Stacked chip scale package(SCSP) attracts more and more attentions in advanced packages application with light weight,thin and small size,high reliability,low power and high storage capability.However,more and more ph...Stacked chip scale package(SCSP) attracts more and more attentions in advanced packages application with light weight,thin and small size,high reliability,low power and high storage capability.However,more and more physical and electrical issues being caused by package-induced stress in SCSP were reported recently.The effect of structural factors,including die thickness,die attach film thickness,die attach film type,and spacer size on package induced stress,was investigated.Analyses were given based on simulation results and provide important suggestion for package design.展开更多
Vascular remodeling is the essential pathogenic process of various cardiovascular disorders,including hypertension,atherosclerosis,stroke,and restenosis after vein graft.The main characterization of vascular remodelin...Vascular remodeling is the essential pathogenic process of various cardiovascular disorders,including hypertension,atherosclerosis,stroke,and restenosis after vein graft.The main characterization of vascular remodeling is abnormal variations of vascular cell phenotype,morphological structure and functions such as migration,hypertrophy,proliferation and apoptosis.Numerous researches revealed that mechanical stress,including shear stress and cyclic stretch,participates in physiological vascular homeostasis,or pathophysiological vascular remodeling.The understanding of mechanobiological mechanism in vascular remodeling will play a unique role in understanding human physiology and disease,and will generate important theoretical and clinical significance [2].Non-coding RNAs are newly recognized RNAs which cannot be translated into proteins but are involved in epigenetic modification of gene regulation.The studies revealed that non-coding RNAs,such as microRNAs(miRNAs)and long noncoding RNAs(long ncRNAs,IncRNA),as well as small interfering RNAs(siRNAs),piwi-interacting RNAs(piRNAs),small nucleolar RNAs(snoRNAs),play essential roles in the regulation of various processes,such as metabolism,development,cell proliferation,cell apoptosis,cell differentiation,oncogenesis and vascular homeostasis[5].However,the roles of non-coding RNAs in the cardiovascular system under mechanical stresses are still not clarified.Our recent researches detected the mechanical regulation of IncRNAs and miRNAs in vascular remodeling.LncRNAs are non-protein-coding transcripts that are longer than 200 nucleotides(nt),which is an arbitrary cut-off value that distinguishes these transcripts from other small RNAs.Unlike the well-established mechanism of microRNA action,the functional mode of IncRNAs is not fully understood.Increasing evidence shows that IncRNAs modulate gene expression via a multilevel-regulated pathway.Given their large number and complicated functional modes,lncRNAs are emerging as important regulators of a variety of cellular responses,developmental processes and diseases.Using a gene microarray,we screened the differences in the IncRNAs and mRNAs between spontaneously hypertensive rats(SHR)and Wistar Kyoto rats(WKY).The results showed that 68 IncRNAs and 255 mRNAs were up-regulated in the aorta of SHR,while 167 IncRNAs and 272 mRNAs were down-regulated.Expressions of the screened IncRNAs,including XR007793,were validated by real-time PCR.A co-expression network was composed,and gene function was analysed using Ingenuity Pathway Analysis.In vitro,vascular smooth muscle cells(VSMCs)were subjected to cyclic stretch at a magnitude of 5%(physiological normotensive cyclic stretch)or 15%(pathological hypertensive cyclic stretch)by Flexercell-5000TM.15%-cyclic-stretch increased XR007793 expression.XR007793 knockdown attenuated VSMC proliferation and migration and inhibited co-expressed genes such as signal transducers and activators of transcription 2(stat2),LIM domain only 2(lmo2)and interferon regulatory factor 7(irf7)[4].Illuminating the role of IncRNAs in vascular remodeling induced by hyper mechanical stretch may provide deeper insight into the mechanobiological mechanism underlying hypertension,and contribute to identifying potential targets for hypertension therapy.miRNAs are endogenous,non-coding,single-stranded RNAs of 18-22 nucleotides that constitute a novel class of gene regulators.miRNAs bind to their target genes within their 3’-untranslated regions(3’-UTRs),leading to direct degradation of mRNA or translational repression by a complete,i.e.in plants,or incomplete,i.e.in animals,complement respectively.Our resent works revealed several important mechano-responsive miRNA and their potential effects in vascular remodeling.Forexample,miRNA-33 is regulated by cyclic stretch in the grafted vessels,which targets to BMP3 and subsequent modulates smad signaling pathway.The miRNA-33-BMP3-smad pathway protects against venous VSMC proliferation in response to arterial cyclic stretch.Therefore,miRNA-33 may be a potential therapeutic target in autologous vein grafted surgery,and locally overexpression of miR-33 may attenuates neointimal hyperplasia of grafted human saphenous vein [3].The unpublished data revealed that 15%cyclic stretch also significantly elevated the expression of miRNA-124-3p which bound to the 3’UTR of Lmna mRNA,and then negatively regulated protein expression of lamin A/C which is the important skeletal proteins in nucleus.In addition to primary intracellular locations of miRNAs,our recent study showed that miRNAs can be secreted and protected extracellularly via inclusion into membrane-derived vesicles including microparticles.Microparticles are extracellular vesicles ranging from 0.1 to 1μm in size and have been shown to deliver various bioactive molecules,i.e.,chemokines,enzymes and miRNAs,to recipient cells.Increasing evidence shows that microparticles play a pivotal role in many pathological processes,such as cancer,inflammatory diseases and cardiovascular disease.Our present study showed that platelet-derived microparticles(PMPs),which are released by active platelets,are important vehicles for communication and play crucial roles in inducing abnormal EC proliferation in hypertension.In briefly,EC proliferation was increased in renal hypertensive rats established by abdominal aortic coarctation compared to control rats and that elevated thrombin in plasma promoted platelet activation,which may induce the release of PMPs.miRNA array and qPCR revealed a higher level of miRNA-142-3p in platelets and PMPs.In vitro,PMPs delivered miRNA-142-3p into ECs and enhanced EC proliferation via Bcl-2-associated transcription factor 1(BCLAF1)and its downstream genes.These results indicated that PMPs deliver miRNA-142-3p from activated platelets into ECs and that miRNA-142-3p may play important roles in EC dysfunction under hypertensive conditions and might be a novel therapeutic target for maintaining EC homeostasis in hypertension[1].These results provide possible mechanisms by which non-coding RNAs regulate cellular functions under different mechanical stresses,and suggest a novel potential therapeutic approach for vascular remodeling.The further studies on noncoding RNAs may provide new insight into understanding the mechanism of vascular remodeling in different various cardiovascular disorders,and may provide novel targets for the maintenance of vascular homeostasis.展开更多
OBJECTIVE To fabricate Silymarin(SM) nanosuspensions(NSs) and evaluate their protective effect on stress-induced liver injury. METHODS SM nanosuspensions were tailored by combination of the anti-solvent precipitation ...OBJECTIVE To fabricate Silymarin(SM) nanosuspensions(NSs) and evaluate their protective effect on stress-induced liver injury. METHODS SM nanosuspensions were tailored by combination of the anti-solvent precipitation and high pressure homogenization(HPH); the formulations were optimized by central composite design. The pharmacokinetics and pharmacodynamics of SM-NSs were also performed.RESULTS In light of the quadratic mathematical equations derived from the Design of Expert Software,the optimal formulation of SM-NSs consisted of PVP 0.34% and F188 0.36%. The morphology of NSs was found to be spherical with a diameter of about 150 nm using transmission electron microscope(TEM)observation. The pharmacokinetics experiment demonstrated that oral administration of SM-NSs significantly increased its bioavailability compared to the coarse powder(Cmax: 9.03 ± 2.39 mg · L^(-1);AUMC_(0→∞):3757.35±227.19 mg·L^(-1)·h; AUC_(0→∞):171.84±26.61 mg·L^(-1)·h). In pharmacodynamics,it was found that restraint stress produced oxidative effects and increased serum AST and ALT levels in mice,both of which were significantly inhibited by SM and SM-NSs; in addition,administration of SM-NSs showed more effective prevention against acute liver injury than SM coarse suspensions(r^2=0.986,0.984,P<0.05). CONCLUSION The results suggest that fabricated SM-NSs exert potent hepatoprotective effects and attenuate restraint stress-induced liver injury. The study provides an effective approach to improving the property of SM,which can be used for treatment of liver diseases.展开更多
In order to perfectly reflect the dynamic corrosion of reinforced concrete (RC) cover in practical engineering,an analytic model of non-uniform corrosion induced cracking was presented based on the elastic-plastic fra...In order to perfectly reflect the dynamic corrosion of reinforced concrete (RC) cover in practical engineering,an analytic model of non-uniform corrosion induced cracking was presented based on the elastic-plastic fracture mechanics theory.Comparisons with the published experimental data show that the predictions given by the present model are in good agreement with the results both for natural exposed experiments and short-time indoor tests (the best difference is about 2.7%).Also it obviously provides much better precision than those models under the assumption of uniform corrosion (the maximal improved precision is about 48%).Therefore,it is pointed out that the so-called uniform corrosion models to describe the cover cracking of RC should be adopted cautiously.Finally,the influences of thickness of local rusty layer around the reinforcing steel bar on the critical corrosion-induced crack indexes were investigated.It is found that the thickness of local rusty layer has great effect on the critical mass loss of reinforcing steel,threshold expansion pressure,and time to cover cracking.For local rusty layer thickness with a size of a=0.5 mm,the time to cover cracking will increase by about one times when a/b (a,semi-minor axis;b,semi-major axis) changes from 0.1 to 1 mm.展开更多
文摘Stacked chip scale package(SCSP) attracts more and more attentions in advanced packages application with light weight,thin and small size,high reliability,low power and high storage capability.However,more and more physical and electrical issues being caused by package-induced stress in SCSP were reported recently.The effect of structural factors,including die thickness,die attach film thickness,die attach film type,and spacer size on package induced stress,was investigated.Analyses were given based on simulation results and provide important suggestion for package design.
基金supported by grants from the National Natural Science Foundation of China ( 11625209,11572199,31670958)
文摘Vascular remodeling is the essential pathogenic process of various cardiovascular disorders,including hypertension,atherosclerosis,stroke,and restenosis after vein graft.The main characterization of vascular remodeling is abnormal variations of vascular cell phenotype,morphological structure and functions such as migration,hypertrophy,proliferation and apoptosis.Numerous researches revealed that mechanical stress,including shear stress and cyclic stretch,participates in physiological vascular homeostasis,or pathophysiological vascular remodeling.The understanding of mechanobiological mechanism in vascular remodeling will play a unique role in understanding human physiology and disease,and will generate important theoretical and clinical significance [2].Non-coding RNAs are newly recognized RNAs which cannot be translated into proteins but are involved in epigenetic modification of gene regulation.The studies revealed that non-coding RNAs,such as microRNAs(miRNAs)and long noncoding RNAs(long ncRNAs,IncRNA),as well as small interfering RNAs(siRNAs),piwi-interacting RNAs(piRNAs),small nucleolar RNAs(snoRNAs),play essential roles in the regulation of various processes,such as metabolism,development,cell proliferation,cell apoptosis,cell differentiation,oncogenesis and vascular homeostasis[5].However,the roles of non-coding RNAs in the cardiovascular system under mechanical stresses are still not clarified.Our recent researches detected the mechanical regulation of IncRNAs and miRNAs in vascular remodeling.LncRNAs are non-protein-coding transcripts that are longer than 200 nucleotides(nt),which is an arbitrary cut-off value that distinguishes these transcripts from other small RNAs.Unlike the well-established mechanism of microRNA action,the functional mode of IncRNAs is not fully understood.Increasing evidence shows that IncRNAs modulate gene expression via a multilevel-regulated pathway.Given their large number and complicated functional modes,lncRNAs are emerging as important regulators of a variety of cellular responses,developmental processes and diseases.Using a gene microarray,we screened the differences in the IncRNAs and mRNAs between spontaneously hypertensive rats(SHR)and Wistar Kyoto rats(WKY).The results showed that 68 IncRNAs and 255 mRNAs were up-regulated in the aorta of SHR,while 167 IncRNAs and 272 mRNAs were down-regulated.Expressions of the screened IncRNAs,including XR007793,were validated by real-time PCR.A co-expression network was composed,and gene function was analysed using Ingenuity Pathway Analysis.In vitro,vascular smooth muscle cells(VSMCs)were subjected to cyclic stretch at a magnitude of 5%(physiological normotensive cyclic stretch)or 15%(pathological hypertensive cyclic stretch)by Flexercell-5000TM.15%-cyclic-stretch increased XR007793 expression.XR007793 knockdown attenuated VSMC proliferation and migration and inhibited co-expressed genes such as signal transducers and activators of transcription 2(stat2),LIM domain only 2(lmo2)and interferon regulatory factor 7(irf7)[4].Illuminating the role of IncRNAs in vascular remodeling induced by hyper mechanical stretch may provide deeper insight into the mechanobiological mechanism underlying hypertension,and contribute to identifying potential targets for hypertension therapy.miRNAs are endogenous,non-coding,single-stranded RNAs of 18-22 nucleotides that constitute a novel class of gene regulators.miRNAs bind to their target genes within their 3’-untranslated regions(3’-UTRs),leading to direct degradation of mRNA or translational repression by a complete,i.e.in plants,or incomplete,i.e.in animals,complement respectively.Our resent works revealed several important mechano-responsive miRNA and their potential effects in vascular remodeling.Forexample,miRNA-33 is regulated by cyclic stretch in the grafted vessels,which targets to BMP3 and subsequent modulates smad signaling pathway.The miRNA-33-BMP3-smad pathway protects against venous VSMC proliferation in response to arterial cyclic stretch.Therefore,miRNA-33 may be a potential therapeutic target in autologous vein grafted surgery,and locally overexpression of miR-33 may attenuates neointimal hyperplasia of grafted human saphenous vein [3].The unpublished data revealed that 15%cyclic stretch also significantly elevated the expression of miRNA-124-3p which bound to the 3’UTR of Lmna mRNA,and then negatively regulated protein expression of lamin A/C which is the important skeletal proteins in nucleus.In addition to primary intracellular locations of miRNAs,our recent study showed that miRNAs can be secreted and protected extracellularly via inclusion into membrane-derived vesicles including microparticles.Microparticles are extracellular vesicles ranging from 0.1 to 1μm in size and have been shown to deliver various bioactive molecules,i.e.,chemokines,enzymes and miRNAs,to recipient cells.Increasing evidence shows that microparticles play a pivotal role in many pathological processes,such as cancer,inflammatory diseases and cardiovascular disease.Our present study showed that platelet-derived microparticles(PMPs),which are released by active platelets,are important vehicles for communication and play crucial roles in inducing abnormal EC proliferation in hypertension.In briefly,EC proliferation was increased in renal hypertensive rats established by abdominal aortic coarctation compared to control rats and that elevated thrombin in plasma promoted platelet activation,which may induce the release of PMPs.miRNA array and qPCR revealed a higher level of miRNA-142-3p in platelets and PMPs.In vitro,PMPs delivered miRNA-142-3p into ECs and enhanced EC proliferation via Bcl-2-associated transcription factor 1(BCLAF1)and its downstream genes.These results indicated that PMPs deliver miRNA-142-3p from activated platelets into ECs and that miRNA-142-3p may play important roles in EC dysfunction under hypertensive conditions and might be a novel therapeutic target for maintaining EC homeostasis in hypertension[1].These results provide possible mechanisms by which non-coding RNAs regulate cellular functions under different mechanical stresses,and suggest a novel potential therapeutic approach for vascular remodeling.The further studies on noncoding RNAs may provide new insight into understanding the mechanism of vascular remodeling in different various cardiovascular disorders,and may provide novel targets for the maintenance of vascular homeostasis.
基金The project supported by Natural Science Foundation of Shandong Province(ZR2014HL103,ZR2016HM21,J13LM51)Taishan Medical University Foundation(2014GCC15)the Foundation of Overseas Distinguished Taishan Scholars of Shandong Province,China
文摘OBJECTIVE To fabricate Silymarin(SM) nanosuspensions(NSs) and evaluate their protective effect on stress-induced liver injury. METHODS SM nanosuspensions were tailored by combination of the anti-solvent precipitation and high pressure homogenization(HPH); the formulations were optimized by central composite design. The pharmacokinetics and pharmacodynamics of SM-NSs were also performed.RESULTS In light of the quadratic mathematical equations derived from the Design of Expert Software,the optimal formulation of SM-NSs consisted of PVP 0.34% and F188 0.36%. The morphology of NSs was found to be spherical with a diameter of about 150 nm using transmission electron microscope(TEM)observation. The pharmacokinetics experiment demonstrated that oral administration of SM-NSs significantly increased its bioavailability compared to the coarse powder(Cmax: 9.03 ± 2.39 mg · L^(-1);AUMC_(0→∞):3757.35±227.19 mg·L^(-1)·h; AUC_(0→∞):171.84±26.61 mg·L^(-1)·h). In pharmacodynamics,it was found that restraint stress produced oxidative effects and increased serum AST and ALT levels in mice,both of which were significantly inhibited by SM and SM-NSs; in addition,administration of SM-NSs showed more effective prevention against acute liver injury than SM coarse suspensions(r^2=0.986,0.984,P<0.05). CONCLUSION The results suggest that fabricated SM-NSs exert potent hepatoprotective effects and attenuate restraint stress-induced liver injury. The study provides an effective approach to improving the property of SM,which can be used for treatment of liver diseases.
基金Project(50925829) supported by the National Science Fund for Distinguished Young Scholars of ChinaProject(50908148) supported by the National Natural Science Foundation of ChinaProjects(2009-K4-23,2010-11-33) supported by the Research of Ministry of Housing and Urban Rural Development of China
文摘In order to perfectly reflect the dynamic corrosion of reinforced concrete (RC) cover in practical engineering,an analytic model of non-uniform corrosion induced cracking was presented based on the elastic-plastic fracture mechanics theory.Comparisons with the published experimental data show that the predictions given by the present model are in good agreement with the results both for natural exposed experiments and short-time indoor tests (the best difference is about 2.7%).Also it obviously provides much better precision than those models under the assumption of uniform corrosion (the maximal improved precision is about 48%).Therefore,it is pointed out that the so-called uniform corrosion models to describe the cover cracking of RC should be adopted cautiously.Finally,the influences of thickness of local rusty layer around the reinforcing steel bar on the critical corrosion-induced crack indexes were investigated.It is found that the thickness of local rusty layer has great effect on the critical mass loss of reinforcing steel,threshold expansion pressure,and time to cover cracking.For local rusty layer thickness with a size of a=0.5 mm,the time to cover cracking will increase by about one times when a/b (a,semi-minor axis;b,semi-major axis) changes from 0.1 to 1 mm.
