Time limits eligibility for thrombolytic treatment in stroke patients.
Explore the source record for details and available documents.
Humans↗
Biomedical subjects
A Villa
Publications and source records attributed to A Villa.
QT interval prolongation as predictor of early mortality in acute ischemic stroke patients.
Explore the source record for details and available documents.
Aged↗
Recombinase activating gene enzymes of lymphocytes.
Expression of T-cell receptor and surface immunoglobulins on T and B lymphocytes, respectively, is strictly dependent on the variable, (diversity) joining exon (V(D)J) recombination process, which is initiated by the lymphoid-specific recombinase activating gene proteins 1 and 2 (RAG1 and RAG2). Recent advances have highlighted the functional organization of the RAG1 and RAG2 proteins and have provided important information on the regulation of RAG gene expression. Depending on the severity of their effects on the V(D)J recombination process, mutations of the RAG genes account for a spectrum of combined immune deficiencies in humans.
DNA Nucleotidyltransferases↗
Recombination activating gene and its defects.
Mutations in recombination activating genes cause a spectrum of severe immunodeficiencies ranging from T-B severe combined immunodeficiency to Omenn syndrome (a particular type of severe combined immunodeficiency presenting a T+ B- profile). Although environmental factors and genetic background could also contribute to the genesis of this pathological condition, a residual recombination activating gene activity allowing for a few recombinational events to occur, is the first determinant of this variability in the clinical picture.
DNA Nucleotidyltransferases↗
The C-C chemokine receptors CCR4 and CCR8 identify airway T cells of allergen-challenged atopic asthmatics.
In vitro polarized human Th2 cells preferentially express the chemokine receptors CCR3, CCR4, and CCR8 and migrate to their ligands: eotaxin, monocyte-derived chemokine (MDC), thymus- and activation-regulated chemokine (TARC), and I-309. We have studied the expression of chemokines and chemokine receptors in the airway mucosa of atopic asthmatics. Immunofluorescent analysis of endobronchial biopsies from six asthmatics, taken 24 hours after allergen challenge, demonstrates that virtually all T cells express IL-4 and CCR4. CCR8 is coexpressed with CCR4 on 28% of the T cells, while CCR3 is expressed on eosinophils but not on T cells. Expression of the CCR4-specific ligands MDC and TARC is strongly upregulated on airway epithelial cells upon allergen challenge, suggesting an involvement of this receptor/ligand axis in the regulation of lymphocyte recruitment into the asthmatic bronchi. In contrast to asthma, T cells infiltrating the airways of patients with chronic obstructive pulmonary disease and pulmonary sarcoidosis produce IFN-gamma and express high levels of CXCR3, while lacking CCR4 and CCR8 expression. These data support the role of CCR4, of its ligands MDC and TARC, and of CCR8 in the pathogenesis of allergen-induced late asthmatic responses and suggest that these molecules could be considered as targets for therapeutic intervention.
Asthma↗
Clinical features of multiple sclerosis in a genetically homogeneous tropical population.
Individuals affected with multiple sclerosis (MS) from a genetically homogeneous Caucasian population in Antioquia, a tropical region of Colombia, were evaluated in order to observe the clinical behavior of the disease. The frequency of clinical manifestations in 65 patients with definite MS from Antioquia was compared with those reported from temperate regions. The most common manifestations were optic neuritis and motor symptoms with absence of cerebellar symptoms. This presentation is significantly different from the frequency distribution at onset in series from temperate regions. These differences suggest that environmental factors could modify the clinical expression of MS in this population.
Asia↗
Human neural stem and progenitor cells: in vitro and in vivo properties, and potential for gene therapy and cell replacement in the CNS.
The generation of unlimited quantities of neural stem and/or progenitor cells derived from the human brain holds great interest for basic and applied neuroscience. In this article we critically review the origins and recent developments of procedures developed for the expansion, perpetuation, identification, and isolation of human neural precursors, as well as their attributes. Factors influencing their in vitro properties, both under division and after differentiation conditions, are evaluated, with the aim of identifying properties common to the different culture systems reported. This analysis suggests that different culture procedures result in cells with different properties, or even in different cells being isolated. With respect to in vivo performance, present evidence obtained in rodents indicate that cultured human neural precursors, in general, are endowed with excellent integrative properties. Differentiation of the implanted cells, in particular in the case of adult recipients, seems not to be complete, and functionality still needs to be demonstrated. In relation to gene transfer and therapy, aspects currently underexplored, initial data support the view that human neural stem and progenitor cells may serve a role as a platform cell for the delivery of bioactive substances to the diseased CNS. Although a large deal of basic research remains to be done, available data illustrate the enormous potential that human neural precursors isolated, expanded, and characterized in vitro hold for therapeutic applications. In spite of this potential, maintaining a critical view on many unresolved questions will surely help to drive this research field to a good end, that is, the development of real therapies for diseases of the human nervous system.
Animals↗
N-terminal RAG1 frameshift mutations in Omenn's syndrome: internal methionine usage leads to partial V(D)J recombination activity and reveals a fundamental role in vivo for the N-terminal domains.
Omenn's syndrome is an autosomal recessive primary immunodeficiency characterized by variable numbers of T lymphocytes of limited clonality, hypereosinophilia, and high IgE levels with a paradoxical absence of circulating B lymphocytes. We have previously attributed this disorder to missense mutations that render the RAG1/RAG2 recombinase only partially active. Here we report seven Omenn's patients with a novel class of genetic lesions: frameshift mutations within the 5' coding region of RAG1. Interestingly, we demonstrate in transient expression experiments that these frameshift deletion alleles remain partially functional for both deletional and inversional recombination and can hence explain the partial rearrangement phenotype observed in these patients. The rearrangement activity is mediated by truncated RAG1 proteins that are generated by alternative ATG usage 3' to the frameshift deletion and that demonstrate improper cellular localization. Taken together, our results suggest a novel mechanism for the development of immunodeficiency in a subset of Omenn's syndrome patients.
Alleles↗
Association of junctional adhesion molecule with calcium/calmodulin-dependent serine protein kinase (CASK/LIN-2) in human epithelial caco-2 cells.
We report here that junctional adhesion molecule (JAM) interacts with calcium/calmodulin-dependent serine protein kinase (CASK), a protein related to membrane-associated guanylate kinases. In Caco-2 cells, JAM and CASK were coprecipitated and found to colocalize at intercellular contacts along the lateral surface of the plasma membrane. Association of JAM with CASK requires the PSD95/dlg/ZO-1 (PDZ) domain of CASK and the putative PDZ-binding motif Phe-Leu-Val(COOH) in the cytoplasmic tail of JAM. Temporal dissociation in the junctional localization of the two proteins suggests that the association with CASK is not required for recruiting JAM to intercellular junctions. Compared with mature intercellular contacts, junction assembly was characterized by both enhanced solubility of CASK in Triton X-100 and reduced amounts of Triton-insoluble JAM-CASK complexes. We propose that JAM association with CASK is modulated during junction assembly, when CASK is partially released from its cytoskeletal associations.
Base Sequence↗
Agrin controls synaptic differentiation in hippocampal neurons.
Agrin controls the formation of the neuromuscular junction. Whether it regulates the differentiation of other types of synapses remains unclear. Therefore, we have studied the role of agrin in cultured hippocampal neurons. Synaptogenesis was severely compromised when agrin expression or function was suppressed by antisense oligonucleotides and specific antibodies. The effects of antisense oligonucleotides were found to be highly specific because they were reversed by adding recombinant agrin and could not be detected in cultures from agrin-deficient animals. Interestingly, the few synapses formed in reduced agrin conditions displayed diminished vesicular turnover, despite a normal appearance at the EM level. Thus, our results demonstrate the necessity of agrin for synaptogenesis in hippocampal neurons.
Agrin↗
Epitope-tagged P(0) glycoprotein causes Charcot-Marie-Tooth-like neuropathy in transgenic mice.
In peripheral nerve myelin, the intraperiod line results from compaction of the extracellular space due to homophilic adhesion between extracellular domains (ECD) of the protein zero (P(0)) glycoprotein. Point mutations in this region of P(0) cause human hereditary demyelinating neuropathies such as Charcot-Marie-Tooth. We describe transgenic mice expressing a full-length P(0) modified in the ECD with a myc epitope tag. The presence of the myc sequence caused a dysmyelinating peripheral neuropathy similar to two distinct subtypes of Charcot-Marie-Tooth, with hypomyelination, altered intraperiod lines, and tomacula (thickened myelin). The tagged protein was incorporated into myelin and was associated with the morphological abnormalities. In vivo and in vitro experiments showed that P(0)myc retained partial adhesive function, and suggested that the transgene inhibits P(0)-mediated adhesion in a dominant-negative fashion. These mice suggest new mechanisms underlying both the pathogenesis of P(0) ECD mutants and the normal interactions of P(0) in the myelin sheath.
Animals↗
Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin.
The interface between apoptosis (programmed cell death) and the cell cycle is essential to preserve homeostasis and genomic integrity. Here, we show that survivin, an inhibitor of apoptosis over-expressed in cancer, physically associates with the cyclin-dependent kinase p34(cdc2) on the mitotic apparatus, and is phosphorylated on Thr(34) by p34(cdc2)-cyclin B1, in vitro and in vivo. Loss of phosphorylation on Thr(34) resulted in dissociation of a survivin-caspase-9 complex on the mitotic apparatus, and caspase-9-dependent apoptosis of cells traversing mitosis. These data identify survivin as a mitotic substrate of p34(cdc2)-cyclin B1 and suggest that survivin phosphorylation on Thr(34) may be required to preserve cell viability at cell division. Manipulation of this pathway may facilitate the elimination of cancer cells at mitosis.
Amino Acid Sequence↗
Ring chromosome 7 and sacral agenesis.
A ring chromosome 7 was found in a 19-month-old girl with microcephaly, growth and developmental delay, multiple angiomas, and partial sacral agenesis. Absent sacrum is a frequent finding in patients with 7q terminal deletions; in fact, genes involved in the sacral agenesis are localized in 7q36. However, this anomaly was not described previously in patients with a ring chromosome 7. High resolution G-banding chromosome and fluorescence in situ hybridization (FISH) demonstrated that our patient lost this region during ring formation.
Chromosome Aberrations↗
Limb deficiencies in infants with trisomy 13.
In 1994, we published a case with trisomy 13 who presented with ectrodactyly [Urioste et al., 1994: Am J Med Genet 53:390-392]. Recently, Kuschel and Gillessen-Kaesbach [2000: Am J Med Genet 90:87-88] presented an infant with trisomy 13 who also had oligodactyly, and they considered their case as the second published with oligodactyly. Here, we present three cases with any type of limb deficiencies who, together with the one that was published previously [Urioste et al., 1994], correspond to the total of 75 cases with trisomy 13 identified in the Spanish Collaborative Study of Congenital Malformations (ECEMC). This gives us a minimum frequency of 5.33% (CI:1.45-13.65) for trisomy 13 cases having limb deficiencies whereas these defects have a frequency of 5.51 per 10,000 births in our population. Consequently, we think that limb deficiencies could be considered as one of the defects that constitute the spectrum of anomalies observed in infants with trisomy 13.
Abnormalities, Multiple↗
Acquisition of intact allogeneic human leukocyte antigen molecules by human dendritic cells.
In an attempt to transduce monocyte-derived dendritic cells (DCs) by a retroviral vector coding for a cell surface marker, we were confronted by the observation of high transfer of the surface molecule in the absence of vector proviral DNA in the treated cells. Indeed, DCs acquired the surface marker by a mechanism independent of the vector machinery, requiring cell-to-cell contact and involving transfer of lipids and a variety of intact membrane proteins. Most important, this property of DCs also includes acquisition of foreign human leukocyte antigen (HLA) molecules. Consequently, DCs become immunological hybrids as they display their own and foreign HLA molecules. The newly acquired HLA is fully functional because it allows recognition by allo-specific T lymphocytes and the binding and presentation of antigen peptides.
Cell Communication↗
Integrin LFA-1 interacts with the transcriptional co-activator JAB1 to modulate AP-1 activity.
Integrin adhesion receptors transduce signals that control complex cell functions which require the regulation of gene expression, such as proliferation, differentiation and survival. Their intracellular domain has no catalytic function, indicating that interaction with other transducing molecules is crucial for integrin-mediated signalling. Here we have identified a protein that interacts with the cytoplasmic domain of the beta2 subunit of the alphaL/beta2 integrin LFA-1. This protein is JAB1 (Jun activation domain-binding protein 1), a coactivator of the c-Jun transcription factor. We found that JAB1 is present both in the nucleus and in the cytoplasm of cells and that a fraction of JAB1 colocalizes with LFA-1 at the cell membrane. LFA-1 engagement is followed by an increase of the nuclear pool of JAB1, paralleled by enhanced binding of c-Jun-containing AP-1 complexes to their DNA consensus site and increased transactivation of an AP-1-dependent promoter. We suggest that signalling through the LFA-1 integrin may affect c-Jun-driven transcription by regulating JAB1 nuclear localization. This represents a new pathway for integrin-dependent modulation of gene expression.
Animals↗
Mechanism of residence of cytochrome b(5), a tail-anchored protein, in the endoplasmic reticulum.
Endoplasmic reticulum (ER) proteins maintain their residency by static retention, dynamic retrieval, or a combination of the two. Tail-anchored proteins that contain a cytosolic domain associated with the lipid bilayer via a hydrophobic stretch close to the COOH terminus are sorted within the secretory pathway by largely unknown mechanisms. Here, we have investigated the mode of insertion in the bilayer and the intracellular trafficking of cytochrome b(5) (b[5]), taken as a model for ER-resident tail-anchored proteins. We first demonstrated that b(5) can acquire a transmembrane topology posttranslationally, and then used two tagged versions of b(5), N-glyc and O-glyc b(5), containing potential N- and O-glycosylation sites, respectively, at the COOH-terminal lumenal extremity, to discriminate between retention and retrieval mechanisms. Whereas the N-linked oligosaccharide provided no evidence for retrieval from a downstream compartment, a more stringent assay based on carbohydrate acquisition by O-glyc b(5) showed that b(5) gains access to enzymes catalyzing the first steps of O-glycosylation. These results suggest that b(5) slowly recycles between the ER and the cis-Golgi complex and that dynamic retrieval as well as retention are involved in sorting of tail-anchored proteins.
Acetylgalactosamine↗
Dendritic cells acquire the MAGE-3 human tumor antigen from apoptotic cells and induce a class I-restricted T cell response.
In an attempt to transduce monocyte-derived dendritic cells (DCs) with a retroviral vector coding for an intracytoplasmic tumor antigen (TAA), we were confronted by the evident dissociation between the ability of the treated DCs to induce a TAA-specific response, and the presence of integrated vector proviral DNA. The TAA, i.e., MAGE-3, was acquired by DCs and presented to immune effectors, thanks to the property of DCs to uptake the apoptotic bodies released by the irradiated vector-producing cells. Indeed, we observed that upon irradiation vector-producing cells underwent apoptotic cell death, monitored by annexin V and propidium iodide staining, and were phagocytosed by DCs. Lymphocytes obtained from a patient affected by a MAGE-3(+) melanoma, were stimulated in vitro with autologous DCs previously exposed to irradiated MAGE-3-expressing cells. This procedure led to the induction of MAGE-3-specific cytotoxic effectors, directed against a yet unknown MAGE-3 epitope presented by HLA-A*B5201 molecules. These data demonstrate that DCs can present engulfed human TAAs, thus providing strategies for cancer vaccination.
3T3 Cells↗