Hydrology and oxygen addition drive nutrients, metals, and methylmercury cycling in a hypereutrophic water supply reservoir

Impaired water quality in Mediterranean climate reservoirs is mainly associated with eutrophication and internal nutrient loading. To improve water quality in hypereutrophic Hodges Reservoir, California, United States, a hypolimnetic oxygenation system (HOS), using pure oxygen gas, was implemented in 2020. This study encompasses 3 years of pre-oxygenation data (2017–2019) and 2 years of post-oxygenation data (2020–2021) to understand the cycling of nutrients, metals, and mercury in the reservoir. During the wet year of 2017, mildly reduced conditions lasted until mid-summer in the enlarged reservoir. Nutrients and metals were seen in the hypolimnion including ammonia (~2 mg-N/L), manganese (~0.5 mg/L), phosphate (~0.5 mg-P/L), and sulfide (~10 mg/L). Production of methylmercury (MeHg), an important bioaccumulative toxin, was favored from April to June with a hypolimnetic accumulation rate of around 200 ng/m2·d. In contrast, the dry year of 2018 exhibited higher hypolimnetic concentrations of ammonia (~4 mg-N/L), manganese (~1 mg/L), phosphate (>0.5 mg-P/L), and sulfide (>15 mg/L). The rapid onset of highly reduced conditions in 2018 corresponded with low MeHg hypolimnetic accumulation (~50 ng/m2·d). It seems that mildly reduced conditions were associated with higher MeHg accumulation, while sulfidic, reduced conditions impaired inorganic mercury bioavailability for MeHg production and/or promoted microbial demethylation. Sulfide also appeared to act as a sink for iron via FeS precipitation, and potentially for manganese via MnS precipitation or manganese coprecipitation with FeS. Mass flux estimates for 2017–2019 indicate that much of the nutrients that accumulated in the hypolimnion moved via turbulent diffusion into the epilimnion at loading rates far exceeding thresholds predicting eutrophic conditions. After oxygenation in 2020–2021, the reservoir water column was highly oxidized but showed a lack of thermal stratification, suggesting reservoir operations in combination with HOS implementation inadvertently mixed the water column in this relatively shallow reservoir. Post-oxygenation, concentrations of ammonia, phosphate, manganese, and mercury in bottom waters all decreased, likely in response to oxidized conditions. Oxygenated bottom waters exhibited elevated nitrate, a byproduct of ammonia nitrification, and iron, a byproduct of FeS oxidation, indicating a lake-wide response to oxygenation

Dysfunctional ryanodine receptor and cardiac hypertrophy: role of signaling molecules

Mice with three amino acid mutations in the calmodulin binding domain of type-2 ryanodine receptor ion channel (Ryr2ADA/ADA mice) have impaired intracellular Ca2+ handling and cardiac hypertrophy with death at an early age. In this report, the role of signaling molecules implicated in cardiac hypertrophy of Ryr2ADA/ADA mice was investigated. Calcineurin A-β (CNA-β) and nuclear factor of activated T cell (NFAT) signaling were monitored in mice carrying either luciferase transgene driven by NFAT-dependent promoter or knockout of CNA-β. NFAT transcriptional activity in Ryr2ADA/ADA hearts was not markedly upregulated at embryonic day 16.5 compared with wild-type but significantly increased at postnatal days 1 and 10. Ablation of CNA-β extended the life span of Ryr2ADA/ADA mice and enhanced cardiac function without improving sarcoplasmic reticulum Ca2+ handling or suppressing the expression of genes implicated in cardiac hypertrophy. Embryonic day 16.5 Ryr2ADA/ADA mice had normal heart weights with no major changes in Akt1 and class II histone deacetylase phosphorylation and myocyte enhancer factor-2 activity. In contrast, phosphorylation levels of Erk1/2, p90 ribosomal S6 kinases (p90RSKs), and GSK-3β were increased in hearts of embryonic day 16.5 homozygous mutant mice. The results indicate that an impaired calmodulin regulation of RyR2 was neither associated with an altered CNA-β/NFAT, class II histone deacetylase (HDAC)/MEF2, nor Akt signaling in embryonic day 16.5 hearts; rather increased Erk1/2 and p90RSK phosphorylation levels likely leading to reduced GSK-3β activity were found to precede development of cardiac hypertrophy in mice expressing dysfunctional ryanodine receptor ion channel

Biologic activity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic stem cell transplantation

Through an immune-mediated graft-versus-leukemia effect, allogeneic hematopoietic stem cell transplantation (HSCT) affords durable clinical benefits for many patients with hematologic malignancies. Nonetheless, subjects with high-risk acute myeloid leukemia or advanced myelodysplasia often relapse, underscoring the need to intensify tumor immunity within this cohort. In preclinical models, allogeneic HSCT followed by vaccination with irradiated tumor cells engineered to secrete GM-CSF generates a potent antitumor effect without exacerbating the toxicities of graft-versus-host disease (GVHD). To test whether this strategy might be similarly active in humans, we conducted a Phase I clinical trial in which high-risk acute myeloid leukemia or myelodysplasia patients were immunized with irradiated, autologous, GM-CSF-secreting tumor cells early after allogeneic, nonmyeloablative HSCT. Despite the administration of a calcineurin inhibitor as prophylaxis against GVHD, vaccination elicited local and systemic reactions that were qualitatively similar to those previously observed in nontransplanted, immunized solid-tumor patients. While the frequencies of acute and chronic GVHD were not increased, 9 of 10 subjects who completed vaccination achieved durable complete remissions, with a median follow-up of 26 months (range 12–43 months). Six long-term responders showed marked decreases in the levels of soluble NKG2D ligands, and 3 demonstrated normalization of cytotoxic lymphocyte NKG2D expression as a function of treatment. Together, these results establish the safety and immunogenicity of irradiated, autologous, GM-CSF-secreting leukemia cell vaccines early after allogeneic HSCT, and raise the possibility that this combinatorial immunotherapy might potentiate graft-versus-leukemia in patients