The 7xxx series alloys are heat treatable wrought aluminium alloys based on the Al-Zn-Mg（-Cu） system. They are widely used in high-performance structural aerospace and transportation applications. Apart from composi...The 7xxx series alloys are heat treatable wrought aluminium alloys based on the Al-Zn-Mg（-Cu） system. They are widely used in high-performance structural aerospace and transportation applications. Apart from compositional, casting and thermo-mechanical processing effects, the balance of properties is also significantly influenced by the way in which the materials are heat-treated. This paper describes the effects of homogenisation, solution treatment, quenching and ageing treatments on the evolution of the microstructure and properties of some important medium to high-strength 7xxx alloys. With a focus on recent work at Monash University, where the whole processing route from homogenisation to final ageing has been studied for thick plate products, it is reported how microstructural features such as dispersoids, coarse constituent particles, fine-scale precipitates, grain structure and grain boundary characteristics can be controlled by heat treatment to achieve improved microstructure-property combinations. In particular, the paper presents methods for dissolving unwanted coarse constituent particles by controlled high- temperature treatments, quench sensitivity evaluations based on a systematic study of continuous cooling precipitation behaviour, and ageing investigations of one-, two- and three-step ageing treatments using experimental and modelling approaches, in each case, the effects on both the microstructure and the resulting properties are discussed.展开更多
Inflammatory bowel diseases are characterised by inflammation that compromises the integrity of the epithelial barrier. The intestinal epithelium is not only a static barrier but has evolved complex mechanisms to cont...Inflammatory bowel diseases are characterised by inflammation that compromises the integrity of the epithelial barrier. The intestinal epithelium is not only a static barrier but has evolved complex mechanisms to control and regulate bacterial interactions with the mucosal surface. Apical tight junction proteins are critical in the maintenance of epithelial barrier function and control of paracellular permeability. The characterisation of alterations in tight junction proteins as key players in epithelial barrier function in inflammatory bowel diseases is rapidly enhancing our understanding of critical mechanisms in disease pathogenesis as well as novel therapeutic opportunities. Here we give an overview of recent literature focusing on the role of tight junction proteins, in particular claudins, in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.展开更多
A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cyto-plasmic constituents, and contributes significantly to the degree of myocardial isc...A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cyto-plasmic constituents, and contributes significantly to the degree of myocardial ischemia-reperfusion （I/R） injury. This tightly orchestrated cata-bolic cellular‘housekeeping’ process provides cells with a new source of energy to adapt to stressful conditions. This process was first described as a pro-survival mechanism, but increasing evidence suggests that it can also lead to the demise of the cell. Autophagy has been implicated in the pathogenesis of multiple cardiac conditions including myocardial I/R injury. However, a debate persists as to whether autophagy acts as a protec-tive mechanism or contributes to the injurious effects of I/R injury in the heart. This controversy may stem from several factors including the va-riability in the experimental models and species, and the methodology used to assess autophagy. This review provides updated knowledge on the modulation and role of autophagy in isolated cardiac cells subjected to I/R, and the growing interest towards manipulating autophagy to increase the survival of cardiac myocytes under conditions of stress-most notably being I/R injury. Perturbation of this evolutionarily conserved intracellular cleansing autophagy mechanism, by targeted modulation through, among others, mammalian target of rapamycin （mTOR） inhibitors, adenosine monophosphate-activated protein kinase （AMPK） modulators, calcium lowering agents, resveratrol, longevinex, sirtuin activators, the proapoptotic gene Bnip3, IP3 and lysosome inhibitors, may confer resistance to heart cells against I/R induced cell death. Thus, therapeutic ma-nipulation of autophagy in the challenged myocardium may benefit post-infarction cardiac healing and remodeling.展开更多
Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer.The cagA gene product,CagA,is delivered into gastric epithelial cells via the bacterial type IV secretio...Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer.The cagA gene product,CagA,is delivered into gastric epithelial cells via the bacterial type IV secretion system.Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala(EPIYA)motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and-independent manners.Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks:sustained proliferation,evasion of growth suppressors,invasiveness,resistance to cell death,and genomic instability.Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation.The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation.Since Helicobacter pylori infection triggers a proinflammatory response in host cells,a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa.Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions,the multistep nature of gastric cancer development should include a“hit-and-run”process of CagA action.Thus,acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the“hit-and-run”process of gastric carcinogenesis.展开更多
Natural rivers are commonly characterized by a main channel for primary flow conveyance and a floodplain, often partially covered with vegetation such as shrubs or trees, to carry extra flow during floods. The hydraul...Natural rivers are commonly characterized by a main channel for primary flow conveyance and a floodplain, often partially covered with vegetation such as shrubs or trees, to carry extra flow during floods. The hydraulic resistance due to vegetation on the floodplain typically causes a further reduction of flow velocity and increases the velocity difference between the main channel and the floodplain. As a consequence a strong lateral shear layer leads to the exchange of mass and momentum between the main channel and floodplain, which in turn affects the overall channel conveyance and certain fluvial processes. The prediction of the lateral velocity distribution is important for many flood alleviation schemes, as well as for studies on sediment transport and dispersion in such channels. The present paper proposes a method for predicting the depth-averaged velocity in compound channels with partially vegetated floodplains, based on an analytical solution to the depth-integrated Reynolds-Averaged Navier-Stokes equation with a term included to account for the effects of vegetation. The vegetation is modelled via an additional term in the momentum equation to account for the additional drag force. The method includes the effects of bed friction, drag force, lateral turbulence and secondary flows, via four coefficients f, CD, λ & Γ respectively. The predicted lateral distributions of depth-averaged velocity agree well with the experimental data. The analytical solutions can also be used to predict the distribution of boundary shear stresses, which adds additional weight to the method proposed.展开更多
Method development has always been and will continue to be a core driving force of microbiome science, In this perspective, we argue that in the next decade, method development in microbiome analysis will be driven by...Method development has always been and will continue to be a core driving force of microbiome science, In this perspective, we argue that in the next decade, method development in microbiome analysis will be driven by three key changes in both ways of thinking and technological platforms： ① a shift from dissecting microbiota structure by sequencing to tracking microbiota state, function, and intercellular interaction via imaging; ② a shift from interrogating a consortium or population of cells to probing individual cells; and ③a shift from microbiome data analysis to microbiome data science. Some of the recent methoddevelopment efforts by Chinese microbiome scientists and their international collaborators that underlie these technological trends are highlighted here. It is our belief that the China Microbiome Initiative has the opportunity to deliver outstanding ＂Made-in-China＂ tools to the international research community, by building an ambitious, competitive, and collaborative program at the forefront of method development for microbiome science.展开更多
The R-spondin family of proteins are Wnt agonists, and the complete embryonic disruption of Rspo2 results in skeletal developmental defects that recapitulate the phenotype observed with Lrp5/6 deficiency. Previous wor...The R-spondin family of proteins are Wnt agonists, and the complete embryonic disruption of Rspo2 results in skeletal developmental defects that recapitulate the phenotype observed with Lrp5/6 deficiency. Previous work has shown that R-spondin-2(Rspo2, RSPO2) is both highly expressed in Wnt-stimulated pre-osteoblasts and its overexpression induces osteoblast differentiation in the same cells, supporting its putative role as a positive autocrine regulator of osteoblastogenesis. However, the role of Rspo2 in regulating osteoblastogenesis and bone formation in postnatal bone has not been explored. Here we show that limb-bud progenitor cells from Rspo2 knockout mice undergo reduced mineralization during osteoblastogenesis in vitro and have a corresponding alteration in their osteogenic gene expression profile. We also generated the first Rspo2 conditional knockout(Rspo2 floxed) mouse and disrupted Rspo2 expression in osteoblast-lineage cells by crossing to the Osteocalcin-Cre mouse line(OcnCre + Rspo2 ^(f/f)). Ocn-Cre + Rspo2 f/fmale and female mice at 1, 3, and 6 months were examined. Ocn-Cre + Rspo2 f/fmice are decreased in overall body size compared to their control littermates and have decreased bone mass. Histomorphometric analysis of1-month-old mice revealed a similar number of osteoblasts and mineralizing surface per bone surface with a simultaneous decrease in mineral apposition and bone formation rates. Consistent with this observation, serum osteocalcin in 3-month-old Ocn-Cre +Rspo2 f/fwas reduced, and bone marrow-mesenchymal stem cells from Ocn-Cre + Rspo2 f/fmice undergo less mineralization in vitro.Finally, gene expression analysis and immunohistochemistry of mature bone shows reduced beta-catenin signaling in Ocn-Cre +Rspo2 f/f. Overall, RSPO2 reduces osteoblastogenesis and mineralization, leading to reduced bone mass.展开更多
Background Klotho proteins （α- and β） are membrane-based circulating proteins that regulate cell metabolism, as well as the lifespan modulating activity of Fibroblast Growth Factors （FGFs）. Recent data has shown...Background Klotho proteins （α- and β） are membrane-based circulating proteins that regulate cell metabolism, as well as the lifespan modulating activity of Fibroblast Growth Factors （FGFs）. Recent data has shown that higher plasma circulating Klotho levels reduce cardio- vascular risk, suggesting Klotho has a protective role in cardiovascular diseases. However, although so far it has been identified in various organs, it is unknown whether cardiomyocytes express Klotho and FGFs, and whether high cardiovascular risk could affect cardiac expres- sion ofKlotho, FGFs and other molecules. Methods We selected 20 patients with an estimated 10-year high atherosclerotic cardiovascular disease and 10 age-matched control subjects with an estimated 10-year low risk undergone cardiac surgery for reasons other than coronary artery by-pass. In myocardial biopsies, we evaluated by immuno-histochemistry whether Klotho and FGFs were expressed in cardiomyo- cytes, and whether higher cardiovascular risk influenced the expression of other molecules involved in endoplasmic reticulum stress, oxida- tive stress, inflammation and fibrosis. Results Only cardiomyocytes of patients with a higher cardiovascular risk showed lower expression of Klotho, but higher expressions of FGFs. Furthermore, higher cardiovascular risk was associated with increased expression of oxidative and endoplasmic reticular stress, inflammation and fibrosis. Conclusions This study showed for the first time that Klotho proteins are ex- pressed in human cardiomyocytes and that cardiac expression of Klotho is down-regulated in higher cardiovascular risk patients, while expression of stress-related molecules were significantly increased.展开更多
The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNA...The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNAs,tRNA,mt-tRNA,and rRNA species as well as non-coding RNAs.With emerging knowledge of RNA binding proteins that act as writer,reader,and eraser effector proteins,comes a new understanding of physiological processes controlled by these systems.Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain,give rise to different forms of disease.In this review,we discuss accumulating evidence that changes in the m^(6)A and m^(5)C methylation systems contribute to neurocognitive disorders.Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m^(6)A RNA reader protein.Subsequently,familial mutations within the m^(6)A writer gene METTL5,m^(5)C writer genes NSUN2,NSUN3,NSUN5,and NSUN6,as well as THOC2 and THOC6 that form a protein complex with the m^(5)C reader protein ALYREF,were recognized to cause intellectual development disorders.Similarly,differences in expression of the m^(5)C writer and reader effector proteins,NSUN6,NSUN7,and ALYREF in brain tissue are indicated in individuals with Alzheimer's disease,individuals with a high neuropathological load or have suffered traumatic brain injury.Likewise,an abundance of m^(6)A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases,Alzheimer's disease,and individuals with high cognitive reserve.m^(6)A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson's disease tissue,whilst modified RNAs are misplaced within diseased cells,particularly where synapses are located.In parahippocampal brain tissue,m^(6)A modification is enriched in transcripts associated with psychiatric 展开更多
By offering greatly enhanced control of light compared to conventional step-index structures, photonic crystal fibres are radically improving the performance of linear and nonlinear fibre devices, including gas-Raman ...By offering greatly enhanced control of light compared to conventional step-index structures, photonic crystal fibres are radically improving the performance of linear and nonlinear fibre devices, including gas-Raman cells, super-continuum generators, soliton systems and cladding-pumped lasers.展开更多
Antiphospholipid syndrome (APS) is a thromboinflammatory disease with a variety of clinical phenotypes. Primary thrombosis prophylaxis should take an individualized risk stratification approach. Moderate-intensity vit...Antiphospholipid syndrome (APS) is a thromboinflammatory disease with a variety of clinical phenotypes. Primary thrombosis prophylaxis should take an individualized risk stratification approach. Moderate-intensity vitamin K antagonist such as warfarin remains the primary strategy for secondary thrombosis prophylaxis among APS patients, especially for patients with predominantly venous disease. For now, direct oral anti-coagulants should be avoided in most APS patients, especially those with history of arterial manifestations. Obstetric APS management should be tailored based on an individual patient’s antiphospholipid antibody profile, and obstetric and thrombotic history. Pharmacological agents beyond anticoagulants may be considered for the management of microthrombotic and nonthrombotic manifestations of APS, although more data are needed. A relatively recent discovery in the area of APS pathogenesis is the implication of neutrophil extracellular traps in thrombin generation and initiation of inflammatory cascades. APS is a complex thromboinflammatory disease with a broad clinical spectrum. Personalized therapy according to an individual’s unique thrombosis and obstetric risk should be advocated.展开更多
Thrombotic events,both arterial and venous,are a major health concern worldwide. Further,autoimmune diseases,such as systemic lupus erythematosus,anti-neutrophil cytoplasmic antibody(ANCA)-associated vasculitis,and an...Thrombotic events,both arterial and venous,are a major health concern worldwide. Further,autoimmune diseases,such as systemic lupus erythematosus,anti-neutrophil cytoplasmic antibody(ANCA)-associated vasculitis,and antiphospholipid syndrome,predispose to thrombosis,and thereby push the risk for these morbid events even higher. In recent years,neutrophils have been identified as important players in both arterial and venous thrombosis. Specifically,chromatin-based structures called neutrophil extracellular traps(NETs) play a key role in activating the coagulation cascade,recruiting platelets,and serving as scaffolding upon which the thrombus can be assembled. At the same time,neutrophils and NETs are emerging as important mediators of pathogenic inflammation in the aforementioned autoimmune diseases. Here,we first review the general role of NETs in thrombosis. We then posit that exaggerated NET release contributes to the prothrombotic diatheses of systemic lupus erythematosus,ANCA-associated vasculitis,and antiphospholipid syndrome.展开更多
Tumor cell proliferation, infiltration, migration, and neovascularization are known causes of treatment resistance in glioblastoma multiforme(GBM). The purpose of this study was to determine the effect of radiation on...Tumor cell proliferation, infiltration, migration, and neovascularization are known causes of treatment resistance in glioblastoma multiforme(GBM). The purpose of this study was to determine the effect of radiation on the growth characteristics of primary human GBM developed in a nude rat. Primary GBM cells grown from explanted GBM tissues were implanted orthotopically in nude rats. Tumor growth was confirmed by magnetic resonance imaging on day 77(baseline) after implantation. The rats underwent irradiation to a dose of 50 Gy delivered subcuratively on day 84 postimplantation(n = 8), or underwent no radiation(n = 8). Brain tissues were obtained on day 112(nonirradiated) or day 133(irradiated). Immunohistochemistry was performed to determine tumor cell proliferation(Ki-67) and to assess the expression of infiltration marker(matrix metalloproteinase-2, MMP-2) and cell migration marker(CD44). Tumor neovascularization was assessed by microvessel density using von-Willebrand factor(vWF) staining. Magnetic resonance imaging showed well-developed, infiltrative tumors in 11 weeks postimplantation. The proportion of Ki-67-positive cells in tumors undergoing radiation was(71 ± 15)% compared with(25 ± 12)% in the nonirradiated group(P = 0.02). The number of MMP-2-positive areas and proportion of CD44-positive cells were also high in tumors receiving radiation, indicating great invasion and infiltration. Microvessel density analysis did not show a significant difference between nonirradiated and irradiated tumors. Taken together, we found that subcurative radiation significantly increased proliferation, invasion, and migration of primary GBM. Our study provides insights into possible mechanisms of treatment resistance following radiation therapy for GBM.展开更多
We present detailed characterization of laser-driven fusion and neutron production(-10^(5)/second) using 8 mJ, 40 fs laser pulses on a thin(<1 μm) D_2O liquid sheet employing a measurement suite. At relativistic i...We present detailed characterization of laser-driven fusion and neutron production(-10^(5)/second) using 8 mJ, 40 fs laser pulses on a thin(<1 μm) D_2O liquid sheet employing a measurement suite. At relativistic intensity(~ 5 × 10^(18)W/cm^(2))and high repetition rate(1 kHz), the system produces deuterium±deuterium(D-D) fusion, allowing for consistent neutron generation. Evidence of D-D fusion neutron production is verified by a measurement suite with three independent detection systems: an EJ-309 organic scintillator with pulse-shape discrimination, a ~3He proportional counter and a set of 36 bubble detectors. Time-of-flight analysis of the scintillator data shows the energy of the produced neutrons to be consistent with 2.45 MeV. Particle-in-cell simulations using the WarpX code support significant neutron production from D-D fusion events in the laser±target interaction region. This high-repetition-rate laser-driven neutron source could provide a low-cost, on-demand test bed for radiation hardening and imaging applications.展开更多
基金The Aluminium Corporation of China Ltd.(Chalco)for supporting aspects of this work financiallyproviding AA7150 materials as part of the Australia-China International Centre for Light Alloy Research(ICLAR)+1 种基金Monash University for developing the retrogression and reageing Matlab model (as part of the PhD project of Dr Adrian GROSVENOR)The ARC Centre of Excellence for Design in Light Metals and its Directors (first Prof Barry MUDDLE and then Prof Xin-hua WU) for supporting
文摘The 7xxx series alloys are heat treatable wrought aluminium alloys based on the Al-Zn-Mg（-Cu） system. They are widely used in high-performance structural aerospace and transportation applications. Apart from compositional, casting and thermo-mechanical processing effects, the balance of properties is also significantly influenced by the way in which the materials are heat-treated. This paper describes the effects of homogenisation, solution treatment, quenching and ageing treatments on the evolution of the microstructure and properties of some important medium to high-strength 7xxx alloys. With a focus on recent work at Monash University, where the whole processing route from homogenisation to final ageing has been studied for thick plate products, it is reported how microstructural features such as dispersoids, coarse constituent particles, fine-scale precipitates, grain structure and grain boundary characteristics can be controlled by heat treatment to achieve improved microstructure-property combinations. In particular, the paper presents methods for dissolving unwanted coarse constituent particles by controlled high- temperature treatments, quench sensitivity evaluations based on a systematic study of continuous cooling precipitation behaviour, and ageing investigations of one-, two- and three-step ageing treatments using experimental and modelling approaches, in each case, the effects on both the microstructure and the resulting properties are discussed.
基金Supported by The Association for International Cancer Research(AICRto Dr.Al-Hassi HO)+6 种基金ScotlandFunded by the AICRgrant No.120234a BBSRC Strategic Research Grant(to English N and Knight SCWMNIP33458)the St Mark’s Hospital FoundationUnited Kingdom
文摘Inflammatory bowel diseases are characterised by inflammation that compromises the integrity of the epithelial barrier. The intestinal epithelium is not only a static barrier but has evolved complex mechanisms to control and regulate bacterial interactions with the mucosal surface. Apical tight junction proteins are critical in the maintenance of epithelial barrier function and control of paracellular permeability. The characterisation of alterations in tight junction proteins as key players in epithelial barrier function in inflammatory bowel diseases is rapidly enhancing our understanding of critical mechanisms in disease pathogenesis as well as novel therapeutic opportunities. Here we give an overview of recent literature focusing on the role of tight junction proteins, in particular claudins, in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer.
文摘A physiological sequence called autophagy qualitatively determines cellular viability by removing protein aggregates and damaged cyto-plasmic constituents, and contributes significantly to the degree of myocardial ischemia-reperfusion （I/R） injury. This tightly orchestrated cata-bolic cellular‘housekeeping’ process provides cells with a new source of energy to adapt to stressful conditions. This process was first described as a pro-survival mechanism, but increasing evidence suggests that it can also lead to the demise of the cell. Autophagy has been implicated in the pathogenesis of multiple cardiac conditions including myocardial I/R injury. However, a debate persists as to whether autophagy acts as a protec-tive mechanism or contributes to the injurious effects of I/R injury in the heart. This controversy may stem from several factors including the va-riability in the experimental models and species, and the methodology used to assess autophagy. This review provides updated knowledge on the modulation and role of autophagy in isolated cardiac cells subjected to I/R, and the growing interest towards manipulating autophagy to increase the survival of cardiac myocytes under conditions of stress-most notably being I/R injury. Perturbation of this evolutionarily conserved intracellular cleansing autophagy mechanism, by targeted modulation through, among others, mammalian target of rapamycin （mTOR） inhibitors, adenosine monophosphate-activated protein kinase （AMPK） modulators, calcium lowering agents, resveratrol, longevinex, sirtuin activators, the proapoptotic gene Bnip3, IP3 and lysosome inhibitors, may confer resistance to heart cells against I/R induced cell death. Thus, therapeutic ma-nipulation of autophagy in the challenged myocardium may benefit post-infarction cardiac healing and remodeling.
基金Our studies presented in this review article were supported by Grants-in-Aid for Scientific Research“S”(#16H06373 to M.H.),“A”(#22240085 and#25250016 to M.H.)and“C”(#19K05945 to A.T.-K.)Grants-in-Aid for Innovative Areas(#3205,#22114001,and#22114002 to M.H.)+4 种基金Grants-in-Aid for Japan Society for the Promotion of Science(JSPS)Fellows(#07J03878 to A.T.-K.and#19J12668 to C.T.K.)Grants-in-Aid for Young Scientists“B”(#24700965 and#15K18399 to A.T.-K.)the Graduate Program for Leaders in Life Innovation(GPLLI,to C.T.K.)from the Ministry of Education,Culture,Sports,Science and Technology(MEXT)of Japan,by CREST(#120200000396 to M.H.)Japan Science and Technology Agency,by the Uehara Memorial Foundation(#137 in 2016 to A.T.-K.)by the Max-Planck Society,Germany。
文摘Chronic infection with Helicobacter pylori cagA-positive strains is the strongest risk factor for gastric cancer.The cagA gene product,CagA,is delivered into gastric epithelial cells via the bacterial type IV secretion system.Delivered CagA then undergoes tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala(EPIYA)motifs in its C-terminal region and acts as an oncogenic scaffold protein that physically interacts with multiple host signaling proteins in both tyrosine phosphorylation-dependent and-independent manners.Analysis of CagA using in vitro cultured gastric epithelial cells has indicated that the nonphysiological scaffolding actions of CagA cell-autonomously promote the malignant transformation of the cells by endowing the cells with multiple phenotypic cancer hallmarks:sustained proliferation,evasion of growth suppressors,invasiveness,resistance to cell death,and genomic instability.Transgenic expression of CagA in mice leads to in vivo oncogenic action of CagA without any overt inflammation.The in vivo oncogenic activity of CagA is further potentiated in the presence of chronic inflammation.Since Helicobacter pylori infection triggers a proinflammatory response in host cells,a feedforward stimulation loop that augments the oncogenic actions of CagA and inflammation is created in CagA-injected gastric mucosa.Given that Helicobacter pylori is no longer colonized in established gastric cancer lesions,the multistep nature of gastric cancer development should include a“hit-and-run”process of CagA action.Thus,acquisition of genetic and epigenetic alterations that compensate for CagA-directed cancer hallmarks may be required for completion of the“hit-and-run”process of gastric carcinogenesis.
文摘Natural rivers are commonly characterized by a main channel for primary flow conveyance and a floodplain, often partially covered with vegetation such as shrubs or trees, to carry extra flow during floods. The hydraulic resistance due to vegetation on the floodplain typically causes a further reduction of flow velocity and increases the velocity difference between the main channel and the floodplain. As a consequence a strong lateral shear layer leads to the exchange of mass and momentum between the main channel and floodplain, which in turn affects the overall channel conveyance and certain fluvial processes. The prediction of the lateral velocity distribution is important for many flood alleviation schemes, as well as for studies on sediment transport and dispersion in such channels. The present paper proposes a method for predicting the depth-averaged velocity in compound channels with partially vegetated floodplains, based on an analytical solution to the depth-integrated Reynolds-Averaged Navier-Stokes equation with a term included to account for the effects of vegetation. The vegetation is modelled via an additional term in the momentum equation to account for the additional drag force. The method includes the effects of bed friction, drag force, lateral turbulence and secondary flows, via four coefficients f, CD, λ & Γ respectively. The predicted lateral distributions of depth-averaged velocity agree well with the experimental data. The analytical solutions can also be used to predict the distribution of boundary shear stresses, which adds additional weight to the method proposed.
基金We are grateful to the support from the National Natural Science Foundation of China （NSFC） （31425002, 91231205, 81430011, 61303161, 31470220, and 31327001）, and the Frontier Science Research Program, the Soil-Microbe System Function and Regulation Program, and the Science and Technology Service Network Initiative （STS） from the Chinese Academy of Sciences （CAS）.
文摘Method development has always been and will continue to be a core driving force of microbiome science, In this perspective, we argue that in the next decade, method development in microbiome analysis will be driven by three key changes in both ways of thinking and technological platforms： ① a shift from dissecting microbiota structure by sequencing to tracking microbiota state, function, and intercellular interaction via imaging; ② a shift from interrogating a consortium or population of cells to probing individual cells; and ③a shift from microbiome data analysis to microbiome data science. Some of the recent methoddevelopment efforts by Chinese microbiome scientists and their international collaborators that underlie these technological trends are highlighted here. It is our belief that the China Microbiome Initiative has the opportunity to deliver outstanding ＂Made-in-China＂ tools to the international research community, by building an ambitious, competitive, and collaborative program at the forefront of method development for microbiome science.
基金supported by the National Institutes of Health (NIH) National Institute of Arthritis and Musculoskeletal Diseases (NIAMS)funding of the University of Pennsylvania Center for Musculoskeletal Disorders (PCMD) (P30AR069619)the University of Michigan Integrative Musculoskeletal Health Core Center (P30AR069620)+1 种基金supported by NIH NIAMS R01AR066028supported by NIH NIAMS F31AR065858
文摘The R-spondin family of proteins are Wnt agonists, and the complete embryonic disruption of Rspo2 results in skeletal developmental defects that recapitulate the phenotype observed with Lrp5/6 deficiency. Previous work has shown that R-spondin-2(Rspo2, RSPO2) is both highly expressed in Wnt-stimulated pre-osteoblasts and its overexpression induces osteoblast differentiation in the same cells, supporting its putative role as a positive autocrine regulator of osteoblastogenesis. However, the role of Rspo2 in regulating osteoblastogenesis and bone formation in postnatal bone has not been explored. Here we show that limb-bud progenitor cells from Rspo2 knockout mice undergo reduced mineralization during osteoblastogenesis in vitro and have a corresponding alteration in their osteogenic gene expression profile. We also generated the first Rspo2 conditional knockout(Rspo2 floxed) mouse and disrupted Rspo2 expression in osteoblast-lineage cells by crossing to the Osteocalcin-Cre mouse line(OcnCre + Rspo2 ^(f/f)). Ocn-Cre + Rspo2 f/fmale and female mice at 1, 3, and 6 months were examined. Ocn-Cre + Rspo2 f/fmice are decreased in overall body size compared to their control littermates and have decreased bone mass. Histomorphometric analysis of1-month-old mice revealed a similar number of osteoblasts and mineralizing surface per bone surface with a simultaneous decrease in mineral apposition and bone formation rates. Consistent with this observation, serum osteocalcin in 3-month-old Ocn-Cre +Rspo2 f/fwas reduced, and bone marrow-mesenchymal stem cells from Ocn-Cre + Rspo2 f/fmice undergo less mineralization in vitro.Finally, gene expression analysis and immunohistochemistry of mature bone shows reduced beta-catenin signaling in Ocn-Cre +Rspo2 f/f. Overall, RSPO2 reduces osteoblastogenesis and mineralization, leading to reduced bone mass.
文摘Background Klotho proteins （α- and β） are membrane-based circulating proteins that regulate cell metabolism, as well as the lifespan modulating activity of Fibroblast Growth Factors （FGFs）. Recent data has shown that higher plasma circulating Klotho levels reduce cardio- vascular risk, suggesting Klotho has a protective role in cardiovascular diseases. However, although so far it has been identified in various organs, it is unknown whether cardiomyocytes express Klotho and FGFs, and whether high cardiovascular risk could affect cardiac expres- sion ofKlotho, FGFs and other molecules. Methods We selected 20 patients with an estimated 10-year high atherosclerotic cardiovascular disease and 10 age-matched control subjects with an estimated 10-year low risk undergone cardiac surgery for reasons other than coronary artery by-pass. In myocardial biopsies, we evaluated by immuno-histochemistry whether Klotho and FGFs were expressed in cardiomyo- cytes, and whether higher cardiovascular risk influenced the expression of other molecules involved in endoplasmic reticulum stress, oxida- tive stress, inflammation and fibrosis. Results Only cardiomyocytes of patients with a higher cardiovascular risk showed lower expression of Klotho, but higher expressions of FGFs. Furthermore, higher cardiovascular risk was associated with increased expression of oxidative and endoplasmic reticular stress, inflammation and fibrosis. Conclusions This study showed for the first time that Klotho proteins are ex- pressed in human cardiomyocytes and that cardiac expression of Klotho is down-regulated in higher cardiovascular risk patients, while expression of stress-related molecules were significantly increased.
基金funded by Notingham University and the Neuroscience Support Group Charity,UK(to HMK)supported by a CONACYT PhD scholarshipMD?was supported by the Postdoctoral Research Fellowship Program of TUBITAK。
文摘The study of modified RNA known as epitranscriptomics has become increasingly relevant in our understanding of disease-modifying mechanisms.Methylation of N6 adenosine(m^(6)A)and C5 cytosine(m^(5)C)bases occur on mRNAs,tRNA,mt-tRNA,and rRNA species as well as non-coding RNAs.With emerging knowledge of RNA binding proteins that act as writer,reader,and eraser effector proteins,comes a new understanding of physiological processes controlled by these systems.Such processes when spatiotemporally disrupted within cellular nanodomains in highly specialized tissues such as the brain,give rise to different forms of disease.In this review,we discuss accumulating evidence that changes in the m^(6)A and m^(5)C methylation systems contribute to neurocognitive disorders.Early studies first identified mutations within FMR1 to cause intellectual disability Fragile X syndromes several years before FMR1 was identified as an m^(6)A RNA reader protein.Subsequently,familial mutations within the m^(6)A writer gene METTL5,m^(5)C writer genes NSUN2,NSUN3,NSUN5,and NSUN6,as well as THOC2 and THOC6 that form a protein complex with the m^(5)C reader protein ALYREF,were recognized to cause intellectual development disorders.Similarly,differences in expression of the m^(5)C writer and reader effector proteins,NSUN6,NSUN7,and ALYREF in brain tissue are indicated in individuals with Alzheimer's disease,individuals with a high neuropathological load or have suffered traumatic brain injury.Likewise,an abundance of m^(6)A reader and anti-reader proteins are reported to change across brain regions in Lewy bodies diseases,Alzheimer's disease,and individuals with high cognitive reserve.m^(6)A-modified RNAs are also reported significantly more abundant in dementia with Lewy bodies brain tissue but significantly reduced in Parkinson's disease tissue,whilst modified RNAs are misplaced within diseased cells,particularly where synapses are located.In parahippocampal brain tissue,m^(6)A modification is enriched in transcripts associated with psychiatric
文摘By offering greatly enhanced control of light compared to conventional step-index structures, photonic crystal fibres are radically improving the performance of linear and nonlinear fibre devices, including gas-Raman cells, super-continuum generators, soliton systems and cladding-pumped lasers.
基金Dr.Knight is supported by a pilot grant for preclinical studies from Jazz Pharmaceuticals。
文摘Antiphospholipid syndrome (APS) is a thromboinflammatory disease with a variety of clinical phenotypes. Primary thrombosis prophylaxis should take an individualized risk stratification approach. Moderate-intensity vitamin K antagonist such as warfarin remains the primary strategy for secondary thrombosis prophylaxis among APS patients, especially for patients with predominantly venous disease. For now, direct oral anti-coagulants should be avoided in most APS patients, especially those with history of arterial manifestations. Obstetric APS management should be tailored based on an individual patient’s antiphospholipid antibody profile, and obstetric and thrombotic history. Pharmacological agents beyond anticoagulants may be considered for the management of microthrombotic and nonthrombotic manifestations of APS, although more data are needed. A relatively recent discovery in the area of APS pathogenesis is the implication of neutrophil extracellular traps in thrombin generation and initiation of inflammatory cascades. APS is a complex thromboinflammatory disease with a broad clinical spectrum. Personalized therapy according to an individual’s unique thrombosis and obstetric risk should be advocated.
基金Supported by NIH K08AR066569a career development award from the Burroughs Wellcome Fund(Knight JS)Kazzaz NM was supported by Security Forces Hospital Program,Ministry of Interior,Riyadh,Saudi Arabia
文摘Thrombotic events,both arterial and venous,are a major health concern worldwide. Further,autoimmune diseases,such as systemic lupus erythematosus,anti-neutrophil cytoplasmic antibody(ANCA)-associated vasculitis,and antiphospholipid syndrome,predispose to thrombosis,and thereby push the risk for these morbid events even higher. In recent years,neutrophils have been identified as important players in both arterial and venous thrombosis. Specifically,chromatin-based structures called neutrophil extracellular traps(NETs) play a key role in activating the coagulation cascade,recruiting platelets,and serving as scaffolding upon which the thrombus can be assembled. At the same time,neutrophils and NETs are emerging as important mediators of pathogenic inflammation in the aforementioned autoimmune diseases. Here,we first review the general role of NETs in thrombosis. We then posit that exaggerated NET release contributes to the prothrombotic diatheses of systemic lupus erythematosus,ANCA-associated vasculitis,and antiphospholipid syndrome.
基金supported by grants from the National Institutes of Health (NIH) [No. K25CA129173 (MMA), R01CA122031 (ASA), and 1R01CA160216 (ASA)]
文摘Tumor cell proliferation, infiltration, migration, and neovascularization are known causes of treatment resistance in glioblastoma multiforme(GBM). The purpose of this study was to determine the effect of radiation on the growth characteristics of primary human GBM developed in a nude rat. Primary GBM cells grown from explanted GBM tissues were implanted orthotopically in nude rats. Tumor growth was confirmed by magnetic resonance imaging on day 77(baseline) after implantation. The rats underwent irradiation to a dose of 50 Gy delivered subcuratively on day 84 postimplantation(n = 8), or underwent no radiation(n = 8). Brain tissues were obtained on day 112(nonirradiated) or day 133(irradiated). Immunohistochemistry was performed to determine tumor cell proliferation(Ki-67) and to assess the expression of infiltration marker(matrix metalloproteinase-2, MMP-2) and cell migration marker(CD44). Tumor neovascularization was assessed by microvessel density using von-Willebrand factor(vWF) staining. Magnetic resonance imaging showed well-developed, infiltrative tumors in 11 weeks postimplantation. The proportion of Ki-67-positive cells in tumors undergoing radiation was(71 ± 15)% compared with(25 ± 12)% in the nonirradiated group(P = 0.02). The number of MMP-2-positive areas and proportion of CD44-positive cells were also high in tumors receiving radiation, indicating great invasion and infiltration. Microvessel density analysis did not show a significant difference between nonirradiated and irradiated tumors. Taken together, we found that subcurative radiation significantly increased proliferation, invasion, and migration of primary GBM. Our study provides insights into possible mechanisms of treatment resistance following radiation therapy for GBM.
基金supported by Air Force Office of Scientific Research(AFOSR)Award number 23AFCOR004(PM:Dr.Andrew B.Stickrath)partially supported by DTRANSREC Award number HDTRA-1343332。
文摘We present detailed characterization of laser-driven fusion and neutron production(-10^(5)/second) using 8 mJ, 40 fs laser pulses on a thin(<1 μm) D_2O liquid sheet employing a measurement suite. At relativistic intensity(~ 5 × 10^(18)W/cm^(2))and high repetition rate(1 kHz), the system produces deuterium±deuterium(D-D) fusion, allowing for consistent neutron generation. Evidence of D-D fusion neutron production is verified by a measurement suite with three independent detection systems: an EJ-309 organic scintillator with pulse-shape discrimination, a ~3He proportional counter and a set of 36 bubble detectors. Time-of-flight analysis of the scintillator data shows the energy of the produced neutrons to be consistent with 2.45 MeV. Particle-in-cell simulations using the WarpX code support significant neutron production from D-D fusion events in the laser±target interaction region. This high-repetition-rate laser-driven neutron source could provide a low-cost, on-demand test bed for radiation hardening and imaging applications.
