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Background: Mitral annular calcification has been associated with various systemic and cardiac diseases, with a higher prevalence in women and patients over 70. A possible association between mitral annular calcification [...]

The compressive behavior under uniaxial strain of Colorado Mason sand, that contains primarily silica sand, at high strain rates was investigated on a 24.4-meter-long split Hopkinson pressure bar. A hardened carbon steel tube was used to provide passive confinement for the sand, along with two tungsten carbide rods capped at both ends for compression. To attain a desired bulk mass density for sand, the assembly was shaken in different directions randomly to consolidate the sand, and it was subsequently placed between the incident and transmission bars for dynamic compression. To determine the triaxial volumetric and deviatoric behavior, both unsorted dry sand and partially saturated sand specimens were compressed at high strain rates. The axial and circumferential responses of the cylindrical sand specimen were measured under stiff passive confinement. The effect of initial mass density was investigated, and the stress–strain relationships were also evaluated to determine whether a power-law relationship with mass density was followed. The effect of water content on the constitutive behavior was investigated, as well as the compressibility and energy absorption density as a function of the applied axial stress. For both intact and impacted sand, a Weibull distribution function was found appropriate to describe the sand size distribution. Further sand size distribution was analyzed for the three types of sand grains. The internal structures and fragments of sand were observed by X-ray micro-computed tomography, and the fracture/crushing mechanism was identified for the three types of sand grains. The experimentally-observed constitutive behavior of sand can be analyzed further in the future for constitutive modeling and mesoscale/macroscale simulations under high strain rate loading.

Previous observational studies suggest that the surface time‐varying magnetic field of Mars originates in large part from the dynamo currents in the Martian ionosphere. However, whether there are significant differences in the strength, configuration, diurnal, and seasonal variations of the dynamo currents above different regions need to be further studied. In this study, using the ionospheric parameters from Mars Climate Database version 5.3 (MCD v5.3) and 7 years of MAVEN magnetic field measurements, we compare the ionospheric dynamo currents above the landing sites of InSight (4.50°N, 135.62°E) and Zhurong (25.07°N, 109.90°E) and the resulting surface magnetic variations at the two landing sites by conducting a modeling study. We find that the average dynamo current as well as its diurnal magnetic field amplitude on the Martian surface is significantly stronger at InSight than that at Zhurong due to the stronger background magnetic field strength and more perpendicular angle between magnetic field and neutral wind vectors in the dynamo region, though the conductivities is always weaker over InSight landing site. The seasonal variation of the current intensity (represented by differences between northern winter and summer solstices) is prominent over InSight than that over Zhurong because the heliospheric distance effect‐resulted conductivity difference is the dominate factor for the seasonal variations over InSight while both the heliospheric distance and solar zenith angle (SZA) contribute to the current intensity at different Ls over Zhurong. The two factors partially offset each other and lead to a smaller seasonal variation. The role of crustal field, as well as the latitude effects on dynamo currents is also discussed. This study provides an attempt to promote the understanding of the solar wind‐induced magnetosphere‐ionosphere‐surface coupling process. Ionospheric dynamo current is the result of the coupling between solar wind‐magnetosphere‐ionosphere‐atmosphere, and is one of the important sources of the time‐varying magnetic field on the surface of the terrestrial planets such as Earth and Mars. Earth's ionospheric dynamo current, also known as Sq current, exhibits longitudinal, latitudinal, local time, and seasonal variations based on magnetic field measurements from large amount of the geomagnetic observatories and satellites. Unlike the Earth, InSight and Zhurong are the only two lander/rover, which can measure the surface magnetic field and reflect the Martian ionospheric dynamo current. It is suggestive to compare the differences of the dynamo currents and the resulting surface magnetic field at the two landing sites. Unfortunately, due to the limited exploration duration at each location (∼40 min), it is difficult to determine an accurate external magnetic field on the Martian surface from Zhurong magnetometer. Wind‐driven dynamo current modeling is a powerful tool to investigate the difference in the dynamo current and surface magnetic field at the two landing sites. This study comprehensively investigates and compares the dynamo current intensities and seasonal variations, and the reasons for the differences between InSight and Zhurong landing sites. We compare the Martian ionospheric dynamo current over InSight and Zhurong landing sites through modelingThe current and surface field are significantly stronger over InSight due to strong |B| and more perpendicular B‐V angleWeaker seasonal variation appears at Zhurong due to offset between the heliospheric distance and solar zenith angle at solstices We compare the Martian ionospheric dynamo current over InSight and Zhurong landing sites through modeling The current and surface field are significantly stronger over InSight due to strong |B| and more perpendicular B‐V angle Weaker seasonal variation appears at Zhurong due to offset between the heliospheric distance and solar zenith angle at solstices

Introduction: Ability to access needed dental care may vary among population subgroups. We assessed 1) the differences in the proportions of adults who reported unmet dental care needs in the past 12 months and the associated barriers (structural, financial, and cognitive) in 2015 to 2016 versus 2003 to 2004 by race/ethnicity and 2) the subgroups that are more likely to report unmet dental care needs.Methods: Data of 10,029 respondents aged ≥19 y from the 2003–2004 and 2015–2016 National Health and Nutrition Examination Surveys were used. Chi-square tests assessed the differences in the proportions of adults who reported not getting the needed dental care between the periods. A multiple logistic regression model was run to identify characteristics that were significantly associated with unmet need after adjusting for other factors.Results: Overall, 19.4% of the adults reported an unmet dental care need in 2015 to 2016, as compared with 21% in 2003 to 2004. The overall unmet dental care need decreased only in the Hispanic groups (34% to 28%, P= 0.045) between 2003–2004 and 2015–2016. Between the periods, unmet need decreased among Hispanics aged 19 to 64 y (35% to 28%, P= 0.02), Hispanics with some college education or above (33.5% to 21.0%, P= 0.008), and nonpoor Hispanic adults (29.8% to 20.4%, P= 0.048). No significant differences were observed in the proportions of adults reporting structural (P= 0.09), financial (P= 0.86), or cognitive (P= 0.07) barriers between the periods. When compared with their counterparts, nonelderly adults, women, Hispanics, adults with a high school education, those with less than a high school education, and poor adults were significantly more likely to report unmet dental care needs.Conclusions: Racial and ethnic disparities in accessing and receiving the needed dental care still exist. Financial barriers to dental care are the most commonly cited reasons for not getting the needed dental care.Knowledge Transfer Statement: The results of the study will inform policy makers, public health planners, and dental professionals about subgroups that still face difficulty in receiving the dental care they need. Policy makers should develop new policies to mitigate the financial barriers that are still prevalent. Dental professionals can mitigate the public’s cognitive and financial barriers by educating the community through outreach programs and by providing services to low-income populations at reduced charges or through alternative payment plans.

Objective: To investigate the association of complement C4 null genes (C4Q0, including C4AQ0 and C4BQ0) and C2 gene with systemic lupus erythematosus (SLE) in southwest Han Chinese; 136 patients with [...]

Purpose: Papillary thyroid microcarcinoma (PTMC) frequently presents a favorable clinical outcome, while aggressive invasiveness can also be found in some of this population. Identifying the risk clinical factors of high-volume (> 5) central lymph node metastasis (CLNM) in PTMC patients could help oncologists make a better-individualized clinical decision. Methods: We retrospectively reviewed the clinical characteristics of adult patients with PTC in the Surveillance, Epidemiology, and End Results (SEER) database between Jan 2010 and Dec 2015 and in one medical center affiliated to Chongqing Medical University between Jan 2018 and Oct 2020. Univariate and multivariate logistic regression analyses were used to determine the risk factors for high volume of CLNM in PTMC patients. Results: The male gender (OR = 2.02, 95% CI 1.46–2.81), larger tumor size (> 5 mm, OR = 1.64, 95% CI 1.13–2.38), multifocality (OR = 1.87, 95% CI 1.40–2.51), and extrathyroidal invasion (OR = 3.67; 95% CI 2.64–5.10) were independent risk factors in promoting high-volume of CLNM in PTMC patients. By contrast, elderly age (≥ 55 years) at diagnosis (OR = 0.57, 95% CI 0.40–0.81) and PTMC-follicular variate (OR = 0.60, 95% CI 0.42–0.87) were determined as the protective factors. Based on these indicators, a nomogram was further constructed with a good concordance index (C-index) of 0.702, supported by an external validating cohort with a promising C-index of 0.811. Conclusion: A nomogram was successfully established and validated with six clinical indicators. This model could help surgeons to make a better-individualized clinical decision on the management of PTMC patients, especially in terms of whether prophylactic central lymph node dissection and postoperative radiotherapy should be warranted.

Tension cracks were generated by past megathrust earthquakes along the coastal forearc of Chile‐Peru. To explain why elastic rebound in an offshore earthquake can cause widespread permanent deformation onshore, we propose a model in which the near‐surface material exhibits viscoelastic behavior, analogous to laboratory‐observed behavior of petroleum reservoir rocks. Because of near‐surface relaxation, interseismic deformation builds up stress only in the deeper crust. Elastic rebound of the deeper crust during an earthquake induces near‐surface tension to generate cracks. We numerically demonstrate the proposed mechanism using hypothetical and real megathrust earthquakes. The location of the zone of peak tension, assumed to be responsible for the crack generation, is controlled by downdip rupture termination. A rupture farther downdip or terminating more gradually causes the zone of peak tension to be farther landward and broader. The tension cracks thus may contain important information on megathrust rupture dynamics. Earthquakes are the operation of elastic rebound. Tension cracks induced by megathrust earthquakes observed in Chile‐Peru therefore require special explanation. In this work, we propose a testable model for these cracks. We propose that the cemented soil and the highly fractured shallow bedrock in this area exhibit a viscoelastic behavior analogous to petroleum reservoir rocks. When the megathrust is locked in preparation for the next earthquake, the deeper crust is elastically shortened like a spring, but the shallow material deforms in a viscous fashion and do not store energy. During the megathrust earthquake, elastic rebound of the deeper crust induces tension in the shallow material, causing it to crack. If we assume that the observed crack distribution is controlled by the peak tension during the earthquake, it can be used to constrain how the megathrust rupture terminates in the deep end, which helps to understand the physics of earthquakes. Viscoelastic relaxation of near‐surface material allows permanent interseismic shortening contemporaneous with deeper elastic deformationElastic rebound of deeper crust in earthquakes induces tension in the relaxed shallow material, explaining cracks in Chile‐Peru forearcCrack distribution, assumed to be controlled by peak coseismic tension, contains important information on megathrust rupture termination

The time changes of permittivity, damping and velocity of sound are studied for PbFe0.5Nb0.5O3and PbFe0.5Nb0.5O3–7PbTiO3single crystals in the electric fields of 0 < E< 6 kV/cm. The room-temperature local symmetry of these compounds is shown to be rather more monoclinic than rhombohedral, which is typical of other similar systems. No abrupt sound attenuation anomalies are observed upon the phase transition into the ferroelectric phase in the electric field. The effects seem to be far from the crystal symmetry changes and are attributed to the gradual transition of near-range monoclinic domains into long-range monoclinic domains, as well as to the emergence of the ferroelectric phase. The polarized phase induced in the electric field is only partially stable.

ABSTRACTNi–B/SiC composite coatings were electrodeposited using trimethylamine borane as a boron source. The effects of bath composition and operating parameters on the microstructure and properties of the composite coatings were investigated. The results show that Ni–B/SiC composite coating exhibits uniform structure with a desirable interface. Incorporation of SiC particles led to a significant increase in hardness. Both boron and SiC content in the coating increases initially and then decreases as the current density increased. Incorporation of inert SiC particles also enhanced their corrosion resistance, which attributed to the dense structure, barrier effect and the reduction in the active surface area of Ni–B matrix. XPS analysis indicated that the as-deposited coating contains metallic nickel, oxide or hydroxide nickel, and the SiC particles. Owing to dispersion hardening of the added SiC particles and the reduction in the active surface area of Ni–B matrix, Ni–B/SiC composite coating shows superior anti-corrosion and wear resistance.

Correlating electromechanical and dielectric properties with nanometre-scale order is the defining challenge for the development of piezoelectric oxides. Current lead (Pb)-based relaxor ferroelectrics can serve as model systems with which to unravel these correlations, but the nature of the local order and its relation to material properties remains controversial. Here we employ recent advances in diffuse scattering instrumentation to investigate crystals that span the phase diagram of PbMg1/3Nb2/3O3-xPbTiO3(PMN-xPT) and identify four forms of local order. From the compositional dependence, we resolve the coupling of each form to the dielectric and electromechanical properties observed. We show that relaxor behaviour does not correlate simply with ferroic diffuse scattering; instead, it results from a competition between local antiferroelectric correlations, seeded by chemical short-range order, and local ferroic order. The ferroic diffuse scattering is strongest where piezoelectricity is maximal and displays previously unrecognized modulations caused by anion displacements. Our observations provide new guidelines for evaluating displacive models and hence the piezoelectric properties of environmentally friendly next-generation materials. How local order affects the excellent piezoelectric properties of Pb-based relaxor ferroelectrics is unclear, but neutron diffuse scattering shows that non-relaxor distortions are implicated, indicating the important role of oxygen atoms.

ABSTRACTIn this study, a low-temperature salt bath nitrocarburising method was used to modify the surface of AISI 316 stainless steel. The results showed that nitrogen and carbon atoms were coinstantaneously diffused into the austenite lattice during the nitrocarburising treatment. A supersaturated solid solution with nitrogen and carbon atoms, which has a face centre tetragonal structure, was formed. Moreover, the surface hardness of salt bath nitrocarburised AISI 316 reached 900 HV0.05which was four times the hardness of the untreated sample. By adjusting treating time and treating temperature, both the surface hardness and the corrosion resistance of the stainless steel were enhanced. Overall, a nitrocarburised layer having the advantages of high hardness, favourable hardness gradient and excellent corrosion resistance was obtained on AISI 316 stainless steel surface by using low-temperature salt bath nitrocarburising.

Background: Hesperetin, a natural component of citrus fruits, is indicated to have beneficial anti-inflammatory effects on injury and various cancers as a transforming growth factor beta (TGF-β) inhibitor. However, little evidence associates hesperetin with liver fibrosis. Objective: Work from our laboratory aims at finding the mechanism by which hesperetin attenuates liver fibrosis. Methods: Bile duct ligation (BDL) was used to induce liver fibrosis in mice and the findings were determined using enzyme-linked immunosorbent assay, quantitative realtime polymerase chain reaction, western blotting and immunohistochemical staining. Results: Data from Immunohistochemical staining and injury score indicated that pathological lesions were reduced by hesperetin treatment. Decreasing levels of several serum parameters including cytokines tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), liver enzyme alanine aminotransferase (ALT) and aspartate aminotransferase (AST), fibrosis indicators laminin (LN), hyaluronic acid (HA) and hydroxylproline (Hyp) suggested similar results to the immunohistochemical. In addition, our data verified hesperetin could suppress the formation of extracellular matrix and hepatocyte apoptosis in vitro, together with promoting hepatic stellate cell death in vivo, which was considered to be associated with the inhibition of TGF-β1/Smad pathways. Conclusion: In the present study, the favorable role of hesperetin extracted from citrus peels was verified to prevent the progression of BDL-induced liver fibrosis via inhibiting TGF-β1/Smad pathway-mediated extracellular matrix progression and apoptosis.

This paper presents the research on the closed-loop data-driven design of the process monitoring system. The core of the study is the closed-loop identification of the data-driven stable kernel representation (SKR) of the system. The proposed method takes into account the effects of feedback controller and the noise information in the closed-loop is directly extracted from a single LQ decomposition. The main results and the proposed methods are verified and demonstrated through randomly generated numerical examples.

Increasing evidence indicates that long noncoding RNAs (lncRNAs) have important roles in various physiological processes and dysfunction of lncRNAs could be a prevalent cause in human diseases. Here we functionally characterized the nuclear-enriched lncRNA SNHG1, which is highly expressed in multiple types of cancer. We also provide evidence that SNHG1promotes cancer cell growth by regulating gene expression both in cisand in trans. SNHG1was involved in the AKT signaling pathway as it promotes the neighboring transcription of the protein-coding gene SLC3A2in cisby binding the Mediator complex to facilitate the establishment of enhancer–promoter interaction. In trans, SNHG1directly interacted with central domain of FUBP1 and antagonize the binding of FBP-interacting repressor to FUBP1, thereby coordinating the expression of the oncogene MYC. Collectively, our findings demonstrate that lncRNA SNHG1can function both in cisand in transwith distinct mechanisms to regulate transcription, promoting tumorigenesis and cancer progression.

Clindamycin causes cutaneous adverse drug reactions (cADRs), sometimes with the mechanisms of pathogenicity or risk factors unknown. This study aims to assess whether HLA alleles are associated with clindamycin-related cADRs in the Han Chinese population. We performed an association study of 12 subjects with clindamycin-related cADRs, 279 controls and 26 clindamycin-tolerant subjects. Subjects who received clindamycin through intravenous drip were analyzed separately. Unbiased, in silicodocking was conducted. We found 6 out of 12 clindamycin-induced cADR patients carried HLA-B*51:01, and all of them received clindamycin via intravenous drip (6/9). The carrier frequency of HLA-B*51:01is significantly higher compared with the control group (P=0.0006; OR=9.731, 95% CI: 2.927–32.353) and the clindamycin-tolerant group (OR=24.000, 95% CI: 3.247–177.405). In silicodocking showed clindamycin is potentially more stable inside HLA-B*51:01 protein. Our results suggested, for the first time, that HLA-B*51:01is a risk allele for clindamycin-related cADRs in Han Chinese, especially when clindamycin is administered via intravenous drip.

(J Clin Anesth. 2021;72:110270)Contrary to conventional wisdom, previous studies have established the similarity of the gastric volume (GV) of women with full-term pregnancies to that of nonpregnant women. This finding is relevant to assessing the risk threshold for receiving anesthesia based on preoperative ultrasound determination of the quantity of gastric contents. Cut-off values for measurements of the antral cross-sectional area (CSA) indicate reliably if the stomach contents are too great for safe anesthesia administration. Incidence of advanced maternal age (AMA) pregnancy is also increasing, and with it the caseload of elective cesarean deliveries (CD) in the world-wide AMA population. Although it is not fully understood why, AMA pregnant women have lower GV than their younger counterparts. Further investigation is merited to assess the necessity of longer preoperative fasting times in AMA women undergoing CD. This study compares GV in nonpregnant women to women with AMA pregnancy to determine if there is elevated risk of aspiration as assessed by gastric ultrasound.

In this paper, with the help of the Youla parameterization, the realizations of feedback control systems are discussed which results in a preferable and more convenient way to realize plug-and-play (PnP) control without modifying pre-designed control systems. Furthermore, based on the equivalence of different realizations of the Youla parameterization, a link between the standard feedback and the observer-based state feedback control system is given so that the well developed observer-based control techniques, like LQG/H2control etc., can be achieved in the standard feedback control system via PnP control design. The effectiveness of the proposed PnP design schemes is verified using a direct current (DC) motor benchmark system.

Energetic ion distributions in the near‐Earth plasma sheet can provide important information for understanding the entry of ions into the magnetosphere and their transportation, acceleration, and losses in the near‐Earth region. In this study, 11 years of energetic proton and oxygen observations (> ~274 keV) from Cluster/Research with Adaptive Particle Imaging Detectors were used to statistically study the energetic ion distributions in the near‐Earth region. The dawn‐dusk asymmetries of the distributions in three different regions (dayside magnetosphere, near‐Earth nightside plasma sheet, and tail plasma sheet) are examined in Northern and Southern Hemispheres. The results show that the energetic ion distributions are influenced by the dawn‐dusk interplanetary magnetic field (IMF) direction. The enhancement of ion intensity largely correlates with the location of the magnetic reconnection at the magnetopause. The results imply that substorm‐related acceleration processes in the magnetotail are not the only source of energetic ions in the dayside and the near‐Earth magnetosphere. Energetic ions delivered through reconnection at the magnetopause significantly affect the energetic ion population in the magnetosphere. We also believe that the influence of the dawn‐dusk IMF direction should not be neglected in models of the particle population in the magnetosphere. We present the statistical observation of energetic ion distributions in the dayside magnetosphere and near‐Earth plasma sheetThe dawn‐dusk asymmetry of the distribution shows strong IMF dependenceThe location of magnetic reconnection at the magnetopause influences the dawn‐dusk asymmetry

Multiple drug resistance is a challenging issue in the clinic. There is growing evidence that the G-protein-coupled estrogen receptor (GPER) is a novel mediator in the development of multidrug resistance in both estrogen receptor (ER)-positive and -negative breast cancers, and that cancer-associated fibroblasts (CAFs) in the tumor microenvironment may be a new agent that promotes drug resistance in tumor cells. However, the role of cytoplasmic GPER of CAFs on tumor therapy remains unclear. Here we first show that the breast tumor cell-activated PI3K/AKT (phosphoinositide 3-kinase/AKT) signaling pathway induces the cytoplasmic GPER translocation of CAFs in a CRM1-dependent pattern, and leads to the activation of a novel estrogen/GPER/cAMP/PKA/CREB signaling axis that triggers the aerobic glycolysis switch in CAFs. The glycolytic CAFs feed the extra pyruvate and lactate to tumor cells for augmentation of mitochondrial activity, and this energy metabolically coupled in a ‘host–parasite relationship’ between catabolic CAFs and anabolic cancer cells confers the tumor cells with multiple drug resistance to several conventional clinical treatments including endocrine therapy (tamoxifen), Her-2-targeted therapy (herceptin) and chemotherapy (epirubicin). Moreover, the clinical data from 18F-fluorodeoxyglucose positron emission tomography/computed tomography further present a strong association between the GPER/cAMP/PKA/CREB pathway of stromal fibroblasts with tumor metabolic activity and clinical treatment, suggesting that targeting cytoplasmic GPER in CAFs may rescue the drug sensitivity in patients with breast cancer. Thus, our data define novel insights into the stromal GPER-mediated multiple drug resistance from the point of reprogramming of tumor energy metabolism and provide the rationale for CAFs as a promising target for clinical therapy.

A vital step in the development of heart failure is the transition from compensatory cardiac hypertrophy to decompensated dilated cardiomyopathy (DCM) during cardiac remodeling under mechanical or pathological stress. However, the molecular mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we investigate whether Gab1, a scaffolding adaptor protein, protects against hemodynamic stress-induced DCM and heat failure. We first observed that the protein levels of Gab1 were markedly reduced in hearts from human patients with DCM and from mice with experimental viral myocarditis in which DCM developed. Next, we generated cardiac-specific Gab1 knockout mice (Gab1-cKO) and found that Gab-cKO mice developed DCM in hemodynamic stress-dependent and age-dependent manners. Under transverse aorta constriction (TAC), Gab1-cKO mice rapidly developed decompensated DCM and heart failure, whereas Gab1 wild-type littermates exhibited adaptive left ventricular hypertrophy without changes in cardiac function. Mechanistically, we showed that Gab1-cKO mouse hearts displayed severe mitochondrial damages and increased cardiomyocyte apoptosis. Loss of cardiac Gab1 in mice impaired Gab1 downstream MAPK signaling pathways in the heart under TAC. Gene profiles further revealed that ablation of Gab1 in heart disrupts the balance of anti- and pro-apoptotic genes in cardiomyocytes. These results demonstrate that cardiomyocyte Gab1 is a critical regulator of the compensatory cardiac response to aging and hemodynamic stress. These findings may provide new mechanistic insights and potential therapeutic target for DCM and heart failure.

Methazolamide is an intraocular pressure-lowering drug that is used in the treatment of glaucoma and other ophthalmologic abnormalities. The use of methazolamide has been shown to cause Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in patients of Asian ancestry. Methazolamide-induced SJS/TEN is associated with the presence of HLA-B59 serotype/HLA-B*59:01in Korean and Japanese populations. To better understand the genetic risk factors for these adverse reactions in the Han Chinese population, we characterized the HLAclass I genotypes of eight Chinese patients with methazolamide-induced SJS/TEN from 2008 to 2014. The frequency of HLA-B*59:01was 87.5% (7/8) in the case patients, which was significantly different from 0% (0/30) in the methazolamide-tolerant patients (odds ratio (OR)=305.0; P=6.3 × 10-7) and 0.35% (1/283) in healthy subjects from the human major histocompatibility complex database (OR=1974.0; P=2.0 × 10-12). HLA-C*01:02, which is closely linked to HLA-B*59:01, had a weaker but notable association with methazolamide-induced SJS/TEN compared with the tolerant controls (OR=12.1; P=0.016) and general population (OR=15.5; P=2.0 × 10-3). The distribution of the HLA-B*59:01-C*01:02haplotype was also significantly different in cases and controls. This study demonstrated a strong association between HLA-B*59:01and methazolamide-induced SJS/TEN in the Han Chinese population for the first time. Pretherapy screening for HLA-B*59:01would be useful to reduce the risk of methazolamide-induced SJS/TEN.

The AMP-activated protein kinase, a key regulator of energy homeostasis, has a critical role in metabolic disorders and cancers. AMPK is mainly regulated by cellular AMP and phosphorylation by upstream kinases. Here, we show that PIKE-A binds to AMPK and blocks its tumor suppressive actions, which are mediated by tyrosine kinase Fyn. PIKE-A directly interacts with AMPK catalytic alpha subunit and impairs T172 phosphorylation, leading to repression of its kinase activity on the downstream targets. Mutation of Fyn phosphorylation sites on PIKE-A, depletion of Fyn, or pharmacological inhibition of Fyn blunts the association between PIKE-A and AMPK, resulting in loss of its inhibitory effect on AMPK. Cell proliferation and oncogenic assays demonstrate that PIKE-A antagonizes tumor suppressive actions of AMPK. In human glioblastoma samples, PIKE-A expression inversely correlates with the p-AMPK levels, supporting that PIKE-A negatively regulates AMPK activity in cancers. Thus, our findings provide additional layer of molecular regulation of the AMPK signaling pathway in cancer progression.

Endothelial cells (ECs) apoptosis is an initial event in transplant arteriosclerosis (TA), resulting in allograft function loss. To elucidate the precise mechanisms of ECs apoptosis leading to neointimal smooth muscle cells (SMCs) accumulation during TA. We induced apoptosis in cultured ECs by overexpressing p53 through lentivirus-mediated transfection. ECs apoptosis induced the production of transforming growth factor (TGF)-β1 in both apoptotic and neighboring viable cells, leading to increased TGF-β1 in the culture media. Conditioned media from Ltv-p53-transfected ECs further promoted transition of cultured ECs to SM-like cells by activating TGF-β/Smad3, PI3K/Akt/mTOR, and MAPK/ERK signaling in a TGF-β-dependent manner. In transgenic rat aorta transplantation models, inhibition of ECs apoptosis in Bcl-xL+/+knock-in rat aortic allografts significantly reduced TGF-β1 production both in allograft endothelia and in blood plasma, which in turn decreased accumulation of SM22α+ cells from transgenic recipient ECs originally marked with EGFP knock-in in neointima and alleviated TA. Systemic treatment with SIS3, AP23573, or PD98059 also prevented recipient ECs-originated SM-like cells accumulation and intima hyperplasia in aortic allografts. These data suggest that allograft EC apoptosis induced recipient endothelial–mesenchymal (smooth muscle) transition via TGF-β signaling, resulting in recipient EC-derived SMC accumulation as a major mechanism of vascular remodeling during TA.

Numerical simulation of AC losses in superconductors with gaint flux creep was carried out based on the collective creep model of the vortex glass. Influence of physical parameters, including frequency (f) and the amplitude (Bac) of AC field, current density distribution (j), DC field (Bd), and temperature (T) on AC losses was studied based on a unified method and the Maxwell equations. The frequency-dependent AC losses is the most important among the results which differ from the static models. Also, AC losses derived in the flux creep state are larger than those in the critical-state when the sample is only partly penetrated by the field, which is the second difference between the flux creep model and the static models. Moreover, the dependence of AC losses on Bacare derived and compared with that based on the Bean model. Preliminary comparison with experiments showed that the procedure could give qualitative understanding and estimation of AC losses in superconductors with giant flux creep.

We have observed numerically the history effect, based on bulk flux pinning framework, in the susceptibility χ(T) (acs), experimentally measured in different samples. The dependencies of history effect in χ(T) on frequency, ac and dc fields, and bulk pinning strength are calculated. Our calculation matches well the behavior of χ in 2H–NbSe2, showing the bulk model works well. It is also shown that bulk pinning and surface pinning will result in a history effect of very different characteristics. In addition, the numerical result shows that a peak in critical current density, which is usually accompanied by the vortex melting transition, may not be observed as a dip in acs in some cases, which is a dynamic response of a sample to applied as field and is dependent on ac field frequency and amplitude.

Inhibition of plasma kallikrein is a validated mechanism for prevention of hereditary angioedema (HAE) attacks. STAR-0215 is a long-acting monoclonal antibody inhibitor of plasma kallikrein. We sought to generate a mechanistic quantitative systems pharmacology (QSP) model to explore the potential for reduction of HAE attacks with different dosing regimens of STAR-0215.

The 1 mol.-%Sr and 1 mol.-%Sn codoped (Ba0·84Ca0·15Sr0·01)(Ti0·90Zr0·09Sn0·01)O3(BCSTZS) ceramics were synthesised by the normal solid state sintering method. The electric field and temperature dependence of the ferroelectric properties of the BCSTZS ceramics were investigated. Their energy storage density depending on electric field and temperature was determined from the polarisation–electric field (P–E) hysteresis loops. According to the dielectric analysis, the BCSTZS ceramics experience three-phase transitions upon cooling. At room temperature, the pyroelectric coefficient pcalculated from the remnant polarisation–temperature (Pr–T) curve is 1116·7 μC K− 1m− 2, and the figures of merit Fdis 18·1 μPa− 1/2, Fvis 0·013 m2C− 1and Fiis 479·3 pm V− 1respectively. The pyroelectric figures of merit exhibit high frequency stability over a wide range from 100 to 2000 Hz, whereas these values vary gradually with the increase in temperature, which deserves further research to improve their stability. The excellent pyroelectric property of the BCSTZS ceramics is considered as correlating with a polymorphic phase transition occurring around room temperature. The present study demonstrates that the lead free BCSTZS ceramics are promising candidate for replacing the lead zirconate titanate based ceramics.

The objective of this study was to investigate the effects of amylose (AM):amylopectin (AP) ratio, extrusion, storage duration, and enzyme supplementation on starch digestibility of corn. Three corn varieties with high (0.60; HA), medium (0.44; MA), and low (0.39; LA) AM:AP ratios, respectively, were selected from 74 corn samples to evaluate the in vitro and in vivo digestibility of starch. In Exp. 1, during wk 4 after extrusion, resistant starch (RS) content of the 3 selected corn varieties (LA, MA, and HA) increased (P< 0.05) each week and starch digestibility in vitro decreased as storage time increased (P< 0.05). The AM:AP ratio affected the formation of RS (P< 0.01). The RS content of the 3 corn varieties was ranked as LA < MA < HA in each week (P< 0.05). Correlation analysis showed that AM:AP ratio and storage duration were both positively correlated with RS content (P< 0.01). Furthermore, a significant quadratic relation was found between storage duration and RS content in each corn variety as well as storage duration and digestibility. Starch digestibility was negatively correlated with RS content (P< 0.001). In Exp. 2, digestion trials were performed on cannulated pigs with BW of 13.20 ± 0.94 kg. Extrusion increased ileal digestibility of GE and starch of either HA or LA compared with the enzyme-supplemented diets (P< 0.001). Enzyme supplementation did not improve ileal energy and starch digestibility. The ileal digestibility of starch and GE of LA varieties was greater than HA samples (P< 0.05). The results implied that AM:AP ratio and storage duration after extrusion may be important determinants of RS formation and digestibility of starch for corn. In addition, RS content could be an important indicator of digestibility of starch in extruded corn. Using a lower AM:AP ratio corn or reducing the storage duration of extruded corn would help to reduce the formation of RS and improve the starch bioavailability of corn for piglets.

In this paper, a data-driven scheme of key performance indicator (KPI) monitoring, prediction and KPI related fault detection is applied to the wastewater treatment process (WWTP). By means of a data-driven realization of the so-called left coprime factorization (LCF) of the process, the efficient monitoring and prediction of chemical oxygen demand (COD) concentration in the effluent flow are realized both for the situation that COD is measurable and unmeasurable. The well established Benchmark Simulation Model no. 1 (BSM1) is utilized for the demonstration of the effectiveness of this approach.

The evolution of microstructures and texture subjected to a burnishing process in pure copper was investigated by transmission electron microscopy and electron backscattered diffraction. The grains of the top surface underwent significant refinement with a minimum grain size of ~100 nm. The grain refinement was dominated by dislocation activities, including formation of dislocation cells, transformation of cell walls into sub-grain boundaries, development of highly disoriented sub-boundaries and generation of equiaxed grains. Shear strain induced by friction affected the strain state at the first pass of burnishing, resulting in a {001}<110> shear texture. Brass orientation developed well at the early stage of burnishing. Then, with a further increase in plastic strain, Brass orientation decreased, while the Goss orientation was observed, which mainly owing to the transformation from Brass to Goss orientation by rotation along the a-fibre. Moreover, dynamic recrystallisation occurred as the strain increased.

Thermomechanical processing involving a wide range of strain (5–80) followed by annealing was applied to a type 316L austenitic stainless steel to encourage grain boundary engineered (GBE) structure. As a result of GBE process, the total length fraction of low Scoincidence site lattice boundaries increased noticeably in conjunction with different levels of grain growth. The GBE structures resulted in significant decreases in the degree of sensitisation following exposure at 948 K for 20 h and assessment through double loop electrochemical potentiokinetic reactivation tests. Strain of low level (5) was more effective than medium to high strain in inspiring GBE. The role of grain size on the sensitisation process has also been discussed. Additionally, abnormal grain growth contributes to the optimisation of GBE structure.

The influence of different conditions of applying a dc electric field (0 < E< 4 kV/cm) on the behavior of optical transmission and on the acoustic parameters (sound velocity and attenuation) in the [001]- and [011]-oriented single crystals 33Pb(In1/2Nb1/2)O3-35PbMg1/3Nb2/3O3-32PbTiO3existing near the morphotropic phase boundary has been investigated. It has been found that the optical transmission, sound velocity, and attenuation sharply change near the phase transition in a narrow range of electric fields for any method of their applying. In the field applied along [001], the change in the sound velocity due to the phase transition is 1.5 times greater than that in the field applied along [011]. This is caused by a larger contribution of the piezoelectric effect to the elastic modulus determining the sound velocity along [001] as compared to [011]. It has been shown that the number, symmetry, and stability of the phases formed in the field depend on the conditions of applying the field.

To retain a large fraction of austenite in 5 wt-Mn alloyed transformation induced plasticity (TRIP) steel after short intercritical annealing (IA), the influence of the carbide that precipitates during various heating processes on austenitisation kinetics and amount of retained austenite was investigated. It was found that a considerable amount of Mn rich cementite particles precipitated when heating was interrupted at 550°C for 5 min; they remained undissolved during IA at 650°C, impairing the austenitisation kinetics and decreasing the fraction of retained austenite. In contrast, relatively fine para-carbide particles precipitated extensively, without Mn enrichment, when heating was interrupted at 250°C for 20 min. Both, experimental investigations and numerical simulations, indicate that these para-carbide particles were quickly dissolved during IA, thereby accelerating the austenitisation kinetics and increasing the fraction of retained austenite. In addition, the influence of the heating rate was investigated and is discussed. It is concluded that the carbide particles that precipitate before IA can either positively or negatively influence the fraction of retained austenite in the TRIP steel, depending on whether they dissolve during IA. Moreover, their dissolution kinetics strongly depends on the extent of Mn enrichment of the carbide compared to that of austenite, which can be predicted by the presented numerical simulations on dissolution kinetics of cementite.

Dissimilar joints of copper to aluminium were produced by high power ultrasonic welding (USW). The interfacial reaction between copper and 6061 aluminium alloy as a function of welding time was studied. The intermetallic compound (IMC) layer is mainly composed of CuAl2and Cu9Al4. The thickness of the IMC layer increases with the welding time. For a relatively long welding time (0·7 s) in USW, the dendritic solidification microstructure was observed in local regions, owing to the occurrence of the eutectic reaction, α-Al+θ→L, in the welding process. The lap shear load (or strength) of the joints first increases and then decreases with increasing welding time, and the failure of the joints occurred dominantly at the interface. This is mainly attributed to the development of IMC layer at the interface.

Until now it is still questionable whether ions are accelerated to energies above 100 keV in the near‐Earth current sheet (CS), in the vicinity of a possible near‐Earth neutral line. By using 11 years of 3‐D energetic ion flux data for protons, helium, and oxygen (~150 keV–1 MeV) from the RAPID instrument on board Cluster 4, we statistically study the energetic ion acceleration by investigating ion anisotropies in the near‐Earth magnetotail (−20 RE< X<−16 RE). It is found that the earthward (tailward) anisotropy of the energetic (>150 keV) ions (protons, He+, and O+) tend to become higher as the earthward (tailward) plasma bulk flows (measured by Cluster Ion Spectrometry experiment) become stronger. During such periods the presence of a strong acceleration source tailward (earthward) of Cluster spacecraft (S/C) is confirmed by the hardening energy spectra of the earthward (tailward) energetic ion flows. A good statistical correlation between tailward bulk flow, negative Bz, and the tailward anisotropy of energetic ions indicates that the strong ion acceleration might be related to a near‐Earth reconnection, which occurred earthward of the Cluster S/C. The energetic ion anisotropies do not show a clear dependence on the AEindex, which may indicate that the acceleration source(s) for the energetic ions could be spatially localized. We present the observational evidence of ion acceleration in the plasma sheetThe acceleration of ions to energies > 150 keV may occur in the near‐Earth CSThe acceleration is a spatially localized process

Recent observations suggest that the mean mesoscale oceanic zonal velocity field is dominated by alternating jet‐like features often referred to as striations. Here the generating dynamics of Northeast Pacific striations are explored with a set of 120 year eddy‐permitting model simulations. Simulations are conducted with decreasing complexity toward idealized configurations retaining the essential dynamics and forcing necessary for striation development. For each simulation, we diagnose the spin‐up of the ocean model and the sensitivity of striation generation to topography, coastal geometry, and wind stress, which modulates the gyre circulation and the nonlinearity of the flow field. Results indicate that Northeast Pacific striations develop predominantly at the eastern boundary and migrate westward in congruence with beta‐plumes in both the nonlinear and quasi‐linear regimes. Mean striations are governed by coastline geometry, which provides quasi‐steady vorticity sources energized by eastern boundary current instabilities. Northeast Pacific striations form as coastal vorticity propagates offshore via beta‐plumesVorticity is anchored by coastal geometry, so striations remain stationaryStriation magnitude is constrained at the shelf by potential vorticity trapping

A study is reported of various modes of dc electric field application (0 < E< 3 kV/cm) on structural phase transformations and behavior of the phase boundary in [001]-oriented 30PbIn1/2Nb1/2O3-37PbMg1/3Nb2/3O3-33PbTiO3single crystals located close to the morphotropic phase boundary. Dielectric methods of investigation have been complemented for the first time with optical methods. It has been found that the number, symmetry, and stability of the phases formed in the field depend on the actual mode of field application. The E-Tphase diagrams have been constructed for different field application modes. It has been shown that phase diagrams obtained for the same crystal are different for different field application modes.

External low‐frequency ultrasound (USD) in combination with microbubbles has been reported to recanalize thrombotically occluded arteries in animal models.

Age-related macular degeneration (AMD) is a leading cause of visual impairment in aging populations in industrialized countries. Here we investigated whether the genotype of vascular endothelial growth factor A (VEGFA) gene is associated with response to anti-VEGF therapy. 223 eyes with neovascular AMD were treated with intravitreal anti-VEGF therapy. Responders were defined as patients who had an improvement in best corrected visual acuity (BCVA) of at least 5 letters or one line on the EDTRS visual acuity chart along with resolution of intraretinal or subretinal fluid over 12 months. Patients who did not meet the definition of responders were classified as poor-responders. The vision of responders (n = 148) improved while the vision of poor-responders (n = 75) worsened (P <0.001). Responders on average had a decrease in central foveal thickness (CFT), while poor-responders had an increase in CFT (P <0.001). Compared with the responder group, the poor-responder group had a higher frequency of the risk (T) allele (Allelic P = 0.019) and TT genotype (P = 0.002 under a recessive model) for the VEGFA-rs943080 polymorphism. VEGFA expression was 1.8-fold higher in cells with the VEGFA rs943080 TT genotype than in cells with the VEGFA rs943080 CC genotype (P = 0.012). Age, gender, smoking, diabetes mellitus, and hypertension did not play a significant role in treatment response, but BMI was found to be significantly different between responders and poorresponders (P = 0.033). In conclusion, we demonstrated a potential pharmacogenetic relationship between the VEGFA gene and treatment response to anti-VEGF therapy. The studies are registered at ClinicalTrials.gov under the identifiers NCT00474695 (http://clinicaltrials. gov/ct2/show/NCT00474695) and NCT01464723 (http://clinicaltrials.gov/ct2/show/NCT01464723).

Pseudoternary xBaTiO3–yCaTiO3–(1-x-y)BaZrO3(BT–CT–BZ) lead free piezoelectric ceramics were prepared by the conventional solid state reaction method sintered at 1450–1510°C for 2 h. Sintering conditions, composition and polarisation conditions exert great influences on structure and electrical properties of the sintered BT–CT–BZ ceramics. The synthesised BT–CT–BZ ceramics exhibit rather large bulk density and densified microstructure morphology, although slight content of pyrochlore phase impurity exists. With increasing CaTiO3content, crystal structure of the BT–CT–BZ ceramics changes gradually from rhombohedral perovskite structure, across morphotropic phase boundary (MPB) composition and to tetragonal one. The dielectric response character changes successively from broad dielectric peaks to narrow ones accompanied by slight content of dielectric frequency dispersion, whereas the MPB effect is not apparent. The temperature of dielectric constant maximum TCincreases almost linearly with increasing CaTiO3content. The BT–CT–BZ ceramics exhibit fully developed, saturated and symmetric polarisation–electric field P–Ehysteresis loops, excellent piezoelectric property and perfect electromechanical resonance response peaks, in which the MPB effects are detected clearly by ferroelectric and piezoelectric properties measurements.