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Biology subjects

Osawa, T.

Publications and source records attributed to Osawa, T..

4 recordsLinked to original sources

A tabular foundation model rivals established species distribution models from presence-only records

Predicting where something occurs from records of where it has been observed, without reliable records of absence, is a common problem in science. Species distribution models (SDMs) such as MaxEnt address it in fields from biological conservation and climate-change assessment to the mapping of disease vectors and archaeological sites, but must be tuned for each dataset. Tabular foundation models, pre-trained on synthetic prediction tasks, predict new datasets without per-dataset training. Only one study has tested them as SDMs, and it fine-tuned on survey data from the evaluated regions. We evaluated tabular foundation models on the standard SDM benchmark (225 species in six regions, with independent presence-absence surveys), under the protocol used to compare 21 methods, and on 120 virtual species with known distributions. Without tuning, a tabular foundation model, TabPFN 3.5, equalled the best published approach, a five-model ensemble (mean AUC 0.732). Fine-tuned on presence-background tasks from other regions, it became the best single model on the benchmark (0.736), outperformed MaxEnt (0.728) and boosted regression trees after correction for multiple comparisons, and was better calibrated than MaxEnt, although six regions were too few to establish the advantage for new regions. Fine-tuning on presence-absence surveys of other species helped only when they came from the evaluated regions. On virtual species, it recovered simple additive relationships less well than regression-based methods but complex ones at least as well when records were unbiased, and was worse with environmentally biased records. Tabular foundation models are competitive SDMs without per-dataset tuning, but they are sensitive to environmentally biased records.

ecology↗

Mechanism of bridge-type phospholipid transfer by Atg2 for autophagosome biogenesis

Autophagosome biogenesis requires delivery of millions of phospholipids. In budding yeast, Atg2 and Atg18 couple the ER to the isolation membrane for lipid transport, yet the mechanism is poorly understood. Combining molecular dynamics simulations, in vitro imaging-based lipid transfer assays, and in vivo analyses, we show that Atg1-mediated phosphorylation activates Atg2 as a lipid-transfer bridge. Simulations reveal that Atg2 contains a water-excluding hydrophobic cavity that accommodates [~]25 phospholipids with bilayer-like fluidity. Atg1 phosphorylates an N-terminal helix of Atg2 in vitro and in vivo, thereby opening the ER-facing entrance to the Atg2 cavity and enabling lipid flow between membranes in silico and in vitro. Consistently, phosphodeficient but not phosphomimetic mutations impair autophagy. Cavity narrowing along the conduit disrupts lipid alignment in silico, phosphorylation-activated bridge-type lipid transfer in vitro, and ER-to-isolation-membrane lipophilic dye flow and autophagosome expansion in vivo. These data suggest that Atg1 gates Atg2-mediated bridge-type lipid transport to build autophagosomes.

cell biology↗

Identifying simultaneous inhibition of riboflavin metabolism and MEK as a novel therapeutic strategy for pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) remains a formidable challenge with a survival rate of approximately 10%, largely due to the lack of diagnostic and therapeutic options. To identify novel therapeutic targets for PDAC, we previously developed a Drosophila melanogaster model, the 4-hit fly, which mimics the alterations in KRAS, TP53, CDKN2A, and SMAD4 genes observed in PDAC. Through whole-body genetic screening using the 4-hit model, we identified riboflavin (RF) metabolism as a novel potential therapeutic target for PDAC. Additionally, transcript levels of four out of five genes that are involved in RF metabolism were elevated in human PDAC compared to non-tumor tissues. Roseoflavin (RoF), an antimetabolite of RF, resulted in a variety range of metabolic changes, decreased mitochondrial respiratory chain activity, and suppressed proliferation in cultured PDAC cells. Furthermore, the combination of RoF with the MEK inhibitor drug trametinib significantly suppressed the growth of human PDAC xenografts compared to either treatment alone. These findings underscore that dual targeting of RF metabolism and MEK represents a novel therapeutic strategy for PDAC.

cancer biology↗

Glutamine deficiency in solid tumors confers resistance to ribosomal RNA synthesis inhibitors

Ribosome biogenesis involves the processing of precursor ribosomal RNAs (pre-rRNAs) and sequential assembly with ribosomal proteins. Here we report that nutrient deprivation severely impairs pre-rRNA processing and leads to the accumulation of unprocessed rRNAs. Upon nutrient restoration, the accumulated pre-rRNAs are processed into mature rRNAs that are utilized for ribosome biogenesis. Failure to accumulate pre-rRNAs under nutrient deprivation leads to perturbed ribosome assembly during nutrient restoration and subsequent apoptosis via uL5/uL18-mediated activation of p53. Restoration of glutamine alone activates p53 by triggering uL5/uL18 translation. Induction of uL5/uL18 protein synthesis by glutamine was dependent on the translation factor eukaryotic elongation factor 2 (eEF2), which was in turn dependent on Raf/MEK/ERK signalling. Depriving cells of glutamine prevents the activation of p53 by rRNA synthesis inhibitors. Our data reveals a mechanism that cancer cells can exploit to suppress p53-mediated apoptosis during fluctuations in environmental nutrient availability.

cancer biology↗