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•FSC process can join surface-treated sheet metals with good strength & short time.•Fatigue behaviors of FSC joints in TS & CT specimens were investigated.•Critical fatigue cracks and ...failure modes were identified.•Fatigue lives were well estimated by interfacial & kinked crack fatigue models.•Fatigue data of FSC joints were well correlated by effective global & local SIFs.
Joining alclad AA2024-T3 sheets is difficult for conventional welding processes due to ductile surface cladding layers. Friction stir clinching (FSC) was therefore proposed to overcome this problem. Here, two types of specimens, tensile-shear and cross-tension, were made to investigate general fatigue behavior of FSC joints. Critical fatigue cracks and failure modes were identified by photos and micrographs. Interfacial and kinked crack fatigue models consist of local and global stress intensity factors (SIFs) and a Paris law approach were taken for fatigue life estimations. The fatigue life estimations well agreed with the experimental fatigue data. The fatigue data of FSC joints in above specimens were well correlated by effective SIF ranges.
Vav1 is a Rho/Rac (Ras-related C3 botulinum toxin substrate) guanine nucleotide exchange factor expressed in hematopoietic and endothelial cells that are involved in a wide range of cellular ...functions. It is also stabilized under hypoxic conditions when it regulates the accumulation of the transcription factor HIF (Hypoxia Inducible Factor)-1α, which activates the transcription of target genes to orchestrate a cellular response to low oxygen. One of the genes induced by HIF-1α is GLUT (Glucose Transporter)-1, which is the major glucose transporter expressed in vessels that supply energy to the brain. Here, we identify a role for Vav1 in providing glucose to the brain. We found that Vav1 deficiency downregulates HIF-1α and GLUT-1 levels in endothelial cells, including blood-brain barrier cells. This downregulation of GLUT-1, in turn, reduced glucose uptake to endothelial cells both in vitro and in vivo, and reduced glucose levels in the brain. Furthermore, endothelial cell-specific Vav1 knock-out in mice, which caused glucose uptake deficiency, also led to a learning delay in fear conditioning experiments. Our results suggest that Vav1 promotes learning by activating HIF-1α and GLUT-1 and thereby distributing glucose to the brain. We further demonstrate the importance of glucose transport by endothelial cells in brain functioning and reveal a potential new axis for targeting GLUT-1 deficiency syndromes and other related brain diseases.
The biology of haematopoietic stem cells (HSCs) has predominantly been studied under transplantation conditions
. It has been particularly challenging to study dynamic HSC behaviour, given that the ...visualization of HSCs in the native niche in live animals has not, to our knowledge, been achieved. Here we describe a dual genetic strategy in mice that restricts reporter labelling to a subset of the most quiescent long-term HSCs (LT-HSCs) and that is compatible with current intravital imaging approaches in the calvarial bone marrow
. We show that this subset of LT-HSCs resides close to both sinusoidal blood vessels and the endosteal surface. By contrast, multipotent progenitor cells (MPPs) show greater variation in distance from the endosteum and are more likely to be associated with transition zone vessels. LT-HSCs are not found in bone marrow niches with the deepest hypoxia and instead are found in hypoxic environments similar to those of MPPs. In vivo time-lapse imaging revealed that LT-HSCs at steady-state show limited motility. Activated LT-HSCs show heterogeneous responses, with some cells becoming highly motile and a fraction of HSCs expanding clonally within spatially restricted domains. These domains have defined characteristics, as HSC expansion is found almost exclusively in a subset of bone marrow cavities with bone-remodelling activity. By contrast, cavities with low bone-resorbing activity do not harbour expanding HSCs. These findings point to previously unknown heterogeneity within the bone marrow microenvironment, imposed by the stages of bone turnover. Our approach enables the direct visualization of HSC behaviours and dissection of heterogeneity in HSC niches.
We study galaxy mergers using a high-resolution cosmological hydro/N- body simulation with star formation and compare the measured merger timescales with theoretical predictions based on the ...Chandrasekhar formula. In contrast to Navarro et al., our numerical results indicate that the commonly used equation for the merger timescale given by Lacey and Cole systematically underestimates the merger timescales for minor mergers and overestimates those for major mergers. This behavior is partly explained by the poor performance of their expression for the Coulomb logarithm, image. The two alternative forms image and image for the Coulomb logarithm can account for the mass dependence of merger timescale successfully, but both of them underestimate the merger timescale by a factor 2. Since image represents the mass dependence slightly better, we adopt this expression for the Coulomb logarithm. Furthermore, we find that the dependence of the merger timescale on the circularity parameter epsilon is much weaker than the widely adopted power law image, whereas image provides a good match to the data. Based on these findings, we present an accurate and convenient fitting formula for the merger timescale of galaxies in cold dark matter models.
Aberrant TGFβ signaling is common in human cancers and contributes to tumor metastasis. Here, we demonstrate that Gr-1+CD11b+ myeloid cells are recruited into mammary carcinomas with type II TGFβ ...receptor gene (
Tgfbr2) deletion and directly promote tumor metastasis. Gr-1+CD11b+ cells infiltrate into the invasive front of tumor tissues and facilitate tumor cell invasion and metastasis through a process involving metalloproteinase activity. This infiltration of Gr-1+CD11b+ cells also results in increased abundance of TGFβ1 in tumors with
Tgfbr2 deletion. The recruitment of Gr-1+CD11b+ cells into tumors with
Tgfbr2 deletion involves two chemokine receptor axes, the SDF-1/CXCR4 and CXCL5/CXCR2 axes. Together, these data indicate that Gr-1+CD11b+ cells contribute to TGFβ-mediated metastasis through enhancing tumor cell invasion and metastasis.
In this paper we describe two fully mass conservative, energy stable, finite difference methods on a staggered grid for the quasi-incompressible Navier–Stokes–Cahn–Hilliard (q-NSCH) system governing ...a binary incompressible fluid flow with variable density and viscosity. Both methods, namely the primitive method (finite difference method in the primitive variable formulation) and the projection method (finite difference method in a projection-type formulation), are so designed that the mass of the binary fluid is preserved, and the energy of the system equations is always non-increasing in time at the fully discrete level. We also present an efficient, practical nonlinear multigrid method – comprised of a standard FAS method for the Cahn–Hilliard equation, and a method based on the Vanka-type smoothing strategy for the Navier–Stokes equation – for solving these equations. We test the scheme in the context of Capillary Waves, rising droplets and Rayleigh–Taylor instability. Quantitative comparisons are made with existing analytical solutions or previous numerical results that validate the accuracy of our numerical schemes. Moreover, in all cases, mass of the single component and the binary fluid was conserved up to 10−8 and energy decreases in time.
•Two novel staggered grid finite difference methods are provided.•Discrete mass conservation is naturally satisfied due to the discretization.•Energy stability is achieved at the fully discrete level for both methods.•An efficient nonlinear multigrid solver is designed for solving the two methods.
Intragenic CpG dinucleotides are tightly conserved in evolution yet are also vulnerable to methylation-dependent mutation, raising the question as to why these functionally critical sites have not ...been deselected by more stable coding sequences. We previously showed in cell lines that altered exonic CpG methylation can modify promoter start sites, and hence protein isoform expression, for the human TP53 tumor suppressor gene. Here we extend this work to the in vivo setting by testing whether synonymous germline modifications of exonic CpG sites affect murine development, fertility, longevity, or cancer incidence. We substituted the DNA-binding exons 5-8 of Trp53, the mouse ortholog of human TP53, with variant-CpG (either CpG-depleted or -enriched) sequences predicted to encode the normal p53 amino acid sequence; a control construct was also created in which all non-CpG sites were synonymously substituted. Homozygous Trp53-null mice were the only genotype to develop tumors. Mice with variant-CpG Trp53 sequences remained tumor-free, but were uniquely prone to dental anomalies causing jaw malocclusion (p < .0001). Since the latter phenotype also characterises murine Rett syndrome due to dysfunction of the trans-repressive MeCP2 methyl-CpG-binding protein, we hypothesise that CpG sites may exert non-coding phenotypic effects via pre-translational cis-interactions of 5-methylcytosine with methyl-binding proteins which regulate mRNA transcript initiation, expression or splicing, although direct effects on mRNA structure or translation are also possible.
Abstract Biodegradable poly-lactic acid (PLA) – based composites reinforced unidirectionally with high-strength magnesium alloy wires (MAWs) are fabricated by a heat-compressing process and the ...mechanical properties and degradation behavior are studied experimentally and theoretically. The composites possess improved strengthening and toughening properties. The bending strength and impact strength of the composites with 40 vol% MAWs are 190 MPa and 150 kJ/m2 , respectively, although PLA has a low viscosity and an average molecular weight of 60,000 g/mol. The mechanical properties of the composites can be further improved by internal structure modification and interface strengthening and a numerical model incorporating the equivalent section method (ESM) is proposed for the bending strength. Micro arc oxidization (MAO) of the MAWs is an effective interfacial strengthening method. The composites exhibit high strength retention during degradation and the PLA in the composite shows a smaller degradation rate than pure PLA. The novel biodegradable composites have large potential in bone fracture fixation under load-bearing conditions.
Background. Mycobacterium tuberculosis infection in humans results in either latent infection or active tuberculosis. We sought to determine whether a higher frequency of regulatory T (Treg) cells ...predispose an individual toward active disease or whether Treg cells develop in response to active disease. Methods. In cynomolgus macaques infected with a low dose of M. tuberculosis, ∼50% develop primary tuberculosis, and ∼50% become latently infected. Forty-one animals were monitored for 6–8 months to assess the correlation of the frequency of Foxp3+ cells in peripheral blood and airways with the outcome of infection. Results. In all animals, the frequency of Treg cells (CD4+Foxp3+) in peripheral blood rapidly decreased and simultaneously increased in the airways. Latently infected monkeys had a significantly higher frequency of Treg cells in peripheral blood before infection and during early infection, compared with monkeys that developed active disease. Monkeys with active disease experienced increased frequencies of Treg cells among peripheral blood mononuclear cells as they developed disease. Conclusions. Our data suggest that increased frequencies of Treg cells in active disease occur in response to increased inflammation rather than act as a causative factor in progression to active disease.
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