Flaw tolerant nanostructures of biological materials

Abstract Bone-like biological materials have achieved superior mechanical properties through hierarchical composite structures of mineral and protein. Gecko and many insects have evolved hierarchical surface structures to achieve superior adhesion capabilities. We show that the nanometer scale plays a key role in allowing these biological systems to achieve such properties, and suggest that the principle of flaw tolerance may have had an overarching influence on the evolution of the bulk nanostructure of bone-like materials and the surface nanostructure of gecko-like animal species. We demonstrate that the nanoscale sizes allow the mineral nanoparticles in bone to achieve optimum fracture strength and the spatula nanoprotrusions in Gecko to achieve optimum adhesion strength. Strength optimization is achieved by restricting the relevant dimension to nanometer scale so that crack-like flaws do not propagate to break the desired structural link. Continuum and atomistic modeling have been conducted to verify this concept

Roles for heterodimerization of APJ and B2R in promoting cell proliferation via ERK1/2-eNOS signaling pathway

Apelin receptor (APJ) and bradykinin B2 receptor (B2R) play an important role in many physiological processes and share multiple similar characteristics in distribution and functions in the cardiovascular system. We first identified the endogenous expression of APJ and B2R in human umbilical vein endothelial cells (HUVECs) and their co-localization on human embryonic kidney (HEK) 293 cells membrane. A suite of bioluminescence and fluorescence resonance energy transfer (BRET and FRET), proximity ligation assay (PLA), and co-immunoprecipitation (Co-IP) was exploited to demonstrate formation of functional APJ and B2R heterodimer in HUVECs and transfected cells. Stimulation with apelin-13 and bradykinin (BK) increased the phosphorylation of the endothelial nitric oxide synthase (eNOS) in HUVECs, which could be inhibited by the silencing of APJ or B2R, indicating the APJ-B2R dimer is critical for eNOS phosphorylation in HUVECs. Furthermore, the increase of NOS and extracellular signal regulated kinases1/2 (ERK1/2) phosphorylation mediated by APJ/B2R dimer can be inhibited by U0126 and U73122, respectively, suggesting that the heterodimer might activate the PLC/ERK1/2/eNOS signaling pathway, and finally leading to a significant increase in cell proliferation. Thus, we uncovered for the first time the existence of APJ-B2R heterodimer and provided a promising new target in cardiovascular therapeutics

Gut microbiota and acylcarnitine metabolites connect the beneficial association between estrogen and lipid metabolism disorders in ovariectomized mice

Decreased estrogen level is one of the main causes of lipid metabolism disorders and coronary heart disease in women after menopause. Exogenous estradiol benzoate is effective to some extent in alleviating lipid metabolism disorders caused by estrogen deficiency. However, the role of gut microbes in the regulation process is not yet appreciated. The objective of this study was to investigate the effects of estradiol benzoate supplementation on lipid metabolism, gut microbiota, and metabolites in ovariectomized (OVX) mice and to reveal the importance of gut microbes and metabolites in the regulation of lipid metabolism disorders. This study found that high doses of estradiol benzoate supplementation effectively attenuated fat accumulation in OVX mice. There was a significant increase in the expression of genes enriched in hepatic cholesterol metabolism and a concomitant decrease in the expression of genes enriched in unsaturated fatty acid metabolism pathways. Further screening of the gut for characteristic metabolites associated with improved lipid metabolism revealed that estradiol benzoate supplementation influenced major subsets of acylcarnitine metabolites. Ovariectomy significantly increased the abundance of characteristic microbes that are significantly negatively associated with acylcarnitine synthesis, such as Lactobacillus and Eubacterium ruminantium group bacteria, while estradiol benzoate supplementation significantly increased the abundance of characteristic microbes that are significantly positively associated with acylcarnitine synthesis, such as Ileibacterium and Bifidobacterium spp. The use of pseudosterile mice with gut microbial deficiency greatly facilitated the synthesis of acylcarnitine due to estradiol benzoate supplementation and also alleviated lipid metabolism disorders to a greater extent in OVX mice. IMPORTANCE Our findings establish a role for gut microbes in the progression of estrogen deficiency-induced lipid metabolism disorders and reveal key target bacteria that may have the potential to regulate acylcarnitine synthesis. These findings suggest a possible route for the use of microbes or acylcarnitine to regulate disorders of lipid metabolism induced by estrogen deficiency

Strength of Hydrogen Bond Network Takes Crucial Roles in the Dissociation Process of Inhibitors from the HIV-1 Protease Binding Pocket

To understand the underlying mechanisms of significant differences in dissociation rate constant among different inhibitors for HIV-1 protease, we performed steered molecular dynamics (SMD) simulations to analyze the entire dissociation processes of inhibitors from the binding pocket of protease at atomistic details. We found that the strength of hydrogen bond network between inhibitor and the protease takes crucial roles in the dissociation process. We showed that the hydrogen bond network in the cyclic urea inhibitors AHA001/XK263 is less stable than that of the approved inhibitor ABT538 because of their large differences in the structures of the networks. In the cyclic urea inhibitor bound complex, the hydrogen bonds often distribute at the flap tips and the active site. In contrast, there are additional accessorial hydrogen bonds formed at the lateral sides of the flaps and the active site in the ABT538 bound complex, which take crucial roles in stabilizing the hydrogen bond network. In addition, the water molecule W301 also plays important roles in stabilizing the hydrogen bond network through its flexible movement by acting as a collision buffer and helping the rebinding of hydrogen bonds at the flap tips. Because of its high stability, the hydrogen bond network of ABT538 complex can work together with the hydrophobic clusters to resist the dissociation, resulting in much lower dissociation rate constant than those of cyclic urea inhibitor complexes. This study may provide useful guidelines for design of novel potent inhibitors with optimized interactions

Comment on Ziebert & Aranson, “Modular approach for modeling cell motility”

Commentary on the contribution by Falko Ziebert and Igor S. Aranson [1] in this special issue

Local buckling analysis of biological nanocomposites based on a beam-spring model

Biological materials such as bone, tooth, and nacre are load-bearing nanocomposites composed of mineral and protein. Since the mineral crystals often have slender geometry, the nanocomposites are susceptible to buckle under the compressive load. In this paper, we analyze the local buckling behaviors of the nanocomposite structure of the biological materials using a beam-spring model by which we can consider plenty of mineral crystals and their interaction in our analysis compared with existing studies. We show that there is a transition of the buckling behaviors from a local buckling mode to a global one when we continuously increase the aspect ratio of mineral, leading to an increase of the buckling strength which levels off to the strength of the composites reinforced with continuous crystals. We find that the contact condition at the mineral tips has a striking effect on the local buckling mode at small aspect ratio, but the effect diminishes when the aspect ratio is large. Our analyses also show that the staggered arrangement of mineral plays a central role in the stability of the biological nanocomposites