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Biomedical subjects

Xiaolin Wu

Publications and source records attributed to Xiaolin Wu.

33 records · Page 2Linked to original sources
PubMed2005

Large-scale molecular characterization of adeno-associated virus vector integration in mouse liver.

Recombinant adeno-associated virus (rAAV) vector holds promise for gene therapy. Despite a low frequency of chromosomal integration of vector genomes, recent studies have raised concerns about the risk of rAAV integration because integration occurs preferentially in genes and accompanies chromosomal deletions, which may lead to loss-of-function insertional mutagenesis. Here, by analyzing 347 rAAV integrations in mice, we elucidate novel features of rAAV integration: the presence of hot spots for integration and a strong preference for integrating near gene regulatory sequences. The most prominent hot spot was a harmless chromosomal niche in the rRNA gene repeats, whereas nearly half of the integrations landed near transcription start sites or CpG islands, suggesting the possibility of activating flanking cellular disease genes by vector integration, similar to retroviral gain-of-function insertional mutagenesis. Possible cancer-related genes were hit by rAAV integration at a frequency of 3.5%. In addition, the information about chromosomal changes at 218 integration sites and 602 breakpoints of vector genomes have provided a clue to how vector terminal repeats and host chromosomal DNA are joined in the integration process. Thus, the present study provides new insights into the risk of rAAV-mediated insertional mutagenesis and the mechanisms of rAAV integration.

Animals↗
PubMed2005

Weak palindromic consensus sequences are a common feature found at the integration target sites of many retroviruses.

Integration into the host genome is one of the hallmarks of the retroviral life cycle and is catalyzed by virus-encoded integrases. While integrase has strict sequence requirements for the viral DNA ends, target site sequences have been shown to be very diverse. We carefully examined a large number of integration target site sequences from several retroviruses, including human immunodeficiency virus type 1, simian immunodeficiency virus, murine leukemia virus, and avian sarcoma-leukosis virus, and found that a statistical palindromic consensus, centered on the virus-specific duplicated target site sequence, was a common feature at integration target sites for these retroviruses.

Base Sequence↗
PubMed2005

High-resolution genome-wide mapping of transposon integration in mammals.

The Sleeping Beauty (SB) transposon is an emerging tool for transgenesis, gene discovery, and therapeutic gene delivery in mammals. Here we studied 1,336 SB insertions in primary and cultured mammalian cells in order to better understand its target site preferences. We report that, although widely distributed, SB integration recurrently targets certain genomic regions and shows a small but significant bias toward genes and their upstream regulatory sequences. Compared to those of most integrating viruses, however, the regional preferences associated with SB-mediated integration were much less pronounced and were not significantly influenced by transcriptional activity. Insertions were also distinctly nonrandom with respect to intergenic sequences, including a strong bias toward microsatellite repeats, which are predominantly enriched in noncoding DNA. Although we detected a consensus sequence consistent with a twofold dyad symmetry at the target site, the most widely used sites did not match this consensus. In conjunction with an observed SB integration preference for bent DNA, these results suggest that physical properties may be the major determining factor in SB target site selection. These findings provide basic insights into the transposition process and reveal important distinctions between transposon- and virus-based integrating vectors.

Animals↗
PubMed2005

Retroviral integration sites correlate with expressed genes in hematopoietic stem cells.

In this study, we analyzed whether retroviral integration sites in repopulating hematopoietic cells correlate with genes expressed in fractions enriched in hematopoietic stem cells (HSCs). We have previously described microarray studies of two populations enriched in HSCs: CD34+/CD38- and the slow dividing fraction of CD34+/CD38- cells (SDF). Furthermore, we demonstrated that oncoretroviral integrations in severe combined immunodeficient repopulating cells are preferentially located near the transcription start. Here, we have identified 117 corresponding cDNA clones on our micro-array representing genes with retroviral integration sites. These genes revealed a higher mean signal intensity in comparison with either all genes on the array or a subset of control genes with retroviral integrations in HeLa cells. Furthermore, these genes demonstrated a higher expression in CD34+/CD38- cells and SDF. The association of gene expression and retrovirally targeted genes observed here will help to elucidate the molecular characteristics of primitive repopulating hematopoietic cells.

Animals↗
PubMed2004

Heritability and linkage analysis of sensitivity to cisplatin-induced cytotoxicity.

Little is known about the genetic determinants explaining variation in sensitivity to chemotherapeutic cytotoxicity. We characterized the degree of cisplatin sensitivity, using lymphoblastoid cell lines derived from 10 Centre d'Etude du Polymorphisme Humain pedigrees. We estimated the heritability for susceptibility to cisplatin-induced cytotoxicity to be approximately 0.47; therefore, sensitivity to the cytotoxic effects of cisplatin is under appreciable genetic influence. Linkage analysis was performed, and the strongest signal (lod score, 2.16; empirical P = 0.0005) was found on chromosome 1 at 44 cM. Susceptibility to cisplatin-induced cytotoxicity is likely due to multiple loci, with low locus-specific heritability contributing to the trait. These data show the power of using large pedigrees that have been extensively genotyped for evaluating the genetic contribution to sensitivity to cell growth inhibition by anticancer agents.

Antineoplastic Agents↗
PubMed2004

Base-pairing systems related to TNA containing phosphoramidate linkages: synthesis of building blocks and pairing properties.

As part of a project that aims at screening TNA-related oligonucleotide systems in which threose backbone units may have some or all of their oxygen functions replaced by nitrogen, two TNA analogs containing (2'NH)- and (3'NH)-phosphoramidate groups, respectively, in place of phosphodiester groups were synthesized. They show base-pairing properties that are very similar to those of TNA itself. We also synthesized 2',3'-diamino analogs of alpha-L-threofuranosyl mononucleosides, yet attempts to convert them to TNA analogs containing phosphodiamidate linker groups were not successful. Such 2',3'-diamino derivatives of threofuranosyl nucleosides may be of interest, however, as building blocks of TNA analogs that contain non-phosphorous linker groups.

Amides↗
PubMed2004

Determination and analysis of single nucleotide polymorphisms and haplotype structure of the human carboxylesterase 2 gene.

Carboxylesterases are members of the serine esterase super family important in the metabolism of a wide variety of substrates, including xenobiotics and prodrugs. There are two known carboxylesterases expressed in human liver, small intestine and other tissues, carboxylesterase 1 (CES1) and carboxylesterase 2 (CES2). The aim of this study was to identify polymorphisms in the CES2 gene and determine whether these polymorphisms affect expression levels of CES2 or rate of metabolism of irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin). Microsome samples prepared from liver tissues of 78 normal individuals were used to determine the rate of hydrolysis of irinotecan and procaine (an anaesthetic hydrolysed by CES2 but not CES1). The rate of hydrolysis of irinotecan is highly variable among individuals, ranging from 2.7-138 pmol/mg protein/h (mean +/- SD 26.0 +/- 22.9). Fifteen single nucleotide polymorphisms (SNPs) were identified, one is in an exon, 9 are in introns, three are in the 3'-untranslated region (UTR), and two are in the 5'-flanking region. Eight of the 15 SNP loci have rare allele frequencies greater than 5%, of which three were greater than 20%. Genotyping of samples from the SNP Consortium demonstrated different distributions among African-Americans, Asian-Americans and European-Americans. We also analysed the haplotype structure and estimated linkage disequilibrium (LD). A SNP located in the 5'-UTR (5'-UTR-363) was found in LD with loci in intron 1 (Intron1 + 947, Intron1 + 1361, Intron1 + 1643). Haplotypes with homozygous rare alleles on these loci exhibit lower mRNA levels as determined by real time polymerase chain reaction (P < 0.01) and the incorporation of rare alleles in haplotypes correlate with reduced mRNA (P = 0.03). The 5'-UTR-363 SNP is located in one of the three promoters of CES2. However, we did not observe significant differences in CES2 activities (irinotecan and procaine hydrolysis) among individuals with different haplotypes.

3' Untranslated Regions↗
PubMed2004

Optimal context quantization in lossless compression of image data sequences.

In image compression context-based entropy coding is commonly used. A critical issue to the performance of context-based image coding is how to resolve the conflict of a desire for large templates to model high-order statistic dependency of the pixels and the problem of context dilution due to insufficient sample statistics of a given input image. We consider the problem of finding the optimal quantizer Q that quantizes the K-dimensional causal context Ct = (Xt-t1,Xt-t2,...,X t-tK) of a source symbol Xt into one of a set of conditioning states. The optimality of context quantization is defined to be the minimum static or minimum adaptive code length of given a data set. For a binary source alphabet an optimal context quantizer can be computed exactly by a fast dynamic programming algorithm. Faster approximation solutions are also proposed. In case of m-ary source alphabet a random variable can be decomposed into a sequence of binary decisions, each of which is coded using optimal context quantization designed for the corresponding binary random variable. This optimized coding scheme is applied to digital maps and alpha-plane sequences. The proposed optimal context quantization technique can also be used to establish a lower bound on the achievable code length, and hence is a useful tool to evaluate the performance of existing heuristic context quantizers.

Algorithms↗
PubMed2004

Primary-consistent soft-decision color demosaicking for digital cameras (patent pending).

Color mosaic sampling schemes are widely used in digital cameras. Given the resolution of CCD sensor arrays, the image quality of digital cameras using mosaic sampling largely depends on the performance of the color demosaicking process. A common problem with existing color demosaicking algorithms is an inconsistency of sample interpolations in different primary color channels, which is the cause of the most objectionable color artifacts. To cure the problem, we propose a new primary-consistent soft-decision framework (PCSD) of color demosaicking. In the PCSD framework, we make multiple estimates of a missing color sample under different hypotheses on edge or texture directions. The estimates are made via a primary consistent interpolation, meaning that all three primary components of a color are interpolated in the same direction. The final estimate of a color sample is obtained by testing different interpolation hypotheses in the reconstructed full-resolution color image and selecting the best via an optimal statistical decision or inference process. A concrete color demosaicking method of the PCSD framework is presented. This new method eliminates certain types of color artifacts of existing color demosaicking methods. Extensive experimental results demonstrate that the PCSD approach can significantly improve the image quality of digital cameras in both subjective and objective measures. In some instances, our gain over the competing methods can be as much as 7 dB.

Algorithms↗
PubMed2003

Transcription start regions in the human genome are favored targets for MLV integration.

Factors contributing to retroviral integration have been intractable because past studies have not precisely located genomic sites of proviruses in sufficient numbers for significant analysis. In this study, 903 murine leukemia virus (MLV) and 379 human immunodeficiency virus-1 (HIV-1) integrations in the human genome were mapped. The data showed that MLV preferred integration near the start of transcriptional units (either upstream or downstream) whereas HIV-1 preferred integration anywhere in the transcriptional unit but not upstream of the transcriptional start. Defining different integration site preferences for retroviruses will have important ramifications for gene therapy and may aid in our understanding of the factors directing the integration process.

Child↗
PubMed2003

Lossy-to-lossless compression of medical volumetric data using three-dimensional integer wavelet transforms.

We study lossy-to-lossless compression of medical volumetric data using three-dimensional (3-D) integer wavelet transforms. To achieve good lossy coding performance, it is important to have transforms that are unitary. In addition to the lifting approach, we first introduce a general 3-D integer wavelet packet transform structure that allows implicit bit shifting of wavelet coefficients to approximate a 3-D unitary transformation. We then focus on context modeling for efficient arithmetic coding of wavelet coefficients. Two state-of-the-art 3-D wavelet video coding techniques, namely, 3-D set partitioning in hierarchical trees (Kim et al., 2000) and 3-D embedded subband coding with optimal truncation (Xu et al., 2001), are modified and applied to compression of medical volumetric data, achieving the best performance published so far in the literature-both in terms of lossy and lossless compression.

Algorithms↗
PubMed2002

Protein phosphatase type 1 regulates ion homeostasis in Saccharomyces cerevisiae.

Protein phosphatase type 1 (PP1) is encoded by the essential gene GLC7 in Saccharomyces cerevisiae. glc7-109 (K259A, R260A) has a dominant, hyperglycogen defect and a recessive, ion and drug sensitivity. Surprisingly, the hyperglycogen phenotype is partially retained in null mutants of GAC1, GIP2, and PIG1, which encode potential glycogen-targeting subunits of Glc7. The R260A substitution in GLC7 is responsible for the dominant and recessive traits of glc7-109. Another mutation at this residue, glc7-R260P, confers only salt sensitivity, indicating that the glycogen and salt traits of glc7-109 are due to defects in distinct physiological pathways. The glc7-109 mutant is sensitive to cations, aminoglycosides, and alkaline pH and exhibits increased rates of l-leucine and 3,3'-dihexyloxacarbocyanine iodide uptake, but it is resistant to molar concentrations of sorbitol or KCl, indicating that it has normal osmoregulation. KCl suppresses the ion and drug sensitivities of the glc7-109 mutant. The CsCl sensitivity of this mutant is suppressed by recessive mutations in PMA1, which encodes the essential plasma membrane H(+)ATPase. Together, these results indicate that Glc7 regulates ion homeostasis by controlling ion transport and/or plasma membrane potential, a new role for Glc7 in budding yeast.

Aminoglycosides↗
PubMedDate not supplied

Joint classification and pairing of human chromosomes.

We reexamine the problems of computer-aided classification and pairing of human chromosomes, and propose to jointly optimize the solutions of these two related problems. The combined problem is formulated into one of optimal three-dimensional assignment with an objective function of maximum likelihood. This formulation poses two technical challenges: 1) estimation of the posterior probability that two chromosomes form a pair and the pair belongs to a class and 2) good heuristic algorithms to solve the three-dimensional assignment problem which is NP-hard. We present various techniques to solve these problems. We also generalize our algorithms to cases where the cell data are incomplete as often encountered in practice.

Algorithms↗