Biomedical subjects

Jun Zhu

Publications and source records attributed to Jun Zhu.

At least 19 recordsLinked to original sources

PubMed2026

The Znf711-Phf8 complex functions as a transcriptional rheostat essential for neutrophil development.

Neutrophil differentiation is governed by a precise transcriptional and epigenetic program. Here, we identify the zinc finger protein 711 (Znf711) and its partner, the histone demethylase PHD finger protein 8 (Phf8), as essential regulators of terminal granulopoiesis. Contrary to their established role as a transcriptional activator-co-activator pair, we found that the Znf711- Phf8 complex operates through a repressive mechanism. Znf711 promotes neutrophil maturation in a DNA-binding-independent manner by sequestering Phf8. Upon loss of Znf711, Phf8 is recruited by the growth factor independent 1 transcription repressor (Gfi1aa) to the promoter of the master regulator c/ebpα, where SUMOylated Phf8 acts as a corepressor to inhibit its transcription. Furthermore, we delineate a positive feedback loop wherein C/ebpα directly activates znf711 expression, ensuring a high level of c/ebpα at the onset of differentiation. Our findings define the Znf711-Phf8 complex as a critical transcriptional rheostat in neutrophil development.

Humans↗

PubMed2025

Synergic impact mechanisms of cover crop residue on Cd and As availability and native organic carbon mineralization in Cd and As co-contaminated paddy soil.

The synergic impacts of cover crop residue on heavy metal and metalloid availability and soil organic carbon (SOC) mineralization in contaminated paddy soil and the underlying microbial mechanism remain unclear. This study investigated the availability of cadmium (Cd) and arsenic (As) and mineralization of native SOC in paddy soil treated with 0, 0.4 %, 0.8 % and 1.2 % of δ13C-labeled cover crop residue (Astragalus sinicus L.) via 90-day incubation experiments, the related functional genes and functional microbial communities were analyzed using metagenomic binning assembly. Cover crop residue with addition rate from 0.4 % to 1.2 % significantly decreased available Cd by 56 %-85 % but increased available As by 39 %-66 % compared to the control treatment. Cover crop residue resulted in a positive priming effect on native SOC mineralization but benefited SOC sequestration. Cover crop residue increased the abundance of genes encoding iron reductase (mtrABC, pilA, omcB), sulfate reductase (sir, fpr), As(V) reductase (ArsC), organic carbon hydrolases, methanogenesis, and methylotrophy. Genomes associated with Chloroflexota and Bacteroidota encoded all these key pathways, and their abundance increased with cover crop residue application. Cover crop residue decreased soil Eh, dissolved crystalline iron oxides, enriched specific microorganisms, including Chloroflexota and Bacteroidota, and then synergistically promoted the decrease in Cd availability and the increase in As availability and native SOC mineralization in the examined paddy soil. These findings provided practical and feasible guidance for achieving both safe production and carbon sequestration in contaminated paddy fields, highlighting the requirement to cautious utilization of cover crop residue in As-contaminated paddy fileds.

Soil Pollutants↗

PubMed2025

Modulating the PPARγ pathway upregulates NECTIN4 and enhances chimeric antigen receptor (CAR) T cell therapy in bladder cancer.

With the approval of the antibody-drug conjugate enfortumab vedotin (EV), NECTIN4 has emerged as a bona fide therapeutic target in urothelial carcinoma (UC). Here, we report the development of a NECTIN4-directed chimeric antigen receptor (CAR) T cell, which exhibits reactivity across cells expressing a range of endogenous NECTIN4, with enhanced activity in high expressors. We demonstrate that the PPARγ pathway, critical for luminal differentiation, transcriptionally controls NECTIN4, and that the PPARγ agonist rosiglitazone primes and augments NECTIN4 expression, thereby increasing sensitivity to NECTIN4-CAR T cell-mediated killing. NECTIN4-CAR T cells have potent anti-tumor activity even against EV resistant cells, which largely retain NECTIN4 expression, including in a post-EV biopsy cohort. Our results elucidate a therapeutically actionable mechanism that UC cells use to control NECTIN4 expression and suggest therapeutic approaches that leverage PPARγ agonists for rational combinations with NECTIN4-targeting agents in UC, as well as future potential treatment options for EV-refractory patients.

Humans↗

PubMed2023

Ypel5 regulates liver development and function in zebrafish.

YPEL5 is a member of the Yippee-like (YPEL) gene family that is evolutionarily conserved in eukaryotic species. To date, the physiological function of YPEL5 has not been assessed due to a paucity of genetic animal models. Here, using CRISPR/Cas9-mediated genome editing, we generated a stable ypel5-/- mutant zebrafish line. Disruption of ypel5 expression leads to liver enlargement associated with hepatic cell proliferation. Meanwhile, hepatic metabolism and function are dysregulated in ypel5-/- mutant zebrafish, as revealed by metabolomic and transcriptomic analyses. Mechanistically, Hnf4a is identified as a crucial downstream mediator that is positively regulated by Ypel5. Zebrafish hnf4a overexpression could largely rescue ypel5 deficiency-induced hepatic defects. Furthermore, PPARα signaling mediates the regulation of Hnf4a by Ypel5 through directly binding to the transcriptional enhancer of the Hnf4a gene. Herein, this work demonstrates an essential role of Ypel5 in hepatocyte proliferation and function and provides the first in vivo evidence for a physiological role of the ypel5 gene in vertebrates.

Animals↗

PubMed2006

Screening rates and characteristics of health plan members who respond to screening reminders.

INTRODUCTION: Preventive screening is widely recognized as a key component of cost-effective, high-quality health care. Even so, national screening for cancer, diabetes, and cholesterol falls far short of U.S. Preventive Services Task Force recommendations. Although evidence has shown that reminder programs improve preventive screening rates, this study is one of the first to examine the characteristics of health plan members who respond to screening reminders. METHODS: The study sample included active members of a large health plan in Hawaii who were identified by an algorithm as not having received one or more recommended screenings based on age and sex criteria (2000-2003) for breast cancer (n = 44,331), cervical cancer (n = 73,875), colon cancer (n = 131,860), diabetes (n = 86,216), and cholesterol (n = 54,843). Statistical analyses were conducted using Cox proportional hazard and logistic regression models. In the proportional hazard models, reminder letters were treated as time-varying exposures. Hazard ratios, or rate ratios, were used to examine the relationship between health plan member and physician characteristics and the likelihood of responding to the reminders. The effects of additional or multiple reminders among health plan members receiving more than one reminder were examined in multivariable regression models. RESULTS: The impact of health plan member characteristics and number of office visits on the response to reminders varied among the five health-screening types. Health plan members responded better to reminders for diabetes screening than for colon cancer screening. Members sent their second annual reminders were less likely to obtain screening than members sent their first reminder. Members receiving their third (or more) annual reminder were especially recalcitrant. CONCLUSION: Our findings suggest that the response to reminders differs according to patient characteristics. In particular, targeted interventions may be needed to encourage screening for younger and healthier members whose response rate to reminders was low. Further research is needed to determine how health plans can best reach members who do not respond to patient reminders.

Aged↗

PubMed2006

Long-range polony haplotyping of individual human chromosome molecules.

We report a method for multilocus long-range haplotyping on human chromosome molecules in vitro based on the DNA polymerase colony (polony) technology. By immobilizing thousands of intact chromosome molecules within a polyacrylamide gel on a microscope slide and performing multiple amplifications from single molecules, we determined long-range haplotypes spanning a 153-Mb region of human chromosome 7 and found evidence of rare mitotic recombination events in human lymphocytes. Furthermore, the parallel nature of DNA polony technology allows efficient haplotyping on pooled DNAs from a population on one slide, with a throughput three orders of magnitudes higher than current molecular haplotyping methods. Linkage disequilibrium statistics established by our pooled DNA haplotyping method are more accurate than statistically inferred haplotypes. This haplotyping method is well suited for candidate gene-based association studies as well as for investigating the pattern of recombination in mammalian cells.

Chromosome Mapping↗

PubMed2006

Functional mapping for genetic control of programmed cell death.

"Naturally occurring" or "programmed" cell death (PCD) in which the cell uses specialized cellular machinery to kill itself is a ubiquitous phenomenon that occurs early in organ development. Such a cell suicide mechanism that enables metazoans to control cell number and eliminate cells threatening the organism's survival has been thought to be under genetic control. In this report, we develop a novel statistical model for mapping specific genes or quantitative trait loci (QTL) that are responsible for the PCD process based on polymorphic molecular markers. This model incorporates the biological mechanisms of PCD that undergoes two different developmental stages, exponential growth and polynomial death. We derived a parametric approach to model the exponential growth and a nonparametric approach based on the Legendre function to model the polynomial death. A series of stationary and nonstationary models has been used to approximate the structure of the covariance matrix among cell numbers at a multitude of different times. The statistical behavior of our model is investigated through simulation studies and validated by a real example in rice.

Apoptosis↗

PubMed2006

Identification of novel in vivo Raf-1 phosphorylation sites mediating positive feedback Raf-1 regulation by extracellular signal-regulated kinase.

The Ras-Raf-mitogen-activated protein kinase cascade is a key growth-signaling pathway, which uncontrolled activation results in transformation. Although the exact mechanisms underlying Raf-1 regulation remain incompletely understood, phosphorylation has been proposed to play a critical role in this regulation. We report here three novel epidermal growth factor-induced in vivo Raf-1 phosphorylation sites that mediate positive feedback Raf-1 regulation. Using mass spectrometry, we identified Raf-1 phosphorylation on three SP motif sites: S289/S296/S301 and confirmed their identity using two-dimensional-phosphopeptide mapping and phosphospecific antibodies. These sites were phosphorylated by extracellular signal-regulated kinase (ERK)-1 in vitro, and their phosphorylation in vivo was dependent on endogenous ERK activity. Functionally, ERK-1 expression sustains Raf-1 activation in a manner dependent on Raf-1 phosphorylation on the identified sites, and S289/296/301A substitution markedly decreases the in vivo activity of Raf-1 S259A. Importantly, the ERK-phosphorylated Raf-1 pool has 4 times higher specific kinase activity than total Raf-1, and its phosphopeptide composition is similar to that of the general Raf-1 population, suggesting that the preexisting, phosphorylated Raf-1, representing the activatable Raf-1 pool, is the Raf-1 subpopulation targeted by ERK. Our study describes the identification of new in vivo Raf-1 phosphorylation sites targeted by ERK and provides a novel mechanism for a positive feedback Raf-1 regulation.

Amino Acid Sequence↗

PubMed2006

Midline NK/T-cell lymphoma nasal-type: treatment outcome, the effect of L-asparaginase based regimen, and prognostic factors.

PURPOSE: Midline NK/T-cell lymphoma nasal-type is an aggressive neoplasm with poor prognosis in most instances. To improve the treatment outcome, we have tried using L-asparaginase based regimen as salvage regimen plus radiation in CHOP failures, and report here the therapeutic results and prognostic factors. PATIENTS AND METHODS: From March 1992 to January 2005, 46 Chinese patients with midline NK/T-cell lymphoma nasal-type were initially treated with CHOP regimen as first-line chemotherapy. The patients who failed CHOP regimens were altered to receive L-asparaginase based salvage regimen. All the patients received primary involved-field radiation after chemotherapy. RESULTS: Thirteen patients (28.3%) sensitive to CHOP regimen received CHOP regimen for 6 cycles plus locoregional radiation, and achieved complete remission (CR). Thirty-three patients failed CHOP regimen were altered to received L-asparaginase-based salvage regimen for 2 approximately 6 cycles (median 3 cycles) plus locoregional radiation, and seventeen of the 33 CHOP failures (51.5 %) (L-asparaginase group) reached CR. The CR rate for the whole group was 65.2% (30/46 cases). The 5-year overall survival (OS) rates were 64.5% for the whole group and 55.9% for L-asparaginase group, respectively. On univariate analysis, disease stage, fever symptom and performance status were significant factors influencing overall survival. On multivariate analysis, only disease stage and fever symptom remained as independently significant factors influencing OS. CONCLUSION: In this preliminary study, the results indicated that L-asparaginase based regimen might be a promising new salvage chemotherapeutic regimen in CHOP failures and conduce to improve the treatment outcome in midline NK/T-cell lymphoma, nasal-type.

Adolescent↗

PubMed2006

Impacts of QTL x environment interactions on genetic response to marker-assisted selection.

Genotype x environment (GE) interaction is a common characteristic for quantitative traits, and has been a subject of great concern for breeding programs. Simulation studies were conducted to investigate the effects of GE interaction on genetic response to marker-assisted selection (MAS). In our study we demonstrated that MAS is generally more efficient than phenotypic selection in the presence of GE interaction, and this trend is more pronounced for developing broadly adaptable varieties. The utilization of different QTL information dramatically influences MAS efficiency. When MAS is based on QTLs evaluated in a single environment, the causal QTL x environment (QE) interactions usually reduce general response across environments, and the reduction in the cumulative general response is a function of the proportion of QE interactions for the trait studied. However, MAS using QTL information evaluated in multiple environments not only yields higher general response, but the general response obtained is also reasonably robust to QE interactions. The total response achieved by MAS in a specific environment depends largely on the total heritability of traits and is slightly subject to relative changes between general heritability and GE interaction heritability. Two breeding strategies, breeding experiments conducted in one environment throughout and in two environments alternately, were also examined for the implementation of marker-based selection. It was thus concluded that plant breeders should be cautious to utilize QTL information from only one environment and execute breeding studies in another.

Breeding↗

PubMed2006

Bile acids stimulate biofilm formation in Vibrio cholerae.

Vibrio cholerae is a Gram-negative bacterium that causes the acute diarrhoeal disease cholera. After the bacterium is ingested, it passes through the digestive tract, encountering various environmental stresses including the acidic milieu of the stomach and the toxic effects of bile in the duodenum. While these stresses serve as part of a host defence system, V. cholerae has evolved resistance mechanisms that allow it to evade these defences and establish infection. We examined the expression profiles of V. cholerae in response to bile or bile acids and found an induction of biofilm genes. We found that V. cholerae shows significantly enhanced biofilm formation in response to bile acids, and that bacteria within the biofilm are more resistant to the toxicity of bile acids compared with planktonic cells. Bile acid induction of biofilms was found to be dependent on the vps genes (Vibrio polysaccharide synthesis) and their transcriptional activator VpsR, but VpsT is not required. These results contribute to the developing picture of a complex relationship between V. cholerae and its environment within the host during infection.

Bacterial Proteins↗

PubMed2006

Elucidating the murine brain transcriptional network in a segregating mouse population to identify core functional modules for obesity and diabetes.

Complex biological systems are best modeled as highly modular, fluid systems exhibiting a plasticity that allows them to adapt to a vast array of changing conditions. Here we highlight several novel network-based approaches to elucidate genetic networks underlying complex traits. These integrative genomic approaches combine large-scale genotypic and gene expression results in segregating mouse populations to reconstruct reliable genetic networks underlying complex traits such as disease or drug response. We apply these novel approaches to one of the most extensive surveys of gene expression studies ever undertaken in whole brain in a segregating mouse population. More than 23,000 genes were monitored in whole brain samples from more than 300 mice derived from an F2 intercross population and genotyped at over 1200 SNP markers uniformly spread over the entire genome. We explore the topological properties of the brain transcriptional network and highlight different approaches to inferring causal associations among genes by integrating genotypic and expression data. We demonstrate the utility of these approaches by identifying and experimentally validating brain gene expression traits predicted to respond to a strong expression quantitative trait locus (eQTL) for the pituitary tumor-transforming 1 gene (Pttg1) that coincides with the physical location of this gene (a cis eQTL). We identify core functional modules making up the brain transcriptional network in mice that are coherent for core biological processes associated with metabolic disease traits including obesity and diabetes.

Animals↗

PubMed2006

Genetic and phenotypic diversity of quorum-sensing systems in clinical and environmental isolates of Vibrio cholerae.

Vibrio cholerae is the causative agent of cholera, a severe and devastating diarrheal disease. V. cholerae lives naturally in various aquatic habitats during interepidemic periods. Recent studies reveal that quorum-sensing systems, which exist in many bacteria and help them monitor their population densities and regulate various cellular functions, control V. cholerae pathogenesis, biofilm formation, and protease production. In this study we surveyed quorum-sensing systems in 16 geographically diverse V. cholerae strains from epidemic-causing O1 and O139 strains as well as non-O1/non-O139 and environmental isolates and discovered an unexpectedly high rate of dysfunctional components. We also found that a functional quorum-sensing system conferred a survival advantage on bacteria in biofilms when the bacteria were exposed to seawater, though quorum sensing was less important to survival in a planktonic state under the same conditions. These findings suggest that variations in quorum-sensing systems are due to environmental selective pressures and might be beneficial to V. cholerae's fitness under certain conditions found in its natural reservoirs.

Amino Acid Sequence↗

PubMed2006

A LuxR/LuxI-type quorum-sensing system in a plant bacterium, Mesorhizobium tianshanense, controls symbiotic nodulation.

The ability of rhizobia to symbiotically fix nitrogen from the atmosphere when forming nodules on their plant hosts requires various signal transduction pathways. LuxR-LuxI-type quorum-sensing systems have been shown to be one of the players in a number of rhizobium species. In this study, we found that Mesorhizobium tianshanense, a moderate-growth Rhizobium that forms nodules on a number of licorice plants, produces multiple N-acyl homoserine lactone (AHL)-like molecules. A simple screen for AHL synthase genes using an M. tianshanense genomic expression library in Escherichia coli, coupled with a sensitive AHL detector, uncovered a LuxI-type synthase, MrtI, and a LuxR-type regulator, MrtR, in M. tianshanense. Deletions of the mrtI or mrtR locus completely abolished AHL production in M. tianshanense. Using lacZ transcriptional fusions, we found that expression of the quorum-sensing regulators is autoinduced, as mrtI gene expression requires MrtR and cognate AHLs and mrtR expression is dependent on AHLs. Compared with the wild-type strains, quorum-sensing-deficient mutants showed a marked reduction in the efficiency of root hair adherence and, more importantly, were defective in nodule formation on their host plant, Glycyrrhiza uralensis. These data provide strong evidence that quorum sensing plays a critical role in the M. tianshanense symbiotic process.

4-Butyrolactone↗

PubMed2006

The transcriptional regulator VqmA increases expression of the quorum-sensing activator HapR in Vibrio cholerae.

Vibrio cholerae is the causative agent of the severe diarrheal disease cholera. A number of environmental stimuli regulate virulence gene expression in V. cholerae, including quorum-sensing signals. At high cell densities, quorum sensing in V. cholerae invokes a series of signal transduction pathways in order to activate the expression of the master regulator HapR, which then represses the virulence regulon and biofilm-related genes and activates protease production. In this study, we identified a transcriptional regulator, VqmA (VCA1078), that activates hapR expression at low cell densities. Under in vitro inducing conditions, constitutive expression of VqmA represses the virulence regulon in a HapR-dependent manner. VqmA increases hapR transcription as measured by the activity of the hapR-lacZ reporter, and it increases HapR production as measured by Western blotting. Using a heterogenous luxCDABE cosmid, we found that VqmA stimulates quorum-sensing regulation at lower cell densities and that this stimulation bypasses the known LuxO-small-RNA regulatory circuits. Furthermore, we showed that VqmA regulates hapR transcription directly by binding to its promoter region and that expression of vqmA is cell density dependent and autoregulated. The physiological role of VqmA is also discussed.

Gene Expression Regulation, Bacterial↗

PubMed2006

[HLA-A, B, DRB1 gene polymorphism of Beijing population was studied by high-resolution polymerase chain reaction sequence-based typing].

OBJECTIVE: To investigate the gene polymorphism of human leukocyte antigen (HLA)-A, B, DRB1 loci in the population of Beijing region, and research on the application feasibility of polymerase chain reaction sequence-based typing (PCR-SBT) method. METHODS: PCR-SBT method was applied to determine HLA- A, B, DRB1 genotypes of 618 unrelated healthy individuals of Beijing region. RESULTS: A total of 84 different alleles and 199 genotypes of HLA-A, 143 alleles and 366 genotypes of HLA-B, 122 alleles and 286 genotypes of HLA-DRB1 were detected. CONCLUSION: The results showed the characteristics of HLA-A, B, DRB1 distributions, and provided more comprehensive and accurate gene data that may serve as normal reference values for all of Beijing people.

Asian People↗

PubMed2006

[Genetic and correlation analysis for agronomic traits in flue-cured tobacco (Nicotiana tabacum L.)].

By using a genetic model including additive and dominance effects and their interaction with environments, 7 agronomic traits were analyzed for a diallel design in 4 environmental conditions with 14 flue-cured tobacco varieties (or breeding lines) and their 41 F1 crosses. It was revealed that additive effects were the major genetic component for plant height, internode length, and width of leaves. Number of leaves and length of leaves were mainly controlled by dominance x environment interaction effects. Additive x environment interaction effects and dominance x environment interaction effects played a major role for girth of stem. Yield performance was mainly controlled by additive effects and dominance x environment interaction effects. The varieties adapted to local environments tended to have highly positive additive effects. Dominance effects and the dominance x environment interaction effects could perform differently in positive or negative direction for many crosses. The breeding program for hybrids should consider the adaptation of hybrids to specific ecological environments. The analysis of correlation among agronomic traits indicated that most of phenotypic, genotypic, additive and dominance correlation coefficients were positive. Additive correlations were predominance in genetic correlations for most pairs of traits. Yield can be improved by indirect selection on plant height.

Genotype↗

PubMed2005

A bench-scale aeration study using batch reactors on swine manure stabilization to control odour in post treatment storage.

A bench-scale study on swine manure stabilization for odour control was conducted using batch aeration reactors. In trial 1, two aeration lengths, i.e., 0.5 and 4.0 day, were used under uncontrolled ambient temperature that increased gradually over the experimental period. While in trial 2, a 16.0-day aeration scheme was employed under constant 17 degrees C. An airflow rate of 1.2L/s/m(3) was used for both trials to aerate batch reactors containing finishing pig manure with initial total solids (TS) levels ranging from 0.5 to 4.0%. Manure stabilization during the 90-day post-treatment storage was evaluated by the changes in organic materials, nitrogen and volatile fatty acids (VFA). The odour generation potential in the treated manure was determined by the changes in VFA. Up to 827 mL of liquid was lost due to aeration related foaming. The reductions in total volatile solids (TVS), 5-day biochemical oxygen demand (BOD(5)), total Kjeldahl nitrogen (TKN) and VFA during storage were improved when aeration length increased. Low solids levels offered a more advantageous circumstance for manure stabilization and odour control. Biodegradation of organic matter, removal of nitrogen, and breakdown of VFA would increase with increasing ambient temperature. VFA removals in manure under 16.0-day aeration were higher than those under 0.5- and 4.0-day aeration; however, VFA regeneration started to exceed its consumption on day 20 (4 days after the aeration treatment). BOD(5) was the best estimate of VFA concentration in the aerated manure during storage. The 4.0-day aeration scheme was sufficient to stabilize manure to effectively assuage odour generation potential during the 90-day storage under increasing ambient temperature conditions.

Animals↗