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

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

Bacteria-instructed synthesis of polymers for self-selective microbial binding and labelling

The detection and inactivation of pathogenic strains of bacteria continues to be an important therapeutic goal. Hence, there is a need for materials that can bind selectively to specific microorganisms, for diagnostic or anti-infective applications, but which can be formed from simple and inexpensive building blocks. Here, we exploit bacterial redox systems to induce a copper-mediated radical polymerisation of synthetic monomers at cell surfaces, generating polymers in situ that bind strongly to the microorganisms which produced them. This ‘bacteria-instructed synthesis’ can be carried out with a variety of microbial strains, and we show that the polymers produced are self-selective binding agents for the ‘instructing’ cell types. We further expand on the bacterial redox chemistries to ‘click’ fluorescent reporters onto polymers directly at the surfaces of a range of clinical isolate strains, allowing rapid, facile and simultaneous binding and visualisation of pathogens

Acute mountain sickness.

Acute mountain sickness (AMS) is a clinical syndrome occurring in otherwise healthy normal individuals who ascend rapidly to high altitude. Symptoms develop over a period ofa few hours or days. The usual symptoms include headache, anorexia, nausea, vomiting, lethargy, unsteadiness of gait, undue dyspnoea on moderate exertion and interrupted sleep. AMS is unrelated to physical fitness, sex or age except that young children over two years of age are unduly susceptible. One of the striking features ofAMS is the wide variation in individual susceptibility which is to some extent consistent. Some subjects never experience symptoms at any altitude while others have repeated attacks on ascending to quite modest altitudes. Rapid ascent to altitudes of 2500 to 3000m will produce symptoms in some subjects while after ascent over 23 days to 5000m most subjects will be affected, some to a marked degree. In general, the more rapid the ascent, the higher the altitude reached and the greater the physical exertion involved, the more severe AMS will be. Ifthe subjects stay at the altitude reached there is a tendency for acclimatization to occur and symptoms to remit over 1-7 days

A Hydro-Economic Model for Water Level Fluctuations : Combining Limnology with Economics for Sustainable Development of Hydropower

Water level fluctuations in lakes lead to shoreline displacement. The seasonality of flooding or beaching of the littoral area affects nutrient cycling, redox gradients in sediments, and life cycles of aquatic organisms. Despite the ecological importance of water level fluctuations, we still lack a method that assesses water levels in the context of hydropower operations. Water levels in reservoirs are influenced by the operator of a hydropower plant, who discharges water through the turbines or stores water in the reservoir, in a fashion that maximizes profit. This rationale governs the seasonal operation scheme and hence determines the water levels within the boundaries of the reservoir's water balance. For progress towards a sustainable development of hydropower, the benefits of this form of electricity generation have to be weighed against the possible detrimental effects of the anthropogenic water level fluctuations. We developed a hydro-economic model that combines an economic optimization function with hydrological estimators of the water balance of a reservoir. Applying this model allowed us to accurately predict water level fluctuations in a reservoir. The hydro-economic model also allowed for scenario calculation of how water levels change with climate change scenarios and with a change in operating scheme of the reservoir (increase in turbine capacity). Further model development will enable the consideration of a variety of additional parameters, such as water withdrawal for irrigation, drinking water supply, or altered energy policies. This advances our ability to sustainably manage water resources that must meet both economic and environmental demands

Storage volume and water level fluctuations change across seasons.

<p>Seasonal development of the modelled storage level (volume of water in the reservoir in m³ (solid curve) and according daily WLF (grey dotted columns)) in Lake GA in 2010–2011. Lower levels in March through June indicate a lower storage volume in the reservoir, from which the water level increases towards October until it decreases again. WLF are depicted as the daily maximum or minimum water level change (in m) in relation to the previous day, i.e., if the column is above the zero isocline of the right y-axis, the WLF represents an increase in water level relative to the level found the prior day. Accordingly, if columns point below the zero isocline, they constitute a decrease in water level. Please note the different resolutions of the y-axes.</p

Differences between natural and anthropogenic water level fluctuations.

<p>List of different annual maximum amplitudes (+/− 0.5m) of natural WLF and ‘anthropogenic’ WLF caused by hydropower operations or a combination of hydropower and other water usages. If available, data on WLF before^§ and after ^* dam construction are provided.</p><p>Differences between natural and anthropogenic water level fluctuations.</p

Modelled storage levels match observed storage levels.

<p>Seasonal development of storage level (m³) (volume of water stored) based on daily values in Lake GA. Solid curve: modelled daily values (reference scenario Sc1), dotted curve: real storage level data provided as daily water levels by the power plant operator Lake GA for 2010–2011.</p

Storage volume and water level fluctuations change across seasons.

<p>Seasonal development of the modelled storage level (volume of water in the reservoir in m³ (solid curve) and according daily WLF (grey dotted columns)) in Lake GA in 2010–2011. Lower levels in March through June indicate a lower storage volume in the reservoir, from which the water level increases towards October until it decreases again. WLF are depicted as the daily maximum or minimum water level change (in m) in relation to the previous day, i.e., if the column is above the zero isocline of the right y-axis, the WLF represents an increase in water level relative to the level found the prior day. Accordingly, if columns point below the zero isocline, they constitute a decrease in water level. Please note the different resolutions of the y-axes.</p