Insensitivity of alkenone carbon isotopes to atmospheric CO₂ at low to moderate CO₂ levels

Atmospheric pCO2 is a critical component of the global carbon system and is considered to be the major control of Earth’s past, present and future climate. Accurate and precise reconstructions of its concentration through geological time are, therefore, crucial to our understanding of the Earth system. Ice core records document pCO2 for the past 800 kyrs, but at no point during this interval were CO2 levels higher than today. Interpretation of older pCO2 has been hampered by discrepancies during some time intervals between two of the main ocean-based proxy methods used to reconstruct pCO2: the carbon isotope fractionation that occurs during photosynthesis as recorded by haptophyte biomarkers (alkenones) and the boron isotope composition (δ11B) of foraminifer shells. Here we present alkenone and δ11B-based pCO2 reconstructions generated from the same samples from the Plio-Pleistocene at ODP Site 999 across a glacial-interglacial cycle. We find a muted response to pCO2 in the alkenone record compared to contemporaneous ice core and δ11B records, suggesting caution in the interpretation of alkenone-based records at low pCO2 levels. This is possibly caused by the physiology of CO2 uptake in the haptophytes. Our new understanding resolves some of the inconsistencies between the proxies and highlights that caution may be required when interpreting alkenone-based reconstructions of pCO2

Discovery and Differential Processing of HLA Class II-Restricted Minor Histocompatibility Antigen LB-PIP4K2A-1S and Its Allelic Variant by Asparagine Endopeptidase

Minor histocompatibility antigens are the main targets of donor-derived T-cells after allogeneic stem cell transplantation. Identification of these antigens and understanding their biology are a key requisite for more insight into how graft vs. leukemia effect and graft vs. host disease could be separated. We here identified four new HLA class II-restricted minor histocompatibility antigens using whole genome association scanning. For one of the new antigens, i.e., LB-PIP4K2A-1S, we measured strong T-cell recognition of the donor variant PIP4K2A-1N when pulsed as exogenous peptide, while the endogenously expressed variant in donor EBV-B cells was not recognized. We showed that lack of T-cell recognition was caused by intracellular cleavage by a protease named asparagine endopeptidase (AEP). Furthermore, microarray gene expression analysis showed that PIP4K2A and AEP are both ubiquitously expressed in a wide variety of healthy tissues, but that expression levels of AEP were lower in primary acute myeloid leukemia (AML). In line with that, we confirmed low activity of AEP in AML cells and demonstrated that HLA-DRB1*03:01 positive primary AML expressing LB-PIP4K2A-1S or its donor variant PIP4K2A-1N were both recognized by specific T-cells. In conclusion, LB-PIP4K2A-1S not only represents a novel minor histocompatibility antigen but also provides evidence that donor T-cells after allogeneic stem cell transplantation can target the autologous allelic variant as leukemia-associated antigen. Furthermore, it demonstrates that endopeptidases can play a role in cell type-specific intracellular processing and presentation of HLA class II-restricted antigens, which may be explored in future immunotherapy of AML

Composição isotópica de Nd na componente terrígena de sedimentos como marcador de eventos de Heinrich:estudo de um caso na margem continental NW Ibérica

The OMEX core KC 024-19 was studied aiming at to assess the influence of climate changes on the origin and transport of the sediments of the Galician continental slope, in the last 40 ka. The results show that sea level variation played a major role in the supply of the terrigenous sediments coming from the nearby continental areas, whose basement has a Variscan age. Additionally, coarse-grained clastic materials, corresponding to ice-rafted debris (IRD), were deposited through melting of icebergs during the Heinrich events (HE), in the last glaciation. The last four HE were identified in the core. The measured Nd isotope ratios reveal that there was a strong contribution of continental crustal sources significantly older than the Variscan basement for HE 1, 2 and 4. The most likely provenance of the coarse clasts deposited during these three events lie in NE America or Greenland, and the carrier icebergs should be fragments of the Laurentide Ice Sheet. In contrast, the HE 3 layer displays εNd values in the range of the compositions of the most common sediments in the core and, therefore, its IRD should have European source(s), which supports previous results obtained in other places of the European Atlantic margin.O core OMEX KC 024-19 foi estudado tendo em vista avaliar o papel das mudanças climáticas nos processos de transporte e nas fontes de sedimentos depositados no talude continental da Galiza, durante os últimos 40 ka. Os resultados obtidos, usando diferentes metodologias, apontam para uma grande influência das mudanças do nível do mar no fornecimento de sedimentos terrígenos a partir das áreas continentais próximas, cujo soco é de idade varisca. Para além disso, nos eventos de Heinrich (HE), ocorridos durante a última glaciação, foram recebidos nesta área materiais detríticos grosseiros transportados por icebergues em fusão (IRD). Foram identificados, neste core, os quatro últimos HE. As razões isotópicas de Nd revelam que durante os HE 1, 2 e 4 houve contribuição importante de fontes de crusta continental significativamente mais antiga do que a ibérica. A origem provável dos IRD desses três eventos estará no NE da América ou na Gronelândia, podendo os icebergues que os transportaram ter origem na LIS (Laurentide Ice Sheet). Já o HE 3, não se distingue, em termos de εNd, dos sedimentos mais comuns no core, pelo que os IRD correspondentes deverão ter origem europeia, o que corrobora resultados obtidos noutros locais da margem atlântica europeia

Carbon isotope offsets between benthic foraminifer species of the genus Cibicides (Cibicidoides) in the glacial sub-Antarctic Atlantic

©2016. American Geophysical Union. All Rights Reserved. Epibenthic foraminifer δ 13 C measurements are valuable for reconstructing past bottom water dissolved inorganic carbon δ 13 C (δ 13 C DIC ), which are used to infer global ocean circulation patterns. Epibenthic δ 13 C, however, may also reflect the influence of 13 C-depleted phytodetritus, microhabitat changes, and/or variations in carbonate ion concentrations. Here we compare the δ 13 C of two benthic foraminifer species, Cibicides kullenbergi and Cibicides wuellerstorfi, and their morphotypes, in three sub-Antarctic Atlantic sediment cores over several glacial-interglacial transitions. These species are commonly assumed to be epibenthic, living above or directly below the sediment-water interface. While this might be consistent with the small δ 13 C offset that we observe between these species during late Pleistocene interglacial periods (Δδ 13 C = −0.19 ± 0.31‰, N = 63), it is more difficult to reconcile with the significant δ 13 C offset that is found between these species during glacial periods (Δδ 13 C = −0.76 ± 0.44‰, N = 44). We test possible scenarios by analyzing Uvigerina spp. δ 13 C and benthic foraminifer abundances: (1) C. kullenbergi δ 13 C is biased to light values either due to microhabitat shifts or phytodetritus effects and (2) C. wuellerstorfi δ 13 C is biased to heavy values, relative to long-term average conditions, for instance by recording the sporadic occurrence of less depleted deepwater δ 13 C DIC . Neither of these scenarios can be ruled out unequivocally. However, our findings emphasize that supposedly epibenthic foraminifer δ 13 C in the sub-Antarctic Atlantic may reflect several factors rather than being solely a function of bottom water δ 13 C DIC . This could have a direct bearing on the interpretation of extremely light South Atlantic δ 13 C values at the Last Glacial Maximum

Hydrogen-Peroxide Synthesis and LDL-Uptake Controls Immunosuppressive Properties in Monocyte-Derived Dendritic Cells

Background and Aims: Induction of myeloid-derived suppressor cells (MDSC) is a critical step in immune cell evasion by different cancer types, including liver cancer. In the liver, hepatic stromal cells orchestrate induction of MDSCs, employing a mechanism dependent on hydrogen peroxide (H2O2) depletion. However, the effects on monocyte-derived dendritic cells (moDCs) are unknown. Methods: Monocytes from healthy donors were differentiated to moDCs in the presence of extracellular enzymatic H2O2-depletion (hereinafter CAT-DCs), and studied phenotypically and functionally. To elucidate the underlying molecular mechanisms, we analyzed H2O2- and LDL-metabolism as they are interconnected in monocyte-driven phagocytosis. Results: CAT-DCs were of an immature DC phenotype, particularly characterized by impaired expression of the costimulatory molecules CD80/86. Moreover, CAT-DCs were able to suppress T-cells using indoleamine 2,3-dioxygenase (IDO), and induced IL10/IL17-secreting T-cells—a subtype reported to exert immunosuppression in acute myeloid leukemia. CAT-DCs also displayed significantly increased NADPH-oxidase-driven H2O2-production, enhancing low-density lipoprotein (LDL)-uptake. Blocking LDL-uptake restored maturation, and attenuated the immunosuppressive properties of CAT-DCs. Discussion: Here, we report a novel axis between H2O2- and LDL-metabolism controlling tolerogenic properties in moDCs. Given that moDCs are pivotal in tumor-rejection, and lipid-accumulation is associated with tumor-immune-escape, LDL-metabolism appears to play an important role in tumor-immunology

Whole-Body Electromyostimulation Combined With Individualized Nutritional Support Improves Body Composition in Patients With Hematological Malignancies – A Pilot Study

Patients undergoing the complex treatment for hematological malignancies are exposed to a high physiological and psychological distress inducing fatigue and physical inactivity. In line with cancer-related metabolic changes patients are predisposed for skeletal muscle mass loss that leads to a functional decline, affects therapeutic success, and quality of life. Benefits of physical exercise and nutritional interventions on muscle maintenance are observed in solid cancer patients, but marginally investigated in patients with hematological cancer. We here studied the effects of a combined supportive exercise and nutrition intervention using whole-body electromyostimulation (WB-EMS) training and individualized nutritional support in patients actively treated for hematological malignancy. In a controlled pilot trial, 31 patients (67.7% male; 58.0 ± 16.7 years) with various hematological cancers were allocated to a control group (n = 9) receiving nutritional support of usual care regarding a high protein intake (>1.0 g/kg/d) or to a physical exercise group (n = 22) additionally performing WB-EMS training twice weekly for 12 weeks. Bodyweight and body composition assessed by bioelectrical impedance analysis were measured every 4 weeks. Physical function, blood parameters, quality of life and fatigue were assessed at baseline and after 12 weeks. No WB-EMS-related adverse effects occurred. Patients attending the exercise program presented a higher skeletal muscle mass than controls after 12-weeks (1.51 kg [0.41, 2.60]; p = 0.008). In contrast, patients of the control group showed a higher fat mass percentage than patients of the WB-EMS group (-4.46% [-7.15, -1.77]; p = 0.001) that was accompanied by an increase in serum triglycerides in contrast to a decrease in the WB-EMS group (change ± SD, control 36.3 ± 50.6 mg/dl; WB-EMS -31.8 ± 68.7 mg/dl; p = 0.064). No significant group differences for lower limb strength, quality of life, and fatigue were detected. However, compared to controls the WB-EMS group significantly improved in physical functioning indicated by a higher increase in the 6-min-walking distance (p = 0.046). A combined therapeutic intervention of WB-EMS and protein-rich nutritional support seems to be safe and effective in improving skeletal muscle mass and body composition in hematological cancer patients during active oncological treatment. Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT02293239

Whole-Body Electromyostimulation Combined With Individualized Nutritional Support Improves Body Composition in Patients With Hematological Malignancies – A Pilot Study

Patients undergoing the complex treatment for hematological malignancies are exposed to a high physiological and psychological distress inducing fatigue and physical inactivity. In line with cancer-related metabolic changes patients are predisposed for skeletal muscle mass loss that leads to a functional decline, affects therapeutic success, and quality of life. Benefits of physical exercise and nutritional interventions on muscle maintenance are observed in solid cancer patients, but marginally investigated in patients with hematological cancer. We here studied the effects of a combined supportive exercise and nutrition intervention using whole-body electromyostimulation (WB-EMS) training and individualized nutritional support in patients actively treated for hematological malignancy. In a controlled pilot trial, 31 patients (67.7% male; 58.0 ± 16.7 years) with various hematological cancers were allocated to a control group (n = 9) receiving nutritional support of usual care regarding a high protein intake (>1.0 g/kg/d) or to a physical exercise group (n = 22) additionally performing WB-EMS training twice weekly for 12 weeks. Bodyweight and body composition assessed by bioelectrical impedance analysis were measured every 4 weeks. Physical function, blood parameters, quality of life and fatigue were assessed at baseline and after 12 weeks. No WB-EMS-related adverse effects occurred. Patients attending the exercise program presented a higher skeletal muscle mass than controls after 12-weeks (1.51 kg [0.41, 2.60]; p = 0.008). In contrast, patients of the control group showed a higher fat mass percentage than patients of the WB-EMS group (-4.46% [-7.15, -1.77]; p = 0.001) that was accompanied by an increase in serum triglycerides in contrast to a decrease in the WB-EMS group (change ± SD, control 36.3 ± 50.6 mg/dl; WB-EMS -31.8 ± 68.7 mg/dl; p = 0.064). No significant group differences for lower limb strength, quality of life, and fatigue were detected. However, compared to controls the WB-EMS group significantly improved in physical functioning indicated by a higher increase in the 6-min-walking distance (p = 0.046). A combined therapeutic intervention of WB-EMS and protein-rich nutritional support seems to be safe and effective in improving skeletal muscle mass and body composition in hematological cancer patients during active oncological treatment.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT02293239

AAV2-Mediated Combined Subretinal Delivery of IFN-α and IL-4 Reduces the Severity of Experimental Autoimmune Uveoretinitis

We previously showed that adeno-associated virus 2 (AAV2) mediated subretinal delivery of human interferon-alpha (IFN-α) could effectively inhibit experimental autoimmune uveoretinitis (EAU). In this study we investigated whether subretinal injection of both AVV2.IFN-α and AAV2.IL-4 had a stronger inhibition on EAU activity. B10RIII mice were subretinally injected with AAV2.IFN-α alone (1.5×107 vg), AAV2.IL-4 alone (3.55×107 vg), and AAV2.IFN-α combined with AAV2.IL-4. PBS, AAV2 vector encoding green fluorescent protein (AAV2.GFP) (5×107 vg) was subretinally injected as a control. IFN-α and IL-4 were effectively expressed in the eyes from three weeks to three months following subretinal injection of AAV2 vectors either alone or following combined administration and significantly attenuated EAU activity clinically and histopathologically. AAV2.IL-4 showed a better therapeutic effect as compared to AAV2.IFN-α. The combination of AAV2.IL-4 and AAV2.IFN-α was not significantly different as compared to AAV2.IL-4 alone. There was no difference concerning DTH (delayed-type hypersensitivity) reaction, lymphocyte proliferation and IL-17 production among the investigated treatment groups, suggesting that local retinal gene delivery did not affect the systemic immune response

A novel survival model of cardioplegic arrest and cardiopulmonary bypass in rats: a methodology paper

<p>Abstract</p> <p>Background</p> <p>Given the growing population of cardiac surgery patients with impaired preoperative cardiac function and rapidly expanding surgical techniques, continued efforts to improve myocardial protection strategies are warranted. Prior research is mostly limited to either large animal models or <it>ex vivo </it>preparations. We developed a new <it>in vivo </it>survival model that combines administration of antegrade cardioplegia with endoaortic crossclamping during cardiopulmonary bypass (CPB) in the rat.</p> <p>Methods</p> <p>Sprague-Dawley rats were cannulated for CPB (n = 10). With ultrasound guidance, a 3.5 mm balloon angioplasty catheter was positioned via the right common carotid artery with its tip proximal to the aortic valve. To initiate cardioplegic arrest, the balloon was inflated and cardioplegia solution injected. After 30 min of cardioplegic arrest, the balloon was deflated, ventilation resumed, and rats were weaned from CPB and recovered. To rule out any evidence of cerebral ischemia due to right carotid artery ligation, animals were neurologically tested on postoperative day 14, and their brains histologically assessed.</p> <p>Results</p> <p>Thirty minutes of cardioplegic arrest was successfully established in all animals. Functional assessment revealed no neurologic deficits, and histology demonstrated no gross neuronal damage.</p> <p>Conclusion</p> <p>This novel small animal CPB model with cardioplegic arrest allows for both the study of myocardial ischemia-reperfusion injury as well as new cardioprotective strategies. Major advantages of this model include its overall feasibility and cost effectiveness. In future experiments long-term echocardiographic outcomes as well as enzymatic, genetic, and histologic characterization of myocardial injury can be assessed. In the field of myocardial protection, rodent models will be an important avenue of research.</p