The heterogeneity of cellular metabolism in the tumour microenvironment of hepatocellular carcinoma with portal vein tumour thrombus.

Given the growing interest in the metabolic heterogeneity of hepatocellular carcinoma (HCC) and portal vein tumour thrombus (PVTT). This study comprehensively analysed the metabolic heterogeneity of HCC, PVTT, and normal liver samples using multi-omics combinations. A single-cell RNA sequencing dataset encompassing six major cell types was obtained for integrated analysis. The optimal subtypes were identified using cluster stratification and validated using spatial transcriptomics and fluorescent multiplex immunohistochemistry. Then, a combined index based meta-cluster was calculated to verify its prognostic significance using multi-omics data from public cohorts. Our study first depicted the metabolic heterogeneity landscape of non-malignant cells in HCC and PVTT at multiomics levels. The optimal subtypes interpret the metabolic characteristics of PVTT formation and development. The combined index provided effective predictions of prognosis and immunotherapy responses. Patients with a higher combined index had a relatively poor prognosis (p <0.001). We also found metabolism of polyamines was a key metabolic pathway involved in conversion of metabolic heterogeneity in HCC and PVTT, and identified ODC1 was significantly higher expressed in PVTT compared to normal tissue (p =0.03). Our findings revealed both consistency and heterogeneity in the metabolism of non-malignant cells in HCC and PVTT. The risk stratification based on cancer-associated fibroblasts and myeloid cells conduce to predict prognosis and guide treatment. This offers new directions for understanding disease development and immunotherapy responses.

LDLR is an entry receptor for Crimean-Congo hemorrhagic fever virus.

Crimean-Congo hemorrhagic fever virus (CCHFV) is the most widespread tick-born zoonotic bunyavirus that causes severe hemorrhagic fever and death in humans. CCHFV enters the cell via clathrin-mediated endocytosis which is dependent on its surface glycoproteins. However, the cellular receptors that are required for CCHFV entry are unknown. Here we show that the low density lipoprotein receptor (LDLR) is an entry receptor for CCHFV. Genetic knockout of LDLR impairs viral infection in various CCHFV-susceptible human, monkey and mouse cells, which is restored upon reconstitution with ectopically-expressed LDLR. Mutagenesis studies indicate that the ligand binding domain (LBD) of LDLR is necessary for CCHFV infection. LDLR binds directly to CCHFV glycoprotein Gc with high affinity, which supports virus attachment and internalization into host cells. Consistently, a soluble sLDLR-Fc fusion protein or anti-LDLR blocking antibodies impair CCHFV infection into various susceptible cells. Furthermore, genetic knockout of LDLR or administration of an LDLR blocking antibody significantly reduces viral loads, pathological effects and death following CCHFV infection in mice. Our findings suggest that LDLR is an entry receptor for CCHFV and pharmacological targeting of LDLR may provide a strategy to prevent and treat Crimean-Congo hemorrhagic fever.

Analysis of functional and pathway association of differential co-expressed genes: a case study in drug addiction.

Drug addiction has been considered as a kind of chronic relapsing brain disease influenced by both genetic and environmental factors. At present, many causative genes and pathways related to diverse kinds of drug addiction have been discovered, while less attention has been paid to common mechanisms shared by different drugs underlying addiction. By applying a co-expression meta-analysis method to mRNA expression profiles of alcohol, cocaine, heroin addicted and normal samples, we identified significant gene co-expression pairs. As co-expression networks of drug group and control group constructed, associated function term pairs and pathway pairs reflected by co-expression pattern changes were discovered by integrating functional and pathway information respectively. The results indicated that respiratory electron transport chain, synaptic transmission, mitochondrial electron transport, signal transduction, locomotory behavior, response to amphetamine, negative regulation of cell migration, glucose regulation of insulin secretion, signaling by NGF, diabetes pathways, integration of energy metabolism, dopamine receptors may play an important role in drug addiction. In addition, the results can provide theory support for studies of addiction mechanisms.

Mex3B inhibits DC-STAMP mRNA level and osteoclastogenesis.

Bone homeostasis is maintained through continuous remodeling by osteoclast-driven bone resorption and osteoblast-mediated bone formation. Osteoclasts are multinucleated giant cells (MNCs) differentiated from myeloid progenitors of the monocytic lineage. During osteoclast maturation, DC-STAMP (dendritic cell specific transmembrane protein) has been shown as a master determinant of osteoclast cell fusion. In this study, we demonstrate that Mex3B inhibits osteoclast fusion protein DCSTAMP expression and osteoclastogenesis. During differentiation of osteoclasts, the expression of Mex3B is down-regulated by cytokines such as RANKL and TNFa, resulting in relief of Mex3B-mediated down-regulation of DC-STAMP mRNA level. Our findings not only reveal critical mechanisms on regulation of DC-STAMP-mediated osteoclastogenesis, but also point to Mex3B as a potential therapeutic target for the treatment of human bone diseases.

[Molecular basic of interaction between disease resistance gene and avirulence gene].

Plant-pathogen interaction is the more important phytopathological subjects. Landmark progress in the past 10 years have resulted in the identification of functional R genes from the host and Avr genes from the pathogen,additionally interaction between their encoded productions. This paper reviewed the two models of R-Avr interaction, namely "receptor-ligand model" and "guard model", and discussed how to utilize the R gene during crop breeding and commercial production.

[Genetic analysis and molecular markers of a novel stripe rust resistance gene YrHua in wheat originated from Psathyrostachys huashanica Keng].

The H9020-17-5,a common wheat-Psathyrostachys huashanica Keng translocation line, possesses excellent resistance to wheat stripe rust. Genetic analysis of F2 and BC1 populations derived from H9020-17-5 x Mingxian169 indicated that resistance to stripe rust in H9020-17-5 was a dominant character controlling by single gene originated from Ps. huashanica. This resistance gene originated from Ps. huashanica was first reported in the present study and named as YrHua. In order to map the resistance gene YrHua, AFLP approach was employed to analyze the 119 individuals of H9020-17-5 x Mingxian169 F2 population which were inoculated by stripe rust isolate CY30. As a result,two markers, PM14(301) and PM42(249) were found to be linked to the resistance gene YrHua,and the genetic distances between the markers and target gene were 5.4 cM and 2.7 cM, respectively. For the convenience of marker-assisted selection in wheat breeding, one of the two AFLP markers was converted to PCR marker using a pair of special primers based on the DNA sequence of PM14 (301) and the polymorphism of restriction site. Our research results provided a useful tool for marker-assisted selection and laid a foundation of fine mapping and map based cloning of YrHua gene.