Background and purpose: Apremilast is an orally administered phosphodiesterase‐4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory ...effects of apremilast on pro‐inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis.
Experimental approach: Apremilast was tested in vitro against endotoxin‐ and superantigen‐stimulated PBMC, bacterial peptide and zymosan‐stimulated polymorphonuclear cells, immunonoglobulin and cytokine‐stimulated NK cells, and ultraviolet B light‐activated keratinocytes. Apremilast was orally administered to beige‐severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed.
Key results: Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon‐γ and tumour necrosis factor (TNF)‐α, and interleukins (IL)‐2, IL‐12 and IL‐23. Production of TNF‐α by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF‐α, human leukocyte antigen‐DR and intercellular adhesion molecule‐1 in the lesioned skin.
Conclusions and implications: Apremilast displayed a broad pattern of anti‐inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF‐α, IL‐12 and IL‐23 production, as well as NK and keratinocyte responses by this phosphodiesterase‐4 inhibitor suggests a novel approach to the treatment of psoriasis.
Summary Objective Knee osteoarthritis (KOA) is a common disease that is characterized by the degeneration of joint cartilage in the knee. Genetic factors have been implicated in KOA. Recently, ...several genetic studies have suggested that susceptibility to KOA is affected by the number of aspartic acid (D) residues in the amino-terminal of the asporin protein, but evidence remains conflicting. Therefore, the objective of the present meta-analysis was to investigate whether or not the D-repeat polymorphism is associated with susceptibility to KOA. Methods A systematic search of all relevant studies published through Dec 2012 was conducted using the MEDLINE, EMBASE, OVID, and ScienceDirect. Allelic counts were evaluated for the D14 and D13 alleles respectively. The included studies were only assessed in the analysis of the following allele model: D14 allele vs others alleles combined, D13 allele vs others alleles combined, and D14 allele vs D13 allele. Results Seven studies (eight comparisons) with 5515 total participants (2334 KOA patients and 3181 controls), which involved four Caucasian and four Asian populations, were eligible for inclusion. Meta-analysis was conducted for genotype D14 vs others combined, D13 vs others combined, and D14 vs D13. In the stratification based on ethnicity, studies were divided into Caucasian and Asian populations. We did not detect positive association between KOA and the D14 allele in Asian populations (OR = 1.527, 95% CI: 0.879–2.653) and in Caucasian populations (OR = 1.053, 95% CI: 0.905–1.225). There was also no positive association between susceptibility to KOA and D13 allele in Asian populations (OR = 0.950, 95% CI: 0.732–1.233) and in Caucasian populations (OR = 0.866, 95% CI: 0.723–1.037). Conclusion The present results suggest that the D-repeat of asporin gene (ASPN) may not be a major susceptibility locus in the Caucasian and Asian populations with KOA. Because of the limitations of the present meta-analysis, accurate conclusions could not be drawn based on the current evidence, and further studies with large sample size are required.
Carbon nanotubes (CNTs) were dispersed into Al matrix by multi-pass friction stir processing (FSP) to fabricate 4.5vol.% CNT/2009Al composites. The maximum strength of the composites was obtained ...with three-pass FSP and was attributed to the combined effect of CNT cluster reduction, grain refinement, and CNT shortening. A CNT shortening model is proposed to describe the CNT length change with FSP passes. The model indicates that the reciprocal of the CNT length has a linear relationship with the duration of the mechanical effect, which was verified by our and other investigators’ experimental results on various mechanical processes. Based on the concept of the load transfer efficiency of CNTs in the Al matrix, a universal strength model considering the microstructural parameters – the aspect ratio of CNTs, grain size, and concentration of CNT clusters and pores – is proposed to predict the strengthening of the CNT/2009Al composites with and without CNT clusters. The predictions are in good agreement with the experimental results.
Carbon nanotube (CNT)/aluminum composites were fabricated by a combination of powder metallurgy and subsequent friction stir processing (FSP). Microstructural observations indicated that the CNTs ...were singly dispersed in the composites. The CNTs tended to be dispersed along grain boundaries resulting in a much finer grain size. Although the CNTs were shortened and some Al4C3 formed in the matrix, the layer structures of the CNTs were well retained. Raman spectroscopy also showed that the damage to CNTs during FSP was not severe. Compared to that of unreinforced Al, the yield strength of 1wt.% and 3wt.% CNT/Al composites increased by 23.9% and 45.0%, respectively. A strength equation relating with load transfer and the grain refinement was proposed to describe the increase of the yield strength of the composites.
•Temperature significantly influence the micro-properties of granite.•Volumetric porosity increases as temperature increases between 400 °C and 800 °C.•Heterogeneity and anisotropy of granite are ...dominated by initial cracks below 200 °C.•Granite is nearly homogeneous and isotropic when temperature is sufficiently high (e.g. 1000 °C).
The thermal effects on micro-properties of granite were experimentally studied. The volumetric porosity was observed by the X-ray Computed Tomography (CT) technique and three-dimensional (3D) image reconstruction. Two indexes (heterogeneity coefficient and anisotropy coefficient) were proposed to describe the micro-properties of granite. The thermal effects on these two indexes were discussed. The results shows that micro-porosity increases as temperature increases between 400 °C and 800 °C. It is slightly influenced by temperature beyond this range. Both of the heterogeneity and anisotropy of thermal treated granite increase to their maximums as temperature increases to 500 °C, than decrease to constants as temperature further increases. The heterogeneity and anisotropy of granite are mainly dominated by the initial cracks below 200 °C. The thermal induced cracks are mainly in the regions of lower density mineral grains below 400 °C. Boundary cracks and trans-granular cracks generate significantly above 500 °C.
This paper extends the numerical manifold method (NMM) for footwall slope stability analysis. A fracturing algorithm based on the Mohr–Coulomb criterion with a tensile cutoff is implemented into the ...NMM code. The developed program is first calibrated by simulating four typical crack problems. It is then applied to analyze the potential footwall slope instability. Parametric studies with respect to dip of a bedding plane, orientation of a predominant joint set, the bedding profile, etc., are carried out. Numerical results indicate that the developed program can simulate the opening and sliding along pre-existing discontinuities, fracturing through intact rock, as well as kinematics of the failed slope, and can also reproduce the major failure mechanisms observed in footwall slope collapses. The NMM is promising for such problems and deserves to be further developed to be practically used in natural/excavated rock slope stability analysis and open pit slope design.
► A fracturing algorithm based on the Mohr–Coulomb criterion is coupled in the NMM. ► No
a priori assumption, interface element, or remeshing is required in the modeling. ► The developed NMM in fracturing modeling under various loading types is verified. ► Failure mechanisms observed in footwall slope collapse are numerically reproduced.
Delayed pollination is widely used to overcome pre‐fertilization incompatibility, but its regulatory mechanisms are unclear. When Nicotiana tabacum was cross‐pollinated with pollen of N. alata, the ...incompatibility occurring in the basal 1/4 region of the style (pollinated at anthesis: 0‐day‐old pistil) was overcome by delayed pollination (of 6‐day‐old pistil), and the morphological changes and corresponding physiological basis are explored here.
The structure and ultrastructure of the pistil were observed under fluorescence microscopy and transmission electron microscopy. Differentially expressed proteins were screened with a monoclonal antibody chip for Nicotiana, and protein expression and distribution were analysed by immunofluorescence. Cellulase and pectinase activities were tested using enzyme‐linked immunosorbent assay kits.
The style of Nicotiana is solid in the basal region and pollen tubes grow in the extracellular spaces (ECM) of the transmitting tissue (TTS) cells. Seven of the 22 identified proteins were cell wall‐associated proteins and were expressed at higher levels during pistil senescence. Cellulase and pectinase activities increased. The TTS cells in the basal 1/4 region of the 0‐day‐old style were polygonal and tightly arranged, with narrow ECM, but these were oval or partially dissolved in the 6‐day‐old pistil, leading to wider ECM and richer secretions.
The increased expression of cell wall proteins and enhanced enzyme activity during pistil senescence might partially be responsible for the cells becoming oval and the ECM enlarged, providing the morphological basis for delayed pollination overcoming the pre‐fertilization incompatibility between N. tabacum and N. alata.
The transmitting tissue cells becoming oval and the extracellular spaces enlarged in senescent pistils and play a role in overcoming pollen‐pistil incompatibility via delayed pollination.
A route combining friction stir processing and subsequent rolling processing was established to fabricate 1.5–4.5vol.% carbon nanotube (CNT)-reinforced 2009Al composites. Microstructural observations ...indicated that CNTs were individually dispersed and directionally aligned in the aluminum matrix of the CNT/2009Al composites. The tube structure of the CNTs was retained and the CNT–Al interface was bonded without pores. As a result, great increases in yield strength, ultimate tensile strength, and Young’s modulus were achieved when a higher concentration of CNTs was incorporated. Moreover, the composites exhibited good ductility. In particular, 3vol.% CNT/2009Al composite exhibited an ultimate tensile strength of 600MPa and elongation of 10%, much higher strength–ductility than the corresponding values for CNT/Al composites fabricated by other processes.
Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. ...Telomeres were shorter in tumors than in normal tissues and longer in sarcomas and gliomas than in other cancers. Among 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications and transcript fusions and predictive of telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, characterized by undetectable TERT expression and alterations in ATRX or DAXX, demonstrated elongated telomeres and increased telomeric repeat-containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT nor harbored alterations in ATRX or DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.
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