High pressure torsion (HPT) under a pressure of 6GPa through 1 and 2 revolutions have been used to follow the evolution of microstructures and properties in an Al0.1CoCrFeNi high-entropy alloy (HEA). ...The plastic-deformation mechanisms of the HEA include dislocation slip at low strains and twinning at high strains at room temperature. The planar dislocation slip on the normal face-centered-cubic slip system, {111}〈110〉, and nanoscaled deformation twins with a thickness from several nanometers to 40nm, accompanied with some secondary twins. The hardness of the Al0.1CoCrFeNi HEA increases from 135Hv at hot-isostatic pressed (HIPed) state to about 482Hv after HPT processing. The HEAs have a relatively high initial hardness and high work hardening, compared with traditional alloys. The creep resistance of the HEA processed by HPT was determined by a nanoindentation technique. The strain rate sensitivity, m, increases with the decreasing of grain size, for smaller activation volume and the dominant deformation mechanism changing from the dislocation slip to grain-boundary slide. The present results give the plastic-deformation mechanism and mechanical properties evolution of single-phase HEA processed by HPT at room temperature.
Epithelial-mesenchymal transition (EMT) is regarded as a crucial contributing factor to cancer progression. Diverse factors have been identified as potent EMT inducers in ovarian cancer. However, ...molecular mechanism sustaining EMT of ovarian cancer cells remains elusive. Here we show that the presence of SOS1/EPS8/ABI1 complex is critical for sustained EMT traits of ovarian cancer cells. Consistent with the role of SOS1/EPS8/ABI1 complex as a Rac1-specific guanine nucleotide exchange factor, depleting Rac1 results in the loss of most of mesenchymal traits in mesenchymal-like ovarian cancer cells, whereas expressing constitutively active Rac1 leads to EMT in epithelial-like ovarian cancer cells. With the aid of clinically tested inhibitors targeting various EMT-associated signaling pathways, we show that only combined treatment of mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2) and Src inhibitors can abolish constitutively active Rac1-led EMT and mesenchymal traits displayed by mesenchymal-like ovarian cancer cells. Further experiments also reveal that EMT can be induced in epithelial-like ovarian cancer cells by co-expressing constitutively active MEK1 and Src rather than either alone. As the activities of Erk and Src are higher in ovarian cancer cells with constitutively active Rac1, we conclude that Rac1 sustains ovarian cancer cell EMT through simultaneous activation of MEK1/2 and Src signaling pathways. Importantly, we demonstrate that combined use of MEK1/2 and Src inhibitors effectively suppresses development of intraperitoneal xenografts and prolongs the survival of ovarian cancer-bearing mice. This study suggests that cocktail of MEK1/2 and Src inhibitors represents an effective therapeutic strategy against ovarian cancer progression.
A new set of AlFeCoNiCx (x = 0, 0.02, 0.04, 0.08, 0.17) high-entropy alloys (HEAs) were designed and fabricated. The microstructure, phase evolution and mechanical behaviors of the alloys were ...systematically investigated. Results show that the matrix alloy exhibits coarse columnar structure, while the C-doped alloys exhibit typical dendrite microstructure. The dendritic region (DR) is composed of single B2 phase, while the interdendritic region (ID) consists of FCC and E21 phases and presents an ultrafine cellar structure caused by the coexisting of ordering and spinodal decomposition. Interestingly, both the strength and compressive strain greatly increased with the increase of carbon content. Particularly, the AlFeCoNiC0.08 HEA possessed the most excellent mechanical properties, superior to many other HEAs with the yield strength, fracture strength, and fracture strain as high as 1115 MPa, 2517 MPa and 48.8%, respectively. The mechanical properties of the AlFeCoNiC0.17 alloy were weakened by the presence of graphite. Further, it is found that there is close relationship between the fracture morphology and alloy properties. Overall, in this study the improved microstructure and mechanical properties of the AlFeCoNi HEA have been accomplished by carbon doping, and our findings could shed light on a new alloy-design route to achieve bulk ultrafine structure materials with desired properties via the direct solidification.
Aims/hypothesis
Sirtuin-1 (SIRT1) is a potential therapeutic target to combat insulin resistance and type 2 diabetes. This study aims to identify a microRNA (miRNA) targeting SIRT1 to regulate ...hepatic insulin sensitivity.
Methods
Luciferase assay combined with mutation and immunoblotting was used to screen and verify the bioinformatically predicted miRNAs. miRNA and mRNA levels were measured by real-time PCR. Insulin signalling was detected by immunoblotting and glycogen synthesis. Involvement of SIRT1 was studied with adenovirus, inhibitor and SIRT1-deficient hepatocytes. The role of
miR-181a
in vivo was explored with adenovirus and locked nucleic acid antisense oligonucleotides.
Results
miR-181a
targets the 3′ untranslated region (3′UTR) of
Sirt1
mRNA through a
miR-181a
binding site, and downregulates SIRT1 protein abundance at the translational level.
miR-181a
is increased in insulin-resistant cultured hepatocytes and liver, and in the serum of diabetic patients. Overexpression of
miR-181a
decreases SIRT1 protein levels and activity, and causes insulin resistance in hepatic cells. Inhibition of
miR-181a
by antisense oligonucleotides increases SIRT1 protein levels and activity, and improves insulin sensitivity in hepatocytes. Ectopic expression of
SIRT1
abrogates the effect of
miR-181a
on insulin sensitivity, and inhibition of SIRT1 activity or SIRT1 deficiency markedly attenuated the improvement in insulin sensitivity induced by antisense
miR-181a
. In addition, overexpression of
miR-181a
by adenovirus impairs hepatic insulin signalling, and intraperitoneal injection of locked nucleic acid antisense oligonucleotides for
miR-181a
improves glucose homeostasis in diet-induced obesity mice.
Conclusions/interpretation
miR-181a
regulates SIRT1 and improves hepatic insulin sensitivity. Inhibition of
miR-181a
might be a potential new strategy for treating insulin resistance and type 2 diabetes.
The effects of rare-earth element, Y, additions on the microstructures and mechanical properties of CoCrFeNi alloy have been investigated. The new series of CoCrFeNiYx (x = 0, 0.05, 0.1, 0.2, and ...0.3) high entropy alloys were synthesized by vacuum arc-melting method. Microstructure characterizations were performed by the means of X-ray diffraction, scanning electron microscope, and transmission electron microscope. It was found that alloying Y element could lead to the formation of a simple hexagonal structure phase (CaCu5 type). And another Ni3Y-type hexagonal structure phase was observed in the alloy with higher Y contents (0.3 at%). The phase evolution of the present alloy system was evaluated using the previous criteria (ΔHmix−δ,Ω−δ,Δχ, VEC, and Λ). The results of the nanoindentation measurements on different phases indicated that the hexagonal structure phases (~ 10.5 GPa) had a higher nanohardness than the face-centered cubic phase (~ 3 GPa). Furthermore, the maximum shear stress of the incipient plasticity was calculated to be 3.2 GPa for the face-centered cubic phase and 5.2 GPa for the hexagonal structure phase. The dislocation nucleation under the indenter in different phases was also discussed. The Vickers hardness and yield strength increased with increasing the Y content, while the fracture strength and plastic strain decreased. The strengthening mechanisms of the present alloys included solid-solution strengthening and the second phase strengthening. Fracture surface observations suggested a ductile fracture in the face-centered cubic phase and a cleavage fracture in the hexagonal structure phase for the alloys containing Y element. The results of this investigation can provide a guide for the design of new high entropy alloy system with excellent properties.
Based on the first-principles method, we investigated the electronic properties of a BAs/arsenene (As) van der Waals (vdW) heterostructure and found that it has an intrinsic type-II band alignment ...with a direct band gap of 0.25 eV, which favors the separation of photogenerated electrons and holes. The band gap can be effectively modulated by applying vertical strain and external electric field, displaying a large alteration in the band gap
via
the strain and experiencing an indirect-to-direct band gap transition. Moreover, the band gap of the heterostructure varies almost linearly with external electric field, and the semiconductor-to-metal transition can be realized in the presence of a strong electric field. The calculated band alignment and optical absorption reveal that the BAs/As heterostructure could present an excellent light-harvesting performance. The absorption strength can be tuned mainly by interlayer coupling, while external electric field shows clear regulating effects on the absorption strength and absorption edge.
The CBM (VBM) of the heterostructure is mainly contributed by the BAs (arsenene), which will favor the separation of photogenerated electron-hole pairs.
Transporter gene knockout rats are practically advantageous over murine models for pharmacokinetic and excretion studies, but their phenotypic characterization is lacking. At present, relevant ...aspects of pharmacokinetics, metabolism, distribution, and excretion of transporter probes P-glycoprotein (P-gp): loperamide and paclitaxel; breast cancer resistance protein (Bcrp): sulfasalazine; and multidrug resistance-associated protein 2 (Mrp2): carboxydichlorofluorescein were studied systematically across SAGE P-gp, Bcrp, and Mrp2 knockout rats. In Mdr1a knockout rats, loperamide and paclitaxel oral bioavailability was 2- and 4-fold increased, respectively, whereas clearance was significantly reduced (40-42%), consistent with the expected 10- to 20-fold reduction in paclitaxel excretion. N-Desmethyl-loperamide pharmacokinetics were not altered in any of the three knockouts after oral loperamide. In rats lacking P-gp, paclitaxel brain partitioning was significantly increased (4-fold). This finding is consistent with observations of loperamide central nervous system opioid pharmacology in Mdr1a knockout rats. Sulfasalazine oral bioavailability was markedly increased 21-fold in Bcrp knockouts and, as expected, was also 2- to 3-fold higher in P-gp and Mrp2 knockout rats. The sulfapyridine metabolite/parent ratio was decreased 10-fold in rats lacking Bcrp after oral, but not intravenous, sulfasalazine administration. Carboxydichlorofluorescein biliary excretion was obliterated in Mrp2 knockout rats, resulting in 25% decreased systemic clearance and 35% increased half-life. In contrast, carboxydichlorofluorescein renal clearance was not impaired in the absence of Mrp2, Bcrp, or P-gp. In conclusion, SAGE Mdr1a, Bcrp, and Mrp2 knockout rats generally demonstrated the expected phenotypes with respect to alterations in pharmacokinetics of relevant probe substrates; therefore, these knockout rats can be used as an alternative to murine models whenever a larger species is practically advantageous or more relevant to the drug discovery/development program.
Dengue is the fastest spreading mosquito-transmitted disease in the world. In China, Guangzhou City is believed to be the most important epicenter of dengue outbreaks although the transmission ...patterns are still poorly understood. We developed an autoregressive integrated moving average model incorporating external regressors to examine the association between the monthly number of locally acquired dengue infections and imported cases, mosquito densities, temperature and precipitation in Guangzhou. In multivariate analysis, imported cases and minimum temperature (both at lag 0) were both associated with the number of locally acquired infections (P < 0.05). This multivariate model performed best, featuring the lowest fitting root mean squared error (RMSE) (0.7520), AIC (393.7854) and test RMSE (0.6445), as well as the best effect in model validation for testing outbreak with a sensitivity of 1.0000, a specificity of 0.7368 and a consistency rate of 0.7917. Our findings suggest that imported cases and minimum temperature are two key determinants of dengue local transmission in Guangzhou. The modelling method can be used to predict dengue transmission in non-endemic countries and to inform dengue prevention and control strategies.
Summary Background Olfactory and gustatory dysfunctions (OGDs) are key symptoms of coronavirus disease 2019 (COVID-19), which may lead to neurological complications, and lack of effective treatment. ...This may be because post-disease treatments may be too late to protect the olfactory and gustatory functions. Aim To evaluate the effectiveness of early use of saline nasal irrigation (SNI), corticosteroid nasal spray, and saline or chlorhexidine gluconate mouthwash for preventing OGDs in COVID-19. Design This study was a double-blind randomized controlled trial. Methods The study was conducted from 5 May to 16 June 2022. We recruited patients from three hospitals who were admitted with COVID-19 but without OGDs on the day of admission. Olfactory and gustatory functions were evaluated using the Taste and Smell Survey and the numerical visual analog scale. Participants were randomized to the saline, drug or control groups. The control group received no intervention, saline group received SNI plus saline nasal spray and mouthwash, and the trial group received SNI plus budesonide nasal spray and chlorhexidine gluconate mouthwash. Participants were assessed again on the day of discharge. Results A total of 379 patients completed the trial. The prevalence of OGDs was significantly lower in the saline (11.8%, 95% CI, 6.6–19.0%; P < 0.001) and drug (8.3%, 95% CI, 4.1–14.8%; P < 0.001) groups than in the control group (40.0%, 95% CI, 31.8–48.6%). Additionally, both interventions reduced the severity of OGDs. Conclusions We demonstrated effective strategies for preventing COVID-19-related OGDs, and the findings may guide early management of severe acute respiratory disease coronavirus 2 (SARS-CoV-2) infection to reduce the incidence of COVID-19-related complications.
Abstract
We present a systematic analysis of type C quasiperiodic oscillation (QPO) observations of H1743-322 throughout the Rossi X-ray Timing Explorer era. We find that, while different outbursts ...have significant flux differences, they show consistent positive correlations between the QPO fractional rms amplitude and nonthermal fraction of the emission, which indicate an independence of the intrinsic QPO rms on individual outburst brightnesses in H1743-322. However, the dependence of the QPO rms on frequency is different between the outburst rise and decay phases, where the QPO fractional rms of the decay phase is significantly lower than that of the rise phase at low frequencies. The spectral analysis also reveals different ranges of coronal temperature between the two outburst stages. A semiquantitative analysis shows that the Lense–Thirring precession model could be responsible for the QPO rms differences, requiring a variable coronal geometric shape. However, the variable-Comptonization model could also account for the findings. The fact that the rms differences and the hysteresis traces in the hardness–intensity diagram accompany each other indicates a connection between the two phenomena. By correlating the findings with QPO phase lags and the quasi-simultaneous radio flux previously published, we propose there could be corona-jet transitions in H1743-322 similar to those that have been recently reported in GRS 1915+105.
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