Site selective adsorption of the spin crossover complex Fe(phen)\u3csub\u3e2\u3c/sub\u3e(NCS)\u3csub\u3e2\u3c/sub\u3e on Au(111)

The iron(II) spin crossover complex Fe(1,10-phenanthroline)2(NCS)2, dubbed Fe-phen, has been studied with scanning tunneling microscopy, after adsorption on the \u27herringbone\u27 reconstructed surface of Au(111) for sub-monolayer coverages. The Fe-phen molecules attach, through their NCS-groups, to the Au atoms of the fcc domains of the reconstructed surface only, thereby lifting the herringbone reconstruction. The molecules stack to form 1D chains, which run along the Au[110] directions. Neighboring Fe-phen molecules are separated by approximately 2.65 nm, corresponding to 9 atomic spacings in this direction. The molecular axis, defined by the two phenanthroline groups, is aligned perpendicular to the chain axis, along the Au [221] direction, thereby bridging over 5 atomic spacings, in this direction. Experimental evidence suggests that the molecular spins are locked in a mixed state in the sub-monolayer regime at temperatures between 100 K and 300 K

Distinct effects of inflammation on preconditioning and regeneration of the adult zebrafish heart

The adult heart is able to activate cardioprotective programmes and modifies its architecture in response to physiological or pathological changes. While mammalian cardiac remodelling often involves hypertrophic expansion, the adult zebrafish heart exploits hyperplastic growth. This capacity depends on the responsiveness of zebrafish cardiomyocytes to mitogenic signals throughout their entire life. Here, we have examined the role of inflammation on the stimulation of cell cycle activity in the context of heart preconditioning and regeneration. We used thoracotomy as a cardiac preconditioning model and cryoinjury as a model of cardiac infarction in the adult zebrafish. First, we performed a spatio-temporal characterization of leucocytes and cycling cardiac cells after thoracotomy. This analysis revealed a concomitance between the infiltration of inflammatory cells and the stimulation of the mitotic activity. However, decreasing the immune response using clodronate liposome injection, PLX3397 treatment or anti-inflammatory drugs surprisingly had no effect on the re- entry of cardiac cells into the cell cycle. In contrast, reducing inflammation using the same strategies after cryoinjury strongly impaired cardiac cell mitotic activity and the regenerative process. Taken together, our results show that, while the immune response is not necessary to induce cell-cycle activity in intact preconditioned hearts, inflammation is required for the regeneration of injured hearts in zebrafish

Preconditioning boosts regenerative programmes in the adult zebrafish heart

During preconditioning, exposure to a non-lethal harmful stimulus triggers a body-wide increase of survival and pro-regenerative programmes that enable the organism to better withstand the deleterious effects of subsequent injuries. This phenomenon has first been described in the mammalian heart, where it leads to a reduction of infarct size and limits the dysfunction of the injured organ. Despite its important clinical outcome, the actual mechanisms underlying preconditioning-induced cardioprotection remain unclear. Here, we describe two independent models of cardiac preconditioning in the adult zebrafish. As noxious stimuli, we used either a thoracotomy procedure or an induction of sterile inflammation by intraperitoneal injection of immunogenic particles. Similar to mammalian preconditioning, the zebrafish heart displayed increased expression of cardioprotective genes in response to these stimuli. As zebrafish cardiomyocytes have an endogenous proliferative capacity, preconditioning further elevated the re-entry into the cell cycle in the intact heart. This enhanced cycling activity led to a long-term modification of the myocardium architecture. Importantly, the protected phenotype brought beneficial effects for heart regeneration within one week after cryoinjury, such as a more effective cell-cycle reentry, enhanced reactivation of embryonic gene expression at the injury border, and improved cell survival shortly after injury. This study reveals that exposure to antecedent stimuli induces adaptive responses that render the fish more efficient in the activation of the regenerative programmes following heart damage. Our results open a new field of research by providing the adult zebrafish as a model system to study remote cardiac preconditioning

LIM protein Ajuba promotes liver cell proliferation through its involvement in DNA replication and DNA damage control.

The LIM-domain protein Ajuba is associated with cell proliferation, a fundamental process of tissue regeneration and cancer. We report that in the liver, Ajuba expression is increased during regeneration and in tumor cells and tissues. Knockout of Ajuba using CRISPR/Cas9 is embryonic lethal in mice. shRNA targeting of Ajuba reduces cell proliferation, delays cell entry into S-phase, reduces cell survival and tumor growth in vivo, and increases expression of the DNA damage marker γH2AX. Ajuba binding partners include proteins involved in DNA replication and damage, such as SKP2, MCM2, MCM7 and RPA70. Taken together, our data support that Ajuba promotes liver cell proliferation associated with development, regeneration, and tumor growth and is involved in DNA replication and damage repair

Supplemental Materials: Novel Isotypic g/z-Subunits Reveal Three Coatomer Complexes in Mammals

Fig. A 1 shows a Western blot analyzing the specificity of the antibodies against g- and z-isotypes. These antibodies were probed in different mammalian species (Fig. A 2). Coatomer was labeled with [35S]-methionine for different time periods, and the incorporation of [35S]-methionine as well as the corresponding stoichiometries of the coatomer subunits are shown in Fig. A 3. Characterization of anti-coatomer antibody 883 is depicted in Fig. A 4

Loss of claudin-3 impairs hepatic metabolism, biliary barrier function and cell proliferation in the murine liver.

BACKGROUND & AIMS Tight junctions in the liver are essential to maintain the blood-biliary-barrier, however the functional contribution of individual tight junction proteins to barrier- and metabolic homeostasis remains largely unexplored. Here, we describe the cell type specific expression of tight junction genes in the murine liver, and explore the regulation and functional importance of the transmembrane protein claudin-3 in liver metabolism, barrier function and cell proliferation. METHODS The cell type specific expression of hepatic tight junction genes is described using our mouse liver single cell sequencing dataset. Differential gene expression in Cldn3-/- and Cldn3+/+ livers was assessed in young and aged mice by RNA-seq and hepatic tissue was analysed for lipid content and bile acid composition. A surgical model of partial hepatectomy (PHx) was used to induce liver cell proliferation. RESULTS Claudin-3 is a highly expressed tight junction protein found in the liver and is expressed predominantly in hepatocytes and cholangiocytes. The histology of Cldn3-/- livers showed no overt phenotype, and the canalicular tight junctions appeared intact. Nevertheless, by RNAseq we detected a downregulation of metabolic pathways in the livers of Cldn3-/- young and aged mice as well as a decrease in lipid content and a weakened biliary-barrier for primary bile acids, such as TCA, TCDCA and TMCA. Coinciding with defects in the biliary barrier and lower lipid metabolism, there was a diminished hepatocyte proliferative response in Cldn3-/- mice following PHx. CONCLUSION Our data shows that in the liver, claudin-3 is necessary to maintain metabolic homeostasis, retention of bile acids, and optimal hepatocyte proliferation during liver regeneration

Impaired liver regeneration in aged mice can be rescued by silencing Hippo core kinases MST1 and MST2.

The liver has an intrinsic capacity to regenerate in response to injury or surgical resection. Nevertheless, circumstances in which hepatocytes are unresponsive to proliferative signals result in impaired regeneration and hepatic failure. As the Hippo pathway has a canonical role in the maintenance of liver size, we investigated whether it could serve as a therapeutic target to support regeneration. Using a standard two-thirds partial hepatectomy (PH) model in young and aged mice, we demonstrate that the Hippo pathway is modulated across the phases of liver regeneration. The activity of the core kinases MST1 and LATS1 increased during the early hypertrophic phase and returned to steady state levels in the proliferative phase, coinciding with activation of YAP1 target genes and hepatocyte proliferation. Moreover, following PH in aged mice, we demonstrate that Hippo signaling is anomalous in non-regenerating livers. We provide pre-clinical evidence that silencing the Hippo core kinases MST1 and MST2 with siRNA provokes hepatocyte proliferation in quiescent livers and rescues liver regeneration in aged mice following PH. Our data suggest that targeting the Hippo core kinases MST1/2 has therapeutic potential to improve regeneration in non-regenerative disorders

Investigating stratospheric changes between 2009 and 2018 with halogenated trace gas data from aircraft, AirCores, and a global model focusing on CFC-11

We present new observations of trace gases in the stratosphere based on a cost-effective sampling technique that can access much higher altitudes than aircraft. The further development of this method now provides detection of species with abundances in the parts per trillion (ppt) range and below. We obtain mixing ratios for six gases (CFC-11, CFC-12, HCFC-22, H-1211, H-1301, and SF6), all of which are important for understanding stratospheric ozone depletion and circulation. After demonstrating the quality of the data through comparisons with ground-based records and aircraft-based observations, we combine them with the latter to demonstrate its potential. We first compare the data with results from a global model driven by three widely used meteorological reanalyses. Secondly, we focus on CFC-11 as recent evidence has indicated renewed atmospheric emissions of that species relevant on a global scale. Because the stratosphere represents the main sink region for CFC-11, potential changes in stratospheric circulation and troposphere–stratosphere exchange fluxes have been identified as the largest source of uncertainty for the accurate quantification of such emissions. Our observations span over a decade (up until 2018) and therefore cover the period of the slowdown of CFC-11 global mixing ratio decreases measured at the Earth's surface. The spatial and temporal coverage of the observations is insufficient for a global quantitative analysis, but we do find some trends that are in contrast with expectations, indicating that the stratosphere may have contributed to the slower concentration decline in recent years. Further investigating the reanalysis-driven model data, we find that the dynamical changes in the stratosphere required to explain the apparent change in tropospheric CFC-11 emissions after 2013 are possible but with a very high uncertainty range. This is partly caused by the high variability of mass flux from the stratosphere to the troposphere, especially at timescales of a few years, and partly by large differences between runs driven by different reanalysis products, none of which agree with our observations well enough for such a quantitative analysis