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

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

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

Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems

RNA molecules perform diverse regulatory functions in natural biological systems, and numerous synthetic RNA-based control devices that integrate sensing and gene-regulatory functions have been demonstrated, predominantly in bacteria and yeast. Despite potential advantages of RNA-based genetic control strategies in clinical applications, there has been limited success in extending engineered RNA devices to mammalian gene-expression control and no example of their application to functional response regulation in mammalian systems. Here we describe a synthetic RNA-based regulatory system and its application in advancing cellular therapies by linking rationally designed, drug-responsive, ribozyme-based regulatory devices to growth cytokine targets to control mouse and primary human T-cell proliferation. We further demonstrate the ability of our synthetic controllers to effectively modulate T-cell growth rate in response to drug input in vivo. Our RNA-based regulatory system exhibits unique properties critical for translation to therapeutic applications, including adaptability to diverse ligand inputs and regulatory targets, tunable regulatory stringency, and rapid response to input availability. By providing tight gene-expression control with customizable ligand inputs, RNA-based regulatory systems can greatly improve cellular therapies and advance broad applications in health and medicine

Ventilation of the abyssal Southern Ocean during the late Neogene: A new perspective from the subantarctic Pacific

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94630/1/palo1532.pd

Sex Determination in Honeybees: Two Separate Mechanisms Induce and Maintain the Female Pathway

Sex determination in honeybees is realized by the csd and the fem gene that establish and maintain, throughout development, sexual fates via the control of alternative splicing

Synchronous and proportional deglacial changes in Atlantic meridional overturning and northeast Brazilian precipitation

Changes in heat transport associated with fluctuations in the strength of the Atlantic meridional overturning circulation (AMOC) are widely considered to affect the position of the Intertropical Convergence Zone (ITCZ), but the temporal immediacy of this teleconnection has to date not been resolved. Based on a high-resolution marine sediment sequence over the last deglaciation, we provide evidence for a synchronous and near-linear link between changes in the Atlantic interhemispheric sea surface temperature difference and continental precipitation over northeast Brazil. The tight coupling between AMOC strength, sea surface temperature difference, and precipitation changes over northeast Brazil unambiguously points to a rapid and proportional adjustment of the ITCZ location to past changes in the Atlantic meridional heat transport