Analyzing the geometric relationships among genomic sequences from a mathematical perspective and revealing the laws hidden within these relationships is a crucial challenge in bioinformatics.The natural vector method...Analyzing the geometric relationships among genomic sequences from a mathematical perspective and revealing the laws hidden within these relationships is a crucial challenge in bioinformatics.The natural vector method constructs a genome space by extracting statistical moments of k-mers to illuminate the relationships among genomes.This approach highlights a fundamental law in biology known as the convex hull principle,which states that natural vectors corresponding to different types of biological sequences form distinct,non-overlapping convex hulls.Previous studies have validated this important principle across various datasets.However,they often focused on specific kingdoms and did not thoroughly analyze the significance of the dimensions required for the convex hull separation.In this study,we integrate all reliable sequences from different kingdoms to construct the grand biological universe,within which we comprehensively validate the multi-level convex hull principle.We demonstrate that the separation of convex hulls arises from biological properties rather than mathematical characteristics of high-dimensional spaces.Furthermore,we develop suitable metrics within the grand biological universe to facilitate efficient sequence classification.This research advances the convex hull principle through both theoretical development and experimental validation,making significant contributions to the understanding of the geometric structure of genome space.展开更多
Patients with type 2 diabetes mellitus(T2DM)have an increased risk of cancer.The effect of glucose metabolism onγδT cells and their impact on tumor surveillance remain unknown.Here,we showed that high glucose induce...Patients with type 2 diabetes mellitus(T2DM)have an increased risk of cancer.The effect of glucose metabolism onγδT cells and their impact on tumor surveillance remain unknown.Here,we showed that high glucose induced Warburg effect type of bioenergetic profle in Vy9vδ2 T cells,leading to excessive lactate accumulation,which further inhibited lytic granule secretion by impairing the traffcking of cytolytic machinery to the Vy9vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro,in vivo and in patients.Strikingly,activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vy9vδ2 T cells.These results suggest that the impaired antitumor activity of Vy9vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance.展开更多
基金supported by grants from the National Natural Science Foundation of China(12171275)the Tsinghua University Education Foundation fund.
文摘Analyzing the geometric relationships among genomic sequences from a mathematical perspective and revealing the laws hidden within these relationships is a crucial challenge in bioinformatics.The natural vector method constructs a genome space by extracting statistical moments of k-mers to illuminate the relationships among genomes.This approach highlights a fundamental law in biology known as the convex hull principle,which states that natural vectors corresponding to different types of biological sequences form distinct,non-overlapping convex hulls.Previous studies have validated this important principle across various datasets.However,they often focused on specific kingdoms and did not thoroughly analyze the significance of the dimensions required for the convex hull separation.In this study,we integrate all reliable sequences from different kingdoms to construct the grand biological universe,within which we comprehensively validate the multi-level convex hull principle.We demonstrate that the separation of convex hulls arises from biological properties rather than mathematical characteristics of high-dimensional spaces.Furthermore,we develop suitable metrics within the grand biological universe to facilitate efficient sequence classification.This research advances the convex hull principle through both theoretical development and experimental validation,making significant contributions to the understanding of the geometric structure of genome space.
基金Seed Funding for Strategic Interdisciplinary Research Scheme,University of Hong Kong,and the General Research Fund,Research Grants Council of Hong Kong(17122222,17122519,17126317),Hong Kong SAR,ChinaThis work was also partly supported by the National Natural Science Foundation of China(32000616),China.
文摘Patients with type 2 diabetes mellitus(T2DM)have an increased risk of cancer.The effect of glucose metabolism onγδT cells and their impact on tumor surveillance remain unknown.Here,we showed that high glucose induced Warburg effect type of bioenergetic profle in Vy9vδ2 T cells,leading to excessive lactate accumulation,which further inhibited lytic granule secretion by impairing the traffcking of cytolytic machinery to the Vy9vδ2 T-cell-tumor synapse by suppressing AMPK activation and resulted in the loss of antitumor activity in vitro,in vivo and in patients.Strikingly,activating the AMPK pathway through glucose control or metformin treatment reversed the metabolic abnormalities and restored the antitumor activity of Vy9vδ2 T cells.These results suggest that the impaired antitumor activity of Vy9vδ2 T cells induced by dysregulated glucose metabolism may contribute to the increased cancer risk in T2DM patients and that metabolic reprogramming by targeting the AMPK pathway with metformin may improve tumor immunosurveillance.
