Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome

The homeodomain transcription factor distal-less homeobox 3 gene (DLX3) is required for hair, tooth and skeletal development. DLX3 mutations have been found to be responsible for Tricho-Dento-Osseous (TDO) syndrome, characterized by kinky hair, thin-pitted enamel and increased bone density. Here we show that the DLX3 mutation (c.533 A>G; Q178R) attenuates osteogenic potential and senescence of bone mesenchymal stem cells (BMSCs) isolated from a TDO patient, providing a molecular explanation for abnormal increased bone density. Both DLX3 mutations (c.533 A>G and c.571_574delGGGG) delayed cellular senescence when they were introduced into pre-osteoblastic cells MC3T3-E1. Furthermore, the attenuated skeletal aging and bone loss in DLX3 (Q178R) transgenic mice not only reconfirmed that DLX3 mutation (Q178R) delayed cellular senescence, but also prevented aging-mediated bone loss. Taken together, these results indicate that DLX3 mutations act as a loss of function in senescence. The delayed senescence of BMSCs leads to increased bone formation by compensating decreased osteogenic potentials with more generations and extended functional lifespan. Our findings in the rare human genetic disease unravel a novel mechanism of DLX3 involving the senescence regulation of bone formation

Pre-Clinical Evaluation of a Novel Nanoemulsion-Based Hepatitis B Mucosal Vaccine

Hepatitis B virus infection remains an important global health concern despite the availability of safe and effective prophylactic vaccines. Limitations to these vaccines include requirement for refrigeration and three immunizations thereby restricting use in the developing world. A new nasal hepatitis B vaccine composed of recombinant hepatitis B surface antigen (HBsAg) in a novel nanoemulsion (NE) adjuvant (HBsAg-NE) could be effective with fewer administrations.Physical characterization indicated that HBsAg-NE consists of uniform lipid droplets (349+/-17 nm) associated with HBsAg through electrostatic and hydrophobic interactions. Immunogenicity of HBsAg-NE vaccine was evaluated in mice, rats and guinea pigs. Animals immunized intranasally developed robust and sustained systemic IgG, mucosal IgA and strong antigen-specific cellular immune responses. Serum IgG reached > or = 10(6) titers and was comparable to intramuscular vaccination with alum-adjuvanted vaccine (HBsAg-Alu). Normalization showed that HBsAg-NE vaccination correlates with a protective immunity equivalent or greater than 1000 IU/ml. Th1 polarized immune response was indicated by IFN-gamma and TNF-alpha cytokine production and elevated levels of IgG(2) subclass of HBsAg-specific antibodies. The vaccine retains full immunogenicity for a year at 4 degrees C, 6 months at 25 degrees C and 6 weeks at 40 degrees C. Comprehensive pre-clinical toxicology evaluation demonstrated that HBsAg-NE vaccine is safe and well tolerated in multiple animal models.Our results suggest that needle-free nasal immunization with HBsAg-NE could be a safe and effective hepatitis B vaccine, or provide an alternative booster administration for the parenteral hepatitis B vaccines. This vaccine induces a Th1 associated cellular immunity and also may provide therapeutic benefit to patients with chronic hepatitis B infection who lack cellular immune responses to adequately control viral replication. Long-term stability of this vaccine formulation at elevated temperatures suggests a direct advantage in the field, since potential excursions from cold chain maintenance could be tolerated without a loss in therapeutic efficacy

Evidence-based uncertainty quantification for bending properties of bimetal composites

Bimetal or laminated metal composites consisting of several metal or alloy layers can efficiently absorb the advantageous properties of each metal when utilised as raw materials for future remanufacturing. Their mechanical response characteristics and failure modes face uncertain challenges during the processing owing to the existence of heterogenous interfacial transition zones between layers. This work aims to study the uncertainty quantification in bending processing of a novel bimetal composite as a result of uncertain interfacial zones using an efficient evidence-based reliability analysis method. An analytical model for bending characteristics of bimetal composite was first established based on the deterministic material properties of each component layer, and it was employed to quantitatively analyse the bending uncertainty properties of 2205 duplex stainless steel/AH36 carbon steel bimetal composite (2205/AH36 BC) considering the epistemic uncertainty in geometric dimensions and mechanical properties of component 2205 and AH36 layers. The variation ranges of tangential stress and bending moment along the thickness direction of composite during bending process were effectively estimated, and the confidence level of each possible in the corresponding upper and lower boundaries was given for the tangential stress at each position. The analysis results illustrated that the uncertainty quantification for bending deformation properties of bimetal composite can more comprehensively understand the mechanical behaviors of composite, and provide an effective guidance for the forming fabrication of bimetal composite structure

Experimental Study on the Deformation and Mechanical Properties of Bamboo Forest Slopes

In this paper, model tests on a plain soil slope and a bamboo-rooted slope under slope top loading were carried out to analyze the slope surface displacement, the change in earth pressure, and the failure mode of the slope. Furthermore, the influence of rainfall on the deformation and mechanical properties of bamboo-rooted slope sliding was studied. The results show that: (1) the failure mode of the plain soil slope was block sliding failure, while the failure mode of the bamboo-rooted slope was progressive backward failure. (2) Under the slope top load, the slope displacement shows the rule that the top of the slope was large and the foot of the slope was small. The presence of bamboo rhizomes had a negligible effect on the slope displacement, but it significantly contributed to the sliding area’s increase. (3) Compared with the plain soil slope, the earth pressure in the area of the foot of the slope under the same level of the load was elevated more obviously by the bamboo-rooted slope, which indicates that bamboo rhizomes could play a specific role in reinforcing the slope. Still, the scope of its influence was limited and mainly concentrated in the shallow soil. (4) There was a significant increase in the displacement of the bamboo-rooted slope under rainfall conditions, and the magnitude of the upward slope earth pressure was small in the process of step-by-step loading. The test results may have important guiding significance for the in-depth study of the instability law and disaster prevention in bamboo forest areas

Influences of Increased Pressure Foaming on the Cellular Structure and Compressive Properties of In Situ Al-4.5%Cu-xTiB2 Composite Foams with Different Particle Fraction

Metallic foams have drawn increasing attention in applications ranging from lightweight structures to energy absorption devices. Mechanical properties of metallic foams depend on both their microstructure and cellular structure. In situ Al-4.5%Cu-xTiB2 composites were used as start materials for fabrication of closed-cell foams through liquid route under atmosphere pressure and increased pressure, aiming at simultaneously strengthening the cell wall material and optimizing the cellular structure. Macro-structural features of the foams were determined by micro X-ray computed tomography (µCT); results exhibit that increasing weight ratio of in situ TiB2 particles leads to coarsened cell structure for foams made under atmosphere pressure, due to the increase in critical thickness of cell wall rupture. Significant reduction of cell size and increase in cell circularity were observed for foams fabricated under increased pressure. Quasi static compression test results indicate that yield strength of foam samples increases with increasing particle fraction and refinement of cell structure. Microstructure observation shows that the continuous network at interdendritic regions consists of in situ TiB2 particles and intermetallic compounds are responsible for the reduced ductility of cell wall materials and the reduction in energy absorption efficiency of foams with high particle fraction. The influences of cell structure on the normalized strength and specific energy absorption were also discussed, and it was found that the improvement of yield strength and energy absorption of composite foams attributes to both the reinforcement of in situ TiB2 particles and the refinement of cellular structure

Perpetual Humanoid Control for Real-time Simulated Avatars

We present a physics-based humanoid controller that achieves high-fidelity motion imitation and fault-tolerant behavior in the presence of noisy input (e.g. pose estimates from video or generated from language) and unexpected falls. Our controller scales up to learning ten thousand motion clips without using any external stabilizing forces and learns to naturally recover from fail-state. Given reference motion, our controller can perpetually control simulated avatars without requiring resets. At its core, we propose the progressive multiplicative control policy (PMCP), which dynamically allocates new network capacity to learn harder and harder motion sequences. PMCP allows efficient scaling for learning from large-scale motion databases and adding new tasks, such as fail-state recovery, without catastrophic forgetting. We demonstrate the effectiveness of our controller by using it to imitate noisy poses from video-based pose estimators and language-based motion generators in a live and real-time multi-person avatar use case.Comment: Project page: https://zhengyiluo.github.io/PHC

Heterogeneous bimetallic sulfides based seawater electrolysis towards stable industrial-level large current density

Direct seawater electrolysis is an attractive technology for scalable hydrogen production as well as seawater desalination, which however demands efficient and robust anodic catalysts that can sustain oxygen evolution reaction (OER) against chloride corrosion. Here we report an outstanding anodic catalyst consisting of threedimensional standing arrays of hetero-lateral Ni3S2/Co3S4 (NiCoS) nanosheets uniformly grown on Ni foam for alkaline seawater electrolysis, in which the in-situ derived Ni/Co (oxy)hydroxide surface layer endows abundant active sites and superior resistance to chloride corrosion. Combined with an efficient hydrogen evolution reaction catalyst of Ni/Mo sulfides, a two-electrode electrolyzer affords an industrial-level high current density up to 800 mA cm− 2 at a super low voltage of 2.08 V for overall alkaline seawater splitting steadily over 100 h without chloride corrosion at room temperature. Furthermore, powered by a commercial single III-V triplejunction solar cell, the integrated system demonstrates light-driven overall seawater splitting with an impressive 15.13 % solar-to-hydrogen efficiency. This work is instrumental in the development of seawater electrolysis for sustainable hydrogen production by renewable energy sources.This work was supported by the National Natural Science Foundation of China (Nos. 11974303 and 11574263), the ANU Futures Scheme (Q4601024), the Australian Research Council (DP190100295, LE190100014), the Qing Lan Project of Jiangsu Province (No. 137050317), and the Advanced Talent Development Plan of Yangzhou University (No. 137080051)