A class of large cell-like extracellular vesicles
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Rapid brain tumor classification from sparse epigenomic data
Although the intraoperative molecular diagnosis of the approximately 100 known brain tumor entities described to date has been a goal of neuropathology for the past decade, achieving this within a clinically relevant timeframe of under 1 h after biopsy collection remains elusive. Advances in third-generation sequencing have brought this goal closer, but established machine learning techniques rely on computationally intensive methods, making them impractical for live diagnostic workflows in clinical applications. Here we present MethyLYZR, a naive Bayesian framework enabling fully tractable, live classification of cancer epigenomes. For evaluation, we used nanopore sequencing to classify over 200 brain tumor samples, including 10 sequenced in a clinical setting next to the operating room, achieving highly accurate results within 15 min of sequencing. MethyLYZR can be run in parallel with an ongoing nanopore experiment with negligible computational overhead. Therefore, the only limiting factors for even faster time to results are DNA extraction time and the nanopore sequencer’s maximum parallel throughput. Although more evidence from prospective studies is needed, our study suggests the potential applicability of MethyLYZR for live molecular classification of nervous system malignancies using nanopore sequencing not only for the neurosurgical intraoperative use case but also for other oncologic indications and the classification of tumors from cell-free DNA in liquid biopsies.
Coupling of cell shape, matrix and tissue dynamics ensures embryonic patterning robustness
Tissue patterning coordinates morphogenesis, cell dynamics and fate specification. Understanding how precision in patterning is robustly achieved despite inherent developmental variability during mammalian embryogenesis remains a challenge. Here, based on cell dynamics quantification and simulation, we show how salt-and-pepper epiblast and primitive endoderm (PrE) cells pattern the inner cell mass of mouse blastocysts. Coupling cell fate and dynamics, PrE cells form apical polarity-dependent actin protrusions required for RAC1-dependent migration towards the surface of the fluid cavity, where PrE cells are trapped due to decreased tension. Concomitantly, PrE cells deposit an extracellular matrix gradient, presumably breaking the tissue-level symmetry and collectively guiding their own migration. Tissue size perturbations of mouse embryos and their comparison with monkey and human blastocysts further demonstrate that the fixed proportion of PrE/epiblast cells is optimal with respect to embryo size and tissue geometry and, despite variability, ensures patterning robustness during early mammalian development.
Packaged release and targeted delivery of cytokines by migrasomes in circulation
In dynamic systems like the circulatory system, establishing localized cytokine gradients is challenging. Upon lipopolysaccharide (LPS) stimulation, we observed that monocytes release numerous migrasomes enriched with inflammatory cytokines, such as TNF-α and IL-6. These cytokines are transported into migrasomes via secretory carriers, leading to their immediate exocytosis or eventual release from detached migrasomes. We successfully isolated TNF-α and IL-6-enriched, monocyte-derived migrasomes from the blood of LPS-treated mice. Total secretion analysis revealed a substantial amount of TNF-α and IL-6 released in a migrasome-packaged form. Thus, detached, monocyte-derived migrasomes represent a type of extracellular vesicle highly enriched with cytokines. Physiologically, these cytokine-laden migrasomes rapidly accumulate at local sites of inflammation, effectively creating a concentrated source of cytokines. Our research uncovers novel mechanisms for cytokine release and delivery, providing new insights into immune response modulation.
Cell-associated galectin 9 interacts with cytotoxic T cells confers resistance to tumor killing in nasopharyngeal carcinoma through autophagy activation
Immune effector cells, including cytotoxic T lymphocytes (CTLs) play essential roles in eliminating cancer cells. However, their functionality is often compromised, even when they infiltrate the tumor microenvironment (TME) or are transferred to cancer patients adoptively. In this study, we focused on galectin 9 (G9), an inhibitory ligand that we observed to be predominately positioned on the plasma membrane and readily interacts with CD8 + CTL in the TME of nasopharyngeal carcinoma (NPC). We discovered that cell-cell contact between activated effector CTLs and target tumor cells (TarTC) with G9 overexpression led to cellular death defects. Despite the formation of CTL–TarTC conjugates, there is no impact on the cell number nor viability of CTL, and the release of cytolytic content and associated activity were not completely abrogated. Instead, this interaction promoted autophagy and restricted necrosis in the TarTC. Furthermore, reducing G9 expression in tumor cells enhanced the suppressive effect on tumor growth upon adoptive transfer of activated effector CTL. Additionally, inhibiting autophagy effectively controlled tumor growth in cases of G9 overexpression. Therefore, we highlight the contribution of G9 in facilitating the resistance of NPC to CTL-mediated killing by inducing a selection-cell death state in tumor cells, characterized by increased autophagy and decreased necrosis.
Optical sorting: past, present and future
Optical sorting combines optical tweezers with diverse techniques, including optical spectrum, artificial intelligence (AI) and immunoassay, to endow unprecedented capabilities in particle sorting. In comparison to other methods such as microfluidics, acoustics and electrophoresis, optical sorting offers appreciable advantages in nanoscale precision, high resolution, non-invasiveness, and is becoming increasingly indispensable in fields of biophysics, chemistry, and materials science. This review aims to offer a comprehensive overview of the history, development, and perspectives of various optical sorting techniques, categorised as passive and active sorting methods. To begin, we elucidate the fundamental physics and attributes of both conventional and exotic optical forces. We then explore sorting capabilities of active optical sorting, which fuses optical tweezers with a diversity of techniques, including Raman spectroscopy and machine learning. Afterwards, we reveal the essential roles played by deterministic light fields, configured with lens systems or metasurfaces, in the passive sorting of particles based on their varying sizes and shapes, sorting resolutions and speeds. We conclude with our vision of the most promising and futuristic directions, including AI-facilitated ultrafast and bio-morphology-selective sorting. It can be envisioned that optical sorting will inevitably become a revolutionary tool in scientific research and practical biomedical applications.
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