Biomedical subjects

Yong Zhao

Publications and source records attributed to Yong Zhao.

At least 19 recordsLinked to original sources

PubMed2026

Multilevel Exploration of Shared Genetic Architecture Between Primary Biliary Cholangitis and Four Autoimmune Diseases.

INTRODUCTION: Primary Biliary Cholangitis (PBC) frequently coexists with various autoimmune diseases, such as Multiple Sclerosis (MS), Psoriasis (PS), Rheumatoid Arthritis (RA), and Sjögren's Syndrome (SS). Understanding the genetic associations between these diseases is crucial for providing deeper insights into their shared pathogenic mechanisms and comorbidity patterns. METHODS: This study utilized genome-wide association study summary data of PBC and four autoimmune diseases (MS, PS, RA, and SS). A multi-stage analytical pipeline was employed to systematically investigate the genetic associations between the diseases. The analytical approach consisted of three stages: first, linkage disequilibrium score regression and high-definition likelihood methods were applied to estimate overall genetic correlations between the diseases; second, local genetic correlation analysis was conducted to pinpoint genetic signals in specific chromosomal regions; third, conditional/conjunctional false discovery rate (cond/conjFDR) algorithms were used to quantitatively assess genetic overlap and identify shared susceptibility loci. RESULTS: Genome-wide analysis revealed significant genetic associations between PBC and the four autoimmune diseases (MS, PS, RA, and SS). Regional analysis showed local genetic correlations across various chromosomal segments. cond/conjFDR analysis confirmed genetic intersections among the diseases and identified several critical genetic polymorphic loci that influence disease susceptibility. DISCUSSION: This study comprehensively delineates the shared genetic architecture underlying PBC and four autoimmune diseases through integrative analyses of multiple genome-wide approaches. The results highlight strong genetic correlations, particularly between PBC and MS, PS, RA, and SS, and identify key shared susceptibility genes, including CLEC16A, CD58, CD86, STAT4, IRF5, TYK2, and TNFAIP3, which collectively mediate immune dysregulation through autophagy, cytokine signaling, and NF-κB pathways. These findings not only extend current understanding of the molecular mechanisms driving autoimmune comorbidity but also provide potential genetic targets for future functional validation and therapeutic exploration. CONCLUSION: This study provides comprehensive genomic evidence for the genetic connections between PBC and the four autoimmune diseases (MS, PS, RA, and SS), offering valuable insights into the shared pathological mechanisms underlying their comorbidities.

Humans↗

PubMed2025

Multi-Omics insights into OsZFP252-OsGA20ox5 mediated drought tolerance in rice through stomatal and vascular regulation.

Rice growth is highly dependent on water availability, and drought stress significantly impacts its entire life cycle. However, previous studies lack systematic investigations into drought-responsive candidate genes across the full life cycle of rice. This study integrates transcriptomic and phenotypic data from two rice lines, IR64 (drought-sensitive) and DK151 (drought-tolerant), under varied environmental conditions at distinct growth stages. Using k-means clustering, 13 369 genes were categorized into 17 distinct expression patterns, revealing drought-responsive genes specifically upregulated or downregulated under drought stress. Weighted co-expression network analysis (WGCNA) further identified four gene modules strongly correlated with drought-related phenotypes, co-localizing 2859 drought-responsive genes through both approaches. Proteomics and metabolomics were supplemented at the booting stage, where phenotypic and transcriptomic differences under drought were most pronounced. Integrated omics results demonstrate gibberellin (GA) and abscisic acid (ABA) pathways play a key role during drought tolerance in rice, and 79 high-confidence drought-resistant candidate genes were prioritized from the 2859 drought-responsive genes. Among these, Gibberellin 20-oxidase 5 (OsGA20ox5) was identified as a key negative regulator of drought tolerance. Furthermore, the transcription factor zinc finger protein 252 (OsZFP252) directly binds to the OsGA20ox5 promoter, repressing its expression and enhancing ABA biosynthesis, thereby improving drought tolerance by increasing stomatal closure and expanding vascular bundle water transport capacity. Notably, the drought-tolerant haplotype 2-4 (Hap2-4) of OsGA20ox5 provides valuable insights for drought-resistant breeding.

Oryza↗

PubMed2007

Thymic epithelial progenitor cells and thymus regeneration: an update.

The thymus provides the essential microenvironment for T-cell development and maturation. Thymic epithelial cells (TECs), which are composed of thymic cortical epithelial cells (cTECs) and thymic medullary epithelial cells (mTECs), have been well documented to be critical for these tightly regulated processes. It has long been controversial whether the common progenitor cells of TECs could give rise to both cTECs and mTECs. Great progress has been made to characterize the common TEC progenitor cells in recent years. We herein discuss the sole origin paradigm with regard to TEC differentiation as well as these progenitor cells in thymus regeneration.

Animals↗

PubMed2007

A novel approach to generate host antitumor T cells: adoptive immunotherapy by T cells maturing in xenogeneic thymus.

Mouse or human T cells developing in xenogeneic porcine thymus are functional. With efficient peripheral repopulation of mouse T cells by grafting fetal pig thymus (FP THY), B6 nude mice were immunized with inactivated syngeneic melanoma, B16 cells. Splenocytes from B16-immunized FP THY-grafted B6 nude mice efficiently killed B16, but not EL4 target cells in cytotoxicity assays in vitro. Adoptive transfer of splenocytes from B16-immunizd FP THY-grafted B6 nude mice to B16-bearing B6 mice significantly prolonged recipient survival and inhibited B16 solid tumor growth when B16 cells were injected IV or SC, respectively, compared with the identical controls. Splenocytes from nonimmunized FP THY-grafted B6 nude mice failed to protect B6 mice from B16-induced mortality. The present data have demonstrated that mouse T cells maturing in xenogeneic thymus have the ability to kill syngeneic tumor cells. This study may offer a novel resource to produce host antitumor T cells for adoptive immunotherapy of tumor patients.

Animals↗

PubMed2006

A potential side effect of cyclosporin A: inhibition of CD4(+)CD25(+) regulatory T cells in mice.

BACKGROUND: CD4CD25 regulatory T (Treg) cells are essential for the induction and maintenance of immunologic self-tolerance as well as transplant tolerance. The effects of cyclosporin A (CsA), a widely used immunosuppressive agent, on CD4CD25Treg cells in mice were investigated. METHODS: Balb/c mice were injected with CsA or control solution for one month. The levels, phenotype, and function of CD4CD25Treg cells in these mice were then assayed. RESULTS: The percentages and total cell numbers of CD4CD25Treg cells in the peripheral blood and spleen were significantly reduced after the treatment with CsA. The total numbers of CD4CD25Treg cells in the thymus of CsA-treated mice were markedly reduced as compared to the control mice. However, the percentage of CD4CD25Treg cells in the thymus of CsA-treated mice was markedly enhanced. More CD4CD25Treg cells expressing high levels of CD44 and CD45RB, and less CD4CD25Treg cells expressing CD62L were observed in CsA-treated mice, compared with the control mice. CD4CD25Treg cells expressed slightly lower levels of Foxp3 in CsA-treated mice. Furthermore, CsA markedly impaired the immunosuppressive function of CD4CD25Treg cells. CONCLUSIONS: CsA significantly impaired the development and function of CD4CD25Treg cells. The present studies suggest that CsA may block the potential induction of immune tolerance and increase the susceptibility to develop autoimmune diseases while preventing graft rejection.

Animals↗

PubMed2006

Enhancement of photocurrent generation by honeycomb structures in organic thin films.

A light-emitting poly (distyryldimethylbenzene-co-triethylene glycol) rod-coil block copolymer was used to fabricate films with three-dimensionally ordered honeycomb structures by the breath-figure method. Photocurrent generation and photovoltaic performance are studied, and the dependence of photocurrent on applied electric field is investigated. Introducing the ordered porous structure significantly improves the photoelectric conversion behavior, because porous structures not only enhance the light-harvesting efficiency but also benefit charge separation and charge transfer. This phenomenon may have great prospects for enhancing the photovoltaic behavior of organic thin-film devices.

Journal Article↗

PubMed2006

Immune regulation of T lymphocyte by a newly characterized human umbilical cord blood stem cell.

Previous work identified a novel type of stem cell from human umbilical cord blood, designated cord blood-stem cells (CB-SC). To further evaluate their immune characteristics, we cocultured CB-SC with allogeneic peripheral blood lymphocytes in the presence of phytohaemagglutinin (PHA) or interleukin-2 (IL-2). Results showed that CB-SC could significantly inhibit lymphocyte proliferation and reduce tyrosine phosphorylation of STAT5 in both PHA- and IL-2-stimulated lymphocytes, along with the regulation on the phenotypes of CD4+ and CD8+ T cells. Additionally, CB-SC also suppressed the proliferation of IL-2-stimulated CD4+CD25+ regulatory T cells. Mechanism studies revealed that programmed death receptor-1 ligand 1 (PD-L1) expressed on CB-SC membrane, together with a soluble factor nitric oxide (NO) released by PHA-stimulated CB-SC, not prostaglandin E2 (PGE2) and transforming growth factor-beta1 (TGF-beta1), mainly contributed to the T cell suppression induced by CB-SC, as demonstrated by blocking experiments with a nitric oxide synthase inhibitor (Nomega-nitro-l-arginine, l-NNA) and a neutralizing antibody to PD-L1. Our findings may advance our understanding of the immunobiology of stem cells and facilitate the therapeutic application of cord blood stem cells.

CD4-CD8 Ratio↗

PubMed2006

Genome-scale protein expression and structural biology of Plasmodium falciparum and related Apicomplexan organisms.

Parasites from the protozoan phylum Apicomplexa are responsible for diseases, such as malaria, toxoplasmosis and cryptosporidiosis, all of which have significantly higher rates of mortality and morbidity in economically underdeveloped regions of the world. Advances in vaccine development and drug discovery are urgently needed to control these diseases and can be facilitated by production of purified recombinant proteins from Apicomplexan genomes and determination of their 3D structures. To date, both heterologous expression and crystallization of Apicomplexan proteins have seen only limited success. In an effort to explore the effectiveness of producing and crystallizing proteins on a genome-scale using a standardized methodology, over 400 distinct Plasmodium falciparum target genes were chosen representing different cellular classes, along with select orthologues from four other Plasmodium species as well as Cryptosporidium parvum and Toxoplasma gondii. From a total of 1008 genes from the seven genomes, 304 (30.2%) produced purified soluble proteins and 97 (9.6%) crystallized, culminating in 36 crystal structures. These results demonstrate that, contrary to previous findings, a standardized platform using Escherichia coli can be effective for genome-scale production and crystallography of Apicomplexan proteins. Predictably, orthologous proteins from different Apicomplexan genomes behaved differently in expression, purification and crystallization, although the overall success rates of Plasmodium orthologues do not differ significantly. Their differences were effectively exploited to elevate the overall productivity to levels comparable to the most successful ongoing structural genomics projects: 229 of the 468 target genes produced purified soluble protein from one or more organisms, with 80 and 32 of the purified targets, respectively, leading to crystals and ultimately structures from one or more orthologues.

Animals↗

PubMed2006

The nonopsonic allogeneic cell phagocytosis of macrophages detected by flow cytometry and two photon fluorescence microscope.

Phagocytosis, one of the apparent functions for macrophages, represents an early and crucial event in triggering host defenses against invading pathogens as well as allo- or xenogeneic rejection. Now, some methods have been used in detecting the opsonic phagocytosis of macrophages in xenogeneic settings. Efficient nonopsonic phagocytosis analysis method has not been established yet. In the present studies, allogeneic lymphocytes pre-labeled with 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE) or derived from green fluorescent protein transgeneic B6 mice (GFP-B6 mice) were co-incubated with primary murine peritoneal macrophages (PEMs) for 1-2 h or were injected into murine peritoneal cavity for 30 to 240 min. Assays by flow cytometry (FCM) and two photon laser scanning microscope (TPM) showed an efficient uptake of both allogeneic lymphocytes and xenogeneic chicken red blood cells. The continuing process of nonopsonic phagocytosis of allogeneic lymphocytes by PEMs was recorded by TPM. Furthermore, the phenotype differences of PEMs with or without phagocytosis of allogeneic cells were determined by three-color FCMs. Significantly upregulated expressions of CD11b, CD44, TLR2 and TLR4 on PEMs were observed as early as 6 h after phagocytosis of allogeneic cells. Our present data indicated that the FCM and TPM combined method is a practical approach to detect macrophage nonopsonic phagocytosis of allogeneic lymphocytes and to identify the phenotype alteration of macrophages after phagocytosis.

Animals↗

PubMed2006

Hierarchical and multi-resolution representation of protein flexibility.

MOTIVATION: Conformational rearrangements during molecular interactions are observed in a wide range of biological systems. However, computational methods that aim at simulating and predicting molecular interactions are still largely ignoring the flexible nature of biological macromolecules as the number of degrees of freedom is computationally intractable when using brute force representations. RESULTS: In this article, we present a computational data structure called the Flexibility Tree (FT) that enables a multi-resolution and hierarchical encoding of molecular flexibility. This tree-like data structure allows the encoding of relatively small, yet complex sub-spaces of a protein's conformational space. These conformational sub-spaces are parameterized by a small number of variables and can be searched efficiently using standard global search techniques. The FT structure makes it straightforward to combine and nest a wide variety of motion types such as hinge, shear, twist, screw, rotameric side chains, normal modes and essential dynamics. Moreover, the ability to assign shapes to the nodes in a FT allows the interactive manipulation of flexible protein shapes and the interactive visualization of the impact of conformational changes on the protein's overall shape. We describe the design of the FT and illustrate the construction of such trees to hierarchically combine motion information obtained from a variety of sources ranging from experiment to user intuition, and describing conformational changes at different biological scales. We show that the combination of various types of motion helps refine the encoded conformational sub-spaces to include experimentally determined structures, and we demonstrate searching these sub-spaces for specific conformations.

Algorithms↗

PubMed2006

Mps1 phosphorylation by MAP kinase is required for kinetochore localization of spindle-checkpoint proteins.

The spindle checkpoint delays anaphase onset until all chromosomes have achieved bipolar attachment to the spindle microtubules. Unattached kinetochores activate the spindle checkpoint by recruiting several spindle-checkpoint proteins, including Mps1, Mad1, Mad2, Bub1, Bub3, and BubR1 (Mad3 in yeast). In vertebrate cells, active MAP kinase (MAPK) is also enriched at unattached kinetochores and is required for the spindle checkpoint. It has been shown that the kinase activity of Mps1 is required for the spindle checkpoint and for kinetochore localization of Bub1, Bub3, Mad1, and Mad2 . We herein demonstrate that MAPK phosphorylates Mps1 at S844 in Xenopus egg extracts. Interestingly, changing S844 to unphosphorylatable alanine (S844A) has no effect on the kinase activity of Mps1, although it abolishes the checkpoint function of Mps1. Biochemical and immunofluorescence studies show that S844A mutation perturbs kinetochore localization of Mps1 and other spindle-checkpoint proteins, whereas the phosphorylation-mimicking S844D mutant restores their functions. Our studies suggest that Mps1 phosphorylation by MAPK at S844 might create a phosphoepitope that allows Mps1 to interact with kinetochores. In addition, our results indicate that active Mps1 must localize to kinetochores in order to execute its checkpoint function.

Animals↗

PubMed2006

The mortality of MOP3 deficient mice with a systemic functional failure.

MOP3 (also known as BMAL1), a master regulator of circadian rhythm, plays important roles in the regulation of cell differentiation and general physical functions. In the present studies, MOP3 deficient mice had significantly reduced body weight and showed remarkable mortality around six months of age. The levels of AST, ALT, BUN, or UREA in the blood of about four month-old MOP3(-/-) mice were significantly higher than MOP3(+/-) or MOP3(+/+) littermates. However, no apparent pathological changes in the livers, hearts, lungs or kidneys of about four month-old MOP3(-/-) mice were observed. In addition, altered levels of white blood cells, lymphocytes, and platelets in peripheral blood of MOP3(-/-)mice were detected. The results presented herein with MOP3-deficient mice offered the basic principle for the essential roles of MOP3 in keeping normal survival abilities in mice. This study may have significant clinical impacts on the consideration about the abnormality of circadian rhythms and sleeping disorders caused physical and metabolism dysfunctions as well as the mortality.

ARNTL Transcription Factors↗

PubMed2006

MOP3, a component of the molecular clock, regulates the development of B cells.

Differentiation and proliferation of haematopoietic progenitor cells occur in intimate contact with the bone marrow microenvironment which is composed of stromal cells and extracellular matrix proteins. MOP3 (also known as brain and muscle Arnt-like protein-1, BMAL1), a master regulator of circadian rhythm, plays important roles in the regulation of cell differentiation and general physical functions. In the present studies, MOP3-deficient mice had significantly reduced levels of B cells in the peripheral blood, spleen and bone marrow compared MOP3(+/-) or MOP3(+/+) littermates. Flow cytometry analysis showed the levels of pre-B cells in bone marrow of MOP3(-/-) mice were similar as that in control mice. Adoptive transfer of MOP3(-/-) bone marrow cells (BMC) to lethally irradiated BALB/c Rag2(-/-) recipients, normal T and B cell development was observed, whereas Adoptive transfer of BALB/c BMC to lethally irradiated MOP3(-/-) recipients, B-cell development was significantly impaired. These results presented herein with MOP3-deficient mice reveal the involvement of MOP3 in the development of B cells, but not other immune cells. The effect of MOP3 on the differentiation of pre-B cells to mature B cells might be mediated by the bone marrow microenvironment. This study also showed a connection between a master regular of circadian rhythm with B-cell development in mice.

ARNTL Transcription Factors↗

PubMed2006

The two simultaneously occurring processes in one immune response: the positive immune reaction and immune tolerance.

The immune response is tightly shaped by both positive and negative signals on different levels. Based on the accumulating data, we hypothesize that, both immune reaction and immune tolerance processes were potentially and simultaneously triggered after antigen challenging. The actual outcome of immune response is dependent on the sum of these two reactions. The hypothesis, if proved to be correct, will significantly improve our understanding the immunity and its related pathological effects. It will influence our choice on immunosuppressive drugs for patients with transplant grafts, autoimmune diseases. As the immunosuppressive drugs may also block the potential immune tolerance process which is beneficial to the patients. Therefore, we should try to develop novel immunosuppressive medicines that selectively inhibit immune reaction but no effects on immune tolerance for patients with allo-grafts or autoimmune diseases. On the other hand, it will impact the immunotherapy for tumors and the development of vaccines.

Humans↗

PubMed2006

Specific immune tolerance of antigen-presenting cells: Hypothesis and significance.

Antigen-presenting cells (APCs) play a crucial role in both innate and adaptive immunity. The mechanisms for APCs to distinguish self and nonself have not been uncovered. In the present manuscript, we hypothesized the balance between the activating and inhibiting receptors on APCs will control the state of APCs. In general, they keep balanced by the endogenous ligands so that APCs are in a non-activating state in the naïve bodies. However, foreign antigens or altered self cells will trigger the activating/inhibiting receptors positively or negatively, so these receptor-mediated signals into APCs will be in tendency to be unbalanced. As long as the activating signals are over the inhibiting receptors, APCs will then be activated to function. This hypothesis will help us to explain how APCs can distinguish self and nonself antigens as well as their close relationships with the occurrence of autoimmune diseases. The activated state of APCs in the early stage of autoimmune diseases may be due to imbalance of the activating/inhibiting receptors on APCs triggered by host endogenous ligands. On the other hand, the poor immunity against tumor cells in the late stage of tumor patients may be partially due to the so-called "tolerance" state of APCs in hosts. We believe that, with the proving by the coming evidences, the impacts of the present hypothesis on basic and clinical immunology would be significant.

Antigen-Presenting Cells↗

PubMed2006

Identification of stem cells from human umbilical cord blood with embryonic and hematopoietic characteristics.

We identified stem cells from the umbilical cord blood, designated cord blood-stem cells (CB-SC). CB-SC displayed important embryonic stem (ES) cell characteristics including expression of ES-cell-specific molecular markers including transcription factors OCT-4 and Nanog, along with stage-specific embryonic antigen (SSEA)-3 and SSEA-4. CB-SC also expressed hematopoietic cell antigens including CD9, CD45 and CD117, but were negative for CD34. CB-SC displayed very low immunogenicity as indicated by expression of a very low level of major histocompatibility complex (MHC) antigens and failure to stimulate the proliferation of allogeneic lymphocytes. CB-SC could give rise to cells with endothelial-like and neuronal-like characteristics in vitro, as demonstrated by expression of lineage-associated markers. Notably, CB-SC could be stimulated to differentiate into functional insulin-producing cells in vivo and eliminated hyperglycemia after transplantation into a streptozotocin-induced diabetic mouse model. These findings may have significant potential to advance stem-cell-based therapeutics.

Animals↗

PubMed2006

Greatwall kinase participates in the Cdc2 autoregulatory loop in Xenopus egg extracts.

Mutations in the Drosophila gene encoding the serine-threonine protein kinase Greatwall have previously been shown to disrupt mitotic progression. To investigate Greatwall's mitotic function, we examined its behavior in Xenopus egg extracts. Greatwall is activated during mitosis by phosphorylation; in vitro evidence indicates that maturation promoting factor (MPF) is an upstream kinase. Conversely, depletion of Greatwall from mitotic extracts rapidly lowers MPF activity due to the accumulation of inhibitory phosphorylations on Cdc2 kinase. Greatwall depletion similarly prevents cycling extracts from entering M phase. The effects of Greatwall depletion can be rescued by the addition of either wild-type (wt) Greatwall or a noninhibitable form of Cdc2 kinase. These results demonstrate that Greatwall participates in an autoregulatory loop that generates and maintains sufficiently high MPF activity levels to support mitosis.

Animals↗

PubMed2006

Toll-like receptors and graft rejection.

Innate immunity plays a role in fighting against invading microorganisms. Emerging evidence suggests that in addition to responding to pathogen-associated molecular patterns of microorganisms, Toll-like receptors (TLRs) can be activated by endogenous ligands expressed by mammalian cells. Clinical and laboratory studies have shown that TLRs may participate in organ graft rejection and transplant immune tolerance, which are briefly reviewed in the present manuscript.

Animals↗