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.
Materials react differently to electric and magnetic fields, and these reactions are known as electromagnetic responses. In many solid materials, unusual electromagnetic responses have been known to only emerge when specific symmetries are broken.
Researchers at Rutgers University, Pohang University of Science and Technology, National Taiwan University and University of Michigan recently observed new electromagnetic effects in ferro-rotational materials, which they reported in a paper in Nature Physics. These are solid materials in which individual crystals collectively rotate, and form ordered rotational domains, without breaking spatial inversion (I) or time-reversal (T) symmetry.
“Twisting is ubiquitous in nature, appearing in DNA structures, climbing vines, and even in quartz crystals that exhibit piezoelectricity. Such twisting is typically three-dimensional and is described by chirality, characterized by left-or right-handedness,” Sang-Wook Cheong, senior author of the paper told Phys.org.
Background: Three-dimensional cellular models provide a more comprehensive representation of in vivo cell properties, encompassing physiological characteristics and drug susceptibility. Methods: Primary hepatocytes were seeded in ultra-low attachment plates to form spheroids, with or without tumoral cells. Spheroid structure, cell proliferation, and apoptosis were analyzed using histological staining techniques. In addition, extracellular vesicles were isolated from conditioned media by differential ultracentrifugation. Spheroids were exposed to cytotoxic drugs, and both spheroid growth and cell death were measured by microscopic imaging and flow cytometry with vital staining, respectively. Results: Concerning spheroid structure, an active outer layer forms a boundary with the media, while the inner core comprises a mass of cell debris.
The relevance of the gut microbiome, the community of microorganisms living in the digestive tract, to human health is a topic of intense interest. However, among the numerous benevolent bacteria living in the gut, there are some species that are harmful to humans.
For example, certain strains of Escherichia coli produce the genotoxin colibactin, which causes DNA damage and is linked with colon cancer. However, the colibactin molecule is complex and unstable, which has made it challenging to elucidate its chemical structure and the mechanism by which it damages DNA. In the culmination of years of research from multiple laboratories, researchers in a new Science study reveal the structure of the active form of colibactin bound to DNA.
The findings go a long way toward explaining the mutation signatures associated with colibactin exposure and provide substantial insight into how colibactin contributes to colorectal carcinogenesis.
Learn more in a new Science Perspective.
The structure of the bacterial genotoxin colibactin bound to DNA shows how it might contribute to cancer risk.
