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As an armor composite material, the damage mechanism, perforation resistance, damage evaluation and enhancement measures of steel-concrete are crucial to the protective design. In this paper, a modified prediction model of residual velocity and perforation resistance was proposed for the steel-liner-concrete composite target (SLCCT), which considered the fracture energy caused by steel liners and concrete. The numerical models were validated by comparing with previous penetration tests and the modified prediction model. Then LS-DYNA was used to analyze how the layer number (1–5) and rear-steel-liner layout influenced the projectile energy consumption, target damage and integral perforation resistance. The conclusions indicated that, when the reduction coefficient of fracture energy [Formula: see text] was taken as 0.1, the modified prediction model of residual velocity and perforation resistance for SLCCTs was firstly proposed and verified. Noteworthily, with regard to thin segmented SLCCTs (the ratio between layer thickness and projectile diameter was no more than 2.5), the structural perforation resistance was weakened with an increase of the layer number, where the ratio of residual and initial kinetic energy [Formula: see text] for five-layer target was approximately 17.9% higher than that of monolithic slab. Furthermore, as the ratio between layer thickness and projectile diameter was no more than 2, the perforation resistance provided by a rear steel liner was particularly prominent compared with each layer concrete in a SLCCT.

The dynamic response and stability of building structures under accidental loads such as earthquake, explosion, and impact have been focused by experts. The significant influence will be induced once the damaged structure begins to collapse. In this study, a reinforced concrete frame structure model was designed and tested to study the dynamic response law of the structure under the condition of the failure of the middle column of the model structure, the remaining structure successively failed the load-bearing column and continued to be subjected to impact load and uniform load. The analytical method was used to calculate the ultimate uniform load subjecting to the structure under the failure of four load-bearing columns, because its value was less than the load in this test, the structure collapsed. The finite element calculation model was established, and compared the simulation results to the test results to verify its rationality. Then, the influence of the impact energy and the structural stores on the dynamic response of the structure were analyzed. The results showed that the peak value of the dynamic response of the damaged structure did not increase strictly with the increase of the number of failure columns, which may be related to the sequence of failure columns.

Background Venous thromboembolism (VTE) is a serious complication in medically ill inpatients. Enoxaparin or unfractionated heparin (UFH) thromboprophylaxis has been shown to reduce VTE in clinical trials; however, comparative effectiveness and differences in hospital costs are unknown in US hospital practice. Objective This study compared clinical and economic outcomes between enoxaparin and UFH thromboprophylaxis in medically ill inpatients. Methods A retrospective cohort study was conducted using the Premier Healthcare Database between 1 January 2010 and 30 September 2016. Inpatients aged ≥ 18 years with a ≥ 6-day hospital stay for serious medical conditions were included. Two patient groups receiving thromboprophylaxis were identified during hospitalization: one receiving enoxaparin and other receiving UFH. Regression models were constructed to compare VTE events, in-hospital mortality, pulmonary embolism (PE)-related mortality, major bleeding, and total hospital costs during both the index hospitalization and the 90-day readmission period between the two groups. Results A total of 242,474 and 134,384 inpatients received enoxaparin or UFH for thromboprophylaxis, respectively. Compared with UFH prophylaxis, enoxaparin was significantly associated with 15%, 9%, 33%, and 41% reduced odds of VTE, in-hospital mortality, PE-related mortality, and major bleeding, respectively, during index hospitalization, and 10% and 19% reduced odds of VTE and bleeding, respectively, during the readmission period. Mean total hospital costs were significantly lower in patients receiving enoxaparin prophylaxis than in those given UFH. Conclusions Thromboprophylaxis with enoxaparin was associated with significantly reduced in-hospital VTE events, death, and major bleeding and lower hospital costs compared with UFH in hospitalized medically ill patients.

Building on self-determination theory and relational attribution theory, in this study we examined how relationship conflicts with leaders and coworkers simultaneously affect employee voice behaviors. We expanded relational attribution theory by developing two new constructs we labeled leader-relational attribution orientation and coworker-relational attribution orientation to describe employees' different responses to relationship conflicts with leaders and coworkers via psychological needs satisfaction. We surveyed 328 employee–leader dyads who were employed at a semiconductor manufacturer to test our hypotheses. We found that leader-relational attribution orientation can strengthen the influences of relationship conflicts with leaders on psychological needs satisfaction and its indirect effects on employee voice behaviors. Coworker-relational attribution orientation can strengthen the influences of relationship conflicts with coworkers on psychological needs satisfaction and its indirect effects on employee voice behaviors. Theoretical and practical implications are discussed.

Enoxaparin and unfractionated heparin (UFH) are guideline-recommended anticoagulants for patients with acute coronary syndrome (ACS), including unstable angina (UA) and myocardial infarction with (STEMI) or without ST-segment elevation (NSTEMI). Prior efficacy and safety evidence are mainly from clinical trials. Economic data are insufficient. This study examined the differences in utilization, effectiveness, safety, and costs in treating ACS between enoxaparin and UFH monotherapy using real-world data. Using data from 859 US hospitals, inpatients ≥ 18 years of age with a diagnosis of an initial episode of ACS between 2010 and 2016 were identified. Outcomes included 30-day risk of non-fatal myocardial infarction (MI), recurrent angina, in-hospital mortality, composite ischemic complication (having MI/recurrent angina/death), major bleeding, and costs. Multivariable regression was used to compare outcomes between enoxaparin and UFH monotherapy. Among 1,048,053 eligible patients (UA: 219,259; NSTEMI: 582,134; STEMI: 246,660), the prevalence of enoxaparin monotherapy was 12.0%, 13.9%, and 5.1%, and the prevalence of UFH monotherapy was 45.1%, 43.1% and 59.8%, for UA, NSTEMI, and STEMI patients, respectively. Enoxaparin was associated with a lower risk of ischemic complications and death among NSTEMI, but not in UA or STEMI patients, and with a lower risk of major bleeding in all patients. Cost savings per patient during index admission and 30-day follow-up for enoxaparin over UFH was $2972 for UA, $2475 for NSTEMI, and $3050 for STEMI. Enoxaparin was associated with a lower risk of ischemic complications (including death), lower costs, and better safety than UFH among NSTEMI patients. Improving upstream selection of anticoagulants in appropriate populations may help optimize clinical outcomes and costs.

Objective Concerns have been raised about severe acute localized reactions (SALR) following intra-articular (IA) hyaluronic acid (HA) injections for knee osteoarthritis (OA). We compared surrogate SALR measures between hylan G-F 20 and non-hylan G-F 20 HA patients and evaluated corresponding SALR risk factors for hylan G-F 20 patients. Design Knee OA patients were identified from the Optum Clinformatics dataset (January 2006 to June 2016), stratified into hylan G-F 20 and non-hylan G-F 20 HA users. Occurrences of surrogate SALR measures including inflammation/infection, intra-articular corticosteroid (CS) injections, arthrocentesis/aspiration, and office visits were evaluated within 3 days of HA use. Risk factors were evaluated using logistic regression. Results The cohort involved 748,428 HA patients (23.2% in the hylan G-F 20 group). Inflammation/infection rate was 0.001% for hylan G-F 20 and 0.002% for non-hylan G-F 20 HA groups. Risk of CS injection (any diagnosis) was greater for hylan G-F 20 patients by 28% ( P < 0.001). Combined rates of CS injection and arthrocentesis/aspiration (any diagnosis) were comparable for both groups (hylan G-F 20, 2.2%; non-hylan G-F 20 HA, 2.6%). The risk of any visit or studied responses was lower for the hylan G-F 20 cohort by 12% ( P < 0.001). Clinical characteristics, such as CS injections within 1 week before HA and fluoroscopic imaging, were associated with the outcomes. Conclusions The diagnosis of inflammations or infections within 3 days of the HA injection was extremely rare. The overall risk of surrogate SALR measures was similar for hylan G-F 20 and non-hylan G-F 20 HA patients.

LBA661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (Wainberg et al. Eur J Cancer 2021;151:14–24; NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Herein, we present results from NAPOLI-3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel + gemcitabine as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated metastatic PDAC were randomized (1:1) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence or absence of liver metastases. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when ≥ 543 events were observed using a stratified log-rank test with an overall 1-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were well balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. The median OS was 11.1 months in the NALIFIROX arm as compared with 9.2 months in the Gem+NabP arm (HR 0.84 [95% CI 0.71–0.99]; p = 0.04); PFS was also significantly improved (7.4 months vs 5.6 months; HR 0.70 [0.59–0.84]; p = 0.0001). Grade 3/4 treatment-emergent adverse events (TEAEs) with ≥ 10% frequency in patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in treatment-naïve patients with mPDAC. The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components. Funding: Funded by Ipsen. Clinical trial information: NCT04083235 .[Table: see text]

Background Cluster randomised trials (CRTs) are increasingly used to evaluate non-pharmacological interventions for improving child health. Although methodological challenges of CRTs are well documented, the characteristics of school-based CRTs with pupil health outcomes have not been systematically described. Our objective was to describe methodological characteristics of these studies in the United Kingdom (UK). Methods MEDLINE was systematically searched from inception to 30th June 2020. Included studies used the CRT design in schools and measured primary outcomes on pupils. Study characteristics were described using descriptive statistics. Results Of 3138 articles identified, 64 were included. CRTs with pupil health outcomes have been increasingly used in the UK school setting since the earliest included paper was published in 1993; 37 (58%) studies were published after 2010. Of the 44 studies that reported information, 93% included state-funded schools. Thirty six (56%) were exclusively in primary schools and 24 (38%) exclusively in secondary schools. Schools were randomised in 56 studies, classrooms in 6 studies, and year groups in 2 studies. Eighty percent of studies used restricted randomisation to balance cluster-level characteristics between trial arms, but few provided justification for their choice of balancing factors. Interventions covered 11 different health areas; 53 (83%) included components that were necessarily administered to entire clusters. The median (interquartile range) number of clusters and pupils recruited was 31.5 (21 to 50) and 1308 (604 to 3201), respectively. In half the studies, at least one cluster dropped out. Only 26 (41%) studies reported the intra-cluster correlation coefficient (ICC) of the primary outcome from the analysis; this was often markedly different to the assumed ICC in the sample size calculation. The median (range) ICC for school clusters was 0.028 (0.0005 to 0.21). Conclusions The increasing pool of school-based CRTs examining pupil health outcomes provides methodological knowledge and highlights design challenges. Data from these studies should be used to identify the best school-level characteristics for balancing the randomisation. Better information on the ICC of pupil health outcomes is required to aid the planning of future CRTs. Improved reporting of the recruitment process will help to identify barriers to obtaining representative samples of schools.

IntroductionCluster randomised trials (CRTs) are studies in which groups (clusters) of participants rather than the individuals themselves are randomised to trial arms. CRTs are becoming increasingly relevant for evaluating interventions delivered in school settings for improving the health of children. Schools are a convenient setting for health interventions targeted at children and the CRT design respects the clustered structure in schools (ie, pupils within classrooms/teachers within schools). Some of the methodological challenges of CRTs, such as ethical considerations for enrolment of children into trials and how best to handle the analysis of data from participants (pupils) that change clusters (schools), may be more salient for the school setting. A better understanding of the characteristics and methodological considerations of school-based CRTs of health interventions would inform the design of future similar studies. To our knowledge, this is the only systematic review to focus specifically on the characteristics and methodological practices of CRTs delivered in schools to evaluate interventions for improving health outcomes in pupils in the UK.Methods and analysisWe will search for CRTs published from inception to 30 June 2020 inclusively indexed in MEDLINE (Ovid). We will identify relevant articles through title and abstract screening, and subsequent full-text screening for eligibility against predefined inclusion criteria. Disagreements will be resolved through discussion. Two independent reviewers will extract data for each study using a prepiloted data extraction form. Findings will be summarised using descriptive statistics and graphs.Ethics and disseminationThis methodological systematic review does not require ethical approval as only secondary data extracted from papers will be analysed and the data are not linked to individual participants. After completion of the systematic review, the data will be analysed, and the findings disseminated through peer-reviewed publications and scientific meetings.PROSPERO registration numberCRD42020201792.

To study the vibration response of the layered medium under impact loading, single-layer concrete slabs, multilayer concrete slabs, and multilayer concrete slabs with a cemented filling layer were used as the working media to simulate the layered medium. A large number of impact loading tests were carried out by using a simple drop hammer device designed by us. The experimental results indicate that, under the impact load, the vibration response of the surface of the medium decreases with the increase in the distance to the impact source, showing the law of fast attenuation near field and slow attenuation far field, and the vibration energy moves to the low-frequency component; the vibration response increases with the increase in the impact energy, and the difference in the vibration response caused by the impact energy decreases as the distance increases; the vibration response is negatively correlated with the thickness of the dielectric layer, and the divergence of vibration response caused by impact energy decreases with the increase in the thickness of the dielectric layer. Due to the existence of the free surface and bedding, the vibration response of the layered medium surface increases with the increase in the number of layers and the vibration velocity response increases with the increase in the distance to the impact source when it is close to the free surface and far from the vibration source. For the filling of the cemented layer, the vibration response of the layered concrete slab becomes more complex under impact loading, showing obvious disorder. At the same time, this paper also used the dimensional analysis method to establish the calculation model of the peak response of vibration velocity of layered media under the impact load, which provided an idea for determining the peak response of vibration velocity of the layered media.

The COVID-19 pandemic has spawned a rare opportunity to study some latent social structures using data science. The Chinese government and its people have been blamed for the outbreak of the virus. Face mask wearing can signal an embodied stigma and Chinese people living outside China have been subject to discrimination, assault, and other hate crimes, particularly at the early stages of the crisis. However, as we accumulate more evidence surrounding mask use, the stigma is shifting. As more scientific data become available and people leave even more information on social media during the lockdown, data science can help better understand the trajectories of the stigma. The insights generated have implications for anti-stigma interventions for future undesirable conditions and diseases.

The use of large-scale Randomised Controlled Trials (RCTs) is fast becoming "the gold standard" of testing the causal effects of policy, social, and educational interventions. RCTs are typically evaluated — and ultimately judged — by the economic, educational, and statistical significance of the Average Treatment Effect (ATE) in the study sample. However, many interventions have heterogeneous treatment effects across different individuals, not captured by the ATE. One way to identify heterogeneous treatment effects is to conduct subgroup analyses, such as focusing on low-income Free School Meal pupils as required for projects funded by the Education Endowment Foundation (EEF) in England. These subgroup analyses, as we demonstrate in 48 EEF-funded RCTs involving over 200,000 students, are usually not standardised across studies and offer flexible degrees of freedom to researchers, potentially leading to mixed results. Here, we develop and deploy a machine-learning and regression-based framework for systematic estimation of Individualised Treatment Effect (ITE), which can show where a seemingly ineffective and uninformative intervention worked, for whom, and by how much. Our findings have implications for decision-makers in education, public health, and medical trials.

Supplemental material, Supplementary_Table_S1_1 for Severe Acute Localized Reactions Following Intra-Articular Hyaluronic Acid Injections in Knee Osteoarthritis by Kevin L. Ong, Maria Runa, Zhimin Xiao, Wilson Ngai, Edmund Lau and Roy D. Altman in CARTILAGE

The mechanical behaviors of granular materials have high complexity. Since the mechanical behaviors of granular materials are difficult to describe theoretically, in this paper, the flow and fracture characteristics of granular materials were discussed by the experimental method. An experimental method was firstly proposed to identify the mechanical behaviors of granular materials under extra loading. An experimental device, which can be used to monitor force and displacement between particles, was invented. The uniaxial compression experiments of granular particles with different materials and grades were carried out, and the overall and local force between particles was obtained and investigated. Due to the flow of particles, the overall force rises in a fluctuating manner and the local force is not distributed evenly. Then, the particle fragments were sieved layer by layer. It was confirmed that the particles and loading strength have great influences on fractures of granular materials.

Lord's Paradox occurs when a continuous covariate is statistically controlled for and the relationship between a continuous outcome and group status indicator changes in both magnitude and direction. This phenomenon poses a challenge to the notion of evidence-based policy, where data are supposed to be self-evident. We examined 50 effect size estimates from 34 large-scale educational interventions and found that impact estimates are affected in magnitude, with or without reversal in sign, when there is substantial baseline imbalance. We also demonstrated that multilevel modeling can ameliorate the divergence in sign and/or magnitude of effect estimation, which, together with project specific knowledge, promises to help those who are presented with conflicting or confusing evidence in decision-making.

We report the first successful field trial of up to 3 Tb/s real-time DP-16 QAM optical superchannel transport over 359-km EDFA-amplified fully managed flexible grid optical infrastructure using production grade hardware and management software from a live network operation center. The spectrum of the flexible grid ROADM was configured according to the requirement of the optical superchannel from a minimum of 37.5 up to 400 GHz with a resolution of 12.5 GHz. Spectral windows larger than 400 GHz were achieved by configuring multiple adjacent spectral slots enabling higher superchannel capacities. The optical superchannels of up to 3 Tb/s propagated alongside standard 50-GHz grid wavelength channels at 100 Gb/s. Stable error-free performance was measured for all sub-channel spacings down to 33.5 GHz, where a record net spectral efficiency of 5.97 b/s/Hz was achieved, an improvement of 49.25% over standard 50 GHz grid. We also show results on optical margin requirements when operating across a range of sub-channel spacings corresponding to different spectral efficiencies. Furthermore, a key technology building block for the 3-Tb/s optical superchannel, 200 G DP-16 QAM was trialed in a live WDM network to evaluate and demonstrate its applicability for deployment.

In blasting operation, some undesirable impacts, such as fly-rock, fragmentation, and back break, are induced. If the blasting design is not optimized, these mentioned impacts would reduce the blasting efficiency. To improve and optimize the blast design, blasting effect evaluation is essential. Due to the complexity of interactions among blasting parameters, empirical methods may not be appropriate for blast design optimization. A two-level mathematical model based on fuzzy mathematics, is proposed in this work. In total, 11 typical parameters were chosen and classified into three groups. The blasting effect is evaluated from three aspects, and then the comprehensive evaluation is given. A blasting effect evaluation system was developed based on the mentioned method on the platform of VC++. Some other techniques, such as image processing, were integrated into the system, which allowed for obtaining all of the parameters rapidly and conveniently. The system was applied in practical bench blast engineering. The results obtained from the system can provide effective information for the optimization of the next blast design.

Excessive accumulation of amyloid-β (Aβ) caused by cleavage of amyloid precursor protein (APP) is thought to be the primary cause of Alzheimer's disease (AD). Two key enzymes ADAM10 and BACE1 are involved in the initial cleavage of APP, resulting in the onset of two pathways, the amyloidogenic pathway and the non-amyloidogenic pathway, respectively. Altering APP metabolism towards the non-amyloidogenic pathway is thought to reduce Aβ production. It has been reported that, in vivo, exogenous neurotrophic factors make APP apt to entering the non-amyloidogenic pathway. Since astrocytes secrete a battery of neurotrophic factors, we investigated the role of astrocyte-derived factors in the dynamics of Aβ generation in neural cells. Results show that C6 glioma cell-conditioned medium (GCM), obtained from cultured astrocyte-derived C6 glioma cells, inhibit Aβ1-42 production and shift APP processing towards the non-amyloidogenic pathway in APPswe-HEK293 cells. Such effect is attributed to two key APP cleavage enzymes, ADAM10 and BACE1. Two neurotrophic factors in the GCM, nerve growth factor and fibroblast growth factor 2, are responsible for the up-regulation of ADAM10 and down-regulation of BACE1, respectively. Our findings enhance our understanding of the relationship between astrocytes and Aβ generation, indicating that stimulation of astrocytic neurotrophic factors could slow AD progression.

Estrogenic compounds have been shown to have great potential for the treatment of Alzheimer's disease as demonstrated by its ability to antagonize amyloid beta peptide (Aβ) induced toxicity, the hallmark of Alzheimer's disease. Key mechanisms include the involvements of both the antioxidant and the anti-apoptotic pathways. However, side effects of estrogens, such as the increased incidence of breast cancer, are of concern for further clinical translation. Approaches to overcome such barriers include the structural modification of estrogenic compounds and the search of phytoestrogens, but these are a long way from being translated into the clinic. We identified a compound similar in structure to human estrogen–ipriflavone, an over-the-counter product marketed in the United States for the treatment of osteoporosis, efficiently antagonized Aβ induced toxicity. Use of a model with SH-SY5Y neural cells, we first demonstrated that ipriflavone potently alleviated H2O2 induced cell death, reduced H2O2 induced elevations of both reactive oxygen species level and apoptosis. We extended our exploration of ipriflavone to Aβ and observed similar effects. These protective effects were comparable to those produced by 17β-estradiol at similar concentrations. Caspase-3 inhibition, PI3K and MAPK activation were shown to be responsible for such antagonism of ipriflavone on Aβ. Our results suggest that ipriflavone, a previously characterized compound, has great potential for expedited clinical translation for the treatment of Alzheimer's disease.

A novel optical superchannel protection scheme is proposed and successfully demonstrated over field fiber links for 400G capacity using main 400G DP-16QAM and protection 400G DP-QPSK superchannels together with in-service OTDR fault localization.

Post-translational modifications (PTMs) of nuclear proteins play essential roles in the regulation of gene transcription and signal transduction pathways. Numerous studies have demonstrated a correlation between specific nuclear protein isoforms and cellular malignant process. This communication reviews the impact of major PTM events such as phosphorylation, acetylation, methylation, ubiquitination, and sumoylation on several important nuclear proteins including p53, histones, proliferating cellular nuclear antigen (PCNA), and retinoblastoma protein (Rb) in the process. In addition, the implications of the PTMs as cancer biomarkers and therapeutic targets are considered.

Since the advent of agriculture, more than one-fourth of Earth's land surface has been converted for agricultural purposes, which conversion from natural to agricultural landscapes dramatically changes the plant communities that are integral to ecosystem processes. By developing perennial crops through breeding would help deal with the multiple issues involving environmental conservation and food security in a world of shrinking resources. It can provide multiple ecosystem services essential for sustainable production more effectively than production systems based on annual crops, such as protecting against soil erosion, conserving water and nutrients, storing more carbon below ground, and building better pest tolerance. This paper presents advantages of perennial crop system in ecological benefits, introduces the important role of perennial crop at the development of sustainable agriculture, and prospects the significant utilization and potential of perennial crop on sustainability of agriculture and environment.

Postmenopausal estrogen depletion is a characterized risk factor for Alzheimer disease (AD), a human disorder linked to high levels of beta-amyloid peptide (Abeta) in brain tissue. Previous studies suggest that estrogen negatively regulates the level of Abeta in the brain, but the molecular mechanism is unknown. Here, we provide evidence that estrogen promotes Abeta degradation mainly through a principal Abeta degrading enzyme, neprilysin, in neuroblastoma SH-SY5Y cells. We also demonstrate that up-regulation of neprilysin by estrogen is dependent on both estrogen receptor alpha and beta (ERalpha and ERbeta), and ligand-activated ER regulates expression of neprilysin through physical interactions between ER and estrogen response elements (EREs) identified in the neprilysin gene. These results were confirmed by in vitro gel shift and in vivo chromatin immunoprecipitation analyses, which demonstrate specific binding of ERalpha and ERbeta to two putative EREs in the neprilysin gene. The EREs also enhance ERalpha- and ERbeta-dependent reporter gene expression in a yeast model system. Therefore, the study described here provides a putative mechanism by which estrogen positively regulates expression of neprilysin to promote degradation of Abeta, reducing risk for AD. These results may lead to novel approaches to prevent or treat AD.

According to the appeared incident dynamic pressure of 1304 working face in a mine, the characteristics of electromagnetic emission signal were analyzed before the dynamic pressure occurred; FLAC3D was used to simulate the impact on pressure relief effect under the conditions of different borehole diameter, space and depths. The results showed that: electromagnetic emission intensity and pulse signals continual increase could be a symbol of shock hazard; the larger the borehole diameter, the smaller the borehole space, the greater the depth of the borehole, and the better relief; borehole depth must exceed a certain range of stress concentration area, otherwise pressure relief effect was not obvious, and even increased the possibility of shock hazard. Based on the above findings, rock burst local prevention and control integration technology of “electromagnetic emission forecasting technology → drilling to determine the range of the risk → large-diameter borehole pressure relief technology → effects checking through electromagnetic emission” which was applied successfully was established.

Estrogenic compounds have been shown to have great potential for the treatment of Alzheimer's disease as demonstrated by its ability to antagonize amyloid beta peptide (Aβ) induced toxicity, the hallmark of Alzheimer's disease. Key mechanisms include the involvements of both the antioxidant and the anti-apoptotic pathways. However, side effects of estrogens, such as the increased incidence of breast cancer, are of concern for further clinical translation. Approaches to overcome such barriers include the structural modification of estrogenic compounds and the search of phytoestrogens, but these are a long way from being translated into the clinic. We identified a compound similar in structure to human estrogen-ipriflavone, an over-the-counter product marketed in the United States for the treatment of osteoporosis, efficiently antagonized Aβ induced toxicity. Use of a model with SH-SY5Y neural cells, we first demonstrated that ipriflavone potently alleviated H2O2 induced cell death, reduced H2O2 induced elevations of both reactive oxygen species level and apoptosis. We extended our exploration of ipriflavone to Aβ and observed similar effects. These protective effects were comparable to those produced by 17β-estradiol at similar concentrations. Caspase-3 inhibition, PI3K and MAPK activation were shown to be responsible for such antagonism of ipriflavone on Aβ. Our results suggest that ipriflavone, a previously characterized compound, has great potential for expedited clinical translation for the treatment of Alzheimer's disease.

Our previous data showed that neprilysin (NEP), a zinc metalloendopeptidase, which can degrade amyloid-beta peptide (Abeta) whose central nerve system accumulation is the primary cause of Alzheimer's disease (AD), responds to estrogen in the brain. Recently, it has been shown that the transcription of the neprilysin gene can be up regulated by progesterone, androgens, and glucocorticoids through two androgen response elements within the NEP gene--an androgen response region (ARR) and an androgen response element (ARE). Through a yeast report gene system, we now find that the ARR but not the ARE respond to estrogen. However, androgen could efficiently enhance the expression of the report gene mainly through ARE. Our results indicate that the decrease of NEP, caused by the decline of estrogen or androgen with aging, may be an important factor leading to Abeta accumulation and AD.