Characterization of a Cutibacterium acnes Camp Factor 1-Related Peptide as a New TLR-2 Modulator in In Vitro and Ex Vivo Models of Inflammation

Cutibacterium acnes (C. acnes) has been implicated in inflammatory acne where highly mutated Christie–Atkins–Munch–Petersen factor (CAMP)1 displays strong toll like receptor (TLR)-2 binding activity. Using specific antibodies, we showed that CAMP1 production was independent of C. acnes phylotype and involved in the induction of inflammation. We confirmed that TLR-2 bound both mutated and non-mutated recombinant CAMP1, and peptide array analysis showed that seven peptides (A14, A15, B1, B2, B3, C1 and C3) were involved in TLR-2 binding, located on the same side of the three-dimensional structure of CAMP1. Both mutated and non-mutated recombinant CAMP1 proteins induced the production of C-X-C motif chemokine ligand interleukin (CXCL)8/(IL)-8 in vitro in keratinocytes and that of granulocyte macrophage-colony stimulating factor (GM-CSF), tumor necrosis factor (TNF)-α, IL-1β and IL-10 in ex vivo human skin explants. Only A14, B1 and B2 inhibited the production of CXCL8/IL-8 by keratinocytes and that of (GM-CSF), TNF-α, IL-1β and IL-10 in human skin explants stimulated with rCAMP1 and C. acnes. Following pretreatment with B2, RNA sequencing on skin explants identified the 10 genes displaying the strongest differential expression as IL6, TNF, CXCL1, CXCL2, CXCL3, CXCL8, IL-1β, chemokine ligand (CCL)2, CCL4 and colony stimulating factor (CSF)2. We, thus, identified a new CAMP1-derived peptide as a TLR-2 modulator likely to be a good candidate for clinical evaluation.     

Alchemical Design of Pharmacological Chaperones with Higher Affinity for Phenylalanine Hydroxylase

Phenylketonuria (PKU) is a rare metabolic disease caused by variations in a human gene, PAH, encoding phenylalanine hydroxylase (PAH), and the enzyme converting the essential amino acid phenylalanine into tyrosine. Many PKU-causing variations compromise the conformational stability of the encoded enzyme, decreasing or abolishing its catalytic activity, and leading to an elevated concentration of phenylalanine in the blood, which is neurotoxic. Several therapeutic approaches have been developed to treat the more severe manifestations of the disorder, but they are either not entirely effective or difficult to adhere to throughout life. In a search for novel pharmacological chaperones to treat PKU, a lead compound was discovered (compound IV) that exhibited promising in vitro and in vivo chaperoning activity on PAH. The structure of the PAH-IV complex has been reported. Here, using alchemical free energy calculations (AFEC) on the structure of the PAH-IV complex, we design a new generation of compound IV-analogues with a higher affinity for the enzyme. Seventeen novel analogues were synthesized, and thermal shift and isothermal titration calorimetry (ITC) assays were performed to experimentally evaluate their stabilizing effect and their affinity for the enzyme. Most of the new derivatives bind to PAH tighter than lead compound IV and induce a greater thermostabilization of the enzyme upon binding. Importantly, the correspondence between the calculated alchemical binding free energies and the experimentally determined ΔΔG_b values is excellent, which supports the use of AFEC to design pharmacological chaperones to treat PKU using the X-ray structure of their complexes with the target PAH enzyme.     

喷射成形Al-Zn-Mg-Cu系超高强度铝合金热处理制度的实验研究

研究了喷射成形Al-Zn-Mg-Cu系超高强度铝合金的沉积态和挤压态的组织,对挤压态合金进行了固溶处理和时效处理,得到了时效硬度曲线,并进行了力学性能测试.结果显示:沉积态合金孔隙较多;挤压态合金内存在大量的颗粒,经能谱分析为富铜相;固溶温度达到490℃时,晶界出现熔化现象.时效硬度曲线表明:采用120℃时效,在15~25h之间达到硬度峰值;采用135℃时效,达到硬度峰值的时间与合金的成分有关,随着Zn含量的增加,达到硬度峰值的时间变短,而抗拉强度基本稳定在700MPa左右.     

局部火灾下钢筋混凝土平面框架结构的耐火性能研究

高温后混凝土与钢筋间的黏结性能影响钢筋混凝土结构的安全评估,实际工程中钢筋混凝土常承受侧向约束作用。为此,该文以高温温度和侧压力为参数,完成了48个钢筋混凝土试件的中心拉拔试验,分析侧压力对高温后试件破坏形态、峰值黏结应力、峰值滑移、残余黏结强度的影响规律,建立了峰值黏结应力随高温温度和侧压力变化的经验公式。将侧压下钢筋-混凝土黏结应力场简化为肋前混凝土挤压力和侧压力的线性叠加,并基于微观传力模型及高温后混凝土的多轴强度破坏准则推导计算了无侧压及单向侧压下的黏结强度理论。研究结果表明：侧压作用和高温温度直接影响试件破坏形态;随着侧压力增加,高温后混凝土与钢筋间的峰值黏结应力、残余黏结强度、峰值滑移逐渐增大,但温度达到500 ℃后,有侧压试件峰值滑移较无侧压试件小;黏结强度理论计算值与实测值较为吻合,能较好地预测高温后混凝土与钢筋间的黏结强度。     

我国钢管混凝土拱桥应用现状与展望

以轴压比、含钢率和钢材强度为参数,进行了8根高强钢管超高强混凝土柱和1根普通强度钢管超高强混凝土对比柱的拟静力试验,分析了各参数对破坏形态、荷载-位移滞回曲线、骨架曲线和各个抗震性能指标(如延性、耗能和强度与刚度退化等)的影响程度。结果表明：压弯破坏为主要破坏模式;弹性刚度受轴压比影响不大,但受含钢率和钢材强度影响较大;极限承载力受轴压比、含钢率和钢材强度影响较大,随前者增大而降低,随后两者增大而增大;延性受轴压比、钢材强度和含钢率影响较大,随前两者增大降低,随后者增大而增大;耗能能力随轴压比增大而减弱,随含钢率和钢材强度增大而增强;刚度和强度退化程度随轴压比增大而降低,随含钢率增大而增大,且前者随钢材强度增大而增大,后者则随钢材强度增大呈减小趋势。通过对比不同规程抗弯刚度计算方法,结果表明：受材料适用范围限制,各规程不适用于该类高强材料组合构件。     

煤矸石基混凝土在井下巷道硬化工程中的应用试验

煤矸石是我国目前排放量较大的固体废弃物之一,利用煤矸石部分或全部代替混凝土粗骨料生产煤矸石基混凝土是其高效利用的途径。通过实验室开展不同煤矸石粗骨料替代率、水胶比、添加剂等条件下的煤矸石基混凝土的抗压强度试验,探究煤矸石基混凝土的基本力学性能,确定煤矸石基混凝土的最佳配合比。研究结果表明：煤矸石基混凝土抗压强度随着煤矸石粗骨料替代率的增大而减小;在胶凝材料中加入质量比为5%的硅灰、0.3%的减水剂有助于迅速提高煤矸石基混凝土的前期强度。在山西李村煤矿二采区胶带巷5^#辅运联巷开展了煤矸石基混凝土的井下硬化试验,验证了煤矸石基混凝土在井下硬化工程中的良好效果。     

Application of strength reduction method to dynamic anti-sliding stability analysis of high gravity dam with complex dam foundation

Considering that there are some limitations in analyzing the anti-sliding seismic stability of dam-foundation systems with the traditional pseudo-static method and response spectrum method,the dynamic strength reduction method was used to study the deep anti-sliding stability of a high gravity dam with a complex dam foundation in response to strong earthquake-induced ground action.Based on static anti-sliding stability analysis of the dam foundation undertaken by decreasing the shear strength parameters of ...     

On the mechanical characterization of materials by Arcan-type specimens

The simple circular notched specimen was originally proposed by Arcan to characterize the elastic properties of fibre-reinforced composites. Unfortunately, its optimized geometry does not allow to measure with reasonable accuracy both the material shear strength and the conditions of failure under a generic biaxial stress state, since the effects of stress concentration on the fillets of the two V-grooves and on the inner circular edges are responsible of premature fractures due to the uniaxial stress states of the notch edges.In a previous numerical study carried out by a parametric two-dimensional finite element model, some of the Authors of this paper found a new optimal geometry of the Arcan specimen able to minimize the notch effect and achieve a uniform pure shear stress field in the gauge cross-section. In the present paper, starting from such a geometry, a new type of Arcan specimen is proposed, having not uniform thickness. An extensive three-dimensional parametric finite element analysis has been done to define its optimal shape. The numerical results show that the new specimen is able to achieve, with a higher probability, material fracture in the minimum cross-section under a pure shear stress distribution which is more uniform than those acting in the Arcan specimen typologies until now proposed.     

建筑垃圾界面膜化对水泥砂浆强度的影响

本文设置了不同的再生集料替代率,和不同的处理方式,并对试验结果进行了对比和分析,研究了垃圾界面膜化对砂浆强度的影响。结果表明,在取代率相同的情况下,再生骨料经过处理以后其强度最大增加25％,而且随着垃圾砂掺量的增加,砂浆强度呈现出总体下降的趋势。     

Coating of TiB2 dispersed Ti50Ni50 superelastic alloy layer onto Ti-6Al-4V alloy by spark and resistance sintering

The spark and resistance sintering (SRS) of a mixture of Ti, Ni, and TiB₂ powders was carried out to form a TiB₂ dispersed TiNi alloy layer onto a Ti-6Al-4V alloy substrate. The strength and delamination resistance of the surface layer were evaluated by three-point bending tests. The results showed that the bending strength of the specimen with the TiNi alloy surface layer without TiB₂ particles sintered at 1273 K was low because the crack initiation occurred at an early stage of loading in a thick interface layer containing brittle Ti-Ti₂Ni eutectic. By decreasing the sintering temperature to 1200 K, the bending strength increased and the crack initiation occurred from the surface because the interface layer was thin and did not contain the brittle Ti-Ti₂Ni eutectic. For the specimens with TiB₂ dispersed TiNi surface layer that was sintered at 1273 K, the bending strength was larger than that of the specimens with TiNi surface layer because the interface layer does not contain the Ti-Ti₂Ni eutectic and compressive residual stress generated in the surface layer during cooling process after SRS suppresses the crack initiation on the surface. The coating of TiB₂ dispersed TiNi alloy onto titanium alloys by SRS provides strong interface to prevent delamination of the surface layer, strong surface due to residual compressive stress, and wear-resistant surface due to the existence of hard TiB₂ particles and superelastic deformation of TiNi matrix.