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Kock Marks posted an update 9 days ago
Data from 77 independent studies are curated, annotated, and synthesized to expose the transcriptional ITH patterns across 1163 tumor samples, representing 24 distinct tumor types. Among the malignant cells, we observe 41 consistent gene expression signatures; each signature comprises dozens of genes whose expression is heightened in a coordinated manner within particular groups of cells within many tumors. Meta-programs account for various cellular processes, including general ones (e.g., the cell cycle and stress responses) and lineage-specific ones, which we categorize as 11 hallmarks of transcriptional ITH. The meta-programs of carcinoma cells, strikingly similar to those in non-malignant epithelial counterparts, indicate that a large proportion of malignant ITH programs are diverse before oncogenesis, reflecting the biology of their origin cells. Meta-program analysis was extended to include six non-malignant cell types, enabling a mapping of intercellular interactions within the tumor microenvironment. To summarize, a pan-cancer single-cell RNA-sequencing dataset, meticulously curated and housed on the Curated Cancer Cell Atlas platform, was employed to systematically delineate transcriptional ITH.
In almost every light-material interaction, the primary step is the electrons’ electrodynamic response to the optical cycles of the incident light wave, which manifests on sub-wavelength and sub-cycle dimensions. Thus, controlling and understanding the electromagnetic interactions within a material, from 2-11, is essential for progress in modern optics and nanophotonics, particularly from 12-19. While electron beams’ diminutive de Broglie wavelengths promise attosecond and angstrom-scale imaging, ultrafast electron microscopy and diffraction techniques have, to date, been restricted to femtosecond time resolution, falling short of capturing fundamental material responses at the light cycle level. Utilizing transmission electron microscopy, we attain attosecond temporal resolution for optical responses, capturing the dynamics within a single excitation light cycle. To modulate an electron wave function into a rapid sequence of electron pulses, we employ a continuous-wave laser24, subsequently resolving electromagnetic near-fields within and around a material as a spatiotemporal movie using an energy filter. In experiments involving nanostructured needle tips, dielectric resonators, and metamaterial antennas, directional chiral surface wave emission, a delay between dipole and quadrupole dynamic behaviors, a subluminal buried waveguide field, and a multi-antenna response with symmetry disruption are detected. The significance of combining electron microscopy with attosecond laser science for comprehending light-matter interactions is rooted in their ability to delineate the fundamental dimensions of these interactions in both space and time.
Extensive transcriptomic datasets are indispensable for mapping gene networks, however, this data requirement creates obstacles for investigations in settings with limited access to data, such as rare disease research and investigations involving clinically inaccessible tissues. Through transfer learning, which leverages deep learning models pre-trained on broad general datasets, the fields of natural language understanding and computer vision have experienced a revolution, permitting the fine-tuning of models for a wide range of downstream tasks with limited task-specific data. Within the context of network biology, with limited data, we developed Geneformer, a deep learning model with attention mechanisms and context awareness, pre-trained on a sizeable corpus of roughly 30 million single-cell transcriptomes, allowing for context-specific predictions. Geneformer, through self-supervised pretraining, acquired a fundamental understanding of network dynamics, its hierarchical structure represented by the attention weights of the model. Fine-tuning Geneformer on a diverse selection of downstream tasks directly tied to chromatin and network dynamics, using a limited amount of task-specific data, consistently enhanced predictive accuracy. In disease modeling applications using limited patient data, Geneformer unearthed promising therapeutic targets for cardiomyopathy. Geneformer’s pretrained deep learning structure allows for fine-tuning for various downstream applications, leading to the quicker identification of critical network regulators and prospective therapeutic targets.
The rhythmic movement of motile cilia and flagella on the surface of cells powers fluid flow and allows for the propulsion of spermatozoa and single-celled eukaryotes. Male infertility and the congenital condition primary ciliary dyskinesia (PCD) are potential consequences of impaired ciliary motility in humans, stemming from the cilia’s compromised ability to clear mucus, thereby fostering chronic respiratory infections. epoxomicin inhibitor The axoneme, a molecular structure constructed from microtubules, ATP-fueled dynein motors, and regulating complexes, propels ciliary movement. The formidable size and multifaceted nature of the axoneme have, until this point, impeded the development of an atomic model, thereby restricting insight into its functional mechanisms. Applying cryo-electron microscopy (cryo-EM) and artificial intelligence-powered structural prediction, we successfully determined the structure of the 96-nanometer modular repeats in the axonemes of the alga Chlamydomonas reinhardtii flagella and human respiratory cilia. Atomic models of axonemes offer insights into the preservation and diversification of their structure, the interconnections between dyneins and their regulatory proteins, and the mechanisms that dictate their repeating pattern. The long-posited mechanotransduction pathway’s regulatory influence on ciliary motility finds a mechanism in correlated conformational alterations of mechanoregulatory complexes, alongside their associated axonemal dynein motors. From the examination of respiratory cilia doublet microtubule structures in four PCD patients, the selective removal of periodically repeating structures is elucidated by the loss of individual docking factors.
The rapid increase in Alzheimer’s disease (AD), the leading cause of dementia, with advancing age remains a mystery, despite age’s established role as a primary risk factor. Myelin sheath integrity and oligodendrocyte health are negatively impacted by brain aging, which is associated with secondary neuroinflammatory responses. Recognizing the crucial function of oligodendrocytes in supporting axonal energy metabolism and neuronal health, we hypothesized that a reduction in myelin integrity may precede and contribute to neuronal amyloid- (A) deposition, the primary neuropathological characteristic of Alzheimer’s disease. We discover, in mouse models of Alzheimer’s Disease, how genetic pathways governing myelin disruption and demyelination significantly influence amyloid plaque accumulation. Mechanistically, disruptions in myelin function lead to the buildup of A-producing machinery within axonal swellings, thereby increasing the cleavage of cortical amyloid precursor protein. Paradoxically, AD mice with compromised myelin sheaths have fewer microglia that corral plaques, even with a larger overall population. Transcriptomic analyses of AD mouse models, focusing on both bulk and single-cell levels, demonstrate a simultaneous induction of microglia signatures that, while sharing similarities, are specifically associated with myelin damage and amyloid plaques, respectively. Although induction was successful, amyloid disease-associated microglia (DAM), typically responsible for clearing amyloid plaques, appear to be diverted to nearby myelin damage. Our data supports a model where age-dependent structural damage to myelin is a driving force behind A plaque formation in both direct and indirect ways, making it an antecedent risk factor for Alzheimer’s disease. The enhancement of oligodendrocyte health and myelin integrity presents a promising therapeutic target for mitigating the development and slowing the progression of Alzheimer’s disease.
Phosphorus, a nutrient considered a key factor in regulating oceanic oxygenation, is thought to have a substantial impact on the oxygen levels in the ocean, as documented in studies 1-3. During the Ediacaran Period (approximately 635 to 549 million years ago), a possible escalation in marine phosphorus levels is posited as a catalyst for the elevation of oxygen levels. Despite this, little information exists regarding the specifics of phosphorus cycling and its evolution throughout this phase. Carbonate-associated phosphate (CAP) from six locations across the globe is used to reconstruct oceanic phosphorus levels during the Shuram excursion (SE), a substantial negative carbon isotope event linked to the concurrent global oceanic oxygenation. Our observations reveal periodic surges in oceanic phosphorus levels concurrent with both the downswing and upswing of the SE. Using a quantitative biogeochemical modeling framework, we propose that the observed data are explainable by the release of carbon dioxide and phosphorus from marine organic matter oxidation, predominantly via sulfate, with an additional release of phosphorus from carbon dioxide-driven weathering on land. The elevated organic-pyrite burial and the resulting ocean oxygenation may be directly linked to the collective influence of these occurrences. Equivalent oceanic phosphorus concentrations, according to our CAP data, appear to characterize both maximum and minimum extents of ocean anoxia in the Southeast. Instead of the integrated nature of phosphorus and ocean anoxia cycles seen in the modern ocean, this observation might suggest a disconnection between the two. Our results suggest that external factors, including sulfate weathering, are more significantly associated with controlling Ediacaran oceanic oxygenation than internal oceanic phosphorus-oxygen cycling alone. Potentially, this contributes to the elucidation of the extended rise in the levels of atmospheric oxygen.
The stability of the Earth system and human well-being are intricately linked; however, their interdependence often goes unacknowledged, and as a result, they are often treated independently. Through the combined use of modeling and literature reviews, we establish quantitative measures for safe and equitable Earth system boundaries (ESBs) for climate, the biosphere, water and nutrient cycles, and aerosols, at global and sub-global scales.
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Start with a huge, uncovered box, or even a kiddie pool, and fill with a thick layer (about 6 inches) of unscented clay or fine sand-like particulate clumping/scoopable litter. For Ollie, you may need to play around with the substrate types to make it more natural. Try using soil or peat.