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Precipitation-hardening high-entropy alloys (PH-HEAs) with good strength−ductility balances are a promising candidate for advanced structural applications. However, current HEAs emphasize near-equiatomic initial compositions, which limit the increase of intermetallic precipitates that are closely related to the alloy strength. Here we present a strategy to design ultrastrong HEAs with high-content nanoprecipitates by phase separation, which can generate a near-equiatomic matrix in situ while forming strengthening phases, producing a PH-HEA regardless of the initial atomic ratio. Accordingly, we develop a non-equiatomic alloy that utilizes spinodal decomposition to create a low-misfit coherent nanostructure combining a near-equiatomic disordered face-centered-cubic (FCC) matrix with high-content ductile Ni 3 Al-type ordered nanoprecipitates. We find that this spinodal order–disorder nanostructure contributes to a strength increase of ~1.5 GPa (>560%) relative to the HEA without precipitation, achieving one of the highest tensile strength (1.9 GPa) among all bulk HEAs reported previously while retaining good ductility (>9%). High entropy alloys usually emphasize equiatomic compositions, which restrict the compositions available to induce strengthening via precipitation. Here the authors use spinodal decomposition in a five-element alloy to obtain high content nanophases and the highest tensile strength reported to date.

While energetic high-entropy alloys (EHEAs) demonstrate tunable performance characteristics, the thermodynamic considerations inherent in their compositional design fundamentally impede the attainment of high-density properties. This study reports a novel dual-phase multi-principal element alloy (MPEA) comprising tungsten (W)-rich dense phase and EHEA-based solid solution phase, synthesized through laser-induced ultrashort-time liquid phase sintering (LULPS). The systematic investigation correlates processing parameters with densification behaviour and W-phase morphological evolution. The results show that with the higher laser energy densities ( E ), the density of the alloy increases, and the W morphologies change from spherical to dendritic or polygonal. Notably, dendritic/polygonal W dominance, elevated matrix W content, and intensified W-W connectivity contribute to property degradation. Therefore, when the E reaches 120J/mm 3 , high-density alloy with the target microstructure can be successfully fabricated. Under dynamic loading, this alloy demonstrated superior strength−ductility combination (compressive strength: ~2.37 GPa, fracture strain: ~33%) and energy release characteristics. This provides a new insight for the design and development of advanced materials.

For low-fluidity alloys such as TiNb-rich high-entropy alloys, casting parts with complex geometry normally encounter the forming problems like incomplete filling, shrinkage cavities and porosity. Additive manufacturing (AM) is suitable for fabricating those complex parts. However, for the regular portion of a complex part such as the disc of an impeller, AM is not a cost-optimal choice. This work proposes a facile route to fabricate high-performance parts with complex geometry, in which the portion with regular geometry is cast whereas the complex portion that requires high performance is additively manufactured. The results show that the failure always occurs in the cast portion of the hybrid manufactured sample rather than at the interface between the AM portion and the cast one. The strong interfacial bonding is quite different from the welding joint which is commonly the weak link. Moreover, compared with the cast portion with coarse equiaxed grains, the equiaxed fine-grained AM portion exhibits higher strength without sacrificing ductility. Hybrid manufacturing does not introduce weakness, but rather can strengthen the targeted portion by a reasonable structural design.

ObjectiveTo investigate the serum protein targets of Qianggu Decoction (强骨饮, QGD) on treating osteoporosis by the proteomics analysis using tandem mass tag (TMT) and liquid chromatographytandem mass spectrometry (LC-MS/MS).MethodsTwenty serum protein samples were recruited (10 patients with primary type I osteoporosis before and after QGD treatment) and the high abundance ratios protein was removed, two serum samples were extracted and labeled with TMT reagent. Then, mass spectrometric detection, identification of differentially expressed proteins and bioinformatics analysis of differentially expressed proteins were carried out.ResultsA total of 60 proteins were identified, within a 99% confidence interval, to be differentially regulated of which, 34 proteins were up-regulated and 26 proteins were down-regulated. Differentially expressed proteins analyzed by Gene Ontology (GO) annotation mainly get involved in 12 different biological processes, 7 types of cellular components, and 6 kinds of molecular functions. Angiotensinogen (AGT), stromelysin-1 (MMP3), heparanase (HPSE) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were screened as candidate protein targets of QGD treatment, which were related to metabolic mechanism of bone remodeling and/or bone collagen of osteoporosis. By the utilization of the protein-protein interaction network analysis tool named STRING10.0, it showed that AGT, MMP3, HPSE and GAPDH were located in the key node of the protein-protein interactions network. Furthermore, AGT, MMP3, HPSE and GAPDH were found to be directly related to BMP, MAPK, Wnt, SMAD and tumor necrosis factor ligand superfamily member 11 (TNFSF11) families.ConclusionsThe proteomics analysis by using TMT combined with LC-MS/MS was a feasible method for screening the potential therapeutic targets associated with QGD treatment. It suggests that AGT, MMP3, HPSE and GAPDH may be candidate protein targets of QGD treatment which can be used as therapeutic effect monitor and early diagnosis of primary type I osteoporosis.

Quantitative parameters of bed combustion, including the thickness of the combustion zone(TCZ), the maximum temperature of the combustion zone(MTCZ), and the bed shrinkage, were characterized through a series of sinter pot tests in transparent quartz pots. The results showed that TCZ first ascended and then descended as the sintering process proceeded. The sintering process was divided into four stages according to the variation rate of the TCZ. A 'relative-coordinate' method was developed to obtain the actual reaction temperature of sinter along the height direction. With increasing the sintering temperature, the reactants transformed and entered into liquid phases. The mineral composition and microstructure of the sinter were characterized through X-ray diffraction and scanning electron microscopy–energy-dispersive X-ray spectroscopy. Liquid phases with greater Fe and Al contents were more likely to form acicular-like silico-ferrite of calcium and aluminum after crystallization because of the outward spread of Al, which led to a better fluidity of the liquid. An evolution mechanism of 'solid-state reaction—liquid phases formation—crystallization' of the mineral phases is proposed.

Background： Whether cholinergic innervations and/or autophagy have a role in the etiopathology of benign prostatic hyperplasia （BPH） is still unknown. This study aimed to investigate the role of cholinergic innervation and autophagy in the etiopathology of BPH. Methods： Male, 13-week-old spontaneous hypertension rats （spontaneous BPH animal model） were divided into three groups： an experimental group （EG, n = 24）, a control group （CG, n = 24）, and a normal control group （NC, n = 10）. The EG animals were intragastrically injected with tolterodine （3.5 mg/kg, twice a day）, CG animals were intragastrically injected with physiological saline, and the NC animals did not receive any treatment. Rats were sacrificed every 4 weeks, and the prostatic gross morphological changes, wet weight/body weight （ww/bw）, dry weight/wet weight （dw/ww）, histological changes, ultrastructural changes, and LC3 immunohistochemistry were continuously observed and compared. Results： The gross morphological and ww/bw changes in the three groups were similar at every stage. The dw/ww （mg/mg） values of the EG at week 17, 21, 25, and 29 were 0.1478 ±0.0034, 0.1653 ± 0.0036, 0.1668 ± 0.0045, and 0.1755±0.0034, respectively, and the CG values were 0.1511 ±0.0029, 0.1734± 0.0020, 0.1837 ±0.0052, and 0.1968 ± 0.0045, respectively. The difference between EG and CG for dw/ww showed statistical significance after 21 weeks of age （week 21： P = 0.016, week 25： P = 0.008, and week 29： P = 0.001）. Both EG and CG, prostatic glandular epithelial cell proliferation, and secretory function improved with age, but in EG, these improvements were slower than those in CG, and all the differences were statistically significant after 21 weeks. An increasing number of autophagosomes in the prostatic glandular cell cytoplasm, attenuation of LC3-I immunohistochemical staining, enhancement of LC3-II staining, and the ratio of LC3-1I/LC3-1 staining were all progressive in both groups, but the rate of change in EG was faster than that in CG, and these differences gained statistical significance after 25 weeks. Comparisons with regard to the above indexes between CG and NC showed no statistical significance at any stage. Conclusions： Cholinergic innervations and activation of autophagy appear to have important functions in the etiopathology of BPH. Drug-mediated blockade of cholinergic innervations could delay the physiopathology processes. Moreover, overactivation of autophagy may also play an important role in this delay.

This study examined the effects of salinity on embryonic development,survival,and growth of the Hong Kong oyster Crassostrea hongkongensis.The embryos,larvae,and juveniles of C.hongkongensis were held in artificial seawater at three different salinities （low,15; medium,23; and high,30） to determine the optimum hatchery and nursery conditions for mass production of the seeds.Results showed that the percentage production of straight-hinged larvae from fertilized eggs was significantly lower at the high salinity than at the low-and medium-salinities （P ＜ 0.05）.The survival rates of larvae and juveniles differed significantly among the three salinity trials,with the highest survival rate observed at the low salinity （P＜ 0.05）.The shell height of larvae was significantly larger at the low salinity than at the high and medium salinities from days 9 to 15 （P＜ 0.05）,whereas that of juveniles was significantly larger at the low salinity than at the high and medium salinities on day 70 （P ＜ 0.05）.These results indicate that the larvae and juveniles of C.hongkongensis are tolerant to a wide range of salinities （15 to 30）,but show better growth and survival at relatively low salinities.Thus,it is recommended to use relatively low salinities in hatchery and nursery systems for improved yields of C.hongkongensis.

Quantitative parameters of bed combustion, including the thickness of the combustion zone (TCZ), the maximum temperature of the combustion zone (MTCZ), and the bed shrinkage, were characterized through a series of sinter pot tests in transparent quartz pots. The results showed that TCZ first ascended and then descended as the sintering process proceeded. The sintering process was divided into four stages according to the variation rate of the TCZ. A “relative-coordinate” method was developed to obtain the actual reaction temperature of sinter along the height direction. With increasing the sintering temperature, the reactants transformed and entered into liquid phases. The mineral composition and microstructure of the sinter were characterized through X-ray diffraction and scanning electron microscopy-energy-dispersive X-ray spectroscopy. Liquid phases with greater Fe and Al contents were more likely to form acicular-like silico-ferrite of calcium and aluminum after crystallization because of the outward spread of Al, which led to a better fluidity of the liquid. An evolution mechanism of “solid-state reaction-liquid phases formation-crystallization” of the mineral phases is proposed.

Background：The postremission therapics for adult patients generally contain consolidation chemotherapy,allogeneic hematopoietic stem cell transplantation and autologous hematopoietic stem cell transplantation （auto-HSCT）.Because of the various results from different centers,the optimal therapy for adult acute lymphoblastic leukemia （ALL） patients is still uncertain.This study aimed to better understand predictive factors and role of auto-HSCT in the postremission thcrapy for adult ALL patients.Methods：The outcomes of 135 adult patients with ALL,who received the first auto-HSCT in Hematopoietic Stem Cell Transplantation Center of Blood Diseases Hospital,Chinese Academy of Medical Sciences from January 1,1994 to February 28,2014,were retrospectively analyzed.Survival curves were estimated using the Kaplan-Meier method and simultaneous effects of multiple covariates were estimated with the Cox model.Results：Overall survival （OS） and disease-free survival （DFS） at 5 years for the whole cohort were 59.1 ± 4.5% and 59.0 ± 4.4%,respectively.The cumulative nonrelapse mortality and relapse rate at 5 years were 4.5 ± 0.03% and 36.6 ± 0.19%.For both OS and DFS,acute T-cell lymphoblastic leukemia,high lactate dehydrogenase （LDH） at diagnosis,blast cell proportion ≥5% on the 15th day of induction therapy,and extramedullary infiltration before HSCT were the poor prognosis factors.In addition,age ≥35 years predicted poor DFS.Only T-ALL and high LDH were the independent undesirable factors associated with OS and DFS in Cox regression model.For 44 patients who had results of pretransplantation minimal residual disease （MRD）,positive MRD （MRD ≥0.01%） indicated poor OS （P =0.044） and DFS （P =0.008）.Furthermore,for the standard risk group,the patients with negative MRD （MRD 〈0.01%） had better results （OS at 18 months was 90.0 ± 9.5%,while for the patients with positive MRD OS was 50.0 ± 35.4%,P =0.003;DFS at 18 months was 90.0 ± 9.5%,while for the positive MRD group DFS was 0%,P 〈 0.001）.Conclusions：This study confirmed that auto-HSCT combined with posttransplantation maintenance chemotherapy could be an option for adult ALL patients and pretransplantation MRD may play a significant role in the direction of therapy for adult ALL patients.

The mutation of B-Rafv600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-Rafv600E is an ideal drug target. This study focused on developing novel B-Rafv600E inhibitors as drug leads against various cancers with B-Rafv600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-Rafv600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-Rafv600E inhibitors. A highly potent fragment binding to the hinge area of B-Rafv600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-Rafv600E inhibitors. Biological evaluation revealed that compound lm is a potent B-Rafv600E inhibitor with an IC50 value of 0.05 μmol/L, which was lower than that of vemurafenib （0.13 μmol/L）. Moreover, the selectivity of lm against B-RafwT was enhanced compared with vemurafenib. In addition, lm exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays, Thus, a highly potent and selective B-Rafv600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.