Evidence for elevated alkalinity in the glacial Southern Ocean

An increase in whole ocean alkalinity during glacial periods could account, in part, for the drawdown of atmospheric CO2 into the ocean. Such an increase was inevitable due to the near elimination of shelf area for the burial of coral reef alkalinity. We present evidence, based on downcore measurements of benthic foraminiferal B/Ca and Mg/Ca from a core in the Weddell Sea, that the deep ocean carbonate ion concentration, [CO32-], was elevated by similar to 25 mu mol/kg during each glacial period of the last 800 kyr. The heterogeneity of the preservation histories in the different ocean basins reflects control of the carbonate chemistry of the deep glacial ocean in the Atlantic and Pacific by the changing ventilation and chemistry of Weddell Sea waters. These waters are more corrosive than interglacial northern sourced waters but not as undersaturated as interglacial southern sourced waters. Our inferred increase in whole ocean alkalinity can be reconciled with reconstructions of glacial saturation horizon depth and the carbonate budget if carbonate burial rates also increased above the saturation horizon as a result of enhanced pelagic calcification. The Weddell records display low [CO32-] during deglaciations and peak interglacial warmth, coincident with maxima in percent CaCO3 in the Atlantic and Pacific oceans. Should the burial rate of alkalinity in the more alkaline glacial deep waters outstrip the rate of alkalinity supply, then pelagic carbonate production by the coccolithophores at the end of the glacial maximum could drive a decrease in ocean [CO32-] and act to trigger the deglacial rise in pCO(2)

Pulses of enhanced North Pacific Intermediate Water ventilation from the Okhotsk Sea and Bering Sea during the last deglaciation

Under modern conditions only North Pacific Intermediate Water is formed in the Northwest Pacific Ocean. This situation might have changed in the past. Recent studies with General Circulation Models indicate a switch to deep-water formation in the Northwest Pacific during Heinrich Stadial 1 (17.5–15.0 kyr) of the last glacial termination. Reconstructions of past ventilation changes based on paleoceanographic proxy records are still insufficient to test whether a deglacial mode of deep-water formation in the North Pacific Ocean existed. Here we present deglacial ventilation records based on radiocarbon-derived ventilation ages in combination with epibenthic stable carbon isotopes from the Northwest Pacific including the Okhotsk Sea and Bering Sea, the two potential source regions for past North Pacific ventilation changes. Evidence for most rigorous ventilation of the mid-depth North Pacific occurred during Heinrich Stadial 1 and the Younger Dryas, simultaneous to significant reductions in Atlantic Meridional Overturning Circulation. Concurrent changes in δ13C and ventilation ages point to the Okhotsk Sea as driver of millennial-scale changes in North Pacific Intermediate Water ventilation during the last deglaciation. Our records additionally indicate that changes in the δ13C intermediate water (700–1750 m water depth) signature and radiocarbon-derived ventilation ages are in antiphase to those of the deep North Pacific Ocean (>2100 m water depth) during the last glacial termination. Thus, intermediate and deep-water masses of the Northwest Pacific have a differing ventilation history during the last deglaciation

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

Eastern Mediterranean surface water temperatures and d18O composition during deposition of sapropels in the late Quaternary

Water column stratification increased at climatic transitions from cold to warm periods during the lateQuaternary and led to anoxic conditions and sapropel formation in the deep eastern Mediterranean basins. Highresolutiondata sets on sea-surface temperatures (SST) (estimated from U37k0 indices) and d18O of planktonicforaminifer calcite (d18Ofc) across late Pleistocene sapropel intervals show that d18Ofc decreased (between 1 and4.6%) and SST increased (between 0.7 and 6.7 C). Maximal d18Oseawater depletion of eastern Mediterraneansurface waters at the transition is between 0.5 and 3.0%, and in all but one case exceeded the depletion seen in awestern Mediterranean core. The depletion in d18Oseawater is most pronounced at sapropel bases, in agreementwith an initial sudden input of monsoon-derived freshwater. Most sapropels coincide with warming trends ofSST. The density decrease by initial freshwater input and continued warming of the sea surface pooled freshwater in the surface layer and prohibited deep convection down to ageing deep water emplaced during cold andarid glacial conditions. An exception to this pattern is glacial sapropel S6; its largest d18Oseawater depletion(3%) is almost matched by the depletion in the western Mediterranean Sea, and it is accompanied by surfacewater cooling following an initially rapid warming phase. A second period of significant isotopic depletion is inisotope stage 6 at the 150 kyr insolation maximum. While not expressed as a sapropel due to cold SST, it is inaccord with a strengthened monsoon in the southern catchment

Удаление сернистых соединений из дизельных топлив с использованием металлосодержащих ионных жидкостей

Данная статья посвящена проблеме удаления сернистых соединений из дизельных топлив. Представлены характеристики полученных экстракционных систем на основе ионных жидкостей и солей металлов (СuBr[2], CoBr[2], NiBr[2]). Показана возможность использования комплексов ионных жидкостей с солями металлов в качестве экстрагентов для удаления серы из дизельного топлива

Impact of Adopting Population Pharmacokinetics for Tailoring Prophylaxis in Haemophilia A Patients: A Historically Controlled Observational Study

Background Performing individual pharmacokinetics (PK) studies in clinical practice can be simplified by adopting population PK-based profiling on limited post-infusion samples. The objective of this study was to assess the impact of population PK in tailoring prophylaxis in patients with haemophilia A. Patients and Methods Individual weekly treatment plans were developed considering predicted plasma factor activity levels and patients' lifestyle. Patients were trained using a visual traffic-light scheme to help modulate their level of physical activity with respect to factor infusions timing. Annualized joint bleeding rate (ABJR), haemophilia-specific quality of life questionnaire for adults (Haemo-QoL-A) and factor utilization were measured for 12 months before and after tailoring, compared within patients and analysed separately for those previously on prophylaxis (P), situational prophylaxis (SP) or on-demand (OD). Results Sixteen patients previously on P, 10 on SP and 10 on OD were enrolled in the study. The median (lower, upper quartile) ABJR changed from 2.0 (0, 4.0) to 0 (0, 1.6) for P (p = 0.003), from 2.0 (2.0, 13.6) to 3.0 (1.4, 7.2) for SP (p = 0.183) and from 16.0 (13.0, 25.0) to 2.3 (0, 5.0) for OD (p = 0.003). The Haemo-QoL-A total score improved for 58% of P, 50% of SP and 29% of OD patients. Factor utilization (IU/kg/patient/year) increased by 2,400 (121; 2,586) for P, 1,052 (308; 1,578) for SP and 2,086 (1,498; 2,576) for OD. One of 138 measurements demonstrated a factor activity level below the critical threshold of 0.03 IU/mL while the predicted level was above the threshold. Conclusion Implementing tailored prophylaxis using a Bayesian forecasting approach in a routine clinical practice setting may improve haemophilia clinical outcomes

External application of liver compresses to reduce fatigue in patients with metastatic cancer undergoing radiation therapy, a randomized clinical trial

Background: Liver compresses are frequently used in integrative medicine as supportive therapy during cancer treatment in order to reduce fatigue. We performed a pilot study to test whether the external application of yarrow liver compresses impacts fatigue in patients with metastatic cancer undergoing radiation therapy. Methods: A randomized prospective pilot trial was performed including patients with brain metastasis or bone metastasis of solid tumors. Patients underwent either palliative radiation therapy (RT) of the metastatic lesions (control group) over two weeks or the same RT with additional external application of yarrow liver compresses once daily during RT. The primary objective was improvement on the general fatigue subscale of the multidimensional fatigue inventory (MFI-20) at the end of treatment, where a mean difference of two points is considered clinically relevant. Secondary objectives included psychological distress, quality of life and qualitative analysis with self-established visual analogue scales (VAS). Mean differences in general fatigue at the end of treatment compared to baseline were analyzed using the ANCOVA test. Results: From 09/2017 to 08/2019 a total of 39 patients were randomized. Due to drop outs 24 patients (12 per group) were available for analysis. Patients in the intervention group received a mean number of 10.5 (range, 7-14) applications of yarrow liver compresses. The mean improvement at the end of therapy on the general fatigue subscale of the MFI-20 was 2 points in favor of the intervention group (p = 0.13), and all other MFI-20 subscales showed at least a trend towards improvement in favor of the intervention group. Likewise, psychological distress and VAS data was improved, the latter reaching statistical significance for the symptoms fatigue, tension and lack of drive. Major toxicities were not observed. Conclusions: External application of liver compresses appears to reduce fatigue within a clinical relevant range in patients with metastatic cancer undergoing radiation therapy. Trial registration: ISRCTN, ICTRP DRKS0001299

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

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 kyr, 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 (δ^{11}B) of foraminifer shells. Here, we present alkenone and δ^{11}B-based pCO₂ reconstructions generated from the same samples from the Pliocene and across a Pleistocene glacial–interglacial cycle at Ocean Drilling Program (ODP) Site 999. We find a muted response to pCO₂ in the alkenone record compared to contemporaneous ice core and δ^{11}B 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

Treatment strategies in primary vitreoretinal lymphoma: a 17-center European collaborative study.

IMPORTANCE: The best treatment option for primary vitreoretinal lymphoma (PVRL) without signs of central nervous system lymphoma (CNSL) involvement determined on magnetic resonance imaging or in cerebrospinal fluid is unknown. OBJECTIVE: To evaluate the outcomes of treatment regimens used for PVRL in the prevention of subsequent CNSL. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted at 17 referral ophthalmologic centers in Europe. We reviewed clinical, laboratory, and imaging data on 78 patients with PVRL who did not have CNSL on presentation between January 1, 1991, and December 31, 2012, with a focus on the incidence of CNS manifestations during the follow-up period. INTERVENTIONS: The term extensive treatment was used for various combinations of systemic and intrathecal chemotherapy, whole-brain radiotherapy, and peripheral blood stem cell transplantation. Therapy to prevent CNSL included ocular radiotherapy and/or ocular chemotherapy (group A, 31 patients), extensive systemic treatment (group B, 21 patients), and a combination of ocular and extensive treatment (group C, 23 patients); 3 patients did not receive treatment. A total of 40 patients received systemic chemotherapy. MAIN OUTCOMES AND MEASURES: Development of CNSL following the diagnosis of PVRL relative to the use or nonuse of systemic chemotherapy and other treatment regimens. RESULTS: Overall, CNSL developed in 28 of 78 patients (36%) at a median follow-up of 49 months. Specifically, CNSL developed in 10 of 31 (32%) in group A, 9 of 21 (43%) in group B, and 9 of 23 (39%) in group C. The 5-year cumulative survival rate was lower in patients with CNSL (35% [95% CI, 50% to 86%]) than in patients without CNSL (68% [95% CI, 19% to 51%]; P = .003) and was similar among all treatment groups (P = .10). Adverse systemic effects occurred in 9 of 40 (23%) patients receiving systemic chemotherapy; the most common of these effects was acute renal failure. CONCLUSIONS AND RELEVANCE: In the present series of patients with isolated PVRL, the use of systemic chemotherapy was not proven to prevent CNSL and was associated with more severe adverse effects compared with local treatment