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Microalgae have been considered as a promising biomass for biofuel production, but freshwater resource consumption during the scaled-up cultivation are still a challenge. Obtaining robust marine strains capable of producing triacylglycerols and high value-added metabolites are critical for overcoming the limitations of water resources and economical feasibility. In this study, a marine microalga with lipid and astaxanthin accumulation capability was isolated from Bohai Bay, China. The alga was named as Coelastrum sp. HA-1 based on its morphological and molecular identification. The major characteristics of HA-1 and the effects of nitrogen on its lipid and astaxanthin accumulations were investigated. Results indicated that the highest biomass, lipid and astaxanthin yields achieved were 50.9 g m−2 day−1, 18.0 g m−2 day−1 and 168.9 mg m−2 day−1, respectively, after cultivation for 24 days. The fatty acids of HA-1, identified in their majority as oleic acid (56.6%) and palmitic acid (25.9%), are desirable biofuel feedstocks. In addition, this alga can be harvested with simple sedimentation, achieving 98.2% removal efficiency after settling for 24 h. These results suggest that Coelastrum sp. HA-1 has several desirable key features that make it a potential candidate for biofuel production.

Graft-vs.-leukemia (GVL) reactivity after HLA-matched allogeneic stem cell transplantation (alloSCT) is mainly mediated by donor T cells recognizing minor histocompatibility antigens (MiHA). If MiHA are targeted that are exclusively expressed on hematopoietic cells of recipient origin, selective GVL reactivity without severe graft-vs.-host-disease (GVHD) may occur. In this phase I study we explored HA-1H TCR gene transfer into T cells harvested from the HA-1H negative stem-cell donor to treat HA-1H positive HLA-A 02:01 positive patients with high-risk leukemia after alloSCT. HA-1H is a hematopoiesis-restricted MiHA presented in HLA-A 02:01. Since we previously demonstrated that donor-derived virus-specific T-cell infusions did not result in GVHD, we used donor-derived EBV and/or CMV-specific T-cells to be redirected by HA-1H TCR. EBV and/or CMV-specific T-cells were purified, retrovirally transduced with HA-1H TCR, and expanded. Validation experiments illustrated dual recognition of viral antigens and HA-1H by HA-1H TCR-engineered virus-specific T-cells. Release criteria included products containing more than 60% antigen-specific T-cells. Patients with high risk leukemia following T-cell depleted alloSCT in complete or partial remission were eligible. HA-1H TCR T-cells were infused 8 and 14 weeks after alloSCT without additional pre-conditioning chemotherapy. For 4/9 included patients no appropriate products could be made. Their donors were all CMV-negative, thereby restricting the production process to EBV-specific T-cells. For 5 patients a total of 10 products could be made meeting the release criteria containing 3-280 × 10 virus and/or HA-1H TCR T-cells. No infusion-related toxicity, delayed toxicity or GVHD occurred. One patient with relapsed AML at time of infusions died due to rapidly progressing disease. Four patients were in remission at time of infusion. Two patients died of infections during follow-up, not likely related to the infusion. Two patients are alive and well without GVHD. In 2 patients persistence of HA-1H TCR T-cells could be illustrated correlating with viral reactivation, but no overt expansion of infused T-cells was observed. In conclusion, HA-1H TCR-redirected virus-specific T-cells could be made and safely infused in 5 patients with high-risk AML, but overall feasibility and efficacy was too low to warrant further clinical development using this strategy. New strategies will be explored using patient-derived donor T-cells isolated after transplantation transduced with HA-1H-specific TCR to be infused following immune conditioning.

A significant share of allogeneic hematopoietic stem cell transplantations (allo-HSCT) results in the relapse of malignant disease. The T cell immune response to minor histocompatibility antigens (MiHAs) promotes a favorable graft-versus-leukemia response. The immunogenic MiHA HA-1 is a promising target for leukemia immunotherapy, as it is predominantly expressed in hematopoietic tissues and presented by the common HLA A*02:01 allele. Adoptive transfer of HA-1-specific modified CD8+ T cells could complement allo-HSCT from HA-1- donors to HA-1+ recipients. Using bioinformatic analysis and a reporter T cell line, we discovered 13 T cell receptors (TCRs) specific for HA-1. Their affinities were measured by the response of the TCR-transduced reporter cell lines to HA-1+ cells. The studied TCRs showed no cross-reactivity to the panel of donor peripheral mononuclear blood cells with 28 common HLA alleles. CD8+ T cells after endogenous TCR knock out and introduction of transgenic HA-1-specific TCR were able to lyse hematopoietic cells from HA-1+ patients with acute myeloid, T-, and B-cell lymphocytic leukemia (n = 15). No cytotoxic effect was observed on cells from HA-1- or HLA-A*02-negative donors (n = 10). The results support the use of HA-1 as a target for post-transplant T cell therapy.

Background Adoptive transfer of minor histocompatibility antigen (MiHA)-specific T cells is a promising therapy for patients with hematological cancers. However, the efficacy of the transferred cells is hampered by the acquisition of terminal effector differentiation and exhaustion features during expansion in vitro thus preventing their function and persistence in vivo . Yet, the factors that induce T-cell differentiation and functional impairment in culture remain poorly defined and are likely to vary depending on the method used for expansion. Methods Using the clinically relevant HLA-A0201-restricted MiHA HA-1 as well as reagents and procedures that are readily transferable to a clinical environment, we designed a novel culture protocol and defined how exhaustion features appeared in function of time. The optimal time points for the expansion of “fit” MiHA-specific T cells were delineated using phenotypic and functional assessments including KLRG-1 and PD-1 surface markers as well as Ki67 staining and cytokine secretion assays. Results Following a priming phase, an enrichment step and a rapid expansion stage, our method generates MiHA-specific T-cell lines. Evidence of phenotypic and functional dysfunction appear in function of culture duration, but display different characteristics following the extension of the priming or rapid expansion phases. While repeated antigen exposure during the priming phase induced the decline of the antigen-specific population and the expression of PD-1 and KLRG-1 on antigen-specific CD8 + T cells, the prolongation of an antigen-free expansion phase induced proliferation arrest and the relative loss of antigen-specific cells without impairing polyfunctional cytokine secretion or inducing PD-1 and KLRG-1 expression. A similar pattern was also observed after stimulating a virus-specific memory repertoire, except for the more rapid acquisition of exhaustion features upon repeated antigen exposure. Conclusion Our results offer novel insights on the impact of culture duration on the acquisition of T-cell exhaustion features. Using a new clinical-compliant protocol, we define critical parameters to monitor in order to optimally differentiate and expand MiHA-specific T cells in culture prior to adoptive transfer.

Minor histocompatibility antigens (mHags) are immunogenic peptides from polymorphic cellular proteins that induce strong T-cell responses after human leukocyte antigen (HLA)-matched, mHag-mismatched stem-cell transplantation 1 , 2 . mHags with broad or limited tissue expression are target antigens for graft-versus-host (GvH) and graft-versus-leukemia (GvL) reactivities 1 . Separation of these activities is crucial for adoptive immunotherapy of leukemia without GvH disease. Therefore, using a skin-explant assay we investigated the in situ activities of cytotoxic T lymphocytes (CTLs) specific for the ubiquitously expressed mHag H-Y and for the hematopoietic-restricted mHags HA-1 and HA-2. H-Y-specific CTLs, visualized by tetrameric HLA–mHag peptide complexes 3 , infiltrated male skin sections within 24 hours, induced severe GvH reactions of grade III–IV and produced high levels of IFN-γ. In contrast, CTLs specific for the hematopoietic system–specific mHags HA-1 and HA-2 induced no or low GvH reactions above background and produced little or no interferon-γ, unless the skin sections were preincubated with HA-1/HA-2 synthetic peptides. These results provide the first in situ dissection of GvH effects by mHag-specific CTLs and show that ubiquitously expressed mHags are the prime targets of GvH disease.

Nitrogen losses are major concerns for agriculture and policy-makers. Intensification of livestock production has contributed to an increase in nutrient surpluses. Here, we performed an exploratory analysis of the variables influencing the nitrogen surplus in Flemish dairy farms. We used the large dataset of the Farm Accountancy Data Network, holding technical and economic data of Flemish farms. A statistical model is proposed by performing multiple linear regression with several variable selection procedures. This approach focuses on a deep statistical analysis and interpretation of the model. The final model contains the following variables: N in fertilizers (kg/ha), N in concentrates (kg/ha), N in by-products (kg/ha) and N in straw (kg/ha), which refer to purchased inputs, livestock units of dairy cows per ha and percentage of arable crops. The input variables show a positive sign, indicating that the higher the nitrogen inputs, the higher the nitrogen surplus. Contrary to current knowledge, a lower nitrogen surplus was observed for farms with a higher number of livestock units of dairy cows per ha, holding the rest of the N inputs constant. A higher stocking density is compatible with a higher agricultural sustainability. The unexpected negative correlation of livestock units of dairy cows per ha with the dependent variable surplus per ha means that the higher the stocking density — under a certain limit — the lower the surplus of nitrogen will be, provided that feed inputs to the farm and cows are kept at a constant level.

Experiments on cultured peritoneal macrophage from mice with HA-1 ascitic hepatoma showed that plasma lipoproteins present in the incubation medium decreased intracellular concentration of interleukin-1β. These changes were most pronounced for high-density lipoproteins (alone or in combination with cortisol). Bacterial and yeast polysaccharides had little effect on interleukin-1β concentration in macrophages. Addition of polysaccharides in combination with lipoproteins was followed by a 2-3-fold decrease in interleukin-1β concentration. A combination of polysaccharides and high-density lipoproteins had the strongest effect. These properties of plasma lipoproteins should be taken into account in the correction of macrophage function during tumor growth.

O estudo objetivou avaliar a produção de forragem e desempenho animal em pastagens de Coastcross + Arachis pintoi; Coastcross + Arachis pintoi com 100 kg ha-1 de N; Coastcross + Arachis pintoi com 200 kg ha-1 de N e Coastcross com 200 kg ha-1 de N, nas estações de inverno, primavera, verão e outono. Utilizou-se o delineamento experimentalem blocos ao acaso, com os tratamentos em parcelas subdivididas, com duas repetições. Foram avaliados: acúmulo de massa de forragem e acúmulo diário de massa de forragem, ganho médio diário (GMD), ganho de peso vivo por área e taxa de lotação. A utilização de Coastcross + 200 kg ha-1 de N e as melhores condições climáticas na primavera e verão favoreceram tanto o acúmulo de massa de forragem (26.764 kg ha-1 de MS) quanto o acúmulo diário de massa de forragem (82 kg ha-1 por dia de MS). A utilização da associação entre Arachis pintoi + 200 kg ha-1 de N e Coastcross + 200 kg ha-1 de N, possibilitou o melhor desempenho animal, com GMD de 0,570 e 0,500 kg e taxa de lotação de 3,51 e 3,26 UA ha-1, respectivamente. A utilização de pastagem consorciada sem a associação com doses de nitrogênio (100 e 200 kg ha-1) não favoreceu (p > 0,05) o acúmulo de massa de forrageme a taxa de acúmulo diária. A utilização de 200 kg ha-1 de N, com e sem a leguminosa, proporcionou o melhor desempenho e lotação animal por área.The objective of this study was to evaluate dry matter production and animal performance in pastures of Coastcross + Arachis pintoi; Coastcross + Arachis pintoi with 100 kg ha-1 of N; Coastcross +Arachis pintoi with 200 kg ha-1 of N and Coastcross with 200 kg ha-1 of N, during winter, spring, summer and autumn. The experimental design was complete randomized blocks with split-plot parcels, with two repetitions. The study evaluated the accumulation of foragemass and dairy accumulation of forage mass, average daily gain (ADG), live weight gain and stocking rate. The used of Coastcross + 200 kg ha-1 of N and the best climatic conditions in the spring and summer, favored the accumulation of forage mass (26,764 kg ha-1 of DM)and daily accumulation of forage mass (82 kg ha-1 day-1 of DM). The use of the association between Arachis pintoi + 200 kg ha-1 of N and Coastcross + 200 kg ha-1 of N, produces best animal performance, with ADG of 0.570 and 0.500 kg and stocking rate of 3,51 and 3.26AU ha-1, respectively. The use of pasture intercropping without association with doses of nitrogen (100 and 200 kg ha-1) did not favor (p > 0.05) the accumulation of forage mass and dairy accumulation of forage mass. The utlization of 200 kg ha-1 of N, with and without the legume, favored greater animal performance and stocking rate.

In order to determine the influence of HA-1 minor histocompatibility antigen mismatch on BMT outcome, we analyzed a pool of 94 thalassemic transplanted patients all selected for the presence of HLA-A(*)0201 allele. The HA-1 typing was performed using SSP analysis. All the patients received bone marrow from HLA-identical MLC nonresponsive siblings. As graft-versus-host-disease (GVHD) prophylaxis, all patients received cyclosporin and short methotrexate. Grades II-IV GVHD occurred in five (33.3%) of the 15 patients with recipient HA-1 disparity compared with 14 (17.7%) of the 79 patients without HA-1 disparity. Despite the higher incidence of acute graft-versus-host-disease (aGVHD) in the group of patients with HA-1 incompatibility, these data were not statistically significant. However, it was interesting to observe that no GVHD developed in any of the 15 cases in which the recipient was HA-1 negative and the donor HA-1 positive.

Intact peritoneal macrophages in vitro secreted the cysteine proteinase inhibitor cystatin C. Polysaccharides stimulated cystatin C secretion: lipopolysaccharide < carboxymethylated beta-D-glucan < sulfoethylated beta-D-glucan. Human plasma low-density- (LDL) and high-density lipoproteins (HDL) are still more potent inducers of cystatin C secretion by macrophages. Peritoneal macrophages from mice with experimental HA-1 hepatoma compared to those from intact mice secreted more cystatin C with maximum polysaccharide-stimulated secretion after 30 min of incubation. LDL and HDL induced cystatin C secretion by tumor macrophages also.