This paper describes the synthesis and characterization of RP­(o-biphenyl)2 phosphine ligands (where R = PhO, Ph, and t-Bu), corresponding gold­(I) chloride precatalysts, gold­(I) triflate catalysts, and gold­(I) π-complexes. All ligands and gold chlorides and three π-complexes were characterized in the solid state. The most significant differences between complexes in the solid state were varying P–Au bond lengths, a consistent reflection of the different electronic character of each phosphine. NMR spectroscopic data on enol ether π-complexes is consistent with increasing cationic character in the alkene fragment, from R = t-Bu to R = Ph and OPh. The intermolecular alkene exchange process for [LAu­(methoxypropene)]­SbF6 (L = PhO­(o-biphenyl)2P) is faster than that of the analogous complex with t-Bu2(o-biphenyl)­P, presumably due to the higher electrophilicity of the former complex. Examination of a series of vinyl silane π-complexes with triaryl phosphine ligands reveals increasing stability and ease of preparation (Ph3P < Ph2P­(o-biphenyl) < PhP­(o-biphenyl)2). These results reveal that incorporation of a second biphenyl substituent into ligand architectures allows preparation of a series of gold π-complexes with increased stability over a range of phosphine donicity.

Introduction: Secondary injury due to neuroinflammation poses a target in ICH research. We have demonstrated elevated serum IL-12 levels in rodents with cardiometabolic syndrome with hypertension compared with normotensive rodents. As hypertension is a risk factor in ICH, it is critical to understand whether there are also local cerebral changes in pro-inflammatory cytokines to explore targets for therapeutics. Methods: A pilot study of autologous-injection ICH was induced in (mREN2)27 (n=7) and control Hanover Sprague-Dawley (SD) (n=7) rats. Animals underwent tail-cuff blood pressure measurement, pre- and post-ICH neurobehavioral testing, and serum cytokine measurements. Sacrifice with brain harvest was performed at 24h and 7h post-ICH. Homogenization of the brain with quantitative measurement of hemoglobin and IL-12 concentrations was performed. Results: IL-12 peaked in the ipsilateral hemisphere in both SD and mREN rats at 24h post-ICH. There was a significant difference in local IL-12 levels between the ipsilateral and contralateral hemispheres at 72h, with minimal IL-12 elevation in the contralateral hemisphere (p=0.05) (Figure 1). Additionally, there was high correlation between hematoma size and IL-12 local expression. While there was no difference in cerebral IL-12 levels between strains, there was a significant elevation in baseline IL-12 serum levels in mREN compared to SD rats, and a trend towards serum elevation at 72h post-ICH. Conclusions: Cerebral IL-12 levels ipsilateral to ICH are significantly elevated compared to contralateral levels and peak 24h post-ICH. While serum IL-12 levels are elevated in rats with cardiometabolic syndrome, this is not seen in brain tissue following ICH. With the high correlation between hematoma size and IL-12 expression, these findings implicate macrophage recruitment from the hematoma as a driver of neuroinflammation and potential therapeutic target to augment surgical interventions for ICH.

Introduction: About 500,000 people worldwide die annually from ruptured intracranial aneurysms (IA). The pathophysiology of aneurysm formation is largely unknown. Piezo1 mechanoreceptors are expressed in endothelial and smooth muscle cells of developing blood vessels. In addition to hemodynamic forces, Piezo1 has been shown to play an inflammatory role, as stiffness-sensing macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Malfunction of Piezo1 mechanoreceptors has been implicated in abdominal aortic aneurysm (AAA) development. With the increasing evidence of relationship between AAA and IAs, it is important to study Piezo1 dysregulation as a potential cause of IA development and/or rupture. Methods: During craniotomy for aneurysm clipping of ruptured and unruptured IAs, we excised and collected the aneurysm dome in four patients. Immunohistochemistry (IHC) was performed for Piezo1 and with CD31 to co-localize Piezo1 in the endothelial cells, and a-SMA to co-localize in smooth muscle cells on all aneurysm domes. Additional specimen was saved for genomic analyses. Results: Piezo1 mechanoreceptor overexpression was found in the smooth muscle layer of IAs, but not in superficial temporal artery (STA) controls, in all four human cerebral aneurysm domes. Additionally, there was significant dysregulation of Piezo1 mechanoreceptors in the IA compared with the regular appearance seen in the control human STA (Figure 1). Overexpression was not seen in human arteriovenous malformation specimens. Conclusions: Our data is the first demonstration of overexpression of Piezo1 mechanoreceptors in a disorganized manner in the walls of human IAs, which may represent a therapeutic target. We hypothesize that vascular shear stress leads to Piezo1-mediated disorganization in arterial smooth muscle cells and pro-inflammatory activation, which may lead to IA development and rupture.

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