A secondary analysis of the TEMPO-2 RCT found no significant improvement in outcomes for minor ischemic stroke patients treated with intravenous tenecteplase, regardless of the presence of disabling deficits.
Question Did outcomes following intravenous tenecteplase for minor ischemic stroke vary based on the presence of disabling deficits?
Findings In this secondary analysis of the TEMPO-2 randomized clinical trial including 884 patients with minor ischemic stroke and proven intracranial occlusion, both patients with and without disabling deficits defined according to US National Institutes of Health Stroke Scale (NIHSS)–based criteria showed a neutral treatment effect from intravenous tenecteplase, with no significant effect modification.
Meaning Current definitions of disabling stroke did not modify the neutral treatment effect of intravenous tenecteplase in patients with minor stroke and intracranial occlusion.
Zhang et al. construct a comprehensive microbial genome catalog from the Qinghai-Xizang Plateau lakes, with 80.78% of genomes representing previously undescribed taxa. Their research provides not only a holistic genomic resource for bioprospecting, but also suggests key salinity adaptation strategies, particularly the dominant role of glycine betaine uptake in hypersaline environments.
The DNA of eukaryotic organisms is packaged by histone proteins into chromatin. The structural organization of chromatin is tied to its function. Loosely packed, more transcriptionally active regions of chromatin are known as euchromatin, whereas highly condensed, less transcriptionally active regions are known as heterochromatin.
Despite advances in the study of chromatin structure over the past 100 years, a biochemical understanding of how basic structural motifs beget higher-order chromatin organization remains lacking.
In a new Science study, researchers present an approach that enables imaging and analysis of the structure of chromatin condensates in situ, which moves the field much closer toward defining the structural chromatin motifs that underpin its nuclear functions.
Learn more in a new Science Perspective.
Cryogenic electron tomography of condensed chromatin enables multiscale analysis of its structure.
Here, Peter Arvan & team generate a mouse model lacking thyroglobulin, finding stimulated thyroid hormone synthesis machinery drives thyrocyte cell death independent of ER stress:
The figure shows limited ER diameter in thyroid tissue from Tg-KO untreated mice.
Address correspondence to: Peter Arvan, Division of Metabolism, Endocrinology & Diabetes, University of Michigan, Brehm Tower rm 5,112, 1000 Wall Street, Ann Arbor, Michigan 48,105, USA. Phone: 734.936.5505; Email: [email protected].
Ye et al. reveal how VMAT2 loads monoamine neurotransmitters into storage vesicles and interacts with neurological drugs, facilitated by the structural flexibility of the transporter. Amphetamine directly triggers monoamine release to induce psychostimulation, likely by bypassing the regular transport cycle. These insights elucidate psychostimulant action and inform therapeutic strategies.
Now online! Melanoma cells escape immune surveillance by releasing MHC-antigen-loaded large EVs, known as melanosomes, that directly engage and impair CD8+ T cell receptors.
Now online! Melanoma cells and melanosomes had distinct MHC class I ligandome profiles (Figure 4 G), but a substantial proportion of the melanosome-derived peptide repertoire overlapped with that of the parent cells (83.8%), implying derivation from the total cellular ligandome (Figure 4 G). Pathway enrichment analysis of the immunopeptidome landscape revealed a positive correlation between pathways enriched in cells and their corresponding melanosomes, with substantial overlaps in functional categories such as class I MHC-mediated antigen processing and presentation, DNA repair, and cell cycle regulation (Figures 4 H and 4I). Given the observed MHC class I-dependent, peptide-specific suppression of CD8+ T cell activity by melanosomes, we hypothesized that melanosomes present immunogenic peptides. Indeed, we have identified 25 tumor-associated antigens (TAAs) in melanosome samples (Figure 4 J) with high-confidence peptide identifications (Figure 4 K). These TAAs are predicted to bind a variety of HLA alleles with high affinity. Strikingly, the majority of these peptides were also detected in the corresponding melanoma cell samples (Figure 4 J). Notably, melanosomes exhibited a statistically significant enrichment in TAA presentation compared with melanoma cells, regardless of IFNγ treatment (Figure 4 L).
Finally, we used whole-exome sequencing to generate a custom proteomic database for proteogenomic analysis of neopeptides/neoantigens. This approach identified three mutation-derived neoantigens within the human melanosome immunopeptidome, two of which were also present in the cellular MHC class I repertoire (Figures 4 M and 4N). Importantly, we analyzed the murine B16F10 cells and secreted melanosome immunopeptidomic data, which recapitulated most of our findings in human cells (Figures S4 A–S4J). Together, these findings suggest that melanosomes, by carrying immunogenic peptides, including TAAs and neoantigens, compete with melanoma cells for CD8+ T cell recognition, thereby contributing to their immunomodulatory effects.
