Biomedical subjects

Jiang Zhu

Publications and source records attributed to Jiang Zhu.

At least 19 recordsLinked to original sources

PubMed2026

Methylation-Associated Differentiation Features Define Biological and Prognostic Heterogeneity in CMS4 Colorectal Cancer.

Consensus molecular subtype 4 (CMS4) colorectal cancer (CRC) is associated with an aggressive clinical course and poor survival, yet the biological basis of heterogeneity within this subtype remains incompletely understood. DNA methylation is an epigenetic mechanism involved in transcriptional regulation, cellular differentiation, and colorectal tumorigenesis. Here, we integrated single-cell RNA sequencing (scRNA-seq), bulk data, and promoter DNA methylation data to characterize CMS4-associated cancer cell states and methylation-related features. Using the scAB algorithm, we integrated scRNA-seq with bulk CMS4 data and identified CMS4-related cells distributed across multiple patients. Single-cell analyses of cell-cell communication and transcriptional regulation revealed a CMS4-related cancer cell population characterized by macrophage migration inhibitory factor (MIF)-centered intercellular communication, enhanced caudal type homeobox 1 (CDX1) and Kruppel-like factor 5 (KLF5) regulon activity, and gene modules enriched in differentiation-related pathways. CytoTRACE analysis further stratified CMS4 cancer cells into poorly and well-differentiated states, yielding 802 differentially expressed genes (DEGs). Linking these differentiation-associated DEGs with bulk expression and promoter methylation data identified 218 methylation-associated DEGs showing significant inverse methylation expression correlations, suggesting a link between differentiation-related heterogeneity and promoter methylation. Univariable Cox regression followed by LASSO regression further prioritized eight genes for construction of the methylation and differentiation-related prognostic model (MeDiff-PM). MeDiff-PM consistently stratified overall survival in the TCGA CMS4 cohort and two independent validation cohorts, with cutoff-independent continuous Cox analyses further supporting its prognostic association across cohorts. And MeDiff-PM remained prognostically significant after adjustment for available clinical variables. High MeDiff-PM risk scores were associated with activation of P53, WNT, and ubiquitin-mediated proteolysis pathways and with consistent predicted drug response differences for compounds across three CMS4 cohorts. While individual in silico knockout analysis suggested links between MeDiff-PM genes and metallothionein-related and immune-associated transcriptional responses. Collectively, these findings indicate that methylation-associated differentiation features represent a molecular dimension of intra-CMS4 heterogeneity and provide a biologically informed framework for prognostic stratification within CMS4 CRC.

Humans↗

PubMed2025

Exosomal proteomics reveals fatty acid metabolism linked to gefitinib resistance in non-small cell lung cancer.

Exosomes play a crucial role in the transmission of drug resistance in tumors. However, the mechanism of exosomes-mediated transmission in non-small cell lung cancer (NSCLC) under gefitinib treatment remains limited. In this work, we demonstrated that exosomes derived from HCC827/GR cells (drug-resistant) enhanced the survivability of HCC827 cells (drug-sensitive) under treatment with gefitinib. A total of 157 shared upregulated proteins between exosomes and their parent cells were identified in the comparison of the gefitinib-resistant groups versus the gefitinib-sensitive groups. Notably, 69 of these shared proteins are enzymes, and many of them were enriched in pathways related to fatty acid metabolism. Among these enzymes involved in fatty acid metabolism, ACC1 exhibited the highest fold change in upregulated expression in both drug-resistant groups (exosomes and cells). Moreover, the expression of ACC1 was upregulated in gefitinib-sensitive cells after uptake of exosomes from gefitinib-resistant cells. The role of ACC1 in enhancing the survival of HCC827/GR cells under gefitinib treatment was demonstrated using an inhibitor and siRNA-mediated knockdown. Specifically, the upregulated ACC1 stabilized fatty acid oxidation and reactive oxygen species levels in HCC827/GR cells, thereby maintaining cellular metabolic homeostasis. Collectively, this work reveals the transmission of drug resistance in NSCLC via exosomes that carry the ACC1 protein.

Humans↗

PubMed2007

Osteoblasts support B-lymphocyte commitment and differentiation from hematopoietic stem cells.

Early B lymphopoiesis in mammals is induced within the bone marrow (BM) microenvironment, but which cells constitute this niche is not known. Previous studies had shown that osteoblasts (OBs) support hematopoietic stem cell (HSC) proliferation and myeloid differentiation. We now find that purified primary murine OBs also support the differentiation of primitive hematopoietic stem cells through lymphoid commitment and subsequent differentiation to all stages of B-cell precursors and mature B cells. Lin(-)Sca-1(+)Rag-2(-) BM cell differentiation to B cells requires their attachment to OBs in vitro, and this developmental process is mediated via VCAM-1, SDF-1, and IL-7 signaling induced by parathyroid hormone (PTH). Addition of cytokines produced by nonosteoblastic stromal cells (c-Kit ligand, IL-6, and IL-3) shifted the cultures toward myelopoiesis. Confirming the role of OBs in B lymphopoiesis, we found that selective elimination of osteoblasts in Col2.3Delta-TK transgenic mice severely depleted pre-pro-B and pro-B cells from BM, preceding any decline in HSCs. Taken together, these results demonstrate that osteoblasts are both necessary and sufficient for murine B-cell commitment and maturation, and thereby constitute the cellular homolog of the avian bursa of Fabricius.

Animals↗

PubMed2006

Structural refinement of protein segments containing secondary structure elements: Local sampling, knowledge-based potentials, and clustering.

In this article, we present an iterative, modular optimization (IMO) protocol for the local structure refinement of protein segments containing secondary structure elements (SSEs). The protocol is based on three modules: a torsion-space local sampling algorithm, a knowledge-based potential, and a conformational clustering algorithm. Alternative methods are tested for each module in the protocol. For each segment, random initial conformations were constructed by perturbing the native dihedral angles of loops (and SSEs) of the segment to be refined while keeping the protein body fixed. Two refinement procedures based on molecular mechanics force fields - using either energy minimization or molecular dynamics - were also tested but were found to be less successful than the IMO protocol. We found that DFIRE is a particularly effective knowledge-based potential and that clustering algorithms that are biased by the DFIRE energies improve the overall results. Results were further improved by adding an energy minimization step to the conformations generated with the IMO procedure, suggesting that hybrid strategies that combine both knowledge-based and physical effective energy functions may prove to be particularly effective in future applications.

Algorithms↗

PubMed2006

Influenza Virus Database (IVDB): an integrated information resource and analysis platform for influenza virus research.

Frequent outbreaks of highly pathogenic avian influenza and the increasing data available for comparative analysis require a central database specialized in influenza viruses (IVs). We have established the Influenza Virus Database (IVDB) to integrate information and create an analysis platform for genetic, genomic, and phylogenetic studies of the virus. IVDB hosts complete genome sequences of influenza A virus generated by Beijing Institute of Genomics (BIG) and curates all other published IV sequences after expert annotation. Our Q-Filter system classifies and ranks all nucleotide sequences into seven categories according to sequence content and integrity. IVDB provides a series of tools and viewers for comparative analysis of the viral genomes, genes, genetic polymorphisms and phylogenetic relationships. A search system has been developed for users to retrieve a combination of different data types by setting search options. To facilitate analysis of global viral transmission and evolution, the IV Sequence Distribution Tool (IVDT) has been developed to display the worldwide geographic distribution of chosen viral genotypes and to couple genomic data with epidemiological data. The BLAST, multiple sequence alignment and phylogenetic analysis tools were integrated for online data analysis. Furthermore, IVDB offers instant access to pre-computed alignments and polymorphisms of IV genes and proteins, and presents the results as SNP distribution plots and minor allele distributions. IVDB is publicly available at http://influenza.genomics.org.cn.

Databases, Genetic↗

PubMed2006

Hydrogen-bonding-mediated anthranilamide homoduplexes. Increasing stability through preorganization and iterative arrangement of a simple amide binding site.

This paper describes the assembly of two new series of self-complementary duplexes by making use of amide units, the simplest assembling units of hydrogen bonding, as binding sites. All the new monomers possess a rigidified anthranilamide skeleton, which is stabilized by intramolecular hydrogen bonding. Amide units are iteratively introduced to one side of the preorganized skeletons to facilitate the formation of intermolecular hydrogen bonding. Compounds 2 and 3 bear two and three CONH(2) units, respectively, while 4, 6, and 7 are incorporated with two, three, and four AcNH units, respectively. For comparison, compound 5, which is similar to 4 but contains one AcNH and one CF(3)CONH unit, is also prepared. X-ray diffraction analysis of 2, 4, and 5 revealed homodimeric motifs in the solid state which are stabilized by two or more intermolecular hydrogen bonds. (1)H NMR investigations in CDCl(3) indicated that all the compounds form hydrogen-bonded homoduplexes. Duplexes 3.3, 6.6, and 7.7 are highly stable in CDCl(3), with a lower K(assoc) limit of 2.3 x 10(5) M(-1). The K(assoc) values of the three duplexes in more polar CDCl(3)/CD(3)CN (9:1, v/v) were determined with the (1)H NMR dilution method. The result opens the way for the development of new polymeric duplexes of well-ordered structures.

Amides↗

PubMed2006

Molecular dynamics simulations of the hydrophobin SC3 at a hydrophobic/hydrophilic interface.

Hydrophobins are small ( approximately 100 aa) proteins that have an important role in the growth and development of mycelial fungi. They are surface active and, after secretion by the fungi, self-assemble into amphipathic membranes at hydrophobic/hydrophilic interfaces, reversing the hydrophobicity of the surface. In this study, molecular dynamics simulation techniques have been used to model the process by which a specific class I hydrophobin, SC3, binds to a range of hydrophobic/hydrophilic interfaces. The structure of SC3 used in this investigation was modeled based on the crystal structure of the class II hydrophobin HFBII using the assumption that the disulfide pairings of the eight conserved cysteine residues are maintained. The proposed model for SC3 in aqueous solution is compact and globular containing primarily beta-strand and coil structures. The behavior of this model of SC3 was investigated at an air/water, an oil/water, and a hydrophobic solid/water interface. It was found that SC3 preferentially binds to the interfaces via the loop region between the third and fourth cysteine residues and that binding is associated with an increase in alpha-helix formation in qualitative agreement with experiment. Based on a combination of the available experiment data and the current simulation studies, we propose a possible model for SC3 self-assembly on a hydrophobic solid/water interface.

Amino Acid Sequence↗

PubMed2006

Detection of carcinoembryonic antigen mRNA in peritoneal washes from gastric cancer patients and its clinical significance.

AIM: To establish a more sensitive method for detection of free cancer cells in peritoneal washes from gastric cancer patients during surgery and to evaluate its clinical significance. METHODS: The carcinoembryonic antigen (CEA) mRNA levels in peritoneal washes from 65 cases of gastric cancer were detected by real-time RT-PCR. Peritoneal lavage cytology (PLC) was applied simultaneously to detection of free cancer cells.Negative controls included peritoneal washes from 5 cases of benign gastric disease and blood samples from 5 adult healthy volunteers. RESULTS: There was no CEA mRNA in peritoneal washes from benign gastric disease patients and in blood of adult healthy volunteers. The positive percentage of free cancer cells detected by real-time RT-PCR was 47.7% and only 12.3% by PLC. The positive rate of CEA mRNA was significantly related with serosa invasion between peritoneal metastasis and stage of gastric cancer. CONCLUSION: Real-time RT-PCR is a sensitive and rapid method for the detection of free cancer cells in peritoneal washes. The presence of free cancer cells in peritoneal washes is related to the pathologic stage of gastric cancer.

Adult↗

PubMed2006

Asymmetric aza-Henry reaction of N-tosyl imine.

An efficient stereoselective aza-Henry reaction of N-tosyl imine, catalyzed by the coordination of diethylzinc with a chiral semi-aza-crown ligand, with moderate to high ee (up to 83%) is reported.

Journal Article↗

PubMed2006

[Characterization and phylogenetic analysis of the cytochrome oxidase subunit I gene of mitochondrial genome from Takifugu fasciatus].

The Takifugu fasciatus mitochondrial cytochrome oxidase I gene (COI) and its associated tRNA genes were sequenced by PCR. The open reading frame of COI gene contains 1,546 bp nucleotides, encoding a putative protein of 515 amino acid residues. The pattern of codon usage of the COI gene is less biased toward A+T. The COI gene of T. fasciatus shows a high degree of homology with that from the other 14 fish species recorded in the GenBank and has 97.6% homology with Takifugu rubripes, 76.5% with Masturus lanceolatus and 75.4% with Mola mola. The phylogenetic trees show that the relationships based on the homology is consistent with the morphological and taxonomic results. Predicted secondary structures of the tRNA genes suggest that they have the classical cloverleaf structures.

Amino Acid Sequence↗

PubMed2005

Host-reactive CD8+ memory stem cells in graft-versus-host disease.

Graft-versus-host disease (GVHD) is caused by alloreactive donor T cells that trigger host tissue injury. GVHD develops over weeks or months, but how this immune response is maintained over time is unknown. In mouse models of human GVHD, we identify a new subset of postmitotic CD44(lo)CD62L(hi)CD8(+) T cells that generate and sustain all allogeneic T-cell subsets in GVHD reactions, including central memory, effector memory and effector CD8(+) T cells, while self-renewing. These cells express Sca-1, CD122 and Bcl-2, and induce GVHD upon transfer into secondary recipients. The postmitotic CD44(lo)CD62L(hi)CD8(+) T cells persist throughout the course of GVHD, are generated in the initial phase in response to alloantigens and dendritic cells and require interleukin-15. Thus, their long life, ability to self-renew and multipotentiality define these cells as candidate memory stem cells. Memory stem cells will be important targets for understanding and influencing diverse chronic immune reactions, including GVHD.

Animals↗

PubMed2005

NF-Ya activates multiple hematopoietic stem cell (HSC) regulatory genes and promotes HSC self-renewal.

Hematopoietic stem cell (HSC) self-renewal and differentiation are influenced through multiple pathways, including homeobox transcription factors, signaling through beta-catenin and Notch-1, telomerase, and p27. How these multiple pathways interact and are orchestrated is currently unknown. We now report that NF-Ya, the regulatory and DNA-binding subunit of the trimeric transcription factor NF-Y, plays a central, integrating role in several of these HSC pathways. NF-Ya is preferentially expressed in HSC-enriched bone marrow subpopulations, and NF-Ya mRNA rapidly declines with HSC differentiation. Overexpression of NF-Ya in primitive hematopoietic cells activates the transcription of multiple HOX4 paralogs, as well as Notch-1, LEF-1, and telomerase RNA. HSCs overexpressing NF-Ya are biased toward primitive hematopoiesis in vitro and show strikingly increased in vivo repopulating abilities after single or sequential bone marrow transplantation. Thus, NF-Ya is a potent cellular regulator of HSC self-renewal.

Animals↗

PubMed2005

Comparative study of generalized Born models: protein dynamics.

In this work, we compare the results of molecular dynamics simulations involving the application of three generalized Born (GB) models to 10 different proteins. The three GB models, the Still, HCT, and modified analytical generalized Born models, were implemented in the computationally efficient gromacs package. The performance of each model was assessed from the backbone rms deviation from the native structure, the number of native hydrogen bonds retained in the simulation, and the experimental and calculated radius of gyration. Analysis of variance (ANOVA) was used to analyze the results of the simulations. The rms deviation measure was found to be unable to distinguish the quality of the results obtained with the three different GB models, whereas the number of native hydrogen bonds and radius of gyration yielded a statistically meaningful discrimination among models. Our results suggest that, of the three, modified analytical generalized Born yields the best agreement between calculated and experimentally derived structures. More generally, our study highlights the need both to evaluate the effects of different variables on the results of simulations and to verify that the results of molecular dynamics simulations are statistically meaningful.

Analysis of Variance↗

PubMed2005

Alloreactive memory T cells are responsible for the persistence of graft-versus-host disease.

Graft-vs-host disease (GVHD) is caused by a donor T cell anti-host reaction that evolves over several weeks to months, suggesting a requirement for persistent alloreactive T cells. Using the C3H.SW anti-C57BL/6 (B6) mouse model of human GVHD directed against minor histocompatibility Ags, we found that donor CD8(+) T cells secreting high levels of IFN-gamma in GVHD B6 mice receiving C3H.SW naive CD8(+) T cells peaked by day 14, declined by day 28 after transplantation, and persisted thereafter, corresponding to the kinetics of a memory T cell response. Donor CD8(+) T cells recovered on day 42 after allogeneic bone marrow transplantation expressed the phenotype of CD44(high)CD122(high)CD25(low), were able to homeostatically survive in response to IL-2, IL-7, and IL-15 and rapidly proliferated upon restimulation with host dendritic cells. Both allogeneic effector memory (CD44(high)CD62L(low)) and central memory (CD44(high)CD62L(high)) CD8(+) T cells were identified in B6 mice with ongoing GVHD, with effector memory CD8(+) T cells as the dominant (>80%) population. Administration of these allogeneic memory CD8(+) T cells into secondary B6 recipients caused virulent GVHD. A similar allogeneic memory CD4(+) T cell population with the ability to mediate persistent GVHD was also identified in BALB/b mice receiving minor histocompatibility Ag-mismatched B6 T cell-replete bone marrow transplantation. These results indicate that allogeneic memory T cells are generated in vivo during GVH reactions and are able to cause GVHD, resulting in persistent host tissue injury. Thus, in vivo blockade of both alloreactive effector and memory T cell-mediated host tissue injury may prove to be valuable for GVHD prevention and treatment.

Animals↗

PubMed2005

Comparative study of generalized born models: Born radii and peptide folding.

In this study, we have implemented four analytical generalized Born (GB) models and investigated their performance in conjunction with the GROMOS96 force field. The four models include that of Still and co-workers, the HCT model of Cramer, Truhlar, and co-workers, a modified form of the AGB model of Levy and co-workers, and the GBMV2 model of Brooks and co-workers. The models were coded independently and implemented in the GROMOS software package and in TINKER. They were compared in terms of their ability to reproduce the results of Poisson-Boltzmann (PB) calculations and in their performance in the ab initio peptide folding of two peptides, one that forms a beta-hairpin in solution and one that forms an alpha-helix. In agreement with previous work, the GBMV2 model is most successful in reproducing PB results while the other models tend to underestimate the effective Born radii of buried atoms. In contrast, stochastic dynamics simulations on the folding of the two peptides, the C-terminus beta-hairpin of the B1 domain of protein G and the alanine-based alpha-helical peptide 3K(I), suggest that the simpler GB models are more effective in sampling conformational space. Indeed, the Still model used in conjunction with the GROMOS96 force field is able to fold the hairpin peptide to a native-like structure without the benefit of enhanced sampling techniques. This is due in part to the properties of the united-atom GROMOS96 force field which appears to be more flexible, and hence to sample more efficiently, than force fields such as OPLSAA. Our results suggest a general strategy which involves using different combinations of force fields and solvent models in different applications, for example, using GROMOS96 and a simple GB model in sampling and OPLSAA and a more accurate GB model in refinement. The fact that various methods have been implemented in a unified way should facilitate the testing and subsequent use of different methods to evaluate conformational free energies in different applications. Our results also bear on some general issues involved in peptide folding and structure prediction which are addressed in the Discussion.

Alanine↗

PubMed2005

[Significance of dynamic detection of WT1 expression on monitoring minimal residual disease in leukemia patients following allogeneic bone marrow transplantation].

OBJECTIVE: To investigate the significance of monitoring Wilms' tumor gene (WT1) expression level in bone marrow of leukemia patients following allogeneic bone marrow transplantation (allo-BMT). METHODS: Real-time quantitative reverse transcription polymerase chain reaction method was established for measuring WT1 and GAPDH expression levels in bone marrow cells of 15 patients with leukemia, including a total of 111 specimens during the follow-up, and in 23 non-leukemia patients by using LightCycler. Normalized WT1 expression level (WT1(N)) was determined as a ratio of WT1 to GAPDH times 10(4). RESULTS: The median expression levels of WT1(N) in 17 samples of newly diagnosed patients, 6 samples of relapsed patients, 88 samples from leukemia patient in complete remission and 23 samples of non-leukemic controls were 40.18 (5.48 to 510.27), 125.89 (34.50 to 273.95), 4.80 (0 to 56.96) and 1.47 (0 to 8.56) respectively. Nonparameter statistic analysis (Mann-Whitney U test) showed that the WT1(N) expression levels in the newly diagnosed group and relapsed group were statistically higher than in those in the complete remission group and non-leukemic controls (all P < 0.01), without significant differences between the complete remission group and control group (P = 0.692) and between the newly diagnosed group and relapsed group (P = 0.595). In general, the dynamic curves of WT1(N) levels following allo-BMT were consistent with the tendency of changes in expression levels of corresponding fusion genes for minimal residual disease (MRD) monitoring. Spearman Rho correlation analysis revealed that the correlation coefficient between the WT1(N) expression levels and BCR/ABL, AML/ETO, PML/RARalpha and MLL/AF17 fusion genes expression were 0.678 (P = 0.00), 0.677 (P = 0.00), 0.806 (P = 0.00) and 0.553 (P = 0.049) respectively. Three patients relapsed after allo-BMT and one patient relapsed before allo-BMT during the follow-up. A re-increment of WT1(N) expression level during follow-up could be detected 40 to 180 days earlier to hematological relapse. CONCLUSION: The WT1 expression level of leukemia patients following allo-BMT measured by real time RT-PCR can be a useful tool for monitoring MRD and warning the clinical relapse during follow-up.

Adolescent↗

PubMed2005

Profile of differentially expressed genes in blood vessels and blood cells of hyperlipidemia rats using suppression subtractive hybridization.

Platelets, macrophages, endothelial cells, and smooth muscle cells can all contribute to atherosclerosis. To investigate the molecular events leading to atherosclerosis involving platelets, macrophages, endothelial cells, and smooth muscle cells, we carried out suppression subtractive hybridization (SSH) to generate a profile of genes overexpressed in the aorta and blood cells in high fat diet rats. From 85 random SSH-cDNA clones, we have screened 23 clones by Northern blotting, which were scored as overexpressed in the aorta and blood cells in high fat diet rats compared to normal diet rats. Sequencing showed that the gene corresponded to the known gene in the public databases, previously shown to be overexpressed in atherosclerosis, heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), and local production was seen in vascular smooth muscle and endothelial cells by RT-PCR and Western blotting. These results show that SSH provides a very efficient means to produce a profile of differentially expressed genes in atherosclerosis. The identified gene may provide novel points of therapeutic intervention and pathophysiological mechanisms in atherosclerosis.

Animals↗

PubMed2005

[Clinical randomized comparative trial of ProMACE-CytaBOM regimen and CHOP regimen in treating non-Hodgkin's lymphoma].

BACKGROUND & OBJECTIVE: CHOP regimen is the routine modality for moderately or highly malignant non-Hodgkin's lymphoma (NHL). Previous reports show that ProMACE-CytaBOM regimen could elevate complete response rate and survival rate of patients with moderately or highly malignant NHL. This study was to compare efficacies and safeties of ProMACE-CytaBOM and CHOP regimens in treating this disease, to indicate the standard treatment for it. METHODS: A total of 146 patients with moderately or highly malignant NHL, verified by pathology or histology, were randomized into trial group (73 patients treated with ProMACE-CytaBOM regimen) and control group (73 patients treated with CHOP regimen). Survival rate was analyzed by Kaplan-Meier method. Chi-square test was performed between groups. RESULTS: The complete response rate, partial response rate, and response rate was significantly higher in ProMACE-CytaBOM group than in CHOP group (39.7% vs. 31.5%, 38.4% vs. 28.8%, and 78.1% vs. 60.3%, respectively, P < 0.05). The 1-, 3-, and 5-year survival rates were significantly higher in ProMACE-CytaBOM group than in CHOP group (89.3% vs. 82.1%, 76.2% vs. 51.4%, and 45.7% vs. 32.3%, respectively, P < 0.05). The major side effects, appeared with no differences (P > 0.05) in incidences between 2 groups, were leukopenia, thrombocytopenia, and nausea. Each group had 1 case of treatment-related death. CONCLUSIONS: The results show higher efficacy of ProMACE-CytaBOM regimen over CHOP regimen. ProMACE-CytaBOM regimen may prolong survival time of patients with moderately or highly malignant NHL.

Adolescent↗