The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled. The cellular location and mechanism by which FcRn protects albumin are partially understood. Here we demonstrate that mice with global or liver-specific FcRn deletion exhibit hypoalbuminemia, albumin loss into the bile, and increased albumin levels in the hepatocyte. In vitro models with polarized cells illustrate that FcRn mediates basal recycling and bidirectional transcytosis of albumin and uniquely determines the physiologic release of newly synthesized albumin into the basal milieu. These properties allow hepatic FcRn to mediate albumin delivery and maintenance in the circulation, but they also enhance sensitivity to the albumin-bound hepatotoxin, acetaminophen (APAP). As such, global or liver-specific deletion of FcRn results in resistance to APAP-induced liver injury through increased albumin loss into the bile and increased intracellular albumin scavenging of reactive oxygen species. Further, protection from injury is achieved by pharmacologic blockade of FcRn-albumin interactions with monoclonal antibodies or peptide mimetics, which cause hypoalbuminemia, biliary loss of albumin, and increased intracellular accumulation of albumin in the hepatocyte. Together, these studies demonstrate that the main function of hepatic FcRn is to direct albumin into the circulation, thereby also increasing hepatocyte sensitivity to toxicity.
Title Linear Mixed-Effects Models using 'Eigen' and S4Contact LME4 Authors
The landscape of the Great Lakes region has been fragmented since the lakes formed starting about 20 000 years ago. Small mammals, such as deer mice (Peromyscus maniculatus (Wagner, 1845)), inhabiting the region therefore face barriers to migration and gene flow, which could complicate ongoing range shifts related to climate change. We analyzed DNA sequences for 481 base pairs of the mitochondrial D-loop to compare mouse genetic structure with the fragmented landscape and geological history of the region. Phylogenetic analyses reveal two distinct lineages of mice in the Great Lakes region. The spatial distribution of these two groups is not congruent with the fragmentation of the landscape; rather, a western group is found from Minnesota through the western Upper Peninsula of Michigan, whereas an eastern group spans southern Ontario and the rest of northern Michigan. The genetic data suggest that the eastern clade colonized Michigan through Ontario from a source shared with southern Appalachian mice, but are less informative for the western clade. Together, these findings suggest that the Great Lakes are relatively porous barriers in the long term but may still have implications for the response of small-mammal communities to climate change.Résumé : Le paysage de la région des Grands Lacs s'est fragmenté depuis le début de la formation des lacs il y a 20 000 ans. Les petits mammifères, comme les souris du crépuscule (Peromyscus maniculatus (Wagner, 1845)) qui habitent la région font face à des barrières qui entravent leur migration et leur flux génique, ce qui pourrait gêner les modifications d'aires de répartition qui se produisent actuellement à cause du changement climatique. Nous avons analysé les séquences d'ADN de 481 paires de bases de la boucle mitochondriale D afin de relier la structure génétique des souris au paysage fragmenté et à l'histoire géologique de la région. Les analyses phylogénétiques révèlent l'existence de deux lignées distinctes de souris dans la région des Grands Lacs. La répartition spatiale de ces deux groupes ne correspond pas à la fragmentation du paysage; au contraire, un groupe occidental se retrouve à partir du Minnesota et couvre la partie ouest de la Péninsule supérieure du Michigan, alors qu'un groupe oriental s'étend sur le sud de l'Ontario et le reste du nord du Michigan. Les données génétiques laissent croire que le clade oriental a colonisé le Michigan en passant par l'Ontario à partir d'une source qui est partagée avec les souris du sud des Appalaches; les données génétiques fournissent moins de renseignements sur le clade occidental. Dans leur ensemble, ces résultats indiquent que les Grands Lacs forment à long terme des barrières relativement poreuses, mais qu'ils risquent d'affecter la réaction des communautés de petits mammifères au changement climatique.[Traduit par la Rédaction]
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