No abstract

Vascular calcification (VC) is regarded as an important pathological change lacking effective treatment and associated with high mortality. Sirtuin 6 (SIRT6) is a member of Sirtuin family, a class III histone deacetylase and a key epigenetic regulator. SIRT6 has a protective role in patients with chronic kidney disease (CKD), however the exact role and molecular mechanism of SIRT6 in VC in CKD patients remains unclear. Here, we demonstrated that SIRT6 was significantly downregulated in peripheral blood mononuclear cells (PBMCs) and in the radial artery tissue of CKD patients with VC. SIRT6-transgenic (SIRT6-Tg) mice showed alleviated VC, while vascular smooth muscle cells (VSMCs)-specific, SIRT6 knocked down mice showed severe VC, in CKD. SIRT6 suppressed the osteogenic transdifferentiation of VSMCs via regulation of runt-related transcription factor 2 (Runx2). Co-immunoprecipitation (co-IP) and immunoprecipitation (IP) assays confirmed that SIRT6 bound to Runx2. Moreover, Runx2 was deacetylated by SIRT6 and further promoted nuclear export via exportin 1(XPO1), which in turn caused degradation of Runx2 through the ubiquitin-proteasome system. These results demonstrated that SIRT6 prevented VC by suppressing the osteogenic transdifferentiation of VSMCs, and as such targeting SIRT6 may be an appealing therapeutic target for VC in CKD.

Tau is a microtubule-associated protein, and the oligomeric and hyperphosphorylated forms of tau are increased significantly after neurotrauma and considered important factors in mediating cognitive dysfunction. Blockade of adenosine A2A receptors, either by caffeine or gene knockout (KO), alleviates cognitive dysfunction after traumatic brain injury (TBI). We postulated that A2AR activation exacerbates cognitive impairment via promoting tau hyperphosphorylation. Using a mouse model of moderate controlled cortical impact, we showed that TBI induced hyperphosphorylated tau (p-tau) in the hippocampal dentate gyrus and spatial memory deficiency in the Morris water maze test at 7 days and 4 weeks after TBI. Importantly, pharmacological blockade (A2AR antagonist ZM241385 or non-selective adenosine receptor antagonist caffeine) or genetic inactivation of A2ARs reduced the level of tau phosphorylation at Ser404 and alleviated spatial memory dysfunction. The A2AR control of p-tau is further supported by the observations that a KO of A2AR decreased the activity of the tau phosphorylation kinases, glycogen synthase kinase-3β (GSK-3β) and protein kinase A (PKA) after TBI, and by that CGS21680 (A2AR agonist) exacerbated okadaic acid-induced tau hyperphosphorylation in cultured primary hippocampal neurons. Lastly, CGS21680-induced neuronal tau hyperphosphorylation and axonal injury were effectively alleviated by individual treatments with ZM241385 (A2AR antagonist), H89 (PKA antagonist) and SB216763 (GSK-3β antagonist), or by the combined treatment with H89 and SB216763. Our findings suggest a novel mechanism whereby A2AR activation triggers cognitive dysfunction by increasing the phosphorylation level of tau protein after TBI and suggest a promising therapeutic and prophylactic strategy by targeting aberrant A2AR signaling via tau phosphorylation.

The existing multi-objective wheel profile optimization methods mainly consist of three sub-modules: (1) wheel profile generation, (2) multi-body dynamics simulation, and (3) an optimization algorithm. For the first module, a comparably conservative rotary-scaling finetuning (RSFT) method, which introduces two design variables and an empirical formula, is proposed to fine-tune the traditional wheel profiles for improving their engineering applicability. For the second module, for the TRAXX locomotives serving on the Blankenburg-Rübeland line, an optimization function representing the relationship between the wheel profile and the wheel-rail wear number is established based on Kriging surrogate model (KSM). For the third module, a method combining the regression capability of KSM with the iterative computing power of particle swarm optimization (PSO) is proposed to quickly and reliably implement the task of optimizing wheel profiles. Finally, with the RSFT-KSM-PSO method, we propose two wear-resistant wheel profiles for the TRAXX locomotives serving on the Blankenburg-Rübeland line, namely S1002-S and S1002-M. The S1002-S profile minimizes the total wear number by 30%, while the S1002-M profile makes the wear distribution more uniform through a proper sacrifice of the tread wear number, and the total wear number is reduced by 21%. The quasi-static and hunting stability tests further demonstrate that the profile designed by the RSFT-KSM-PSO method is promising for practical engineering applications.