Biomedical subjects

Tong Zhu

Publications and source records attributed to Tong Zhu.

At least 37 records · Page 2Linked to original sources

PubMed2005

Amelioration of laminin-alpha2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin.

Congenital muscular dystrophy (CMD) is characterized by severe muscle wasting, premature death in early childhood, and lack of effective treatment. Most of the CMD cases are caused by genetic mutations of laminin-alpha2, which is essential for the structural integrity of muscle extracellular matrix. Here, we report that somatic gene delivery of a structurally unrelated protein, a miniature version of agrin, functionally compensates for laminin-alpha2 deficiency in the murine models of CMD. Adeno-associated virus-mediated overexpression of miniagrin restored the structural integrity of myofiber basal lamina, inhibited interstitial fibrosis, and ameliorated dystrophic pathology. Furthermore, systemic gene delivery of miniagrin into multiple vital muscles significantly improved whole body growth and motility and quadrupled the lifespan (50% survival) of the dystrophic mice. Thus, our study demonstrated the efficacy of somatic gene therapy in a mouse model of CMD.

Agrin↗

PubMed2005

Phytochrome control of the Arabidopsis transcriptome anticipates seedling exposure to light.

Phytochromes mediate a profound developmental shift when dark-grown seedlings are exposed to light. Here, we show that a subset of genes is upregulated in phytochrome B (phyB) mutants even before dark-grown Arabidopsis thaliana seedlings are exposed to light. Most of these genes bear the RY cis motif, which is a binding site of the transcription factor ABSCISIC ACID INSENSITIVE3 (ABI3), and the phyB mutation also enhances ABI3 expression. These changes in transcriptome have physiological consequences, because seedlings of the abi3 mutant showed enhanced responses to pulses of far-red light, whereas ABI3 overexpressers exhibited the opposite pattern. Seedlings of the wild type derived from seeds germinated in full darkness showed enhanced expression of genes bearing the RY cis motif and reduced responses to far-red light. We propose that, via changes in ABI3 expression, light, perceived mainly by phyB in the seed, generates a downstream transdevelopmental phase signal that preconditions the seedling to its most likely environment.

Arabidopsis↗

PubMed2005

A gibberellin-regulated calcineurin B in rice localizes to the tonoplast and is implicated in vacuole function.

Many developmental and environmental signals are transduced through changes in intracellular calcium concentrations, yet only a few calcium-binding proteins have been identified in plants. Calcineurin B-like (CBL) proteins are calcium-binding proteins that are thought to function as plant signal transduction elements. RNA profiling using a rice (Oryza sativa cv Nipponbare) oligonucleotide microarray was used to monitor gene expression in de-embryonated rice grains. This analysis showed that a putative rice CBL gene responded to gibberellic acid, but not abscisic acid, treatment. The CBL gene family in rice contains at least 10 genes and these have extensive similarity to the CBLs of Arabidopsis (Arabidopsis thaliana). In yeast (Saccharomyces cerevisiae) two-hybrid assays, rice CBLs interact with the kinase partners of Arabidopsis CBLs. Only one rice CBL gene, OsCBL2, is up-regulated by GA in the aleurone layer. A homolog with 91% sequence identity to OsCBL2 was cloned from barley (Hordeum vulgare cv Himalaya), and designated HvCBL2. We examined the localization and function of OsCBL2 and HvCBL2 in rice and barley aleurone because changes in cytosolic calcium have been implicated in the response of the aleurone cell to GA. Green fluorescent protein translational fusions of OsCBL2 and OsCBL3 were localized to the tonoplast of aleurone cell protein storage vacuoles and OsCBL4-green fluorescent protein was localized to the plasma membrane. Data from experiments using antisense expression of OsCBL2 and HvCBL2 are consistent with a role for OsCBL2 in promoting vacuolation of barley aleurone cells following treatment with GA.

Amino Acid Sequence↗

PubMed2005

A novel simultaneous modeling approach to estimate linearity of pharmacokinetic parameters, including saturation of intestinal efflux, in the rat.

INTRODUCTION: Various independent methods exist for the estimation of linearity of pharmacokinetic parameters in vivo. A novel simultaneous modeling approach has been developed in the rat that in combination allows estimation of the rate and extent of duodenal absorption, hepatic first pass extraction and saturation of potential dose-dependent duodenal bioavailability (saturation of intestinal efflux). METHODS: Simultaneous modeling of plasma concentrations of a Pfizer compound in the rat were conducted using NONMEM after (1) accelerated intravenous, intraduodenal, and intraportal infusions over 5 h and (2) 5-min intravenous infusions of 0.28 and 1.4 mg doses. RESULTS: The data was best described by a two-compartment linear pharmacokinetic model with good agreement between observed and model predicted plasma concentrations following the various routes of administration. Clearance was estimated to be linear up to plasma concentrations of 1200 ng/ml. The estimated rate constants (+/-asymptotic errors) for intraduodenal absorption (KA), movement of drug from plasma to tissue (K23) and movement of drug from tissue to plasma (K32) were 0.645+/-0.107, 18.0+/-2.98, and 2.02+/-0.209 h(-1), respectively. The rate constants for drug elimination from the central compartment (K20) after 5-min intravenous infusion or accelerated infusion were 3.24+/-0.6 or 6.26+/-1.64 h(-1). The estimated maximal extent of first pass extraction was 17%. The model (including increasing duodenal bioavailability as the amount in the duodenum increases, from a minimum of 5% to a maximum estimated intraportal bioavailability value-83%) indicated a saturable intestinal efflux process. DISCUSSION: This novel study design and the proposed method for data analysis provides a robust and efficient means for assessing the linearity of multiple pharmacokinetic processes while accounting for the multi-compartmental distribution characteristics of the test compound.

Animals↗

PubMed2005

Contribution of dicofol to the current DDT pollution in China.

High DDT concentrations and o,p'-DDT/p,p'-DDT ratios observed in the air over Taihu Lake, a lake near Shanghai, China, led us to suggest that current use of dicofol in the area north of the lake was the main source of the measured DDTs. To examine this hypothesis, samples of commercially available formulated dicofol in China were collected in 2003 to measure the impurities of DDT related compounds (DDTs). The o,p'-DDT/p,p'-DDT ratio in the samples was 7.0, close to the observed value in the air over Taihu Lake. Average contents of o,p'-DDT, p,p'-CI-DDT, o,p'-DDE, and p,p'-DDT in the samples were 114, 69, 44, and 17 g per kg dicofol, respectively. On the basis of a production and distribution survey, total input of DDTs to the environment from the dicofol use in China was estimated to be 8770 t between 1988 and 2002. "Dicofol type DDT pollution", defined as DDT pollution caused by dicofol use and characterized with high o,p'-DDT/p,p'-DDT ratio, might be serious in China, especially in southern and eastern China. The conversion of p,p'-CI-DDT to p,p'-DDE can lead to high p,p'-DDE/p,p'-DDT ratio and could mislead the evaluation of p,p'-DDT resident time in the environment. Therefore, more studies on p,p'-CI-DDT in the environment are needed.

Air Pollutants↗

PubMed2005

Comparative transcriptomics of rice reveals an ancient pattern of response to microbial colonization.

Glomalean fungi induce and colonize symbiotic tissue called arbuscular mycorrhiza on the roots of most land plants. Other fungi also colonize plants but cause disease not symbiosis. Whole-transcriptome analysis using a custom-designed Affymetrix Gene-Chip and confirmation with real-time RT-PCR revealed 224 genes affected during arbuscular mycorrhizal symbiosis. We compared these transcription profiles with those from rice roots that were colonized by pathogens (Magnaporthe grisea and Fusarium moniliforme). Over 40% of genes showed differential regulation caused by both the symbiotic and at least one of the pathogenic interactions. A set of genes was similarly expressed in all three associations, revealing a conserved response to fungal colonization. The responses that were shared between pathogen and symbiont infection may play a role in compatibility. Likewise, the responses that are different may cause disease. Some of the genes that respond to mycorrhizal colonization may be involved in the uptake of phosphate. Indeed, phosphate addition mimicked the effect of mycorrhiza on 8% of the tested genes. We found that 34% of the mycorrhiza-associated rice genes were also associated with mycorrhiza in dicots, revealing a conserved pattern of response between the two angiosperm classes.

DNA, Complementary↗

PubMed2005

Discovery of a potent and selective inhibitor of cyclin-dependent kinase 4/6.

A pharmacological approach to inhibition of cyclin-dependent kinases 4 and 6 (Cdk4/6) using highly selective small molecule inhibitors has the potential to provide novel cancer therapies for clinical use. Achieving high levels of selectivity for Cdk4/6, versus other ATP-dependent kinases, presents a significant challenge. The pyrido[2,3-d]pyrimidin-7-one template provides an effective platform for the inhibition of a broad cross-section of kinases, including Cdks. It is now demonstrated that the modification of pyrido[2,3-d]pyrimidin-7-ones to include a 2-aminopyridine side chain at the C2-position provides inhibitors with exquisite selectivity for Cdk4/6 in vitro. This selectivity profile is recapitulated in cells where the most selective inhibitors create a G(1) block at concentrations up to 100-fold the IC(50) for cell proliferation. On the basis of its selectivity profile and pharmacokinetic profile, compound 43 (PD 0332991) was identified as a drug candidate for the treatment of cancer.

Animals↗

PubMed2005

Contribution of transcriptional regulation to natural variations in Arabidopsis.

BACKGROUND: Genetic control of gene transcription is a key component in genome evolution. To understand the transcriptional basis of natural variation, we have studied genome-wide variations in transcription and characterized the genetic variations in regulatory elements among Arabidopsis accessions. RESULTS: Among five accessions (Col-0, C24, Ler, WS-2, and NO-0) 7,508 probe sets with no detectable genomic sequence variations were identified on the basis of the comparative genomic hybridization to the Arabidopsis GeneChip microarray, and used for accession-specific transcriptome analysis. Two-way ANOVA analysis has identified 60 genes whose mRNA levels differed in different accession backgrounds in an organ-dependent manner. Most of these genes were involved in stress responses and late stages of plant development, such as seed development. Correlation analysis of expression patterns of these 7,508 genes between pairs of accessions identified a group of 65 highly plastic genes with distinct expression patterns in each accession. CONCLUSION: Genes that show substantial genetic variation in mRNA level are those with functions in signal transduction, transcription and stress response, suggesting the existence of variations in the regulatory mechanisms for these genes among different accessions. This is in contrast to those genes with significant polymorphisms in the coding regions identified by genomic hybridization, which include genes encoding transposon-related proteins, kinases and disease-resistance proteins. While relatively fewer sequence variations were detected on average in the coding regions of these genes, a number of differences were identified from the upstream regions, several of which alter potential cis-regulatory elements. Our results suggest that nucleotide polymorphisms in regulatory elements of genes encoding controlling factors could be primary targets of natural selection and a driving force behind the evolution of Arabidopsis accessions.

Arabidopsis↗

PubMed2005

Adeno-associated virus serotype 8 efficiently delivers genes to muscle and heart.

Systemic gene delivery into muscle has been a major challenge for muscular dystrophy gene therapy, with capillary blood vessels posing the principle barrier and limiting vector dissemination. Previous efforts to deliver genes into multiple muscles have relied on isolated vessel perfusion or pharmacological interventions to enforce broad vector distribution. We compared the efficiency of multiple adeno-associated virus (AAV) vectors after a single injection via intraperitoneal or intravenous routes without additional intervention. We show that AAV8 is the most efficient vector for crossing the blood vessel barrier to attain systemic gene transfer in both skeletal and cardiac muscles of mice and hamsters. Serotypes such as AAV1 and AAV6, which demonstrate robust infection in skeletal muscle cells, were less effective in crossing the blood vessel barrier. Gene expression persisted in muscle and heart, but diminished in tissues undergoing rapid cell division, such as neonatal liver. This technology should prove useful for muscle-directed systemic gene therapy.

Animals↗

PubMed2005

Prevention and reversal of lupus in NZB/NZW mice by costimulatory blockade with adeno-associated virus-mediated gene transfer.

OBJECTIVE: To investigate the potency of costimulatory blockade with adeno-associated virus (AAV)-mediated gene transfer in the prevention and reversal of lupus in a murine model. METHODS: AAV vectors expressing CTLA-4Ig or CD40Ig were injected into NZB/NZW mice. Serum levels of transgene expression and autoantibody titers were determined by enzyme-linked immunosorbent assay. The therapeutic effects on proteinuria, renal pathologic features, and survival rate were evaluated. Splenic T cell phenotypes were analyzed by flow cytometry. The humoral immune response to a foreign antigen was also examined in treated mice. RESULTS: A single injection of AAV serotype 8 (AAV8)-CTLA-4Ig in neonatal NZB/NZW mice before the onset of lupus effectively delayed and inhibited autoantibody production, proteinuria, and kidney damage and prolonged their lifespan. In addition, coinjection of AAV8-CTLA-4Ig and AAV8-CD40Ig vectors into neonatal mice achieved a synergistic effect and the best efficacy. The preventive effects were attributed to suppression of CD4+ T cell activation and the transition from naive to memory T cells. Moreover, coinjection of these 2 vectors in adult mice reversed the existing autoantibody levels, suppressed the development of proteinuria, and prolonged their lifespan. The therapeutic effects were found to be dependent on the vector dose. In addition, AAV-mediated long-term gene expression did not severely suppress the host humoral response to foreign antigen. CONCLUSION: Our findings show that delivery of costimulatory inhibitor transgenes by AAV vectors could prevent and reverse lupus in this murine model, suggesting the potential of AAV-mediated gene transfer as an alternative treatment for lupus.

Adenoviridae↗

PubMed2005

Expression profiling reveals COI1 to be a key regulator of genes involved in wound- and methyl jasmonate-induced secondary metabolism, defence, and hormone interactions.

The Arabidopsis gene COI1 is required for jasmonic acid (JA)-induced growth inhibition, resistance to insect herbivory, and resistance to pathogens. In addition, COI1 is also required for transcription of several genes induced by wounding or by JA. Here, we use microarray gene transcription profiling of wild type and coi1 mutant plants to examine the extent of the requirement of COI1 for JA-induced and wound-induced gene transcription. We show that COI1 is required for expression of approximately 84% of 212 genes induced by JA, and for expression of approximately 44% of 153 genes induced by wounding. Surprisingly, COI1 was also required for repression of 53% of 104 genes whose expression was suppressed by JA, and for repression of approximately 46% of 83 genes whose expression was suppressed by wounding. These results indicate that COI1 plays a pivotal role in wound- and JA signalling.

Acetates↗

PubMed2005

Genetic analysis of Arabidopsis GATA transcription factor gene family reveals a nitrate-inducible member important for chlorophyll synthesis and glucose sensitivity.

The Arabidopsis GATA transcription factor family has 30 members, the biological function of most of which is poorly understood. Homozygous T-DNA insertion lines for 23 of the 30 members were identified and analyzed. Genetic screening of the insertion lines in defined growth conditions revealed one line with an altered phenotype, while the other lines showed no obvious change. This line, SALK_001778, has a T-DNA insertion in the second exon of At5g56860 which prevents the expression of the GATA domain. Genetic analysis of the mutant demonstrated that the phenotypic change is caused by a single gene effect and is recessive to the wild-type allele. In wild-type plants, the expression of At5g56860 is shoot-specific, occurs at an early stage of development and is inducible by nitrate. Loss of expression of At5g56860 in the loss-of-function mutant plants resulted in reduced chlorophyll levels. A transcript profiling experiment revealed that a considerable proportion of genes downregulated in the loss-of-function mutants are involved in carbon metabolism and At5g56860 is thus designated GNC (GATA, nitrate-inducible, carbon metabolism-involved). gnc mutants with no GNC expression are more sensitive to exogenous glucose, and two hexose transporter genes, with a possible connection to glucose signaling, are significantly downregulated, while GNC over-expressing transgenic plants upregulate their expression and are less sensitive to exogenous glucose. These observations suggest a function for GNC in regulating carbon and nitrogen metabolism.

Arabidopsis↗

PubMed2004

Expression profiling of rice segregating for drought tolerance QTLs using a rice genome array.

Plants alter their gene expression patterns in response to drought. Sometimes these transcriptional changes are successful adaptations leading to tolerance, while in other instances the plant ultimately fails to adapt to the stress and is labeled as sensitive to that condition. We measured the expression of approximately half of the genes in rice ( approximately 21,000) in phenotypically divergent accessions and their transgressive segregants to associate stress-regulated gene expression changes with quantitative trait loci (QTLs) for osmotic adjustment (OA, a trait associated with drought tolerance). Among the parental lines, a total of 662 transcripts were differentially expressed. Only 12 genes were induced in the low OA parent, CT9993, at moderate dehydration stress levels while over 200 genes were induced in the high OA parent, IR62266. The high and low OA parents had almost entirely different transcriptional responses to dehydration stress suggesting a complete absence of an appropriate response rather than a slower response in CT9993. Sixty-nine genes were up-regulated in all the high OA lines and nine of those genes were not induced in any of the low OA lines. The annotation of four of those genes, sucrose synthase, a pore protein, a heat shock and an LEA protein, suggests a role in maintaining high OA and membrane stability. Of the 3,954-probe sets that correspond to the QTL intervals, very few had a differential expression pattern between the high OA and low OA lines that suggest a role leading to the phenotypic variation. However, several promising candidates were identified for each of the five QTL including a snRNP auxiliary factor, a LEA protein, a protein phosphatase 2C and a Sar1 homolog.

Disasters↗

PubMed2004

The response regulator 2 mediates ethylene signalling and hormone signal integration in Arabidopsis.

Hormones are important regulators of plant growth and development. In Arabidopsis, perception of the phytohormones ethylene and cytokinin is accomplished by a family of sensor histidine kinases including ethylene-resistant (ETR) 1 and cytokinin-response (CRE) 1. We identified the Arabidopsis response regulator 2 (ARR2) as a signalling component functioning downstream of ETR1 in ethylene signal transduction. Analyses of loss-of-function and ARR2-overexpressing lines as well as functional assays in protoplasts indicate an important role of ARR2 in mediating ethylene responses. Additional investigations indicate that an ETR1-initiated phosphorelay regulates the transcription factor activity of ARR2. This mechanism may create a novel signal transfer from endoplasmic reticulum-associated ETR1 to the nucleus for the regulation of ethylene-response genes. Furthermore, global expression profiling revealed a complex ARR2-involving two-component network that interferes with a multitude of different signalling pathways and thereby contributes to the highly integrated signal processing machinery in higher plants.

Arabidopsis↗

PubMed2004

Gene expression signatures from three genetically separable resistance gene signaling pathways for downy mildew resistance.

Resistance gene-dependent disease resistance to pathogenic microorganisms is mediated by genetically separable regulatory pathways. Using the GeneChip Arabidopsis genome array, we compared the expression profiles of approximately 8,000 Arabidopsis genes following activation of three RPP genes directed against the pathogenic oomycete Peronospora parasitica. Judicious choice of P. parasitica isolates and loss of resistance plant mutants allowed us to compare the responses controlled by three genetically distinct resistance gene-mediated signaling pathways. We found that all three pathways can converge, leading to up-regulation of common sets of target genes. At least two temporal patterns of gene activation are triggered by two of the pathways examined. Many genes defined by their early and transient increases in expression encode proteins that execute defense biochemistry, while genes exhibiting a sustained or delayed expression increase predominantly encode putative signaling proteins. Previously defined and novel sequence motifs were found to be enriched in the promoters of genes coregulated by the local defense-signaling network. These putative promoter elements may operate downstream from signal convergence points.

Arabidopsis↗

PubMed2004

Organochlorine pesticides in the air around the Taihu Lake, China.

Organochlorine (OC) pesticides have been used broadly in China's past, yet very little is known about their atmospheric concentrations and transport. In this work, air samples were collected in the Taihu Lake Region, China, from July 23 to August 11, 2002, to measure concentrations of OC pesticides in air. The average concentrations of alpha and gamma- hexachlorocyclohexane (HCH), hexachlorobenzene (HCB), heptachlor (HEPT), alpha-endosulfan, p,p'-DDT, p,p'-DDE, p,p'-DDD, and o,p'-DDT in the air were 74 and 46, 47, 53, 307, 124, 212, 36, and 767 pg m(-3), respectively. It was interesting to note that the concentrations of p,p'-DDT, p,p'-DDE, and o,p'-DDT were all very high, even though the use of technical DDT has been banned in China since 1983. Moreover, the average concentration ratios of o,p'-DDT/p,p'-DDT and p,p'-DDE/p,p'-DDT were as high as 6.3 and 1.8. This suggested that there could be an unknown source of DDT-related compounds (DDTs), especially o,p'-DDT and p,p'-DDE. It is very likely that this unknown source was the application of dicofol, an acaricide manufactured from technical DDT and used mainly on cotton fields to treat mites in China. Backward trajectory analysis also provided consistent evidence that the high air concentrations of DDTs were related to trajectories from the area north of the Yangtze River, where cotton fields account for a significant fraction of land use.

Agriculture↗

PubMed2004

Networks of transcription factors with roles in environmental stress response.

Genome-wide transcriptome analyses have identified hundreds of genes encoding transcription factors that are induced or repressed by a range of environmental stresses. Their complex expression patterns suggest that stress tolerance and resistance are controlled at the transcriptional level by a complicated gene regulatory network. The next steps towards understanding stress biology at the systems level are reconstructing the network and then verifying the roles these transcription factors play in the network.

Algorithms↗

PubMed2004

A comparison of smoking behaviors among medical and other college students in China.

A survey of students' smoking in China (n = 1896), comparing medical students with college students in non-medical majors, was carried out to determine whether a medical education has a preventive effect on smoking uptake. The survey, sampling students from 12 universities in three cities, found no significant differences between medical and non-medical students in smoking prevalence (40.7% versus 45.1% for males, 4.4% versus 6.0% for females), in 'ever smoked' groups, in 'ever smoked 100 cigarettes' groups or in years of smoking. For both student groups, smoking prevalence increased with age and with years of college. However, one significant difference was found among the smokers: medical students were more likely to be occasional smokers than were non-medical students (75.3% occasional smokers among medical students who smoked versus 60.6% among non-medical students). These results suggest that a medical education had little effect on these students' decisions to smoke, but that it may have modified their consumption level. Future studies are needed to ascertain factors affecting the decision to smoke and to identify possible early adopters of a non-smoking culture in China. Action on a societal level is urgently needed to change Chinese social norms regarding smoking.

Adolescent↗