Neptune's deep atmosphere revealed

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94842/1/grl4440.pd

Blockade of αEβ7 integrin suppresses accumulation of CD8+ and Th9 lymphocytes from patients with IBD in the inflamed gut in vivo

Objective: Therapeutically targeting lymphocyte adhesion is of increasing relevance in IBD. Yet, central aspects of the action of anti-adhesion compounds are incompletely understood. We investigated the role of αEβ7 and α4β7 integrins and their blockade by vedolizumab and etrolizumab for trafficking of IBD T lymphocytes in an in vivo model of homing to and retention in the inflamed gut. Design: We explored integrin expression in IBD patients by flow cytometry and immunohistochemistry, while regulation of integrins was studied in T cell cultures. The functional relevance of integrins was assessed by adhesion assays and a recently established humanized mouse model in DSS-treated immunodeficient mice. Results: High expression of αEβ7 was noted on CD8+ and CD4+ Th9 cells, while α4β7 was expressed on CD8+, Th2 and Th17 cells. TCR stimulation and TGF-β were key inducers of αEβ7 on human T cells, while butyric acid suppressed αEβ7. In comparison to α4β7 blockade via vedolizumab, blockade of β7 via etrolizumab surrogate antibody superiorly reduced colonic numbers of CD8+ and Th9 cells in vivo after 3 hours, while no difference was noted after 0.5 hours. AEβ7 expression was higher on CD8+ T cells from IBD patients under vedolizumab therapy. Conclusion: AEβ7 is of key relevance for gut trafficking of IBD CD8+ T cells and CD4+ Th9 cells in vivo and mainly retention might account for this effect. These findings indicate that blockade of αEβ7 in addition to α4β7 may be particularly effective in intestinal disorders with expansion of CD8+ and Th9 cells such as IBD

Uranus deep atmosphere revealed

We have examined Uranus' radio spectrum and the latitudinal variation in its radio brightness temperature. We conclude that Uranus' spectrum cannot be explained with models based upon thermochemical equilibrium. The spectrum can only be matched if there is a low ammonia volume mixing ratio (a few times 10-7 between roughly 150 T 3 at deep tropospheric levels through the formation of an NH4SH-solid cloud, a large concentration of H2S gas is needed, which implies that sulfur must be enhanced relative to its solar value by a factor of a few hundred. We further can constrain the S/N ratio to be at least five times the solar value if the H2O volume mixing ratio is 2O is [greater, approximate]500 x solar. The elemental ratios derived from our work support the theory of planetary accretion by Pollack and Bodenheimer (1989, in Origin and Evolution of Atmospheres (S. Atreya, Ed.)). The constant mixing ratio of NH3 in the 145 T [less, approximate] 240 K range implies either vertical mixing on time scales much shorter than expected from reasonable values of the eddy diffusion coefficient, or supersaturation of NH4SH at levels where T [less, approximate] 240 K. The pole-equator gradient in Uranus' radio brightness temperature implies a latitude-dependent variation in the ammonia mixing ratio, ranging from a few times 10-6 at altitudes where the temperature is 145 T -7 at 145 T -7 down to 280 K in the polar region. Whereas the values in the equator and midlatitudes can be explained by condensation theories, the polar value can only be explained by invoking strong downdrafts of dry air (gas from which most of the ammonia vapor has been removed by condensation). A comparison of images taken at 2- and 6-cm wavelength show a difference in the spatial distribution of the brightness temperature. In addition, images at both wavelengths show time variability in the zonal brightness distribution.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27655/1/0000036.pd

The α4β1 homing pathway is essential for ileal homing of Crohn's disease effector T cells in vivo

The precise mechanisms controlling homing of T effector (Teff) cells to the inflamed gut in Crohn’s disease (CD) are still unclear and clinical outcome data from inflammatory bowel disease (IBD) patients treated with the anti-α4β7 integrin antibody vedolizumab suggest differences between ulcerative colitis (UC) and CD. Methods: Expression of homing molecules was studied with flow cytometry and immunohistochemistry. Their functional role was investigated in in vitro adhesion assays and in a humanized mouse model of T cell homing to the inflamed gut in vivo. Results: Despite in vitro blockade of CD Teff adhesion to MAdCAM-1 and in contrast to previous oberservations in UC, anti-α4β7 treatment did not result in reduced Teff cell homing to the gut in vivo. However, the integrin α4β1 was expressed in higher levels on Teffs from CD patients compared with controls, while its expression in the peripheral blood declined and its expression in the intestine increased during the course of clinical vedolizumab treatment. Consistently, adhesion of CD Teffs to VCAM-1 was blocked by inhibition of α4 and α4β1 in vitro. Moreover, in vivo homing of CD Teffs to the inflamed ileum was reduced by inhibition of α4 and α4β1 integrins, but not α4β7 integrins. Conclusions: Our findings suggest that Teff cell homing to the ileum via the axis α4β1 – VCAM-1 is an essential and non-redundant pathway in CD in vivo possibly affecting efficacy of clinical treatment with anti-adhesion compounds

Rho-A prenylation and signaling link epithelial homeostasis to intestinal inflammation

Although defects in intestinal barrier function are discussed as a key pathogenic factor in patients with inflammatory bowel diseases (IBD), the molecular pathways driving disease-specific alterations of intestinal epithelial cells (IECs) are largely unknown. Here, we performed a novel approach to characterize the transcriptome of IECs from IBD patients using a genome wide approach. We observed disease-specific alterations in IECs with markedly impaired Rho-A signaling in active IBD patients. Localization of epithelial Rho-A was shifted to the cytosol in IBD where Rho-A activation was suppressed due to reduced expression of the Rho-A prenylation enzyme GGTase-I. The functional relevance of this pathway was highlighted by studies in mice with conditional gene targeting in which deletion of RhoA or GGTase-I in IECs caused spontaneous chronic intestinal inflammation with accumulation of granulocytes and CD4+ T cells. This phenotype was associated with cytoskeleton rearrangement and aberrant cell shedding ultimately leading to loss of epithelial integrity and subsequent inflammation. These findings uncover deficient prenylation of Rho-A as a key player in the pathogenesis of IBD. As therapeutic triggering of Rho-A signaling suppressed intestinal inflammation in mice with GGTase-I deficient IECs, our findings open new avenues for treatment of epithelial injury and mucosal inflammation in IBD patients

Functional Contribution and Targeted Migration of Group-2 Innate Lymphoid Cells in Inflammatory Lung Diseases: Being at the Right Place at the Right Time

During the last decade, group-2 innate lymphoid cells (ILC2s) have been discovered and successfully established as crucial mediators of lung allergy, airway inflammation and fibrosis, thus affecting the pathogenesis and clinical course of many respiratory diseases, like for instance asthma, cystic fibrosis and chronic rhinosinusitis. As an important regulatory component in this context, the local pulmonary milieu at inflammatory tissue sites does not only determine the activation status of lung-infiltrating ILC2s, but also influences their motility and migratory behavior. In general, many data collected in recent murine and human studies argued against the former concept of a very strict tissue residency of innate lymphoid cells (ILCs) and instead pointed to a context-dependent homing capacity of peripheral blood ILC precursors and the inflammation-dependent capacity of specific ILC subsets for interorgan trafficking. In this review article, we provide a comprehensive overview of the so far described molecular mechanisms underlying the pulmonary migration of ILC2s and thereby the numeric regulation of local ILC2 pools at inflamed or fibrotic pulmonary tissue sites and discuss their potential to serve as innovative therapeutic targets in the treatment of inflammatory lung diseases

Nr4a1-dependent non-classical monocytes are important for macrophage-mediated wound healing in the large intestine

IntroductionMacrophages play an important role in intestinal wound healing. However, the trajectories from circulating monocytes to gut macrophages are incompletely understood.MethodsTaking advantage of mice depleted for non-classical monocytes due to deficiency for the transcription factor Nr4a1, we addressed the relevance of non-classical monocytes for large intestinal wound healing using flow cytometry, in vivo wound healing assays and immunofluorescence.ResultsWe show that wound healing in Nr4a1-deficient mice is substantially delayed and associated with reduced peri-lesional presence of macrophages with a wound healing phenotype.DiscussionOur data suggest that non-classical monocytes are biased towards wound healing macrophages. These insights might help to understand, how targeting monocyte recruitment to the intestine can be used to modulate intestinal macrophage functions

A low-temperature origin for the planetesimals that formed Jupiter

The four giant planets in the Solar System have abundances of 'metals' (elements heavier than helium), relative to hydrogen, that are much higher than observed in the Sun. In order to explain this, all models for the formation of these planets rely on an influx of solid planetesimals(17). It is generally assumed that these planetesimals were similar, if not identical, to the comets from the Oort cloud that we see today. Comets that formed in the region of the giant planets should not have contained much neon, argon and nitrogen, because the temperatures were too high for these volatile gases to be trapped effectively in ice. This means that the abundances of those elements on the giant planets should be approximately solar. Here we show that argon, krypton and xenon in Jupiter's atmosphere are enriched to the same extent as the other heavy elements, which suggests that the planetesimals carrying these elements must have formed at temperatures lower than predicted by present models of giant-planet formation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62913/1/402269a0.pd

Differential effects of α4β7 and GPR15 on homing of effector and regulatory T cells from patients with UC to the inflamed gut in vivo

Objective: Gut homing of lymphocytes via adhesion molecules has recently emerged as new target for therapy in inflammatory bowel diseases. We aimed to analyze the in vivo homing of effector (Teff) and regulatory (Treg) T cells to the inflamed gut via α4β7 and GPR15. Design: We assessed the expression of homing receptors on T cells in peripheral blood and inflamed mucosa. We studied the migration pattern and homing of Teff and Treg cells to the inflamed gut using intravital confocal microscopy and FACS in a humanized mouse model in DSS-treated NSG (NOD.Cg-Prkdcscid-Il2rgtm1Wjl/SzJ) mice. Results: Expression of GPR15 and α4β7 was significantly increased on Treg rather than Teff cells in peripheral blood of patients with ulcerative colitis (UC) as compared to Crohn´s disease and controls. In vivo analysis in a humanized mouse model showed augmented gut homing of UC Treg cells as compared to controls. Moreover, suppression of UC (but not control) Teff and Treg cell homing was noted upon treatment with the α4β7 antibody vedolizumab. In contrast, siRNA blockade of GPR15 had only effects on homing of Teff cells but did not affect Treg homing in UC. Clinical vedolizumab treatment was associated with marked expansion of UC Treg cells in peripheral blood. Conclusion: α4β7 rather than GPR15 is crucial for increased colonic homing of UC Treg cells in vivo, while both receptors control UC Teff homing. Vedolizumab treatment impairs homing of UC Treg cells leading to their accumulation in peripheral blood with subsequent suppression of systemic effector T cell expansion