Biology subjects

Han, T.

Publications and source records attributed to Han, T..

44 records · Page 3Linked to original sources

bioRxiv2019

An in vivo KRAS allelic series reveals distinct phenotypes of common oncogenic variants

KRAS is the most frequently mutated oncogene in cancer. Tumor sequencing has revealed a complex spectrum of KRAS mutations across different cancer types, yet there is little understanding how specific KRAS alterations impact tumor in initiation, progression, or therapy response. Using high-fidelity CRISPR-based engineering, we created an allelic series of new LSL-Kras mutant mice, reflecting codon 12 and 13 mutations that are highly prevalent in lung (KRASG12C), pancreas (KRASG12R) and colon (KRASG13D) cancers. Induction of each mutation in the developing mouse pancreas reveal striking quantitative and qualitative differences in the degree of ductal transformation and pre-malignant progression. Further, using organoid models we show that KRASG13D mutants respond to EGFR inhibition, while the anti-proliferative effect of KRASG12C-selective inhibitors can be overcome by upstream EGFR signaling. Together, these new mouse strains provide an ideal for investigating KRAS biology in vivo, and for developing pre-clinical precision oncology models of KRAS-mutant pancreas (G12R), colon (G13D), and lung (G12C) cancers.

cancer biology↗

bioRxiv2019

Breaking Medical Data Sharing Boundaries by EmployingArtificial Radiographs

Artificial intelligence (AI) has the potential to change medicine fundamentally. Here, expert knowledge provided by AI can enhance diagnosis by comprehensive and user independent integration of multiple image features. Unfortunately, existing algorithms often stay behind expectations, as databases used for training are usually too small, incomplete, and heterogeneous in quality. Additionally, data protection constitutes a serious obstacle to data sharing. We propose to use generative models (GM) to produce high-resolution artificial radiographs, which are free of personal identifying information. Blinded analyses by computer vision and radiology experts proved the high similarity of artificial and real radiographs. The combination of multiple GM improves the performance of computer vision algorithms and the integration of artificial data into patient data repositories can compensate for underrepresented disease entities. Furthermore, the low computational effort of our method complies with existing IT infrastructure in hospitals and thus facilitates its dissemination. We envision that our approach could lead to scalable databases of anonymous medical images enabling standardized radiomic analyses at multiple sites.

bioinformatics↗

bioRxiv2019

Satellite Imaging of Global Urbanicity relate to Adolescent Brain Development and Behavior

Urbanicity, the impact of living in urban areas, is among the greatest environmental challenges for mental health. While urbanicity might be distinct in different sociocultural conditions and geographic locations, there are likely to exist common features shared in different areas of the globe. Understanding these common and specific relations of urbanicity with human brain and behavior will enable to assess the impact of urbanicity on mental disorders, especially in childhood and adolescence, where prevention and early interventions are likely to be most effective.\n\nWe constructed from satellite-based remote sensing data a factor for urbanicity that was highly correlated with population density ground data. This factor, UrbanSat was utilized in the Chinese CHIMGEN sample (N=831) and the longitudinal European IMAGEN cohort (N=810) to investigate if exposure to urbanicity during childhood and adolescence is associated with differences in brain structure and function in young adults, and if these changes are linked to behavior.\n\nUrbanicity was found negatively correlated with medial prefrontal cortex volume and positively correlated with cerebellar vermis volume in young adults from both China and Europe. We found an increased correlation of urbanicity with functional network connectivity within- and between- brain networks in Chinese compared to European participants. Urbanicity was highly correlated with a measure of perceiving a situation from the perspective of others, as well as symptoms of depression in both datasets. These correlations were mediated by the structural and functional brain changes observed. Susceptibility to urbanicity was greatest in two developmental windows during mid-childhood and adolescence.\n\nUsing innovative technology, we were able to probe the relationship between urban upbringing with brain change and behavior in different sociocultural conditions and geographic locations. Our findings help to identify shared and distinct determinants of adolescent brain development and mental health in different regions of the world, thus contributing to targeted prevention and early-intervention programs for young people in their unique environment. Our approach may be relevant for public health, policy and urban planning globally.

neuroscience↗

bioRxiv2019

RNA promotes phase separation of glycolysis enzymes into yeast G bodies in hypoxia

In hypoxic stress conditions, glycolysis enzymes assemble into singular cytoplasmic granules called glycolytic (G) bodies. Formation of G bodies in yeast is correlated with increased glucose consumption and cell survival. However, the physical properties and organizing principles that define G body formation are unclear. We demonstrate that glycolysis enzymes are non-canonical RNA binding proteins, sharing many common mRNA substrates that are also integral constituents of G bodies. Tethering a G body component, the beta subunit of the yeast phosphofructokinase, Pfk2, to nonspecific endoribonucleases reveals that RNA nucleates G body formation and subsequent maintenance of G body structural integrity. Consistent with a phase separation mechanism of G body formation, recruitment of glycolysis enzymes to G bodies relies on multivalent homotypic and heterotypic interactions. Furthermore, G bodies can fuse in live cells and are largely insensitive to 1,6-hexanediol treatment, consistent with a hydrogel-like state in its composition. Taken together, our results elucidate the biophysical nature of G bodies and demonstrate that RNA nucleates phase separation of the glycolysis machinery in response to hypoxic stress.

cell biology↗

bioRxiv2019

Function and clinical relevance of RHAMM isoforms in pancreatic tumor progression

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers. We previously screened genes upregulated in human hepatocellular carcinomas for their metastatic function in a mouse model of pancreatic neuroendocrine tumor (PNET) and identified that human RHAMMB promoted liver metastasis. It was unknown whether RHAMMB is upregulated in pancreatic cancer or contributes to its progression. In this study, we found that RHAMM protein was frequently upregulated in human PNETs. We investigated alternative splicing isoforms, RHAMMA and RHAMMB, by RNA-Seq analysis of primary PNETs and liver metastases. RHAMMB, but not RHAMMA, was significantly upregulated in liver metastases. RHAMMB was crucial for in vivo metastatic capacity of mouse and human PNETs. RHAMMA, carrying an extra 15-amino acid-stretch, did not promote metastasis in spontaneous and experimental metastasis mouse models. Moreover, RHAMMB was substantially higher than RHAMMA in pancreatic ductal adenocarcinoma (PDAC). RHAMMB, but not RHAMMA, correlated with both higher EGFR expression and poorer survival of PDAC patients. Knockdown of EGFR abolished RHAMMB-driven PNET metastasis. Altogether, our findings suggest a clinically relevant function of RHAMMB, but not RHAMMA, in promoting PNET metastasis in part through EGFR signaling. RHAMMB can thus serve as a prognostic factor for pancreatic cancer.

cancer biology↗

bioRxiv2018

An optimized toolkit for precision base editing

CRISPR base editing is a potentially powerful technology that enables the creation of genetic mutations with single base pair resolution. By re-engineering both DNA and protein sequences, we developed a collection of constitutive and inducible base editing vector systems that dramatically improve the ease and efficiency by which single nucleotide variants can be created. This new toolkit is effective in a wide range of model systems, and provides a means for efficient in vivo somatic base editing.

bioengineering↗

bioRxiv2017

A stable beneficial symbiotic relationship between endophytic fungus Schizophyllum commune and host plant Panax ginseng

Endophytes and plants can establish specific long-term symbiosis through the accumulation of secondary metabolites. Interactions between microbial inhabitants represent a novel area of study for natural products research. In this study, a strain of endophyte 3R-2 that can enhance the biomass and contents of ginsenoside Rc, ginsenoside Rg2 and ginsenoside Rg3 of Panax ginseng hairy roots was screened out via HPLC, which was identified as Schizophyllum commune through the morphological and molecular identification. On the base, we found the infection of the endophyte were obviously observed widely in the P. ginseng and the strain formed a stable relationship with P. ginseng hairy roots in parenchyma cells around through tissues embedding slicing, HE ammonium silver staining and immunofluorescence staining. On the other hand, elicitors of fungus 3R-2 can also significantly promote hairy root growth and contents of several ginsenosides, even several times higher than 3R-2 mycelium did. Moreover, S. commune 3R-2 mycelium and its elicitor could enhance the transcriptional activity of key genes during the ginsenosides biosynthetic pathway dramatically. Thus, endophyte S. commune 3R-2 and its elicitor change the chemical substance content by regulating the expression of genes involved in the secondary metabolite biosynthetic pathway.

plant biology↗

bioRxiv2017

Endophyte Chaetomium globosum D38 and its elicitors promote tanshinones accumulation of Salvia miltiorrhiza

Due to the low yield of tanshinones and their analogues in Salvia miltiorrhiza, there are all kinds of stimulation strategies having been applied to improve tanshinones output in plant tissue cultures. Endophytic fungi have formed various different relationships with their host plants withstanding host and environmental factors, including symbiotic, mutualistic, commensalistic, and parasitic. Thus we take the assumption that endophytic fungi may be an emerging microbial tool used to promote secondary metabolism, which will promote the production of active compounds through endophyte-based biology method. Our study therefore aimed to examine the effects of live endophytic fungus Chaetomium globosum D38 and its elicitors on the accumulation of tanshinones in hairy root cultures of Salvia miltiorrhiza. C. globosum D38 mainly colonized in the intercellular gap of xylem parenchyma cells of S. miltiorrhiza hairy root, during long term co-existence without any toxicity against S. miltiorrhiza hairy root. Moreover, both of the live fungus and its mycelia extracts could induce the production of tanshinones, in special dihydrotanshinone I and cryptotanshinone. The effects of mycelia extracts were much stronger than that of the live fungus on tanshinones synthesis, which increased the transcriptional activity of genes with repect to tanshinone biosynthetic pathway obviously. Our results indicated that both of the live C. globosum D38 and its mycelia extracts could be utilized for tanshinones accumulation in S. miltiorrhiza hairy root. Whats more, D38 also could be made into biotic fertilizer applying into S.miltiorrhiza seddlings, which not only promoted host growth but the tanshinones and phenylpropionic acid accumulation. In the soil environment, D38 had formed bitrophic and mutual beneficial relationship with the host and enhanced the primary metabolism on the whole so as to have facilitative effects on phenylpropionic acid accumulation. To sum up, Chaetomium globosum D38 was a highly effective endophytic fungus for S. miltiorrhiza.

developmental biology↗