In the present work, we investigated the influence of deformation temperature on the formation of a bimodal microstructure and tensile properties of a Mg–9Al–1Zn (AZ91) alloy processed by a single ...pass hard plate rolling (HPR) with a thickness reduction of 55% followed by a short time annealing. Microstructural examinations by electron backscatter diffraction (EBSD) reveal that there exists a narrow deformation temperature window, i.e. it is only feasible to achieve a desired bimodal grain structure in the AZ91 alloy when HPRed at ∼350 °C. It is mainly because that partial dynamic recrystallization (DRX) occurs easily in the sample HPRed at ∼ 350 °C, facilitating the formation of a bimodal microstructure consisting of coarse un–recrystallized grains (>∼70 μm) and fine recrystallized grains (<∼5 μm). In contrast, reducing deformation temperature to ∼300 °C results in a coarse unrecrystallized microstructure containing substantial sub structure, while elevating the deformation temperature to ∼400 °C leads to an almost uniform recrystallized grain structure. Especially, the formation mechanism for the bimodal grain structure at the optimum deformation temperature is explored in terms of Schmidt factors analysis for basal slips (SFbasal) for grains of different size scales. Moreover, the 350 °C HPRed AZ91 sample exhibits a better combination of strength (ultimate tensile strength = ∼374 MPa) and ductility (elongation = ∼19.6%), as compared to the 300 and 400 °C samples. It is mainly attributed to the typical bimodal grain structure and the relatively high SFbasal featured by the fine recrystallized grains as well as the nanometer spherical particles distributing in fine grain interiors.
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•A bimodal grain structure of Mg–9Al–1Zn alloy was achieved by tailoring rolling temperature during hard–plate rolling (HPR).•The formation of bimodal microstructure was explored in terms of Schmidt factors analysis for basal slips (SFbasal).•The formation of bimodal grain structure generated a simultaneous improvement of strength and ductility.
Summary Background Bone metastases are a major burden in men with advanced prostate cancer. We compared denosumab, a human monoclonal antibody against RANKL, with zoledronic acid for prevention of ...skeletal-related events in men with bone metastases from castration-resistant prostate cancer. Methods In this phase 3 study, men with castration-resistant prostate cancer and no previous exposure to intravenous bisphosphonate were enrolled from 342 centres in 39 countries. An interactive voice response system was used to assign patients (1:1 ratio), according to a computer-generated randomisation sequence, to receive 120 mg subcutaneous denosumab plus intravenous placebo, or 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. Randomisation was stratified by previous skeletal-related event, prostate-specific antigen concentration, and chemotherapy for prostate cancer within 6 weeks before randomisation. Supplemental calcium and vitamin D were strongly recommended. Patients, study staff, and investigators were masked to treatment assignment. The primary endpoint was time to first on-study skeletal-related event (pathological fracture, radiation therapy, surgery to bone, or spinal cord compression), and was assessed for non-inferiority. The same outcome was further assessed for superiority as a secondary endpoint. Efficacy analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00321620 , and has been completed. Findings 1904 patients were randomised, of whom 950 assigned to denosumab and 951 assigned to receive zoledronic acid were eligible for the efficacy analysis. Median duration on study at primary analysis cutoff date was 12·2 months (IQR 5·9–18·5) for patients on denosumab and 11·2 months (IQR 5·6–17·4) for those on zoledronic acid. Median time to first on-study skeletal-related event was 20·7 months (95% CI 18·8–24·9) with denosumab compared with 17·1 months (15·0–19·4) with zoledronic acid (hazard ratio 0·82, 95% CI 0·71–0·95; p=0·0002 for non-inferiority; p=0·008 for superiority). Adverse events were recorded in 916 patients (97%) on denosumab and 918 patients (97%) on zoledronic acid, and serious adverse events were recorded in 594 patients (63%) on denosumab and 568 patients (60%) on zoledronic acid. More events of hypocalcaemia occurred in the denosumab group (121 13%) than in the zoledronic acid group (55 6%; p<0·0001). Osteonecrosis of the jaw occurred infrequently (22 2% vs 12 1%; p=0·09). Interpretation Denosumab was better than zoledronic acid for prevention of skeletal-related events, and potentially represents a novel treatment option in men with bone metastases from castration-resistant prostate cancer. Funding Amgen.
ABSTRACT
Rhabdoviruses are single-stranded, negative-sense RNA viruses with broad host range, several of which are important pathogens. Compared with the rhabdoviruses infecting mammals, host factors ...involved in aquatic rhabdovirus infection have remained largely unknown. In the present study, we report the roles of host eukaryotic translation elongation factor 1 alpha (eEF1A) on the infection of
Siniperca chuatsi
rhabdovirus (SCRV, genus
Siniperhavirus
), which is an important pathogen of mandarin fish. eEF1A was identified from SCRV nucleoprotein (N)-based affinity purified proteins. Further protein interaction and mutation assays proved that eEF1A interacted not only with the N protein but also the virus matrix protein (M), which relied on the N-terminal of eEF1A. SCRV infection and overexpression of N or M all stimulated the promoter activity of the eEF1A gene and, thus, upregulated its expression, whereas the upregulated eEF1A inhibited the transcription of SCRV genome. Mechanistically, eEF1A impaired the interactions between N and phosphoprotein (P), or N and N, which are important for the efficient transcription and replication of rhabdovirus. Meanwhile, eEF1A promoted the ubiquitin-proteasome degradation of the M protein, which relied on lysine 48 (K48) of ubiquitin. In addition, we showed that the ubiquitination degradation of M protein relied on C-terminal domain of eEF1A, but inhibition of the N-P or N-N interactions needs its entire length. Collectively, these results revealed two different mechanisms used by eEF1A to resist a fish rhabdovirus, which provided novel insights into the role of eEF1A in rhabdovirus infection and new information for antiviral research.
IMPORTANCE
Although a virus can regulate many cellular responses to facilitate its replication by interacting with host proteins, the host can also restrict virus infection through these interactions. In the present study, we showed that the host eukaryotic translation elongation factor 1 alpha (eEF1A), an essential protein in the translation machinery, interacted with two proteins of a fish rhabdovirus,
Siniperca chuatsi
rhabdovirus (SCRV), and inhibited virus infection via two different mechanisms: (i) inhibiting the formation of crucial viral protein complexes required for virus transcription and replication and (ii) promoting the ubiquitin-proteasome degradation of viral protein. We also revealed the functional regions of eEF1A that are involved in the two processes. Such a host protein inhibiting a rhabdovirus infection in two ways is rarely reported. These findings provided new information for the interactions between host and fish rhabdovirus.
Although a virus can regulate many cellular responses to facilitate its replication by interacting with host proteins, the host can also restrict virus infection through these interactions. In the present study, we showed that the host eukaryotic translation elongation factor 1 alpha (eEF1A), an essential protein in the translation machinery, interacted with two proteins of a fish rhabdovirus,
Siniperca chuatsi
rhabdovirus (SCRV), and inhibited virus infection via two different mechanisms: (i) inhibiting the formation of crucial viral protein complexes required for virus transcription and replication and (ii) promoting the ubiquitin-proteasome degradation of viral protein. We also revealed the functional regions of eEF1A that are involved in the two processes. Such a host protein inhibiting a rhabdovirus infection in two ways is rarely reported. These findings provided new information for the interactions between host and fish rhabdovirus.
Mix and match: The photovoltaic performance of carbon nanotubes with titanium nitride nanoparticles (TiN‐CNTs; see picture), which is comparable to that of conventional platinum counter electrodes, ...is attributed to the ideal combination of the superior electrocatalytic activity of TiN nanoparticles and the high electrical conductivity of CNTs.
SnS2 is used to inhibit the “shuttle effect” and carbon nanotubes (CNTs) are used to improve the conductivity, thus a new Li-S battery cathode material (SnS2/CNTs/S composite) is prepared in this ...paper. Morphological structure and electrochemical properties of the samples were characterized. The results show that among the composite, the CNTs are uniformly wrapped on the surface of SnS2 and S is uniformly loaded on the SnS2/CNTs. The composite has a promising electrochemical performance: the first discharge capacity is 1308.6 mAh g − 1 at 0.1 C and there is a reversible capacity of 1002.3 mAh g−1 after 100 cycles.
A new SnS2/CNTs/S composite is prepared and used as the lithium-sulfur battery cathode material. SnS2 works as the adsorbent to hinder or reduce the shuttle effect of lithium polysulfides. CNTs work as the conductive network of the composite. The synergistic effect come from the SnS2 and CNTs commits to the Li-S battery electrochemical performance. The composite has shown a good electrochemical performance. Display omitted
Tailoring the doping of semiconductors in heterojunction solar cells shows tremendous success in enhancing the performance of many types of inorganic solar cells, while it is found challenging in ...perovskite solar cells because of the difficulty in doping perovskites in a controllable way. Here, a small molecule of 4,4′,4″,4″′‐(pyrazine‐2,3,5,6‐tetrayl) tetrakis (N,N‐bis(4‐methoxyphenyl) aniline) (PT‐TPA) which can effectively p‐dope the surface of FAxMA1−xPbI3 (FA: HC(NH2)2; MA: CH3NH3) perovskite films is reported. The intermolecular charge transfer property of PT‐TPA forms a stabilized resonance structure to accept electrons from perovskites. The doping effect increases perovskite dark conductivity and carrier concentration by up to 4737 times. Computation shows that electrons in the first two layers of octahedral cages in perovskites are transferred to PT‐TPA. After applying PT‐TPA into perovskite solar cells, the doping‐induced band bending in perovskite effectively facilitates hole extraction to hole transport layer and expels electrons toward cathode side, which reduces the charge recombination there. The optimized devices demonstrate an increased photovoltage from 1.12 to 1.17 V and an efficiency of 23.4% from photocurrent scanning with a stabilized efficiency of 22.9%. The findings demonstrate that molecular doping is an effective route to control the interfacial charge recombination in perovskite solar cells which is in complimentary to broadly applied defect passivation techniques.
A small molecule of 4,4′,4″,4′″‐(pyrazine‐2,3,5,6‐tetrayl) tetrakis (N,N‐bis(4‐methoxyphenyl) aniline) (PT‐TPA) is applied to effectively p‐dope the FAxMA1−xPbI3 (FA:HC(NH2)2; MA:CH3NH3) perovskite surface, with obvious conductivity and carrier concentration increase. After applying PT‐TPA into perovskite solar cells, the doping‐induced band bending at the perovskite surface facilitates hole extraction to the hole‐transport layer and expels electrons toward the cathode, which reduces surface charge recombination. The optimized devices demonstrate a stabilized efficiency of 22.9%.
The realization of semiconductor laser diodes on Si substrates would permit the creation of complex optoelectronic circuits, enabling chip-to-chip and system-to-system optical communications. Direct ...epitaxial growth of III-V semiconductor materials on Si or Ge is one of the most promising candidates for the fabrication of electrically pumped light sources on a Si platform. Here, we describe the first quantum-dot laser to be realized on a Ge substrate. To fabricate the laser, a single-domain GaAs buffer layer was first grown on the Ge substrate using the Ga prelayer technique. A long-wavelength InAs/GaAs quantum-dot structure was then fabricated on the high-quality GaAs buffer layer. Lasing at a wavelength of 1,305 nm with a low threshold current density of 55.2 A cm-2 was observed under continuous-wave current drive at room temperature. The results suggest that long-wavelength InAs/GaAs quantum-dot lasers on Si substrates may be realized by epitaxial growth on Ge-on-Si substrates.
Al–Zn–Mg–Cu alloys that are prone to segregation and hot cracks always encounter difficulty in manufacturing large-size workpiece with desirable strength-plasticity synergy, especially when the ...tonnage of the extruder exceeds 6000 tons. This work puts forward a novel idea to address this challenge by joining extruded profiles of Al–Zn–Mg–Cu-based composite reinforced by trace in-situ TiC–TiB2 nanoparticles through friction stir welding (FSW). The extruded profiles of Al–Zn–Mg–Cu-based composite along transverse direction (TD) achieved superior yield strength (σY) of 827 MPa and large plastic strain (εp) of 10.2%. The σY of FSW-ed joint along TD reached 847 MPa, and the εp was maintained at 2.8%. It was found that trace nanoparticles can weaken the grain boundary segregation of the composite ingot significantly, effectively avoiding the hot cracking that may occur during hot extrusion and FSW. In extruded profiles, nanoparticles promoted the nucleation of η′ precipitates, promoted the dislocation multiplication, and increased the proportions of low-angle grain boundaries (LAGBs) within 2°–15° and high-angle grain boundaries (HAGBs), thereby enhancing the strength. Meanwhile, nanoparticles increased the density of LAGBs and facilitated the precipitation of Guinier–Preston (GP) zones, which facilitated to maintain high plasticity of the extruded profiles of composite. Additionally, nanoparticles can effectively inhibit the abnormal grain growth in nugget zone (NZ) during post-weld heat treatment (PWHT), which strengthened the FSW-ed joint. This work elaborated the multiscale microstructure evolution mechanisms, offering guidance to fabricate Al–Zn–Mg–Cu workpieces with infinitely extensive size as required in actual manufacturing and fantastic mechanical performances.
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•Trace in-situ TiC–TiB2 enhanced performance of large-size Al–Zn–Mg–Cu composite.•TiC–TiB2 optimized segregation, recrystallization and precipitation behavior.•TiC–TiB2 inhibited the abnormal grain growth during post-weld heat treatment.•Microstructure evolution and performance improvement mechanisms were revealed.
A comprehensive investigation of the trace additions of in situ novel bimodal-sized (nano and submicron) TiB2 particles on the solidification behavior, microstructure and mechanical property ...evolution of Al–7Si–4Cu alloys were carried out through remelting and dilution-assisted ultrasonic vibration. The results showed that both the primary α-Al dendrites and eutectic Si structure were greatly refined in the presence of 0.7 wt% bimodal-sized TiB2 particles, with a reduction of 79.0% and 53.7% compared to the base alloy, which is far beyond the efficiency of micron-sized TiB2 particles. Additionally, the average diameter of the θ′ precipitates was greatly reduced by 32.7%. Thermal analysis revealed that the bimodal-sized TiB2 particles sharply shifted the nucleation temperature of primary α-Al from 600.7 °C to 607.1 °C; meanwhile, the corresponding recalescence undercooling decreased by 3.6 °C. More importantly, in contrast with the common dilemma of strength-ductility trade-off, the yield strength and elongation to fracture of the inoculated Al–7Si–4Cu alloy were simultaneously and significantly improved by 26.3% and 71.1%, respectively. In this work, the mechanisms of multiscale microstructure refinement and mechanical property enhancement by bimodal-sized TiB2 particles were systematically discussed.
•Bimodal-sized TiB2 particles were in situ synthesized.•α-Al, eutectic Si and θ′ phases were highly refined by bimodal-sized TiB2 particles.•Both the strength and elongation were enhanced by bimodal-sized TiB2 particles.
The regulation of the cancer cell cycle heavily relies on cyclin-dependent kinases (CDKs). Targeting CDKs has been identified as a promising approach for effective cancer therapy. In recent years, ...there has been significant attention paid towards developing small-molecule CDK inhibitors in the field of drug discovery. Notably, five such inhibitors have already received regulatory approval for the treatment of different cancers, including breast tumors, lung malignancies, and hematological malignancies. This review provides an overview of the synthetic routes used to produce 17 representative small-molecule CDK inhibitors that have obtained regulatory approval or are currently being evaluated through clinical trials. It also discusses their clinical applications for treating CDK-related diseases and explores the challenges and limitations associated with their use in a clinical setting, which will stimulate the further development of novel CDK inhibitors. By integrating therapeutic applications, synthetic methodologies, and mechanisms of action observed in various clinical trials involving these CDK inhibitors, this review facilitates a comprehensive understanding of the versatile roles and therapeutic potential offered by interventions targeting CDKs.
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