Due to the rapidly increasing development and use of cellular products, there is a rising demand for non-animal-based test platforms to predict, study and treat undesired immunity. Here, we generated ...human organotypic skin models from human biopsies by isolating and expanding keratinocytes, fibroblasts and microvascular endothelial cells and seeding these components on a collagen matrix or a biological vascularized scaffold matrix in a bioreactor. We then were able to induce inflammation-mediated tissue damage by adding pre-stimulated, mismatched allogeneic lymphocytes and/or inflammatory cytokine-containing supernatants histomorphologically mimicking severe graft versus host disease (GvHD) of the skin. This could be prevented by the addition of immunosuppressants to the models. Consequently, these models harbor a promising potential to serve as a test platform for the prediction, prevention and treatment of GvHD. They also allow functional studies of immune effectors and suppressors including but not limited to allodepleted lymphocytes, gamma-delta T cells, regulatory T cells and mesenchymal stromal cells, which would otherwise be limited to animal models. Thus, the current test platform, developed with the limitation that no professional antigen presenting cells are in place, could greatly reduce animal testing for investigation of novel immune therapies.
With cellular products being on the front run there is a rising demand for non-animal-based test platforms to predict, study and treat undesired immunity. Here, we generated human organotypic skin ...models from human biopsies isolating and expanding keratinocytes, fibroblasts and microvascular endothelial cells finally allowing to seed these components on a collagen matrix or a biological vascularized scaffold matrix in a bioreactor. Afterwards, we were able to induce inflammation-based tissue damage by pre-stimulated mismatched allogeneic lymphocytes and/or inflammatory cytokine containing supernatants histomorphologically mimicking severe graft versus host disease (GvHD) of the skin. The effects could be prevented by the addition of immunosuppressants to the models. Consequently, these models would harbor a promising potential to serve as a test platform for the prediction, prevention and treatment of GvHD. This would also allow functional studies of immune effectors and suppressors including but not limited to allodepleted lymphocytes, gamma-delta T cells, regulatory T cells and mesenchymal stromal cells which would otherwise be limited to animal models. Thus, the current test platform developed with the limitation given that no professional APC are in place could highly reduce animal testing for investigation of novel immune therapies.
In search-and-matching models, the nonlinear nature of search frictions increases average unemployment rates during periods with higher volatility. These frictions are not, however, by themselves ...sufficient to raise unemployment following an increase in perceived uncertainty; though they may do so in conjunction with the common assumption of wages being determined by Nash bargaining. Importantly, option-value considerations play no role in the standard model with free entry. In contrast, when the mass of entrepreneurs is finite and there is heterogeneity in firm-specific productivity, a rise in perceived uncertainty robustly increases the option value of waiting and reduces job creation.
In search-and-matching models, the nonlinear nature of search frictions increases average unemployment rates during periods with higher volatility. These frictions are not, however, by themselves ...sufficient to raise unemployment following an increase in perceived uncertainty; though they may do so in conjunction with the common assumption of wages being determined by Nash bargaining. Importantly, option-value considerations play no role in the standard model with free entry. In contrast, when the mass of entrepreneurs is finite and there is heterogeneity in firm-specific productivity, a rise in perceived uncertainty robustly increases the option value of waiting and reduces job creation.
Near-infrared photoimmunotherapy (NIR-PIT) represents a novel antibody-based strategy for selective cellular depletion. Originally introduced for EGFR-specific cancer cell treatment, NIR-PIT ...displayed distinctive depletion prosperity in several mouse models. Adapted from these findings, a skin selective depletion of an antibody-targeted cell type has a potential of becoming an important therapeutic option in dermatology. Here, we report on a method for the skin selective depletion of CD8 T cells and its therapeutic effect in a humanized mouse model of cutaneous acute graft-versus-host disease (aGVHD). In immunodeficient NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice transplanted with human skin, aGVHD was induced by intravenous injection of mismatched peripheral blood mononuclear cells which resulted in a strong T cell infiltration, inflammation and epithelial skin graft rejection. Skin specific ablation of target cells was induced by the combined function of immuno- and phototherapy activated by near-infrared light. Our data demonstrates strong ablation success by selectively killing skin localized CD8 T cells while sparing systemic immunosuppression. The effect proved to be highly efficient by inhibiting the manifestation of cutaneous aGVHD and diminished the expression of pathological and skin specific biomarkers. Therefore, we hypothesize that localized depletion using NIR-PIT inhibits cutaneous aGVHD mediated by cytotoxic CD8 T cells but prevents systemic ablation, which would reduce marrow engraftment and tumor clearance. Moreover, this study describes the first skin-selective therapeutic success of applying NIR-PIT in a model of human inflammatory skin disease and demonstrates that NIR-PIT can serve as a therapeutic approach for clinical use in dermatology.
Summary
The intensity and frequency of droughts events are projected to increase in future with expected adverse effects for forests. Thus, information on the dynamics of tree water uptake from ...different soil layers during and after drought is crucial.
We applied an in situ water isotopologue monitoring system to determine the oxygen isotope composition in soil and xylem water of European beech with a 2‐h resolution together with measurements of soil water content, transpiration and tree water deficit. Using a Bayesian isotope mixing model, we inferred the relative and absolute contribution of water from four different soil layers to tree water use.
Beech took up more than 50% of its water from the uppermost 5 cm soil layer at the beginning of the 2018 drought, but then reduced absolute water uptake from the drying topsoil by 84%. The trees were not able to quantitatively compensate for restricted topsoil water availability by additional uptake from deeper soil layers, which is related to the fine root depth distribution. Absolute water uptake from the topsoil was restored to pre‐drought levels within 3 wk after rewetting.
These uptake patterns help to explain both the drought sensitivity of beech and its high recovery potential after drought release.
Pulmonary hypertension (PH) is a cardiovascular disease characterised by an increase in pulmonary arterial (PA) resistance leading to right ventricular (RV) failure. Reactive oxygen species (ROS) ...play a major role in PH. OP2113 is a drug with beneficial effects on cardiac injuries that targets mitochondrial ROS. The aim of the study was to address the in vivo therapeutic effect of OP2113 in PH.
PH was induced by 3 weeks of chronic hypoxia (CH-PH) in rats treated with OP2113 or its vehicle via subcutaneous osmotic mini-pumps. Haemodynamic parameters and both PA and heart remodelling were assessed. Reactivity was quantified in PA rings and in RV or left ventricular (LV) cardiomyocytes. Oxidative stress was detected by electron paramagnetic resonance and western blotting. Mitochondrial mass and respiration were measured by western blotting and oxygraphy, respectively.
In CH-PH rats, OP2113 reduced the mean PA pressure, PA remodelling, PA hyperreactivity in response to 5-HT, the contraction slowdown in RV and LV and increased the mitochondrial mass in RV. Interestingly, OP2113 had no effect on haemodynamic parameters, both PA and RV wall thickness and PA reactivity, in control rats. Whereas oxidative stress was evidenced by an increase in protein carbonylation in CH-PH, this was not affected by OP2113.
Our study provides evidence for a selective protective effect of OP2113 in vivo on alterations in both PA and RV from CH-PH rats without side effects in control rats.
High-sensitivity assays for cardiac troponin T (hs-cTnT) are sometimes used to rapidly rule out acute myocardial infarction (AMI).
To estimate the ability of a single hs-cTnT concentration below the ...limit of detection (<0.005 µg/L) and a nonischemic electrocardiogram (ECG) to rule out AMI in adults presenting to the emergency department (ED) with chest pain.
EMBASE and MEDLINE without language restrictions (1 January 2008 to 14 December 2016).
Cohort studies involving adults presenting to the ED with possible acute coronary syndrome in whom an ECG and hs-cTnT measurements were obtained and AMI outcomes adjudicated during initial hospitalization.
Investigators of studies provided data on the number of low-risk patients (no new ischemia on ECG and hs-cTnT measurements <0.005 µg/L) and the number who had AMI during hospitalization (primary outcome) or a major adverse cardiac event (MACE) or death within 30 days (secondary outcomes), by risk classification (low or not low risk). Two independent epidemiologists rated risk of bias of studies.
Of 9241 patients in 11 cohort studies, 2825 (30.6%) were classified as low risk. Fourteen (0.5%) low-risk patients had AMI. Sensitivity of the risk classification for AMI ranged from 87.5% to 100% in individual studies. Pooled estimated sensitivity was 98.7% (95% CI, 96.6% to 99.5%). Sensitivity for 30-day MACEs ranged from 87.9% to 100%; pooled sensitivity was 98.0% (CI, 94.7% to 99.3%). No low-risk patients died.
Few studies, variation in timing and methods of reference standard troponin tests, and heterogeneity of risk and prevalence of AMI across studies.
A single hs-cTnT concentration below the limit of detection in combination with a nonischemic ECG may successfully rule out AMI in patients presenting to EDs with possible emergency acute coronary syndrome.
Emergency Care Foundation.
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