A Framework of Paracellular Transport viaNanoparticles-Induced Endothelial Leakiness

Nanomaterial-induced endothelial leakiness (NanoEL) is an interfacial phenomenon denoting the paracellular transport of nanoparticles that is pertinent to nanotoxicology, nanomedicine and biomedical engineering. While the NanoEL phenomenon is complementary to the enhanced permeability and retention effect in terms of their common applicability to delineating the permeability and behavior of nanoparticles in tumoral environments, these two effects significantly differ in scope, origin, and manifestation. In the current study, the descriptors are fully examined of the NanoEL phenomenon elicited by generic citrate-coated gold nanoparticles (AuNPs) of changing size and concentration, from microscopic gap formation and actin reorganization down to molecular signaling pathways and nanoscale interactions of AuNPs with VE-cadherin and its intra/extracellular cofactors. Employing synergistic in silico methodologies, for the first time the molecular and statistical mechanics of cadherin pair disruption, especially in response to AuNPs of the smallest size and highest concentration are revealed. This study marks a major advancement toward establishing a comprehensive NanoEL framework for complementing the understanding of the transcytotic pathway and for guiding the design and application of future nanomedicines harnessing the myriad functions of the mammalian vasculature

Deletion of heat shock protein 60 in adult mouse cardiomyocytes perturbs mitochondrial protein homeostasis and causes heart failure.

To maintain healthy mitochondrial enzyme content and function, mitochondria possess a complex protein quality control system, which is composed of different endogenous sets of chaperones and proteases. Heat shock protein 60 (HSP60) is one of these mitochondrial molecular chaperones and has been proposed to play a pivotal role in the regulation of protein folding and the prevention of protein aggregation. However, the physiological function of HSP60 in mammalian tissues is not fully understood. Here we generated an inducible cardiac-specific HSP60 knockout mouse model, and demonstrated that HSP60 deletion in adult mouse hearts altered mitochondrial complex activity, mitochondrial membrane potential, and ROS production, and eventually led to dilated cardiomyopathy, heart failure, and lethality. Proteomic analysis was performed in purified control and mutant mitochondria before mutant hearts developed obvious cardiac abnormalities, and revealed a list of mitochondrial-localized proteins that rely on HSP60 (HSP60-dependent) for correctly folding in mitochondria. We also utilized an in vitro system to assess the effects of HSP60 deletion on mitochondrial protein import and protein stability after import, and found that both HSP60-dependent and HSP60-independent mitochondrial proteins could be normally imported in mutant mitochondria. However, the former underwent degradation in mutant mitochondria after import, suggesting that the protein exhibited low stability in mutant mitochondria. Interestingly, the degradation could be almost fully rescued by a non-specific LONP1 and proteasome inhibitor, MG132, in mutant mitochondria. Therefore, our results demonstrated that HSP60 plays an essential role in maintaining normal cardiac morphology and function by regulating mitochondrial protein homeostasis and mitochondrial function

Influence of Mo Segregation at Grain Boundaries on the High Temperature Creep Behavior of Ni-Mo Alloys: An Atomistic Study

Based on molecular dynamics simulations, the creep behaviors of nanocrystalline Ni before and after the segregation of Mo atoms at grain boundaries are comparatively investigated with the influences of external stress, grain size, temperature, and the concentration of Mo atoms taken into consideration. The results show that the creep strain rate of nanocrystalline Ni decreases significantly after the segregation of Mo atoms at grain boundaries due to the increase of the activation energy. The creep mechanisms corresponding to low, medium, and high stress states are respectively diffusion, grain boundary slip and dislocation activities based on the analysis of stress exponent and grain size exponent for both pure Ni and segregated Ni-Mo samples. Importantly, the influence of external stress and grain size on the creep strain rate of segregated Ni-Mo samples agrees well with the classical Bird-Dorn-Mukherjee model. The results also show that segregation has little effect on the creep process dominated by lattice diffusion. However, it can effectively reduce the strain rate of the creep deformation dominated by grain boundary behaviors and dislocation activities, where the creep rate decreases when increasing the concentration of Mo atoms at grain boundaries within a certain range

Zircon U-Pb and Hf isotopes of volcanic rocks from the Batamayineishan Formation in the eastern Junggar Basin

An internal structural study was conducted to investigate U-Pb age, trace elements and Hf isotopes of basaltic zircons from the Batamayineishan Formation. The basalt was obtained from drill well San-Can 1 on the eastern Luliang uplift within the Junggar Basin. Trace element data of zircons show that all samples are magmatic, with similar REE patterns, including positive Ce (δCe=5.06–134), but negative Eu (δEu=0.06-0.55) anomalies and enrichment in heavy rare earth elements. Among 25 grains, the concordant ages were subdivided into three groups; ages of 300.4±1.3 Ma (n=11), 339.2±2.7 Ma (n=3) and 392.0±1.7 Ma (n=8). Three remaining grains were nearly concordant, with ²⁰⁶Pb/²³⁸U ages of 510±7, 488±6 and 453±6 Ma, respectively. The youngest concordant age (i.e., 300.4±1.3 Ma) could be interpreted as the formation age of the studied basaltic rock; this is consistent with the sampling position at the upper part of the Batamayineishan Formation. On the other hand, ages such as Ordovician and early Devonian are consistent with the ages of island-arc volcanic rocks (enrichment in Pb) or ophiolites around the basin. Moreover, the positive ɛ Hf(t) values of the early and middle Paleozoic zircons (+3.6–+10.5) may suggest that the basement traversed by the studied volcanic rocks may be Paleozoic in age, formed from the residual oceanic crust and island-arc complex. The ɛ Hf(t) values (+4.2–+17.1) of the late Paleozoic (∼300.4 Ma) zircons suggest that the basaltic magmas were derived from partial melting of the asthenospheric mantle or depleted lithospheric mantle. These magmas were slightly contaminated by the existence of early-middle Paleozoic materials. The late Carboniferous basalts represent direct eruption of mantle-derived magmas at the upper crustal level during a post-collisional tectonic setting. We therefore consider that extensive vertical growth of the continental crust to have occurred before the late Carboniferous.12 page(s

A novel two-dimensional finite element to study the instability phenomena of sandwich plates

International audienceThis paper presents a two-dimensional finite element model to investigate global and local instability phenomena in sandwich plates. In particular, global buckling and symmetrical and antisymmetrical wrinkling are studied. The classical plate theory is used to model the mechanics of the skins, whereas a higher-order kinematics is adopted for the core. By imposing the continuity of the displacement field at skin/core interfaces and a linear variation of the through-the-thickness shear stresses, a model with nine field variables, resulting 15 degrees of freedom per node is obtained. The weak form of the governing equations is obtained by the principle of virtual work. The equations are discretized by means of the finite element method. The resulting non-linear system is solved by asymptotic numerical method. Several boundary conditions and loads are considered. The presented results are validated towards analytical models and three-dimensional finite element solutions. The numerical investigations show that the assumed kinematics permits to accurately yet efficiently predict the critical load of both global and local buckling as well as the post-bifurcation response

Receptor-Mediated Endocytosis of Nanoparticles: Roles of Shapes, Orientations, and Rotations of Nanoparticles

A complete understanding of the interactions between nanoparticles (NPs) and the cell membrane is essential for the potential biomedical applications of NPs. The rotation of the NP during the cellular wrapping process is of great biological significance and has been widely observed in experiments and simulations. However, the underlying mechanisms of the rotation and their potential influences on the wrapping behavior are far from being fully understood. Here, by coupling the rotation of the NP with the diffusion of the receptors, we set up a model to theoretically investigate the wrapping pathway and the internalization rate of the rotatable NP in the receptor-mediated endocytosis. Based on this model, it is found that the endocytosis proceeds through the symmetric–asymmetric or asymmetric–symmetric–asymmetric wrapping pathway due to the bending and membrane tension competition induced rotation of NP. In addition, we show that the wrapping rate in the direction that the wrapping proceeds can be largely accelerated by the rotation. Moreover, the time to fully wrap the NP depends not only on the size and shape of the NP but also on its rotation and initial orientation. These results reveal the roles of the shape, rotation, and initial orientation of the NP on the receptor-mediated endocytosis and may provide guidelines for the design of NP-based drug delivery systems

Overexpression of c-Myc-dependent heterogeneous nuclear ribonucleoprotein A1 promotes proliferation and inhibits apoptosis in NOTCH1-mutated chronic lymphocytic leukemia cells

Abstract. Background:. NOTCH1 mutation is an essential molecular biologic aberration in chronic lymphocytic leukemia (CLL). CLL patients with NOTCH1 mutation have shown an unfavorable survival and a poor response to chemoimmunotherapy. This study aims to present the mechanisms of adverse prognosis caused by NOTCH1 mutation from the perspective of the splicing factor heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1). Methods:. The microarray data in Gene Expression Omnibus datasets were analyzed by bioinformatics and the function of hnRNPA1 was checked by testing the proliferation and apoptosis of CLL-like cell lines. Afterward, quantitative reverse transcription-polymerase chain reaction and Western blotting were applied to explore the relationship among NOTCH1, c-Myc, and hnRNPA1. Results:. RNA splicing was found to play a vital part in NOTCH1-mutated CLL cells; hence, hnRNPA1 was selected as the focus of this study. Higher expression of hnRNPA1 validated in primary NOTCH1-mutated CLL samples could promote proliferation and inhibit apoptosis in CLL. The expression of hnRNPA1 increased when NOTCH1 signaling was activated by transfection with NOTCH1 intracellular domain (NICD)-overexpressed adenovirus vector and declined after NOTCH1 signaling was inhibited by NOTCH1-shRNA. Higher expression of c-Myc was observed in NICD-overexpressed cells and hnRNPA1 expression was downregulated after applying c-Myc inhibitor 10058-F4. Moreover, in NICD-overexpressed cells, hnRNPA1 expression decreased through c-Myc inhibition. Conclusion:. Overexpression of c-Myc-dependent hnRNPA1 could promote proliferation and inhibit apoptosis in NOTCH1-mutated CLL cells, which might partly account for the poor prognosis of patients with NOTCH1 mutation

Mitigation of Metal Oxide Nanotoxicity with Functional Fibrils

The toxicity of metal oxide nanoparticles has been a central research topic over the past two decades, owing to the domestic and industrial applications of this vast class of nanomaterials [...