SARS-CoV-2 mutations affect antigen processing by the proteasome to alter CD8+ T cell responses

Mutations within viral epitopes can result in escape from T cells, but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two SARS-CoV-2 nucleoprotein CD8+ epitopes, we investigated the contribution of these flanking mutations to proteasomal processing and T cell activation. We found decreased NP9-17-B*27:05 CD8+ T cell responses to the NP-Q7K mutation, likely due to a lack of efficient epitope production by the proteasome, suggesting immune escape caused by this mutation. In contrast, NP-P6L and NP-D103 N/Y mutations flanking the NP9-17-B*27:05 and NP105-113-B*07:02 epitopes, respectively, increased CD8+ T cell responses associated with enhanced epitope production by the proteasome. Our results provide evidence that SARS-CoV-2 mutations outside the epitope could have a significant impact on proteasomal processing, either contributing to T cell escape or enhancement that may be exploited for future vaccine design

C/EBP alpha and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor

Acute erythroid leukemia (AEL) commonly involves both myeloid and erythroid lineage transformation. However, the mutations that cause AEL and the cell(s) that sustain the bilineage leukemia phenotype remain unknown. We here show that combined biallelic Cebpa and Gata2 zinc finger-1 (ZnF1) mutations cooperatively induce bilineage AEL, and that the major leukemia-initiating cell (LIC) population has a neutrophil-monocyte progenitor (NMP) phenotype. In pre-leukemic NMPs Cebpa and Gata2 mutations synergize by increasing erythroid transcription factor (TF) expression and erythroid TF chromatin access, respectively, thereby installing ectopic erythroid potential. This erythroid-permissive chromatin conformation is retained in bilineage LICs. These results demonstrate that synergistic transcriptional and epigenetic reprogramming by leukemia-initiating mutations can generate neomorphic pre-leukemic progenitors, defining the lineage identity of the resulting leukemia

Position of the Third Na+ Site in the Aspartate Transporter GltPh and the Human Glutamate Transporter, EAAT1

Glutamate transport via the human excitatory amino acid transporters is coupled to the co-transport of three Na+ ions, one H+ and the counter-transport of one K+ ion. Transport by an archaeal homologue of the human glutamate transporters, GltPh, whose three dimensional structure is known is also coupled to three Na+ ions but only two Na+ ion binding sites have been observed in the crystal structure of GltPh. In order to fully utilize the GltPh structure in functional studies of the human glutamate transporters, it is essential to understand the transport mechanism of GltPh and accurately determine the number and location of Na+ ions coupled to transport. Several sites have been proposed for the binding of a third Na+ ion from electrostatic calculations and molecular dynamics simulations. In this study, we have performed detailed free energy simulations for GltPh and reveal a new site for the third Na+ ion involving the side chains of Threonine 92, Serine 93, Asparagine 310, Aspartate 312, and the backbone of Tyrosine 89. We have also studied the transport properties of alanine mutants of the coordinating residues Threonine 92 and Serine 93 in GltPh, and the corresponding residues in a human glutamate transporter, EAAT1. The mutant transporters have reduced affinity for Na+ compared to their wild type counterparts. These results confirm that Threonine 92 and Serine 93 are involved in the coordination of the third Na+ ion in GltPh and EAAT1

Implications of O and Mg abundances in metal-poor halo stars for stellar iron yields

Inhomogeneous chemical evolution models of galaxies which try to reproduce the scatter seen in element-to-iron ratios of metal-poor halo stars are heavily dependent on theoretical nucleosynthesis yields of core-collapse supernovae. Hence inhomogeneous models present themselves as a test for stellar nucleosyn- thesis calculations. Applying an inhomogeneous chemical evolution model to our Galaxy reveals a number of shortcomings of existing theoretical nucleosynthesis yields. One problem is the predicted scatter in [O/Fe] and [Mg/Fe] which is too large compared to the one observed in metal-poor halo stars. This can be either due to the O or Mg yields or due to the Fe yields (or both). However, O and Mg are alpha-elements that are produced mainly during hydrostatic burning and thus are not affected by the theoretical uncertainties afflicting the collapse and explosion of a massive star. Stellar iron yields, on the other hand, depend heavily on the choice of the mass-cut between ejecta and proto neutron star and are therefore very uncertain. We present Fe yield distributions as function of progenitor mass that are consistent with the abundance distribution of metal- poor halo stars and are in agreement with observed Ni yields of SNe II with known progenitor masses. The iron yields of lower-mass SNe II (in the range 10-20 Msol) are well constrained by those observations. Present observations, however, do not allow to determine a unique solution for higher-mass SNe. Nevertheless, the main dependence of the stellar iron yield as function of progenitor mass may be derived and can be used as constraint for future supernova/hypernova models. The results are of importance for the earliest stages of galaxy formation when the ISM is dominated by chemical inhomogeneities and the instantaneous mixing approximation is not valid.Comment: 16 pages, 15 figures, submitted to A&A, for higher quality figures contact the author ([email protected]

Neutron star mergers versus core-collapse supernovae as dominant r-process sites in the early Galaxy

The astrophysical nature of r-process sites is a long standing mystery and many probable sources have been suggested in the past, among them lower-mass core-collapse supernovae (in the range 8 - 10 Msol), higher-mass core-collapse supernovae (with masses > 20 Msol) and neutron star mergers. In this work, we present a detailed inhomogeneous chemical evolution study that considers for the first time neutron star mergers as major r-process sources, and compare this scenario to the ones in which core-collapse supernovae act as dominant r-process sites. We conclude that, due to the lack of reliable iron and r-process yields as function of progenitor mass, it is not possible at present to distinguish between the lower-mass and higher-mass supernovae scenarios within the framework of inhomogeneous chemical evolution. However, neutron-star mergers seem to be ruled out as the dominant r-process source, since their low rates of occurrence would lead to r-process enrichment that is not consistent with observations at very low metallicities. Additionally, the considerable injection of r-process material by a single neutron-star merger leads to a scatter in [r-process/Fe] ratios at later times which is much too large compared to observations.Comment: 16 Pages, 6 Figures, submitted to A&