without affecting normal mail classification. Our evaluation shows that at a noise level of 20%, the false negative rate of Spambase and TREC 2006c has increased by about 20%, and the test error of the TREC 2007 dataset has increased to nearly 30%. We compared the classification accuracy of five classic machine learning algorithms (random forest(RF), support vector machine(SVM), decision tree(DT), logistic regression(LR), and NB) and two deep learning models(AlexNet, LeNet) under the proposed label flipping attacks. The experimental results show that two label noises are suitable for various classification models and effectively reduce the accuracy of the models. [ABSTRACT FROM AUTHOR]

Hantaan viruses (HTNVs) are zoonotic pathogens transmitted mainly by rodents and capable of infecting humans. Increasing knowledge of the human response to HTNV infection can guide the development of new preventative vaccines and therapeutic strategies. Here, we show that HTNV can infect CD8+ T cells in vivo in patients diagnosed with hemorrhagic fever with renal syndrome (HFRS). Electron microscopy-mediated tracking of the life cycle and ultrastructure of HTNV-infected CD8+ T cells in vitro showed an association between notable increases in cytoplasmic multivesicular bodies and virus production. Notably, based on a clinical cohort of 280 patients, we found that circulating HTNV-infected CD8+ T cell numbers in blood were proportional to disease severity. These results demonstrate that viral infected CD8+ T cells may be used as an adjunct marker for monitoring HFRS disease progression and that modulating T cell functions may be explored for new treatment strategies. Rongrong Liu et al. find that Hantaan virus, a common cause of hemorrhagic fever with renal syndrome (HFRS) in China, can infect CD8+ T cells and that these cells can support the full viral replication cycle. They also see an association between CD8+ T cells infection and disease progression in HFRS patients. [ABSTRACT FROM AUTHOR]

Antibodies that antagonize extracellular receptor–ligand interactions are used as therapeutic agents for many diseases to inhibit signalling by cell-surface receptors1. However, this approach does not directly prevent intracellular signalling, such as through tonic or sustained signalling after ligand engagement. Here we present an alternative approach for attenuating cell-surface receptor signalling, termed receptor inhibition by phosphatase recruitment (RIPR). This approach compels cis-ligation of cell-surface receptors containing ITAM, ITIM or ITSM tyrosine phosphorylation motifs to the promiscuous cell-surface phosphatase CD452,3, which results in the direct intracellular dephosphorylation of tyrosine residues on the receptor target. As an example, we found that tonic signalling by the programmed cell death-1 receptor (PD-1) results in residual suppression of T cell activation, but is not inhibited by ligand-antagonist antibodies. We engineered a PD-1 molecule, which we denote RIPR-PD1, that induces cross-linking of PD-1 to CD45 and inhibits both tonic and ligand-activated signalling. RIPR-PD1 demonstrated enhanced inhibition of checkpoint blockade compared with ligand blocking by anti-PD1 antibodies, and increased therapeutic efficacy over anti-PD1 in mouse tumour models. We also show that the RIPR strategy extends to other immune-receptor targets that contain activating or inhibitory ITIM, ITSM or ITAM motifs; for example, inhibition of the macrophage SIRPα 'don't eat me' signal with a SIRPα–CD45 RIPR molecule potentiates antibody-dependent cellular phagocytosis beyond that of SIRPα blockade alone. RIPR represents a general strategy for direct attenuation of signalling by kinase-activated cell-surface receptors. A approach termed 'receptor inhibition by phosphatase recruitment' is described for attenuating both tonic and ligand-activated cell-surface receptor signalling. [ABSTRACT FROM AUTHOR]

Background: The double-eyelid operation is the most requested cosmetic surgery in Asians. The incision is usually located at the pretarsal skin 6 mm to 8 mm above palpebral margin. The purpose of this paper is to report a novel approach of double-eyelid operation through a supraciliary incision (SCI). Methods: Three transverse curved lines were drawn on the upper lid skin. The location of line 1 (SCI) was 1.5 mm above the eyelash, line 2 according to the amount of redundant skin excised and line 3 at 3 mm to 4 mm above line 2. After the incisions were made between line 1 and line 2, the subcutaneous dissection is carried out over 5 mm the line 3. Then, the redundant skin and a strip orbicularis oculi muscle were removed to open the orbital septum and to explore underside levator aponeurosis. Along the line 3, the internal buried fixation sutures between dermal tissue and the fusion line of the orbital septum and levator aponeurosis were placed. Finally, the wounds were closed between line 2 and line 1. Results: There were 528 patients who underwent the double-eyelid operation through the supraciliary approach. In long-term follow-up, 288 patients were evaluated at 6 months to 78 months postoperatively. Of those, 266 patients were satisfactory for the result (92.36%) with natural shape and invisible surgical scar. In another 22 patients (7.63%), a revised blepharoplasty was performed in 22 eyelids. Conclusion: The double-eyelid surgery using the SCI has several advantages including less visibility of the incision, the protected subdermal vascular network, the intact continuity of the upper eyelid skin, the combination of the SCI and internal dermal buried suture method. The approach can be considered an efficient technique for Asian patients. Level of Evidence IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

Human social cognition relies heavily on the processing of various visual cues, such as eye contact and facial expressions. Atypical visual perception and integration have been recognized as key phenotypes in individuals diagnosed with autism spectrum disorder (ASD), and may potentially contribute to impediments in normal social development, a hallmark of ASD. Meanwhile, increasing studies on visual function in ASD have pointed to detail-oriented perception, which has been hypothesized to result from heightened response to information of high spatial frequency. However, mixed results of human studies have led to much debate, and investigations using animal models have been limited. Here, using BTBR mice as a model of idiopathic ASD, we assessed retinal stimulus processing by full-field electroretinogram and found impaired photoreceptor function and retina-based alterations mostly in the cone pathway. Using the optokinetic reflex to evaluate visual function, we observed robustly enhanced visual response to finer spatial details and more subtle contrasts at only higher spatial frequencies in the BTBR mice, under both photopic and scotopic conditions. These behavioral results, which are similar to findings in a subset of ASD patients, indicate a bias toward processing information of high spatial frequencies. Together, these findings also suggest that, while enhancement of visual behaviors under both photopic and scotopic conditions might be due to alterations in visual processing common to both rod and cone pathways, these mechanisms are probably downstream of photoreceptor function. [ABSTRACT FROM AUTHOR]

The complex relationship between specific hippocampal oscillation frequency deficit and cognitive dysfunction in the ischemic brain is unclear. Here, using a mouse two-vessel occlusion (2VO) cerebral ischemia model, we show that visual stimulation with a 40 Hz light flicker drove hippocampal CA1 slow gamma and restored 2VO-induced reduction in CA1 slow gamma power and theta-low gamma phase-amplitude coupling, but not those of the high gamma. Low gamma frequency lights at 30 Hz, 40 Hz, and 50 Hz, but not 10 Hz, 80 Hz, and arrhythmic frequency light, were protective against degenerating CA1 neurons after 2VO, demonstrating the importance of slow gamma in cognitive functions after cerebral ischemia. Mechanistically, 40 Hz light flicker enhanced RGS12-regulated CA3-CA1 presynaptic N-type calcium channel-dependent short-term synaptic plasticity and associated postsynaptic long term potentiation (LTP) after 2VO. These results support a causal relationship between CA1 slow gamma and cognitive dysfunctions in the ischemic brain. Brain ischemia has been associated with deficits in neural oscillations. Here in an animal model, the authors show that modulation of low-gamma oscillations using a light flicker can restore low gamma oscillations and protect ischemic neurons. [ABSTRACT FROM AUTHOR]

Fragile X Syndrome results from a loss of Fragile X Mental Retardation Protein (FMRP). We now show that FMRP is a member of a Cav3-Kv4 ion channel complex that is known to regulate A-type potassium current in cerebellar granule cells to produce mossy fiber LTP. Mossy fiber LTP is absent in Fmr1 knockout (KO) mice but is restored by FMRP(1-297)-tat peptide. This peptide further rapidly permeates the blood-brain barrier to enter cells across the cerebellar-cortical axis that restores the balance of protein translation for at least 24 h and transiently reduces elevated levels of activity of adult Fmr1 KO mice in the Open Field Test. These data reveal that FMRP(1-297)-tat can improve function from the levels of protein translation to synaptic efficacy and behaviour in a model of Fragile X syndrome, identifying a potential therapeutic strategy for this genetic disorder. Fragile X Mental Retardation Protein regulates synaptic plasticity and its loss results in Fragile X Syndrome. Here, the authors show that the FMRP(1-297)-tat peptide can permeate the BBB, restore protein translation and mossy fiber LTP, and reduce elevated levels of activity in Fmr1 KO mice. [ABSTRACT FROM AUTHOR]

Objectives: The present study aimed to investigate the role of GSD in different phases of type 2 DM development in the Jinchang cohort study. Methods: A total of 28,760 eligible participants were divided into two mutually exclusive subgroups of normoglycemia (n = 23,725) and prediabetes (n = 5035) at baseline. These subgroups were followed up for incident prediabetes (n = 4512) and incident type 2 diabetes mellitus (n = 754), respectively. Cox proportional hazard models were used to determine hazard ratios (HRs) for incident prediabetes among normoglycemic individuals and incident type 2 diabetes mellitus among prediabetic individuals. Results: The mean duration of follow-up was 2.18 years for incident prediabetes and 2.30 years for incident type 2 diabetes mellitus. GSD is significantly associated with incident type 2 diabetes mellitus among prediabetic individuals (HR = 1.292; 95% CI, 1.071–1.560), but not with incident prediabetes among normoglycemic individuals (HR = 0.999; 95% CI, 0.849–1.079). When gallstone and cholecystectomy were studied separately, only cholecystectomy was found to be significantly associated with incident type 2 diabetes mellitus among individuals with prediabetes (HR = 1.703; 95% CI, 1.299–2.233) and the association seems to be stronger in women (HR = 1.929; 95% CI, 1.242–2.994) than in men (HR = 1.555; 95% CI, 1.077–2.247). Conclusion: Our findings suggest that GSD is more closely related to the late-phase mechanisms in the development of type 2 DM than early-phase mechanisms. [ABSTRACT FROM AUTHOR]

Many biological signals that reflect the human health are relatively weak, and high-resolution Analog-Digital Converters (ADCs) are required to measure them. The over-sampling technology is a method for increasing the accuracy, equal to the accuracy of high resolution ADCs, when an ADC has low resolution. For high resolution ADCs, their accuracy from the over-sampling technology would break its maximum limitation. During our signal collection, there are two items which affect our results: 1. measurement error; 2. non-linear characteristics at the end points. In over-sampling method of detecting weak signal of wearable devices by using the unidirectional saw-tooth shaped function, the magnitude of the shaped function is as close as possible to the integer multiple of the quantization step size to reduce the additional measurement error. To reduce the difficulty of the adding shaped function, which features nonlinearity of the starting point, a new method of detecting the weak signal by adding the bidirectional saw-tooth shaped function is proposed. The experimental results show this method is feasible for improving the ADC resolution. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder caused by survival motor neuron (SMN) protein deficiency leading the loss of motor neurons in the anterior horns of the spinal cord and brainstem. More than 95% of SMA patients are attributed to the homozygous deletion of survival motor neuron 1 (SMN1) gene, and approximately 5% are caused by compound heterozygous with a SMN1 deletion and a subtle mutation. Here, we identified a rare variant c.835-5T>G in intron 6 of SMN1 in a patient affected with type I SMA. We analyzed the functional consequences of this mutation on mRNA splicing in vitro. After transfecting pCI-SMN1, pCI-SMN2, and pCI-SMN1 c.835-5T>G minigenes into HEK293, Neuro-2a, and SHSY5Y cells, reverse transcription polymerase chain reaction (RT-PCR) was performed to compare the splicing effects of these minigenes. Finally, we found that this mutation resulted in the skipping of exon 7 in SMN1, which confirmed the genetic diagnosis of SMA. [ABSTRACT FROM AUTHOR]

Introduction: Several different types of drugs acting on the central nervous system (CNS) have previously been associated with an increased risk of suicide and suicidal ideation (broadly referred to as suicide). However, a differential association between brand and generic CNS drugs and suicide has not been reported.Objectives: This study compares suicide adverse event rates for brand versus generic CNS drugs using multiple sources of data.Methods: Selected examples of CNS drugs (sertraline, gabapentin, zolpidem, and methylphenidate) were evaluated via the US FDA Adverse Event Reporting System (FAERS) for a hypothesis-generating study, and then via administrative claims and electronic health record (EHR) data for a more rigorous retrospective cohort study. Disproportionality analyses with reporting odds ratios and 95% confidence intervals (CIs) were used in the FAERS analyses to quantify the association between each drug and reported suicide. For the cohort studies, Cox proportional hazards models were used, controlling for demographic and clinical characteristics as well as the background risk of suicide in the insured population.Results: The FAERS analyses found significantly lower suicide reporting rates for brands compared with generics for all four studied products (Breslow-Day P < 0.05). In the claims- and EHR-based cohort study, the adjusted hazard ratio (HR) was statistically significant only for sertraline (HR 0.58; 95% CI 0.38-0.88).Conclusion: Suicide reporting rates were disproportionately larger for generic than for brand CNS drugs in FAERS and adjusted retrospective cohort analyses remained significant only for sertraline. However, even for sertraline, temporal confounding related to the close proximity of black box warnings and generic availability is possible. Additional analyses in larger data sources with additional drugs are needed. [ABSTRACT FROM AUTHOR]

Cross-frequency phase-amplitude coupling (PAC) in neuronal oscillations network plays an important functional role in large scale neuronal communication and neuronal encoding. In the present study, a novel approach named permutation mutual information (PMI) was applied in measuring PAC. It is derived from the permutation entropy based on the mutual information theory, by which the mutual information of permutations of two time series can be evaluated. In order to verify the ability of PMI, a numerical test was performed by using both simulation data and experimental data. The performances of PMI were compared with that of two well-known methods, which were the mean vector length (MVL) and the modulation index (MI). It was found that the performance of PMI was similar to that of MI when measuring PAC intensity, but the coupling sensitivity of PMI was the highest among all these three approaches. Moreover, there was the lowest sensitivity in the MVL measurement, suggesting that MVL was a more conservative approach in detecting the existence of PAC. In addition, an ROC analysis showed that PMI performed better in measuring PAC compared to that of others. Furthermore, the experimental data, obtained from rats’ hippocampal CA3 regions, were analyzed by using the three approaches. The result was essentially in line with that of the simulation performances. In a word, the results suggest that PMI is a better choice for assessing PAC under the certain conditions. [ABSTRACT FROM AUTHOR]

A processing strategy involving primary and secondary carbon partitioning is proposed for the hot-rolled quenching and partitioning process through the introduction of proeutectoid ferrite transformation after rolling. The microstructures of the steels were characterized using scanning electron microscopy, transmission electron microscopy, electron probe microanalysis, and x-ray diffraction, and the mechanical properties were evaluated using a universal tensile machine. The blocky retained austenite that distributed along the ferrite grain boundaries was promoted based on the coupling action of the primary and secondary carbon partitioning, which enhanced the transformation-induced plasticity effect during deformation despite the high carbon concentration. A ferrite formation temperature range of ~ 760 to 800 °C was proposed. In addition, from the perspective of industrialization, the observed 'plateau trends' for the retained austenite fraction and product of strength and elongation suggest the availability of a wide processing window of 215-362 °C for controlling the coiling temperature. [ABSTRACT FROM AUTHOR]

Background: The US Food and Drug Administration Adverse Event Reporting System (FAERS), a post-marketing safety database, can be used to differentiate brand versus generic safety signals. Objective: To explore the methods for identifying and analyzing brand versus generic adverse event (AE) reports. Methods: Public release FAERS data from January 2004 to March 2015 were analyzed using alendronate and carbamazepine as examples. Reports were classified as brand, generic, and authorized generic (AG). Disproportionality analyses compared reporting odds ratios (RORs) of selected known labeled serious adverse events stratifying by brand, generic, and AG. The homogeneity of these RORs was compared using the Breslow-Day test. The AG versus generic was the primary focus since the AG is identical to brand but marketed as a generic, therefore minimizing generic perception bias. Sensitivity analyses explored how methodological approach influenced results. Results: Based on 17,521 US event reports involving alendronate and 3733 US event reports involving carbamazepine (immediate and extended release), no consistently significant differences were observed across RORs for the AGs versus generics. Similar results were obtained when comparing reporting patterns over all time and just after generic entry. The most restrictive approach for classifying AE reports yielded smaller report counts but similar results. Conclusion: Differentiation of FAERS reports as brand versus generic requires careful attention to risk of product misclassification, but the relative stability of findings across varying assumptions supports the utility of these approaches for potential signal detection. [ABSTRACT FROM AUTHOR]

An increasing number of studies pays attention to cross-frequency coupling in neuronal oscillations network, as it is considered to play an important role in exchanging and integrating of information. In this study, two generalized algorithms, phase-amplitude coupling-evolution map approach and phase-amplitude coupling-conditional mutual information which have been developed and applied originally in an identical rhythm, are generalized to measure cross-frequency coupling. The effectiveness of quantitatively distinguishing the changes of coupling strength from the measurement of phase-amplitude coupling (PAC) is demonstrated based on simulation data. The data suggest that the generalized algorithms are able to effectively evaluate the strength of PAC, which are consistent with those traditional approaches, such as PAC-PLV and PAC-MI. Experimental data, which are local field potentials obtained from anaesthetized SD rats, have also been analyzed by these two generalized approaches. The data show that the theta-low gamma PAC in the hippocampal CA3-CA1 network is significantly decreased in the glioma group compared to that in the control group. The results, obtained from either simulation data or real experimental signals, are consistent with that of those traditional approaches PAC-MI and PAC-PLV. It may be considered as a proper indicator for the cross frequency coupling in sub-network, such as the hippocampal CA3 and CA1. [ABSTRACT FROM AUTHOR]

Background: To assess the correlations and functions of complement C1r/C1s, Uegf, Bmp1 domain-containing protein-1 (CDCP1) in identifying colorectal cancer (CRC) patients who are at high risk for metastasis. Methods: Tumor specimens from 101 patients were analyzed by real-time polymerase chain reaction to detect CDCP1 expression. CDCP1 expression plasmids and shRNA were used to knock down CDCP1 expression in this study to investigate migratory and invasive abilities by Boyden chambers. The mRNA expression profiles in shCDCP1 transfectants were compared to those in control cells by conducting microarray analysis. Its downstream effectors were also invested in this study. Results: CRC patients with a high CDCP1 expression had a statistically significant lower overall survival and disease-free survival compared to those exhibiting low CDCP1 expression. In vitro, knock-down CDCP1 expression significantly decreased migratory and invasive abilities in HCT116. Aberrant expression of CDCP1 increased cancer cell migration and invasion. By using integrated genomics, we identified ROCK1 (rho-associated, coiled-coil-containing protein kinase 1 pseudogene 1) as a downstream effector in CDCP1-mediated migration and as an invasion mediator. Clinically, ROCK1 and CDCP1 mRNA expression exhibited a strong positive correlation in CRC patient samples. Conclusions: Our results implicated CDCP1 as a key regulator of CRC migration and invasion, and suggest that it is a useful prognostic factor for patients with CRC. Improved identification of a high-risk subset of early metastatic patients may guide indications of individualized treatment in clinical practice. [ABSTRACT FROM AUTHOR]

Objective and design: This study aimed to evaluate the effect of all-trans retinoic acid (atRA) on suppressing the inflammatory response and promoting the osteoblastic differentiation of bone marrow stromal cells (BMSCs) on titanium in a lipopolysaccharide (LPS)-induced microenvironment. Methods: BMSCs were divided into four groups and treated with LPS (1 μg/mL), atRA (1 nmol/L), LPS + atRA, or left untreated. Cells were then cultured on titanium surfaces and cell function compared. BMSC proliferation and osteoblastic differentiation were assessed using the MTT assay, alkaline phosphatase (ALP) activity, alizarin red staining, and quantitative real-time polymerase chain reaction (RT-PCR). Expression levels of inflammatory factors were measured by quantitative RT-PCR and enzyme-linked immunosorbent assay. Results: Increased mineralized nodule formation, ALP activity, osteocalcin, and osteopontin expression levels were detected in LPS + atRA-treated BMSCs after osteogenic induction, when compared with LPS-treated cells. In addition, the high levels of tumor necrosis factor-α, interleukin-1β, and receptor activator of nuclear factor-κ B ligand (RANKL) expression induced by LPS were inhibited after treatment with atRA. Conclusions: Our results showed the effects of atRA on suppressing inflammatory responses and promoting osteoblastic differentiation of BMSCs on titanium in an LPS-induced microenvironment. This indicates the potential therapeutic value of atRA for treating peri-implants inflammatory disease. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to evaluate the effect of early functional loading to plateaued implants on bone formation and implant stability in a dog model. Materials and methods: Early loading (EL), nonloading control, and delayed loading (DL) groups were compared using six beagle dogs under functional loading. The Periotest® values were measured dynamically for 6 weeks. Peri-implant bone architecture was evaluated qualitatively by microcomputed tomography (μCT) and analyzed quantitatively by mineral apposition rates (MAR), bone-to-implant contact (BIC), and bone volumes (BV/TV) after the euthanasia at 3 and 6 weeks after loading. Results: The EL implants showed poor stability at 1 week, but greater stability at 2 and 4 weeks after loading compared to DL implants. There was no significant difference between MAR of EL and unloaded implants at both time intervals. The EL implants displayed a significantly higher MAR when compared to DL implants at 3-5 weeks. A significantly higher BIC for the DL group was observed when compared to the EL group at 3 weeks following loading, however at 6 weeks; no significant difference between these groups was observed. The EL group gained a higher BIC than the no-treatment control group at 6 weeks. Conclusions: For plateaued implant, the decreased healing time (1 week) displays a positive effect on peri-implant bone (re)modeling under functional loading during the early phase. Clinical relevance: The early application of functional loading on plateaued implants can be used clinically to shorten the course of treatment and improve esthetics. [ABSTRACT FROM AUTHOR]

The most common complication for patients with postmenopausal osteoporosis is bone-related defects and fractures. While routine medication has a high probability of undesirable side effects, new approaches have aimed to develop regeneration procedures that stimulate new bone formation while reversing bone loss. Recently, we have synthesized a new hybrid CaP/silk scaffold with a CaP-phase distribution and pore architecture better suited to facilitate cell differentiation and bone formation. The aim of the present study was to compare the involved remodeling process and therapeutic effect of porous CaP/silk composite scaffolds upon local implantation into osteoporotic defects. Wistar rats were used to induce postmenopausal osteoporotic model by bilateral ovariectomy. The pure silk and hybrid CaP/silk scaffolds were implanted into critical sized defects created in distal femoral epiphysis. After 14 and 28 days, the in vivo osteogenetic efficiency was evaluated by μCT analysis, hematoxylin and eosin staining, Safranin O staining, tartrate-resistant acid phosphatase staining, and immunohistochemical assessment. Animals with or without critical-sized defects were used as drill or blank controls, respectively. The osteoporotic defect model was well established with significantly decreased μCT parameters of BV/TV, Tb.N and increased Tb.Sp, porosity, combined with changes in histological observations. During the healing process, the critical-sized drill control defects failed to regenerate appreciable bone tissue, while more significantly increased bone formation and mineralization with dynamic scaffold degradation and decreased osteoclastic bone resorption could be detected within defects with hybrid CaP/silk scaffolds compared to pure silk scaffolds. [ABSTRACT FROM AUTHOR]

This paper presents an integrated and detailed procedure to improve the power management feature implemented in the integrated starter-generator (ISG) parallel hybrid electric vehicle. First, the configuration of the single-shaft ISG hybrid vehicle model established in MATLAB-Simulink environment is given. The vehicle model then is validated by comparing the experimental measurements and the simulation predictions of the traditional vehicle. The baseline rule based control strategy and the optimal control strategy using the dynamic programming (DP) algorithm are introduced. Finally, a suboptimal control strategy which employs the new control rules extracted from the optimal control strategy is designed with the remarkable fuel consumption performance. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the efficacy of fluoride varnish (5% sodium fluoride, Duraphat®, Colgate) in reverting white spot lesions (WSLs) after fixed orthodontic treatment. This study was a randomized, parallel group, controlled clinical trial. Using saline solution as control, 110 participants (mean age ± standard deviation: 16.6 ± 3.2 years) ranging from 12 to 22 years old were randomly assigned to either the test group (group 1) or the control group (group 2). Application of fluoride varnish or saline was applied onto tooth surfaces with WSLs every month during the first 6 months after debonding. The labial (buccal) surfaces of the teeth were assessed by the use of a DIAGNOdent pen (DD) at the baseline, 3- and 6-month follow-up visits. After 6 months, 96 subjects with a total of 209 study teeth (47 subjects, 104 teeth in group 1; 49 subjects, 105 teeth in group 2) remained. The WSLs had a mean DD reading at baseline of 17.66 ± 5.36 in group 1 and 16.19 ± 5.70 in group 2, which decreased by 5.78 and 2.44, respectively, at the 3-month follow-up visit and decreased by 7.56 and 3.09, respectively, at the 6-month follow-up visit. The mean baseline DD readings in the two groups were similar ( t test, P > 0.05). There was statistically significant differences between the mean DD readings of the two groups at the 3-month ( P < 0.05) and at the 6-month follow-up visits ( P < 0.01). Topical fluoride varnish application is effective in reversing WSLs after debonding and should be advocated as a routine caries prevention measure after orthodontic treatment. [ABSTRACT FROM AUTHOR]

The Peptidyl arginine deiminase, type IV ( PADI4) gene has been suggested to have an association with rheumatoid arthritis (RA) in several populations. But its role in Chinese RA is not clarified. We investigated five single-nucleotide polymorphisms (SNPs) of PADI4 as PADI4- 89 (rs11203366), PADI4- 90 (rs11203367), PADI4- 92 (rs874881) PADI4- 94 (rs2240340), and PADI4- 104 (rs1748033) in Chinese Han population. A total of 378 unrelated RA patients and 204 healthy controls were genotyped for the five SNPs. Individual allele, genotype and haplotype frequencies were compared between patients and controls. No significant differences in the frequency of PADI4 alleles, genotypes and haplotypes were observed between the patients and controls except PADI4- 92. These data indicated that PADI4 polymorphisms were unlikely to play an important role in the susceptibility to RA in Chinese Han population. [ABSTRACT FROM AUTHOR]

Handling variable, non-stationary ambient noise is a challenging task for automatic speech recognition (ASR) systems. To address this issue, multi-style, noise condition independent (CI) model training using speech data collected in diverse noise environments, or uncertainty decoding techniques can be used. An alternative approach is to explicitly approximate the continuous trajectory of Gaussian component mean and variance parameters against the varying noise level, for example, using variable parameter hidden Markov model (VPHMM). This paper investigates a more generalized form of variable parameter HMMs (GVP-HMM). In addition to Gaussian component means and variances, it can also provide a more compact trajectory modeling for tied linear transformations. An alternative noise condition dependent (CD) training algorithm is also proposed to handle the bias to training noise condition distribution. Consistent error rate gains were obtained over conventional VP-HMM mean and variance only trajectory modeling on a media vocabulary Mandarin Chinese in-car navigation command recognition task. [ABSTRACT FROM AUTHOR]

Late hematoma or seroma and galactocele caused by augmentation mammaplasty have been reported in patients with silicon breast prostheses but are extremely rare in patients injected with polyacrylamide gel (PAAG). In a retrospective survey, the incidence, clinical manifestations, and management of late hematoma, seroma, and galactocele in 28 of 2,610 patients who underwent breast augmentation with PAAG injection were investigated, and 5 typical cases are presented. The diagnostic and managing methods for this complication have been assessed. The incidence of late hematoma or seroma was 0.65% and that of galactocele was 0.35% among patients with PAAG-injected breast augmentations. The clinical onsets of such late PAAG complications were of two types: rapid enlargement in 17 patients and progressive expansion in another 11 patients. Aspiration, ultrasound, and magnetic resonance imaging (MRI) are useful and sensitive tools for diagnosis. Foreign body reaction, PAAG-related tissue necrosis and fibrosis, and granuloma were shown, and the bacterial cultures in all 12 cases were negative. Needle aspiration with pressure dressing has been advocated as a reliable method for small diseases, and surgical exploration with irrigation-vacuum drainage and evacuation with capsulectomy have been considered more effective for recurrent, large, and long-term cases. In conclusion, these late complications rarely present after large-volume injections of PAAG for breast augmentation. The PAAG-related pathologic inflammatory tissue changes are suggested as the pathogenesis for the complication. Trauma and breastfeeding are considered to be stimulating factors. [ABSTRACT FROM AUTHOR]

In this paper, a facile co-precipitation process for preparing mono-dispersed core-shell structure nanoparticles is reported. The 110 nm SiO cores coated with an yttrium aluminum garnet (YAlO) layer doped with Er were synthesized and the influence of the concentration ratio of [urea]/[metal ions] on the final product was investigated. The structure and morphology of samples were characterized by the X-ray powder diffraction, Fourier transform IR spectroscopy and transmission electron microscopy, respectively. The results indicate that a layer of well-crystallized garnet YAlO:Er were successfully coated on the silica particles with the thickness of 20 nm. The near infrared and upconversion luminescent spectra of the SiO@YAlO:Er powders further confirm that a YAlO:Er coating layer has formed on the surface of silica spherical particles. [ABSTRACT FROM AUTHOR]