Influence of the Central American Seaway and Drake Passage on ocean circulation and neodymium isotopes: A model study

The sensitivity of the neodymium isotopic composition (ϵNd) to tectonic rearrangements of seaways is investigated using an Earth System Model of Intermediate Complexity. The shoaling and closure of the Central American Seaway (CAS) is simulated, as well as the opening and deepening of Drake Passage (DP). Multiple series of equilibrium simulations with various intermediate depths are performed for both seaways, providing insight into ϵNd and circulation responses to progressive throughflow evolutions. Furthermore, the sensitivity of these responses to the Atlantic Meridional Overturning Circulation (AMOC) and the neodymium boundary source is examined. Modeled ϵNd changes are compared to sediment core and ferromanganese (Fe-Mn) crust data. The model results indicate that the North Atlantic ϵNd response to the CAS shoaling is highly dependent on the AMOC state, i.e., on the AMOC strength before the shoaling to shallow depths (preclosure). Three scenarios based on different AMOC forcings are discussed, of which the model-data agreement favors a shallow preclosure (Miocene) AMOC (∼6 Sv). The DP opening causes a rather complex circulation response, resulting in an initial South Atlantic ϵNd decrease preceding a larger increase. This feature may be specific to our model setup, which induces a vigorous CAS throughflow that is strongly anticorrelated to the DP throughflow. In freshwater experiments following the DP deepening, ODP Site 1090 is mainly influenced by AMOC and DP throughflow changes, while ODP Site 689 is more strongly influenced by Southern Ocean Meridional Overturning Circulation and CAS throughflow changes. The boundary source uncertainty is largest for shallow seaways and at shallow sites.

The liver may act as a firewall mediating mutualism between the host and its gut commensal microbiota.

A prerequisite for establishment of mutualism between the host and the microbial community that inhabits the large intestine is the stringent mucosal compartmentalization of microorganisms. Microbe-loaded dendritic cells trafficking through lymphatics are arrested at the mesenteric lymph nodes, which constitute the firewall of the intestinal lymphatic circulation. We show in different mouse models that the liver, which receives the intestinal venous blood circulation, forms a vascular firewall that captures gut commensal bacteria entering the bloodstream during intestinal pathology. Phagocytic Kupffer cells in the liver of mice clear commensals from the systemic vasculature independently of the spleen through the liver's own arterial supply. Damage to the liver firewall in mice impairs functional clearance of commensals from blood, despite heightened innate immunity, resulting in spontaneous priming of nonmucosal immune responses through increased systemic exposure to gut commensals. Systemic immune responses consistent with increased extraintestinal commensal exposure were found in humans with liver disease (nonalcoholic steatohepatitis). The liver may act as a functional vascular firewall that clears commensals that have penetrated either intestinal or systemic vascular circuits.

Segmented filamentous bacterium uses secondary and tertiary lymphoid tissues to induce gut IgA and specific T helper 17 cell responses.

Segmented filamentous bacterium (SFB) is a symbiont that drives postnatal maturation of gut adaptive immune responses. In contrast to nonpathogenic E. coli, SFB stimulated vigorous development of Peyer's patches germinal centers but paradoxically induced only a low frequency of specific immunoglobulin A (IgA)-secreting cells with delayed accumulation of somatic mutations. Moreover, blocking Peyer's patch development abolished IgA responses to E. coli, but not to SFB. Indeed, SFB stimulated the postnatal development of isolated lymphoid follicles and tertiary lymphoid tissue, which substituted for Peyer's patches as inductive sites for intestinal IgA and SFB-specific T helper 17 (Th17) cell responses. Strikingly, in mice depleted of gut organized lymphoid tissue, SFB still induced a substantial but nonspecific intestinal Th17 cell response. These results demonstrate that SFB has the remarkable capacity to induce and stimulate multiple types of intestinal lymphoid tissues that cooperate to generate potent IgA and Th17 cell responses displaying only limited target specificity.

The interplay between the gut microbiota and the immune system.

The impact of the gut microbiota on immune homeostasis within the gut and, importantly, also at systemic sites has gained tremendous research interest over the last few years. The intestinal microbiota is an integral component of a fascinating ecosystem that interacts with and benefits its host on several complex levels to achieve a mutualistic relationship. Host-microbial homeostasis involves appropriate immune regulation within the gut mucosa to maintain a healthy gut while preventing uncontrolled immune responses against the beneficial commensal microbiota potentially leading to chronic inflammatory bowel diseases (IBD). Furthermore, recent studies suggest that the microbiota composition might impact on the susceptibility to immune-mediated disorders such as autoimmunity and allergy. Understanding how the microbiota modulates susceptibility to these diseases is an important step toward better prevention or treatment options for such diseases.

Triple-peptide receptor targeting in vitro allows detection of all tested gut and bronchial NETs.

UNLABELLED A high proportion of gut and bronchial neuroendocrine tumors (NETs) overexpresses somatostatin receptors, especially the sst2 subtype. It has also recently been observed that incretin receptors, namely glucagonlike peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptors, can be overexpressed in gut and bronchial NETs. However, because not all tumors can express these receptors in sufficient amounts, in vivo imaging with a single radioligand may not always be successful. We therefore evaluated with in vitro methods whether a cocktail of radioligands targeting these 3 receptors would improve tumor labeling. METHODS In vitro receptor autoradiography was performed on 55 NETs, comparing in each successive section of tumor the binding with a single radioligand, either (125)I-Tyr(3)-octreotide, (125)I-GLP-1(7-36)amide, or (125)I-GIP(1-30), with the binding using a cocktail of all 3 radioligands, given concomitantly under identical experimental conditions. RESULTS Using the cocktail of radioligands, all tumors without exception showed moderate to very high binding, with a receptor density corresponding to 1,000-10,000 dpm/mg of tissue; conversely, single-ligand binding, although identifying most tumors as receptor-positive, failed to detect receptors or measured only a low density of receptors below 1,000 dpm/mg in a significant number of tumors. In addition, the cocktail of radioligands always provided a homogeneous labeling of the whole tumor, whereas single radioligands occasionally showed heterogeneous labeling. CONCLUSION The study suggests that the use of a cocktail of 3 radioligands binding to somatostatin receptors, GLP-1 receptors, and GIP receptors would allow detecting virtually all NETs and labeling them homogeneously in vivo, representing a significant improvement for imaging and therapy in NETs.

Does somatostatin or gastric inhibitory peptide receptor expression correlate with tumor grade and stage in gut neuroendocrine tumors?

BACKGROUND/AIMS Important characteristics of neuroendocrine neoplasms (NEN) for prognosis and therapeutic decisions are the MIB-1 proliferative index (tumor grade) and tumor stage. Moreover, these tumors express peptide hormone receptors like somatostatin and gastric inhibitory peptide (GIP) receptors which represent important established and potential future targets, respectively, for molecular imaging and radiotherapy. However, the interrelation between tumor proliferation, stage, and peptide receptor amounts has never been assessed. METHODS In 114 gastrointestinal and bronchopulmonary NEN, the proliferative rate assessed with MIB-1 immunohistochemistry and tumor stage were compared with the somatostatin type 2 receptor (sst2) and GIP receptor expression measured quantitatively with in vitro receptor autoradiography. RESULTS NEN generally showed high sst2 and GIP receptor expression. GIP receptor but not sst2 expression correlated with the MIB-1 index. GIP receptor levels gradually increased in a subset of insulinomas and nonfunctioning pancreatic NEN, and decreased in ileal and bronchopulmonary NEN with increasing MIB-1 rate. MIB-1 levels were identified, above which GIP receptor levels were consistently high or low. These MIB-1 levels were clearly different from those defining tumor grade. In grade 3 NEN, GIP receptor levels were always low, while sst2 levels were variable and sometimes extremely high. Conversely, sst2 expression correlated more frequently with tumor stage than GIP receptor expression, with metastasized NEN showing higher sst2 levels than localized tumors. CONCLUSIONS sst2, a clinically crucial molecular target, shows variable and unpredictable expression in NEN irrespective of tumor grade. Therefore, each NEN should be tested for sst2 if clinical applications with somatostatin analogs are considered. Conversely, the potential future role of GIP receptors as molecular targets in NEN may be dependent on the MIB-1 level.

Auf Vorposten ist nicht gut debattiren, soll der Reichsverweser am 17. Juli zu den Regensburgern gesagt und ihnen gerathen haben ...

Boberach: [Hauptwerk:] Frankfurt eignet sich trotz der gefährlichen Nähe zu Frankreich als deutsche Hauptstadt. In Regensburg wären Parlament und Reichsregierung nicht besser aufgehoben. Volksbewaffnung ist erforderlich, um die Märzerrungenschaften zu erhalten. - Welsch (Projektbearbeiter): [Beigefügtes Werk:] Plädoyer des Frankfurter Literaten Funck gegen - an die Adresse der Nationalversammlung gerichtete - Kollektivpetitionen

Die Studenten an die Bewohner Wiens: Seit einigen Tagen durchschleichen beängstigende Gerüchte unsere gut gesinnte Stadt ...

Welsch (Projektbearbeiter): Dementierung von Gerüchten über eine bevorstehende Ausrufung der Republik durch die Akademische Legion. Bekenntnis zur konstitutionellen Monarchie. "Niemand wünscht sehnlicher die Rückkehr unseres gütigen Kaisers, als die Studirenden Wiens"

Kundmachung: Vom 24. des laufenden Monates angefangen wird bei allen Linien die freie Passage von 5 Uhr Morgens bis 8 Uhr Abends ...

Welsch (Projektbearbeiter): Bekanntmachung über die Zulassung des freien Verkehrs aus und nach der Stadt Wien in der Zeit zwischen fünf Uhr morgens und acht Uhr abends (mit dem 24. November 1848)