Structure and functional expression of a human interleukin-8 receptor

Interleukin-8 (IL-8) is a member of a family of pro-inflammatory cytokines. Although the best characterized activities of IL-8 include the chemoattraction and activation of neutrophils, other members of this family have a wide range of specific actions including the chemotaxis and activation of monocytes, the selective chemotaxis of memory T cells, the inhibition of hematopoietic stem cell proliferation, and the induction of neutrophil infiltration in vivo. A complementary DNA encoding the IL-8 receptor from human neutrophils has now been isolated. The amino acid sequence shows that the receptor is a member of the superfamily of receptors that couple to guanine nucleotide binding proteins (G proteins). The sequence is 29% identical to that of receptors for the other neutrophil chemoattractants, fMet-Leu-Phe and C5a. Mammalian cells transfected with the IL-8 receptor cDNA clone bind IL-8 with high affinity and respond specifically to IL-8 by transiently mobilizing calcium. The IL-8 receptor may be part of a subfamily of related G protein-coupled receptors that transduce signals for the IL-8 family of pro-inflammatory cytokines.     

Mitotic recombination within the centromere of a yeast chromosome

Centromeres are the structural elements of eukaryotic chromosomes that hold sister chromatids together and to which spindle tubules connect during cell division. Centromeres have been shown to suppress meiotic recombination in some systems. In this study yeast strains genetically marked within and flanking a centromere, were used to demonstrate that gene conversion (nonreciprocal recombination) tracts in mitosis can enter into and extend through the centromere.     

植物着丝粒的研究进展

着丝粒是许多高等真核生物染色体的重要结构域之一,它的最内层是由串联重复的卫星DNA及其侧翼富集的中度重复元件组成。在整个真核生物类群中,不同物种间着丝粒的DNA序列千差万别,但其功能却相当保守,可确保在有丝分裂和减数分裂过程中染色体的正确分离和传递。近年来,植物着丝粒的结构、功能和进化方面的研究进展较快,故对此进行了综述。     

Gene cloning: exploring cotton functional genomics and genetic improvement

Cotton is the most important natural fiber plant in the world. The genetic improvement of the quality of the cotton fiber and agricultural productivity is imperative under the situation of increasing consumption and rapid development of textile technology. Recently, the study of cotton molecular biology has progressed greatly. A lot of specifically or preferentially expressed cotton fiber genes were cloned and analyzed. On the other hand, identification of stress response genes expressed in cotton was performed by other research groups. The major stress factors were studied including the wilt pathogens Verticillium dahliae, Fusarium oxysporum f. sp. vasinfectum, bacterial blight, root-knot nematode, drought, and salt stress. What is more, a few genes related to the biosynthesis of gossypol, other sesquiterpene phytoalexins and the major seed oil fatty acids were isolated from cotton. In the present review, we focused on the major advances in cotton gene cloning and expression profiling in the recent years.     

Genomic analysis of the human B-lymphotropic virus (HBLV)

The human B-lymphotropic virus (HBLV) has a double-stranded DNA genome of greater than 110 kilobase pairs, which is consistent with its morphological classification as a herpesvirus. A 9000-base pair cloned probe of HBLV detected specific sequences in DNA and RNA of infected cells but did not hybridize to the genomic DNA of other human herpesviruses including the Epstein-Barr virus, human cytomegalovirus, herpes simplex type I, and varicella-zoster virus. Conversely, while probes obtained from each of the known human herpesvirus readily detected the homologous viral DNA, they did not hybridize to genomic HBLV DNA. This evidence, in addition to serological and morphological distinctions and the biological effects of this virus demonstrate that HBLV is a novel human herpesvirus.     

Cloning of complementary DNA encoding a functional human interleukin-8 receptor

Interleukin-8 (IL-8) is an inflammatory cytokine that activates neutrophil chemotaxis, degranulation, and the respiratory burst. Neutrophils express receptors for IL-8 that are coupled to guanine nucleotide-binding proteins (G proteins); binding of IL-8 to its receptor induces the mobilization of intracellular calcium stores. A cDNA clone from HL-60 neutrophils, designated p2, has now been isolated that encodes a human IL-8 receptor. When p2 is expressed in oocytes from Xenopus laevis, the oocytes bind 125I-labeled IL-8 specifically and respond to IL-8 by mobilizing calcium stores with an EC50 of 20 nM. This IL-8 receptor has 77% amino acid identity with a second human neutrophil receptor isotype that binds IL-8 with higher affinity. It also exhibits 69% amino acid identity with a protein reported to be an N-formyl peptide receptor from rabbit neutrophils, but less than 30% identity with all other known G protein-coupled receptors, including the human N-formyl peptide receptor.     

Genomic diversity of human T-lymphotropic virus type III (HTLV-III)

The DNA genomes of human T-lymphotropic virus type III (HTLV-III) isolated from 18 individuals with AIDS or who were at risk for AIDS were evaluated for evidence of variation. Although all of the 18 viral DNA's hybridized throughout their entire genomes to a full-length cloned probe of the original HTLV-III isolate, each of the 18 isolates showed a different restriction enzyme pattern. The number of restriction site differences between isolates ranged from only 1 site in 23 to at least 16 sites in 31. No particular viral genotype was associated with a particular disease state and 2 of the 18 patients had evidence of concurrent infection by more than one viral genotype. Propagation of three different viral isolates in vitro for up to 9 months did not lead to detectable changes in their restriction patterns. These findings indicate that different isolates of HTLV-III comprise a spectrum of highly related but distinguishable viruses and have important implications regarding the pathogenicity of HTLV-III and attempts to develop effective diagnostic, therapeutic, and preventive measures for this virus.     

A regulatory SNP causes a human genetic disease by creating a new transcriptional promoter

We describe a pathogenetic mechanism underlying a variant form of the inherited blood disorder alpha thalassemia. Association studies of affected individuals from Melanesia localized the disease trait to the telomeric region of human chromosome 16, which includes the alpha-globin gene cluster, but no molecular defects were detected by conventional approaches. After resequencing and using a combination of chromatin immunoprecipitation and expression analysis on a tiled oligonucleotide array, we identified a gain-of-function regulatory single-nucleotide polymorphism (rSNP) in a nongenic region between the alpha-globin genes and their upstream regulatory elements. The rSNP creates a new promoterlike element that interferes with normal activation of all downstream alpha-like globin genes. Thus, our work illustrates a strategy for distinguishing between neutral and functionally important rSNPs, and it also identifies a pathogenetic mechanism that could potentially underlie other genetic diseases.     

Requirement of Mis6 centromere connector for localizing a CENP-A-like protein in fission yeast

Mammalian kinetochores contain the centromere-specific histone H3 variant CENP-A, whose incorporation into limited chromosomal regions may be important for centromere function and chromosome segregation during mitosis. However, regulation of CENP-A localization and its role have not been clear. Here we report that the fission yeast homolog SpCENP-A is essential for establishing centromere chromatin associated with equal chromosome segregation. SpCENP-A binding to the nonrepetitious inner centromeres depended on Mis6, an essential centromere connector protein acting during G1-S phase of the cell cycle. Mis6 is likely required for recruiting SpCENP-A to form proper connection of sister centromeres.     

Hierarchical genetic organization of human cortical surface area

Surface area of the cerebral cortex is a highly heritable trait, yet little is known about genetic influences on regional cortical differentiation in humans. Using a data-driven, fuzzy clustering technique with magnetic resonance imaging data from 406 twins, we parceled cortical surface area into genetic subdivisions, creating a human brain atlas based solely on genetically informative data. Boundaries of the genetic divisions corresponded largely to meaningful structural and functional regions; however, the divisions represented previously undescribed phenotypes different from conventional (non-genetically based) parcellation systems. The genetic organization of cortical area was hierarchical, modular, and predominantly bilaterally symmetric across hemispheres. We also found that the results were consistent with human-specific regions being subdivisions of previously described, genetically based lobar regionalization patterns.     

Two histone marks establish the inner centromere and chromosome bi-orientation

For proper partitioning of chromosomes in mitosis, the chromosomal passenger complex (CPC) including Aurora B and survivin must be localized at the center of paired kinetochores, at the site called the inner centromere. It is largely unknown what defines the inner centromere and how the CPC is targeted to this site. Here, we show that the phosphorylation of histone H3-threonine 3 (H3-pT3) mediated by Haspin cooperates with Bub1-mediated histone 2A-serine 121 (H2A-S121) phosphorylation in targeting the CPC to the inner centromere in fission yeast and human cells. H3-pT3 promotes nucleosome binding of survivin, whereas phosphorylated H2A-S121 facilitates the binding of shugoshin, the centromeric CPC adaptor. Haspin colocalizes with cohesin by associating with Pds5, whereas Bub1 localizes at kinetochores. Thus, the inner centromere is defined by intersection of two histone kinases.     

Gene therapy for human genetic disease?

In our view, gene therapy may ameliorate some human genetic diseases in the future. For this reason, we believe that research directed at the development of techniques for gene therapy should continue. For the foreseeable future, however, we oppose any further attempts at gene therapy in human patients because (i) our understanding of such basic processes as gene regulation and genetic recombination in human cells is inadequate; (ii) our understanding of the details of the relation between the molecular defect and the disease state is rudimentary for essentially all genetic diseases; and (iii) we have no information on the short-range and long-term side effects of gene therapy. We therefore propose that a sustained effort be made to formulate a complete set of ethicoscientific criteria to guide the development and clinical application of gene therapy techniques. Such an endeavor could go a long way toward ensuring that gene therapy is used in humans only in those instances where it will prove beneficial, and toward preventing its misuse through premature application. Two recent papers have provided new demonstrations of directed genetic modification of mammalian cells. Munyon et al. (44) restored the ability to synthesize the enzyme thymidine kinase to thymidine kinase-deficient mouse cells by infection with ultraviolet-irradiated herpes simplex virus. In their experiments the DNA from herpes simplex virus, which contains a gene coding for thymidine kinase, may have formed a hereditable association with the mouse cells. Merril et al. (45) reported that treatment of fibroblasts from patients with galactosemia with exogenous DNA caused increased activity of a missing enzyme, alpha-D-galactose-l-phosphate uridyltransferase. They also provided some evidence that the change persisted after subculturing the treated cells. If this latter report can be confirmed, the feasibility of directed genetic modification of human cells would be clearly demonstrated, considerably enhancing the technical prospects for gene therapy.     

Synthesis of functional human hemoglobin in transgenic mice

Human alpha- and beta-globin genes were separately fused downstream of two erythroid-specific deoxyribonuclease (DNase) I super-hypersensitive sites that are normally located 50 kilobases upstream of the human beta-globin gene. These two constructs were coinjected into fertilized mouse eggs, and expression was analyzed in transgenic animals that developed. Mice that had intact copies of the transgenes expressed high levels of correctly initiated human alpha- and beta-globin messenger RNA specifically in erythroid tissue. An authentic human hemoglobin was formed in adult erythrocytes that when purified had an oxygen equilibrium curve identical to the curve of native human hemoglobin A (Hb A). Thus, functional human hemoglobin can be synthesized in transgenic mice. This provides a foundation for production of mouse models of human hemoglobinopathies such as sickle cell disease.     

复杂数量性状的遗传分析及功能作图

大多数重要的生物学、生化和农学性状是数量性状,受1个基因网络控制,且易受环境因素影响。近20年来,随着统计学和分子生物学的迅猛发展,对数量性状的研究也逐渐深入,提出了很多研究方法。文中综述了QTLs的检测方法进展,评价了各种方法的优劣,着重介绍了目前国际上最新提出的多维数量性状的研究方法———功能作图的思想。