Ferroptosis inhibition protects vascular endothelial cells and maintains integrity of the blood-spinal cord barrier after spinal cord injury

Maintaining the integrity of the blood-spinal cord barrier is critical for the recove ry of spinal cord injury.Ferro ptosis contributes to the pathogenesis of spinal cord injury.We hypothesized that ferroptosis is involved in disruption of the blood-s pinal cord barrier.In this study,we administe red the ferroptosis inhibitor liproxstatin-1 intraperitoneally after contusive spinal co rd injury in rats.Liproxstatin-1 improved locomotor recovery and somatosensory evoked potential electrophysiological performance after spinal cord inju ry.Liproxstatin-1 maintained blood-spinal cord barrier integrity by upregulation of the expression of tight junction protein.Liproxstatin-1 inhibited ferroptosis of endothelial cell after spinal cord injury,as shown by the immunofluorescence of an endothelial cell marker(rat endothelium cell antigen-1,RECA-1) and fe rroptosis markers Acyl-CoA synthetase long-chain family member 4 and 15-lipoxygenase.Liproxstatin-1reduced brain endothelial cell ferroptosis in vitro by upregulating glutathione peroxidase 4 and downregulating Acyl-CoA synthetase long-chain family member4 and 15-lipoxygenase.Furthermore,inflammatory cell recruitment and astrogliosis were mitigated after liproxstatin-1 treatment.In summary,liproxstatin-1im proved spinal cord injury recovery by inhibiting ferroptosis in endothelial cells and maintaining blood-s pinal co rd barrier integrity.

基于病例对照母子对数据的遗传关联分析中的经验贝叶斯方法

病例对照母子对数据常用于研究母亲和子代的遗传效应以及环境风险因子对产科和早期生命表型的影响。回溯似然方法可以充分利用已有的信息,如孟德尔遗传、母亲环境因子(协变量)在给定母亲基因型下与子代基因型的条件独立性,从而有效地提高统计推断。如对母亲基因型和环境变量之间不作任何关系假设,则相应估计量比较稳健。而假设母亲基因型和环境变量独立下的估计量可以显著提高统计推断效率,但是当独立性假设不成立时会有系统偏差。本文通过对上述基于回溯似然的两个估计量进行适当的加权,得到了两个经验贝叶斯(empirical Bayes,EB)估计量,这两个EB估计量可以直观地平衡统计效率和稳健性。我们对两个EB估计量建立渐近正态性,并利用该渐近正态性构建遗传效应和基因-环境交互效应的置信区间和显著性检验。模拟和实际数据分析说明了我们新方法的表现。

Carbene-Catalyzed Asymmetric Ring-Opening Reaction of Biaryl Lactams to Access Axially Chiral Biaryls

Axially chiral biaryls represent the most important class of atropisomers,and they widely exist in natural products and biologically active molecules.They also constitute a unique scaffold for chiral ligands and catalysts in organic synthesis.The development of synthetic methods to obtain such chiral compounds has received widespread attention,among which catalytically atroposelective ring-opening of configurationally labile compounds represents one of the most attractive strategies.Various substrates with strained cyclic structures,such as the renowned Bringmann's lactones,can undergo asymmetric transformation into stable atropisomers.Known advancement primarily relies on metal catalyst combined with well-designed chiral ligands,the approaches utilizing organocatalysis as a critical resolution strategy are notably scarce.In this study,we disclosed a N-heterocyclic carbene(NHC)-catalyzed asymmetric ring-opening reaction of biaryl lactams via direct atroposelective nucleophilic activation.The optimized bulky carbene catalyst ensures that the reaction can proceed under mild conditions,affording the desired product with good to excellent yields and atroposelectivity.

Gedunin Degrades Aggregates of Mutant Huntingtin Protein and Intranuclear Inclusions via the Proteasomal Pathway in Neurons and Fibroblasts from Patients with Huntington’s Disease

Huntington's disease(HD) is a deadly neurodegenerative disease with abnormal expansion of CAG repeats in the huntingtin gene. Mutant Huntingtin protein(m HTT) forms abnormal aggregates and intranuclear inclusions in specific neurons, resulting in cell death. Here,we tested the ability of a natural heat-shock protein 90 inhibitor, Gedunin, to degrade transfected m HTT in Neuro-2 a cells and endogenous m HTT aggregates and intranuclear inclusions in both fibroblasts from HD patients and neurons derived from induced pluripotent stem cells from patients. Our data showed that Gedunin treatment degraded transfected m HTT in Neuro-2 a cells, endogenous m HTT aggregates and intranuclear inclusions in fibroblasts from HD patients, and in neurons derived from induced pluripotent stem cells from patients in a dose-and time-dependent manner, and its activity depended on the proteasomal pathway rather than the autophagy route. These findings also showed that although Gedunin degraded abnormal m HTT aggregates and intranuclear inclusions in cells from HD patient, it did not affect normal cells, thus providing a new perspective for using Gedunin to treat HD.

Simultaneous enhancement of strength and ductility in friction stir processed 2205 duplex stainless steel with a bimodal structure:experiments and crystal plasticity modeling

Achieving excellent strength-ductility synergy is a long-lasting research theme for structural materials.However,attempts to enhance strength usually induce a loss of ductility,i.e.,the strength-ductility trade-off.In the present study,the strength-ductility trade-off in duplex stainless steel(DSS)was overcome by developing a bimodal structure using friction stir processing(FSP).The ultimate tensile strength and elongation were improved by 140%and 109%,respectively,compared with those of the asreceived materials.Plastic deformation and concurrent dynamic recrystallization(DRX)during FSP were responsible for the formation of bimodal structure.Incompatible deformation resulted in the accumulation of dislocations at the phase boundaries,which triggered interpenetrating nucleation between the austenite and ferrite phases during DRX,leading to a bimodal structure.The in situ mechanical responses of the bimodal structure during tensile deformation were investigated by crystal plasticity finite element modeling(CPFEM).The stress field distribution obtained from CPFEM revealed that the simultaneous enhancement of strength and ductility in a bimodal structure could be attributed to the formation of a unique dispersion-strengthened system with the austenite and ferrite phases.It is indicated that the present design of alternating fine austenite and coarse ferrite layers is a promising strategy for optimizing the mechanical properties of DSSs.