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161.
Jordi Valls-Margarit Ivn Galvn-Femenía Daniel Matías-Snchez Natalia Blay Montserrat Puiggrs Anna Carreras Cecilia Salvoro Beatriz Corts Ramon Amela Xavier Farre Jon Lerga-Jaso Marta Puig Jose
Francisco Snchez-Herrero Victor Moreno Manuel Perucho Lauro Sumoy Lluís Armengol Olivier Delaneau Mario Cceres Rafael de
Cid David Torrents 《Nucleic acids research》2022,50(5):2464
The combined analysis of haplotype panels with phenotype clinical cohorts is a common approach to explore the genetic architecture of human diseases. However, genetic studies are mainly based on single nucleotide variants (SNVs) and small insertions and deletions (indels). Here, we contribute to fill this gap by generating a dense haplotype map focused on the identification, characterization, and phasing of structural variants (SVs). By integrating multiple variant identification methods and Logistic Regression Models (LRMs), we present a catalogue of 35 431 441 variants, including 89 178 SVs (≥50 bp), 30 325 064 SNVs and 5 017 199 indels, across 785 Illumina high coverage (30x) whole-genomes from the Iberian GCAT Cohort, containing a median of 3.52M SNVs, 606 336 indels and 6393 SVs per individual. The haplotype panel is able to impute up to 14 360 728 SNVs/indels and 23 179 SVs, showing a 2.7-fold increase for SVs compared with available genetic variation panels. The value of this panel for SVs analysis is shown through an imputed rare Alu element located in a new locus associated with Mononeuritis of lower limb, a rare neuromuscular disease. This study represents the first deep characterization of genetic variation within the Iberian population and the first operational haplotype panel to systematically include the SVs into genome-wide genetic studies. 相似文献
162.
Introns are generally believed to evolve too rapidly and too erratically to be of much use in phylogenetic reconstructions.
Few phylogenetically informative intron sequences are available, however, to ascertain the validity of this supposition. In
the present study the supposition was tested on the example of the mammalian class II major histocompatibility complex (Mhc) genes of the DRB family. Since the Mhc genes evolve under balancing selection and are believed to recombine or rearrange frequently, the evolution of their introns
could be expected to be particularly rapid and subject to scrambling. Sequences of intron 4 and 5 DRB genes were obtained from polymerase chain reaction-amplified fragments of genomic DNA from representatives of six eutherian
orders—Primates, Scandentia, Chiroptera, Dermoptera, Lagomorpha, and Insectivora. Although short stretches of the introns
have indeed proved to be unalignable, the bulk of the intron sequences from all six orders, spanning >85 million years (my)
of evolution, could be aligned and used in a study of the tempo and mode of intron evolution. The analysis has revealed the
Mhc introns to evolve at a rate similar to that of other genes and of synonymous sites of non-Mhc genes. No evidence of homogenization or large-scale scrambling of the intron sequences could be found. The Mhc introns apparently evolve largely by point mutations and insertions/deletions. The phylogenetic signals contained in the
intron sequences could be used to identify Scandentia as the sister group of Primates, to support the existence of the Archonta
superorder, and to confirm the monophyly of the Chiroptera.
Received: 26 October 1998 / Accepted: 21 December 1998 相似文献
163.
Hyperkalemic periodic paralysis M1592V mutation modifies activation in human skeletal muscle Na+ channel 总被引:1,自引:0,他引:1
Rojas Cecilia V.; Neely Alan; Velasco-Loyden Gabriela; Palma Veronica; Kukuljan Manuel 《American journal of physiology. Cell physiology》1999,276(1):C259
Mutations in thehuman skeletal muscle Na+ channelunderlie the autosomal dominant disease hyperkalemic periodic paralysis (HPP). Muscle fibers from affected individuals exhibit sustained Na+ currents thought to depolarizethe sarcolemma and thus inactivate normalNa+ channels. We expressed humanwild-type or M1592V mutant-subunits with the 1-subunitin Xenopus laevis oocytes and recordedNa+ currents using two-electrodeand cut-open oocyte voltage-clamp techniques. The most prominentfunctional difference betweenM1592V mutant and wild-typechannels is a 5- to 10-mV shift in the hyperpolarized direction of thesteady-state activation curve. The shift in the activation curve forthe mutant results in a larger overlap with the inactivation curve thanthat observed for wild-type channels. Accordingly, the current throughM1592V channels displays a larger noninactivating component than does that through wild-type channels atmembrane potentials near 40 mV. The functional properties of theM1592V mutant resemble those ofthe previously characterized HPPT704M mutant. Both clinicallysimilar phenotypes arise from mutations located at a distance from theputative voltage sensor of the channel. 相似文献
164.
Selective decrease in paracellular conductance of tight junctions: role of the first extracellular domain of claudin-5 总被引:9,自引:0,他引:9
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Claudin-5 is a protein component of many endothelial tight junctions, including those at the blood-brain barrier, a barrier that limits molecular exchanges between the central nervous system and the circulatory system. To test the contribution of claudin-5 to this barrier function of tight junctions, we expressed murine claudin-5 in Madin-Darby canine kidney II cells. The result was a fivefold increase in transepithelial resistance in claudin-5 transductants and a reduction in conductance of monovalent cations. However, the paracellular flux of neither neutral nor charged monosaccharides was significantly changed in claudin-5 transductants compared to controls. Therefore, expression of claudin-5 selectively decreased the permeability to ions. Additionally, site-directed mutations of particular amino acid residues in the first extracellular domain of claudin-5 altered the properties of the tight junctions formed in response to claudin-5 expression. In particular, the conserved cysteines were crucial: mutation of either cysteine abolishted the ability of claudin-5 to increase transepithelial resistance, and mutation of Cys(64) strikingly increased the paracellular flux of monosaccharides. These new insights into the functions of claudin-5 at the molecular level in tight junctions may account for some aspects of the blood-brain barrier's selective permeability. 相似文献
165.
Angiopoietin decoy secreted at tumor site impairs tumor growth and metastases by inducing local inflammation and altering neoangiogenesis 总被引:3,自引:0,他引:3
Melani C Stoppacciaro A Foroni C Felicetti F Caré A Colombo MP 《Cancer immunology, immunotherapy : CII》2004,53(7):600-608
The extracellular domain of the receptor tyrosine kinase Tie2/TEK (exTEK) has been used as an angiopoietin decoy to study the role of angiopoietins in the tumor–host interactions, using a syngeneic model of experimental metastases and subcutaneous tumor. Soluble exTEK secreted by transfected tumor cells inhibited HUVECs from forming tubes in Matrigel. ExTEK-transfected C26 colon carcinoma and TS/A mammary tumor cells displayed reduced growth rate when injected subcutaneously, and reduced ability to form experimental metastases when injected intravenously. Immunohistochemical analysis of tumors and metastases showed increased leukocytes infiltration and signs of inflammation in exTEK-secreting compared to parental tumor, as well as impairment in neo-vessel growth and organization. However, while neoangiogenesis eventually rescued in the subcutis, it failed to organize in the experimental metastases of exTEK-secreting tumor, contributing to the hampering of metastatic growth and to increased mice survival. The reactive infiltrate of C26TEK contained a different percentage of leukocytes and was responsible for the tumor inhibition. In fact, leukopenia induced by -irradiation of recipient mice or injection into interferon gamma (IFN-) gene knockout (GKO) mice resulted in reduced mouse survival and an increased number of lung metastases. On the other hand, interleukin (IL)-12 treatment prolonged the survival of mice bearing subcutaneous C26TEK but not of those bearing lung metastases, suggesting that IL-12 could exert further antiangiogenic effects at the site where the tumor can restore neoangiogenesis. These results show in vivo that reduced angiopoietin availability at the tumor site induces a local inflammatory response and impairment of neoangiogenesis which act synergistically to limit tumor growth and metastasis.Abbreviations AEC
amino-ethylcarbazole
- ELISA
enzyme-linked immunosorbent assay
- HRP
horseradish peroxidase
- HUVEC
human umbilical vascular endothelial cell
- i.v.
intravenous
- s.c.
subcutaneous
- TBS
Tris-HCl buffered solution 相似文献
166.
Parra A Reyes-Terán G Ramírez-Peredo J Jacquemin B Quiroz V Cárdenas M García-Sancho MC Larrea F Cárdenas M 《Immunology and cell biology》2004,82(1):24-31
The existence of decreased hypothalamic dopaminergic tone in HIV-infected men has been suggested. In a cross-sectional study, we determined 12 h nocturnal basal and pulsatile prolactin (PRL) release levels (by blood sampling every 10 min) and their correlation with CD4+ T cells in seven volunteer HIV-negative, healthy men (group 1), and 21 normoprolactinemic, euthyroid, HIV-infected men divided into 3 groups (each group = 7): (i) group 2, asymptomatic HIV-infected stage A1 men, untreated; (ii) group 3, AIDS stage C3 without active opportunistic infections, untreated; and (iii) group 4, previously stage C3 after at least 6 months of successful highly active antiretroviral therapy. Serum PRL was measured by radioimmunoanalysis and the results were analysed by waveform-independent deconvolution analysis. CD4+ T lymphocytes were measured by flow cytometry and viral load by a nucleic acid sequence-based amplification assay. No differences were detected in the first two groups. In the third group, however, 100% of prolactin secretion was found to be pulsatile with a shorter secretory burst duration (P = 0.04), and a greater circulating half-life and pulse amplitude (P < or = 0.04). Group 4 had the greatest basal prolactin secretion (P < or = 0.04), and a shorter secretory burst duration (P = 0.04 vs group 2), circulating half-life (P = 0.01 vs group 3) and intersecretory burst interval (P = 0.06 vs group 1). PRL approximate entropy was similar among all groups. Linear correlations existed between CD4+ T cell counts and PRL secretory burst half duration (r = 0.62, P = 0.002) and amplitude (r = -0.63, P = 0.001), and in circulating serum half-life (r = - 0.61, P = 0.002) in HIV-infected groups. Viral load showed no correlations. It is suggested that differential changes in nocturnal prolactin secretion among HIV-infected men occurred while maintaining the normal coordinate feedback and/or feedforward control within the lactotropic axis. These changes may represent an adaptative mechanism to sustain, by different means, the maximal physiologic PRL production to stimulate the highest cellular immune response and/or reconstitution in attempting to survive. 相似文献
167.
The aim of this paper was to elucidate the mechanisms behind salivary lubrication with special emphasis on the lubricity of three key components of the pellicle, viz human acidic proline-rich protein 1 (PRP-1), human statherin and bovine submaxillary mucin (BSM). The lubricating properties of the proteins have been assessed by means of colloidal probe atomic force microscopy, and are discussed in relation to their adsorption behaviour. To various extents, the proteins investigated all showed a lubricating effect when adsorbed to silica surfaces. For comparable concentrations, PRP-1 was found to have a more pronounced lubricating effect than BSM, which in turn showed a higher lubricity than statherin. The relative lubricity is in accordance with previously reported relative adsorbed amounts of the three proteins, within the investigated concentration interval. It is concluded that PRP-1 has the highest lubricating capacity as a pure fraction among the preparations investigated, and that the lubricating effect of PRP-1 as a pure fraction is notably large as compared to the lubricity of human whole saliva. 相似文献
168.
PTX3 plays a key role in the organization of the cumulus oophorus extracellular matrix and in in vivo fertilization 总被引:9,自引:0,他引:9
Salustri A Garlanda C Hirsch E De Acetis M Maccagno A Bottazzi B Doni A Bastone A Mantovani G Beck Peccoz P Salvatori G Mahoney DJ Day AJ Siracusa G Romani L Mantovani A 《Development (Cambridge, England)》2004,131(7):1577-1586
PTX3 is a prototypic long pentraxin that plays a non-redundant role in innate immunity against selected pathogens and in female fertility. Here, we report that the infertility of Ptx3(-/-) mice is associated with severe abnormalities of the cumulus oophorus and failure of in vivo, but not in vitro, oocyte fertilization. PTX3 is produced by mouse cumulus cells during cumulus expansion and localizes in the matrix. PTX3 is expressed in the human cumulus oophorus as well. Cumuli from Ptx3(-/-) mice synthesize normal amounts of hyaluronan (HA), but are unable to organize it in a stable matrix. Exogenous PTX3 restores a normal cumulus phenotype. Incorporation in the matrix of inter-alpha-trypsin inhibitor is normal in Ptx3(-/-) cumuli. PTX3 does not interact directly with HA, but it binds the cumulus matrix hyaladherin tumor necrosis factor alpha-induced protein 6 (TNFAIP6, also known as TSG6) and thereby may form multimolecular complexes that can cross-link HA chains. Thus, PTX3 is a structural constituent of the cumulus oophorus extracellular matrix essential for female fertility. 相似文献
169.
170.
This work aims to elucidate the mechanisms involved in the early activation of glucose transport in hematopoietic M07e cells by stem cell factor (SCF) and a reactive oxygen species (ROS) as H2O2. SCF and H2O2 increase Vmax for glucose transport; this enhancement is due to a higher content in GLUT1 in plasma membranes, possibly through a translocation from intracellular stores. Inhibitors of tyrosine kinases or phospholipase C (PLC) remove glucose transport enhancement and prevent translocation. The inhibitory effect of STI-571 suggests a role for c-kit tyrosine kinase on glucose transport activation not only by SCF, but also by H2O2. On the other hand, neither protein kinase C nor phosphoinositide-3-kinase appear to be involved in the acute activation of glucose transport. Our data suggest that i) in M07e cells, SCF and exogenous H2O2 elicit a short-term activation of glucose transport through a translocation of GLUT1 from intracellular stores to plasma membranes; ii) both stimuli could share at least some signaling pathways leading to glucose uptake activation, involving protein tyrosine kinases and PLC iii) H2O2 could act increasing the level of tyrosine phosphorylation through the inhibition of tyrosine phosphatases and mimicking the regulation role of endogenous ROS. 相似文献