Effects of pre-aging on microstructure evolution and deformation mechanisms of hot extruded Mg–6Zn–1Gd–1Er Mg alloys

The influence of pre-aging treatment on the microstructure,texture and mechanical properties of the Mg–6Zn–1Gd–1Er(wt.%)alloy was investigated.The microstructure analysis shows that the presence of pre-aging is beneficial to{1012}twin nucleation at the early stage of extrusion and inhibits the growth of twins and promotes the formation of[1010]-fiber texture components,thus accelerating the complex process of recrystallization.In the middle stage of extrusion,the extruded samples under the condition of solid solution were subjected to dynamic precipitation during severe shear deformation.The precipitation of the second phase particles followed the particle stimulating nucleation(PSN)mechanism,which increased the volume fraction of DRX grains during extrusion.In the extruded samples under the peak-aged condition,the particles appear dissolved during the severe shear deformation strain,which slows down the DRX process.In the later stage of extrusion,the small rod-shaped particles followed the PSN mechanism,and finally formed the strong fiber texture.The extruded alloy exhibits the strongest mechanical properties under the peak-aged state,with ultimate tensile strength(UTS)of 346 MPa,tensile yield strength(TYS)of 217 MPa,and elongation to failure(EL)of 13.6%.The improvement of mechanical properties is mainly attributed to the existence of strong fiber texture,small rod-shaped and block-shaped phases.

Pandemic A/HIN1 2009 Influenza Virus-like Particles Elicited Higher and Broader Immune Responses than the Commercial Panenza Vaccine

Objectives： The aim was to construct 2009 pandemic A/HINI influenza VLPs （virus-like particles） and compare the immunogenicity and protection efficacy with the commercial Panenza vaccine in BALB/c mouse model. Methods： VLPs derived from influenza A/Hong Kong/01/2009 （H 1N 1 ） virus were constructed by Bac-to-Bac baculovirus expression system. VLPs were purified by sucrose density gradient ultracentrifugation and then characterized by Western blotting analysis and transmission electron microscopy. After single dose vaccination with 3 lag of VLPs and equal amount of Panenza vaccine, the immune responses and efficacy of protection induced by VLPs were compared with those elicited by the Panenza vaccine in 6-8 weeks old female BALB/c mice. Key findings： VLPs could induce higher antibody titer as determined by hemagglutinin inhibition and microneutralization assay. Furthermore, we demonstrated that VLPs induced better antibody response to neuraminidase. In addition, VLP vaccinated mice had stronger cell-mediated immune response. As a result, our VLPs conferred 100% protection while the Panenza vaccine only conferred 67% protection. Conclusion： From the results, we concluded that influenza VLPs are highly immunogenic and they are promising to be developed as an alternative strategy to vaccine production in order to control the spread of influenza viruses.

Designing new low alloyed Mg-RE alloys with high strength and ductility via high-speed extrusion

Two new low-alloyed Mg-2RE-0.8Mn-0.6Ca-0.5Zn(wt%,RE=Sm or Y)alloys are developed,which can be produced on an in-dustrial scale via relatively high-speed extrusion.These two alloys are not only comparable to commercial AZ31 alloy in extrudability,but also have superior mechanical properties,especially in terms of yield strength(YS).The excellent extrudability is related to less coarse second-phase particles and high initial melting point of the two as-cast alloys.The high strength-ductility mainly comes from the formation of fine grains,nano-spaced submicron/nano precipitates,and weak texture.Moreover,it is worth noting that the YS of the two alloys can maintain above 160 MPa at elevated temperature of 250°C,significantly higher than that of AZ31 alloy(YS:45 MPa).The Zn/Ca solute segregation at grain boundaries,the improved heat resistance of matrix due to addition of RE,and the high melting points of strengthening particles(Mn,MgZn_(2),and Mg-Zn-RE/Mg-Zn-RE-Ca)are mainly responsible for the excellent high-temperature strength.

Developing new Mg alloy as potential bone repair material via constructing weak anode nano-lamellar structure

The mechanics-corrosion and strength-ductility tradeoffs of magnesium(Mg)alloys have limited their applications in fields such as orthopedic implants.Herein,a fine-grain structure consisting of weak anodic nano-lamellar solute-enriched stacking faults(SESFs)with the average thickness of 8 nm and spacing of 16 nm is constructed in an as-extruded Mg96.9Y1.2Ho1.2Zn0.6Zr0.1(at.%)alloy,obtaining a high yield strength(YS)of 370 MPa,an excellent elongation(EL)of 17%,and a low corrosion rate of 0.30 mm y−1(close to that of high-pure Mg)in a uniform corrosion mode.Through scanning Kelvin probe force microscopy(SKPFM),one-dimensional nanostructured SESFs are identified as the weak anode(∼24 mV)for the first time.The excellent corrosion resistance is mainly related to the weak anodic nature of SESFs and their nano-lamellar structure,leading to the more uniform potential distribution to weaken galvanic corrosion and the release of abundant Y^(3+)/Ho^(3+)from SESFs to form a more protective film with an outer Ca_(10)(PO_(4))_(6)(OH)_(2)/Y_(2)O_(3)/Ho_(2)O_(3) layer(thickness percentage of this layer:72.45%).For comparison,the as-cast alloy containing block 18R long period stacking ordered(LPSO)phase and the heat-treated alloy with fine lamellar 18R-LPSO phase(thickness:80 nm,spacing:120 nm)are also studied,and the characteristics of SESFs and 18R-LPSO phase,such as the weak anode nature of the former and the cathode nature of the latter(37-90 mV),are distinguished under the same alloy composition.Ultimately,we put forward the idea of designing Mg alloys with high mechanical and anti-corrosion properties by constructing"homogeneous potential strengthening microstructure",such as the weak anode nano-lamellar SESFs structure.

Neddylation is a novel therapeutic target for lupus by regulating double negative T cell homeostasis

Systemic lupus erythematosus(SLE),a severe autoimmune disorder,is characterized by systemic inflammatory response,autoantibody accumulation and damage to organs.The dysregulation of double-negative(DN)T cells is considered as a crucial commander during SLE.Neddylation,a significant type of protein post-translational modification(PTM),has been well-proved to regulate T cell-mediated immune response.However,the function of neddylation in SLE is still unknown.Here,we reported that neddylation inactivation with MLN4924,a specific inhibitor of NEDD8-activating enzyme E1(NAE1),or genetic abrogation of Ube2m in T cells decreased DN T cell accumulation and attenuated murine lupus development.Further investigations revealed that inactivation of neddylation blocked Bim ubiquitination degradation and maintained Bim level in DN T cells,contributing to the apoptosis of the accumulated DN T cells in lupus mice.Then double knockout(KO)lupus-prone mice(Ube2m-/-Bim-/-lpr)were generated and results showed that loss of Bim reduced Ube2m deficiency-induced apoptosis in DN T cells and reversed the alleviated lupus progression.Our findings identified that neddylation inactivation promoted Bim-mediated DN T cell apoptosis and attenuated lupus progression.Clinically,we also found that in SLE patients,the proportion of DN T cells was raised and their apoptosis was reduced.Moreover,compared to healthy groups,SLE patients exhibited decreased Bim levels and elevated Cullin1 neddylation levels.Meantime,the inhibition of neddylation induced Bim-dependent apoptosis of DN T cells isolated from SLE patients.Altogether,our findings provide the direct evidence about the function of neddylation during lupus,suggesting a promising therapeutic approach for this disease.

Crack behavior in Mg/Al alloy thin sheet during hot compound extrusion

A novel and effective method to co-extrude metallic alloys is described which named Direct Extrusion and Bending-Shear Deformation.The compound extrusion plates have cracked at 290℃ and 3 mm/s.According to this phenomenon,a model was built to investigate the crack generation and development between the 6061 Al and AZ31 Mg alloy during the compound extrusion process by DEFORM-3D.The cracking behavior of the Mg/Al composite rod with a soft Mg AZ31 core and a hard Al 6061 sleeve were systematically studied to disclose the influence of microstructure on crack in the different regions.The simulation results show that the distribution of strain and velocity has significant differences due to the influence of dies structure and material properties at different locations in the same region.The experimental results show that in the same conditions,there are differences in recrystallization and texture weakening of AZ31 Mg alloys and 6061 Al alloy,which are important factors for the formation of crack.Both the Mg layer and the Al layer have a homogeneous microstructure in the region d.

High speed cutting of AZ31 magnesium alloy

Using LBR-370 numerical control lathe,high speed cutting was applied to AZ31 magnesium alloy.The influence of cutting parameters on microstructure,surface roughness and machining hardening were investigated by using the methods of single factor and orthogonal experiment.The results show that the cutting parameters have an important effect on microstructure,surface roughness and machine hardening.The depth of stress layer,roughness and hardening present a declining tendency with the increase of the cutting speed and also increase with the augment of the cutting depth and feed rate.Moreover,we established a prediction model of the roughness,which has an important guidance on actual machining process of magnesium alloy.

The flow behavior in as-extruded AZ31 magnesium alloy under impact loading

As-extruded AZ31 magnesium alloy samples were compressed at ambient temperature and strain rates of 1000-3000 s^(−1).The fracture surfaces of cracked samples,the evolution of microstructures and macrotextures were detected.The received flow curves exhibit an abnormal behavior at strain rates above 1500 s^(−1).A strain constitutive model based on strain equivalent principle was applied to analyze the flow curves of the damaged samples.The results indicate that the abnormal flow behaviors of the fractured samples are related to the increasing area of crack surfaces,and kinetic energy during dynamic crack nucleation and propagation.The initiation of the micro-crack also causes obvious flow softening in the cracked samples.The shapes of flow stresses of the intact samples are affected by twinning.©2018 Published by Elsevier B.V.on behalf of Chongqing University.

B1-cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation

Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis (LN) remain largely unclear. Here, we report a pathogenic role of anti-phosphatidylserine (PS) autoantibodies in the development of LN. Elevated serum PS-specific IgG levels were measured in model mice and SLE patients, especially in those with LN. PS-specific IgG accumulation was found in the kidney biopsies of LN patients. Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice. ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients. Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice, whereas depletion of B1a cells attenuated lupus progression. In culture, PS-specific B1a cells were significantly expanded upon treatment with chromatin components, while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells. Thus, our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development. Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.

Hot Compression Mechanical Behavior of Solution Heat‑Treated and Pre‑aged Mg–Zn–Gd–Er Alloys

The mechanical behavior of solution heat-treated and pre-aged Mg–6Zn–1Gd–1Er alloys during hot compression(from 180 to 330℃)has been investigated.The results showed that the flow stress curves of the pre-aged sample(PAS)intersected with that of the solution heat-treated sample(SHTS)during hot compression.At 180℃,when the true strain is 0.27 and 0.47,the PAS showed larger and smaller stress(210.80 MPa vs.207.58 MPa and 205.67 MPa vs.207.93 MPa)than the SHTS,respectively.These phenomena were due to the stronger interaction of W phase and dislocations/twins under the strain of 0.27,while dynamic recrystallization softening occurred under the strain of 0.47.When the temperature increased to 330℃,the flow stress of PAS and SHTS showed an opposite trend to that of 180℃.Continuous dynamic recrystallization and particle stimulated nucleation based on slip operations are the main deformation mechanisms under 330℃.At the true strain is 0.33 and 0.53,the PAS has smaller and larger stress(61.32 MPa vs.63.69 MPa and 58.75 MPa vs.57.09 MPa)than the SHTS,respectively.The increasing deformation resistance of dynamic precipitation improved the flow stress under smaller strain and dynamic recrystallization decreased the flow stress under high strain,which resulted the opposite phenomena of SHTS.

Deformation Behavior and Microstructure Evolution of AZ31 Mg Alloy by Forging-Bending Repeated Deformation with Multi-pass Lowered Temperature

In this study, AZ31 Mg alloy was processed by a new severe plasticity deformation methodology with multi-pass lowered temperature, and the deformation behavior and microstructure evolution were investigated by finite element method and electron back-scattered diffraction technique and hardness. The results show that with the increase of deformation pass, the strain gradually springs, and its interval distribution tends to homogenize. Meanwhile, the effective strain increases dramatically with the shear force sudden upgrade in the deformation process. Moreover, the new deformation technique can refine grain size remarkably. With the passes on, {10-12} tensile twins behavior and the pyramidal < c + a > slip are triggered more frequently, leading to the completeness of dynamic recrystallization (DRX) gradually, which weaken and disperse the basal texture obviously. Besides, the standard deviation of hardness is getting smaller, and the maximum can reach 78.40 HV on average, which can be attributed to the even large strain distribution, complete DRX, and the high geometrically necessary dislocation.

Influence of Ca Content on Microstructure and Mechanical Properties of Extruded Mg–Al–Ca–Mn Alloys

Herein,the effects of Ca content on microstructure,texture and mechanical properties of extruded Mg–3Al–0.4Mn–xCa(x=0.4,0.8 and 1.2 wt%)rods are systematically investigated.The results reveal that the alloy,with Ca content of 0.8 wt%,exhibits the highest strength and ductility,possessing an ultimate tensile strength of 267.57 MPa and elongation(EL)of 16%.This is mainly due to the gradual transformation of typical fiber texture into a texture with a[10-11]component parallel to the extrusion direction(ED),which increases the Schmid factor of pyramidal slip and enhances the activation rate of pyramidal(c+a)slip.Simultaneously,the as-formed spherical phases and segregation of Ca at grain boundaries render a significant influence on the strength and ductility of the alloy.

Overview of chemical constituents and pharmacological activities of Piper longum Linn.

Piper longum Linn. is a native of the Indo-Malaya region, belongs to the family Piperaceae. It is a slender aromatic climber widely distributed in the tropical and subtropical regions. As a traditional ethnic drug, P. longum contains various chemical constituents such as alkaloids, volatile oil and lignans. The extract of P. longum has been reported to show various activities like antitumor, antioxidant and hepatoprotective activity. Hence, this paper is presented as a review centered on the main chemical constituents and pharmacological effects of P. longum, aiming at its further development and potential value.

Network pharmacology-based prediction and verification of the molecular targets and pathways for Piper longum Linn,against liver cancer

Liver cancer is a common malignant tumor,which is one of the most common causes of cancer related deaths worldwide,specially,in China.Piper longum Linn,is a traditional Chinese medicine that is used to treat and prevent diseases in clinical practice,however,the active ingredients and potential targets of its action against liver cancer remain unclear.In this study,network pharmacology approach was used to identify active ingredients and the major targets of Piper longum against liver cancer.In addition,the key pathways were also predicted on the network pharmacology level,which might be beneficial to the chemical basis and pharmacological studies of this plant.

Coming of age:the formation and function of age-associated B cells

B cells are generated in the bone marrow during ontogeny and migrate to peripheral lymphoid organs,where they encounter antigens to elicit humoral immunity.During the past decade,many novel B-cell subsets with distinct phenotypes and functions have been identified,and among these subsets,age-associated B cells(ABCs)were first characterized as a B-cell subset that accumulates with age[1].

B-cell-targeted therapies in systemic lupus erythematosus

Autoreactive B cells are one of the key immune cells that have been implicated in the pathogenesis of systemic lupus erythematosus （SLE）. In addition to the production of harmful auto-antibodies （auto-Abs）, B cells prime autoreactive T cells as antigen-presenting cells and secrete a wide range of pro-inflammatory cytokines that have both autocrine and paracrine effects. Agents that modulate B cells may therefore be of potential therapeutic value. Current strategies include targeting B-cell surface antigens, cytokines that promote B-cell growth and functions, and B- and T-cell interactions. In this article, we review the role of B cells in SLE in animal and human studies, and we examine previous reports that support B-cell modulation as a promising strategy for the treatment of this condition. In addition, we present an update on the clinical trials that have evaluated the therapeutic efficacy and safety of agents that antagonize CD20, CD22 and B-lymphocyte stimulator （BLyS） in human SLE. While the results of many of these studies remain inconclusive, belimumab, a human monoclonal antibody against BLyS, has shown promise and has recently been approved by the US Food and Drug Administration as an indicated therapy for patients with mild to moderate SLE. Undoubtedly, advances in B-cell immunology will continue to lead us to a better understanding of SLE pathogenesis and the development of novel specific therapies that target B cells.

IL-17 sustains the plasma cell response via p38-mediated Bcl-xL RNA stability in lupus pathogenesis

Recent studies have demonstrated a central role for plasma cells in the development of autoimmune diseases,such as systemic lupus erythematosus(SLE).Currently,both the phenotypic features and functional regulation of autoreactive plasma cells during SLE pathogenesis remain largely unclear.In this study,we first found that a major subset of IL-17 receptor-expressing plasma cells potently produced anti-dsDNA IgG upon IL-17A(IL-17)stimulation in SLE patients and lupus mice.Using a humanized lupus mouse model,we showed that the transfer of Th17 cell-depleted PBMCs from lupus patients resulted in a significantly reduced plasma cell response and attenuated renal damage in recipient mice compared to the transfer of total SLE PBMCs.Moreover,long-term BrdU incorporation in lupus mice detected highly enriched long-lived BrdU+subsets among IL-17 receptor-expressing plasma cells.Lupus mice deficient in IL-17 or IL-17 receptor C(IL-17RC)exhibited a diminished plasma cell response and reduced autoantibody production with attenuated renal damage,while the adoptive transfer of Th17 cells triggered the plasma cell response and renal damage in IL-17-deficient lupus mice.In reconstituted chimeric mice,IL-17RC deficiency resulted in severely impaired plasma cell generation but showed no obvious effect on germinal center B cells.Further mechanistic studies revealed that IL-17 significantly promoted plasma cell survival via p38-mediated Bcl-xL transcript stabilization.Together,our findings identified a novel function of IL-17 in enhancing plasma cell survival for autoantibody production in lupus pathogenesis,which may provide new therapeutic strategies for the treatment of SLE.

AIM2 deficiency in B cells ameliorates systemic lupus erythematosus by regulating Blimp-1-Bcl-6 axis-mediated B-cell differentiation

Absent in melanoma 2(AIM2)has been reported to be a component of inflammasomes in innate immune cells.Surprisingly,AIM2 is expressed by B cells,and higher AIM2 expression is observed in the B cells from lupus patients.To date,the inflammasome-indepe ndent functi on of AIM2 in B cells remai ns un clear.Here,we report in creased expressi on of AIM2 in human tonsil memory and germinal center(GC)B cells and in memory B cells and plasma cells from the circulation and skin lesions of lupus patients.Conditional knockout of AIM2 in B cells reduces the CD19^(+)B-cell frequency in lymph nodes and spleens,and dampens KLH-induced lgG1-antibody production.In a pristane-induced mouse model of lupus,AIM2 deficiency in B cells attenuates lupus symptoms and reduces the frequency of GC B cells,T follicular helper(Tfh)cells,plasmablast cells,and plasma cells.Furthermore,the loss of AIM2 in human B cells leads to the increased expression of Blimp-1 and reduces the expression of Bcl-6.However,the silendng of Blimp-1 and Bcl-6 has no significant effect on AIM2 expression,indicating that AIM2 might be the upstream regulator for Blimp-1 and Bcl-6.In addition,IL-10 is found to upregulate AIM2 expression via DNA demethylation.Together,our findings reveal that AIM2 is highly expressed in the B cells of lupus patients and promotes B-cell differentiation by modulating the Bcl-6-Blimp-1 axis,providing a novel target for SLE treatment.

A critical role of IL-17 in modulating the B-cell response during H5N1 influenza virus infection

Interleukin-17(IL-17),a member of the IL-17 cytokine family,plays a crucial role in mediating the immune response against extracellular bacteria and fungi in the lung.Although there is increasing evidence that IL-17 is involved in protective immunity against H1 and H3 influenza virus infections,little is known about the role of IL-17 in the highly pathogenic H5N1 influenza virus infection.In this study,we show that H5N1-infected IL-17 knockout(KO)mice exhibit markedly increased weight loss,more pronounced lung immunopathology and significantly reduced survival rates as compared with infected wild-type controls.Moreover,the frequency of B cells in the lung were substantially decreased in IL-17 KO mice after virus infection,which correlated with reduced CXCR5 expression in B cells and decreased CXCL13 production in the lung tissue of IL-17 KO mice.Consistent with this observation,B cells from IL-17 KO mice exhibited a significant reduction in chemokine-mediated migration in culture.Taken together,these findings demonstrate a critical role for IL-17 in mediating the recruitment of B cells to the site of pulmonary influenza virus infection in mice.

An isoleucine-zipper motif enhances costimulation of human soluble trimeric GITR ligand

Glucocorticoid-induced tumor-necrosis factor receptor(GITR)and its ligand,GITRL,play significant roles in regulating immune responses.It is clear that human soluble GITRL(hsGITRL)transduces signal activity through multiple oligomerization states.To develop human soluble trimeric GITRL protein as a potential therapeutic target,we explored the link of the isoleucine-zipper(ILZ)motif to the N-terminus of the human soluble GITRL with two leucine sequences.hsGITRL,with the ILZ motif(ILZ-hsGITRL),was firstly expressed in Escherichia coli,which exhibited a predominant trimer when identified by Sephadex G-100 filtration and non-reducing SDS–polyacrylamide gel electrophoresis(SDS-PAGE).The significantly higher biological activity of the ILZ-hsGITRL compared with hsGITRL was confirmed by CD41 T proliferation,interferon-c(IFN-c)secretion and binding activity assay.To reveal and compare the underlying mechanisms,the level of extracellular signal-regulated kinase-1/2(ERK1/2)phosphorylation was examined,indicating that ILZ-hsGITRL induced more persistent and stronger ERK1/2 activation than hsGITRL.In conclusion,the incorporation of an ILZ motif could markedly improve the costimulation of hsGITRL.