Cardiomyocytes express most known Toll-like receptors. Of these, TLR2, TLR4 and TLR5 signal via NF-kappaB, resulting in decreased contractility and a concerted inflammatory response.

Abstract-Cardiovascular dysfunction as a result of sepsis is the leading cause of death in the critically ill. Cardiomyocytes respond to infectious pathogens with a Toll-like receptor-initiated proinflammatory response in conjunction with a decrease in contractility, although the downstream events linking Toll-like receptor activation and reduced cardiac contractility remain to be elucidated. Using microarray analysis of cardiac tissue exposed to systemic lipopolysaccharide (LPS), we discovered that 2 small calcium-regulating proteins (S100A8 and S100A9) are highly upregulated. HL-1 cardiomyocytes, isolated primary cardiomyocytes, and live mice were exposed to LPS, whereas beating HL-1 cells had S100A8 and S100A9 overexpressed and their calcium flux quantified. Using in vivo microbubble technology, we delivered S100A8 and S100A9 to normal mouse hearts; using the same technology, we inhibited S100A9 production in mouse hearts and subsequently exposed them to LPS. Coimmunoprecipitation of S100A8 and S100A9 identified interaction with RAGE (the receptor for advanced glycation end products), the cardiac function and postreceptor signaling of which were investigated. HL-1 cardiomyocytes, isolated primary cardiomyocytes, and whole hearts exposed to LPS have large increases in S100A8 and S100A9. Cardiac overexpression of S100A8 and S100A9 led to a RAGE-dependent decrease in calcium flux and, in the intact mouse, to a decreased cardiac ejection fraction, whereas knockdown of S100A9 attenuated LPS-induced cardiac dysfunction. Cardiomyocytes exposed to LPS express S100A8 and S100A9, leading to a RAGE-mediated decrease in cardiomyocyte contractility. This finding provides a novel mechanistic link between circulating pathogen-associated molecular products and subsequent cardiac dysfunction. Key Words: S100 proteins Ⅲ RAGE Ⅲ ventricular contractility S epsis causes myocardial dysfunction, which contributes to hypotension, impaired perfusion, and even death. 1 The precise mechanisms linking sepsis to myocardial dysfunction are still unclear; however, it is known that the function of cardiomyocytes extends beyond contraction to provide the motive force driving cardiac output and arterial pressure generation. There is increasing evidence that cardiomyocytes have additional properties, analogous in some respects to innate immune antigen-presenting cells that allow cardiomyocytes to respond to "danger" signals with an innate immune inflammatory and functional response. We have recently shown that cardiomyocytes express multiple Tolllike receptors (TLRs) that signal predominantly through NF-B when stimulated by pathogenic molecules, resulting in decreased cardiomyocyte contractility. 24 However, the downstream elements that link TLRs and cardiomyocyte contractility remain unknown. Because decreased contractility can be observed in isolated cardiomyocytes, we searched for candidate molecules that are highly regulated by exposure to TLR ligands and are capable of either exerting an autocrine effect and/or interacting with key intra...

Free-standing boron nanocages or borospherenes have been observed recently for B40(-) and B40. There is evidence that a family of borospherenes may exist. However, the smallest borospherene is still not known. Here, we report experimental and computational evidence of a seashell-like borospherene cage for B28(-) and B28. Photoelectron spectrum of B28(-) indicated contributions from different isomers. Theoretical calculations showed that the seashell-like B28(-) borospherene is competing for the global minimum with a planar isomer and it is shown to be present in the cluster beam, contributing to the observed photoelectron spectrum. The seashell structure is found to be the global minimum for neutral B28 and the B28(-) cage represents the smallest borospherene observed to date. It is composed of two triangular close-packed B15 sheets, interconnected via the three corners by sharing two boron atoms. The B28 borospherene was found to obey the 2(n + 1)(2) electron-counting rule for spherical aromaticity.

Two low-lying structures are unveiled for the Be B nanocluster system that are virtually isoenergetic. The first, triple-layered cluster has a peripheral B ring as central layer, being sandwiched by two Be rings in a coaxial fashion, albeit with no discernible interlayer Be-Be bonding. The B ring revolves like a flexible chain even at room temperature, gliding freely around the Be prism. At elevated temperatures (1000 K), the Be core itself also rotates; that is, two Be rings undergo relative rotation or twisting with respect to each other. Bonding analyses suggest four-fold (π and σ) aromaticity, offering a dilute and fluxional electron cloud that lubricates the dynamics. The second, helix-type cluster contains a B helical skeleton encompassing a distorted Be prism. It is chiral and is the first nanosystem with a boron helix. Molecular dynamics also shows that at high temperature the helix cluster readily converts into the triple-layered one.