RESUMEN
A gene, ATM, that is mutated in the autosomal recessive disorder ataxia telangiectasia (AT) was identified by positional cloning on chromosome 11q22-23. AT is characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, cancer predisposition, radiation sensitivity, and cell cycle abnormalities. The disease is genetically heterogeneous, with four complementation groups that have been suspected to represent different genes. ATM, which has a transcript of 12 kilobases, was found to be mutated in AT patients from all complementation groups, indicating that it is probably the sole gene responsible for this disorder. A partial ATM complementary DNA clone of 5.9 kilobases encoded a putative protein that is similar to several yeast and mammalian phosphatidylinositol-3' kinases that are involved in mitogenic signal transduction, meiotic recombination, and cell cycle control. The discovery of ATM should enhance understanding of AT and related syndromes and may allow the identification of AT heterozygotes, who are at increased risk of cancer.
Asunto(s)
Ataxia Telangiectasia/genética , Cromosomas Humanos Par 11 , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Proteínas Serina-Treonina Quinasas , Proteínas/genética , Secuencia de Aminoácidos , Proteínas de la Ataxia Telangiectasia Mutada , Ciclo Celular , Proteínas de Ciclo Celular , Mapeo Cromosómico , Cromosomas Artificiales de Levadura , Clonación Molecular , ADN Complementario/genética , Proteínas de Unión al ADN , Femenino , Prueba de Complementación Genética , Predisposición Genética a la Enfermedad , Heterocigoto , Humanos , Masculino , Meiosis , Datos de Secuencia Molecular , Neoplasias/genética , Hibridación de Ácido Nucleico , Fosfatidilinositol 3-Quinasas , Fosfotransferasas (Aceptor de Grupo Alcohol)/química , Fosfotransferasas (Aceptor de Grupo Alcohol)/fisiología , Proteínas/química , Proteínas/fisiología , Tolerancia a Radiación , Eliminación de Secuencia , Transducción de Señal , Proteínas Supresoras de TumorRESUMEN
A brief review of tumor immunotherapies shows significant advancements in academic research and preclinical studies. Analysis of different immune cell pathways, including macrophage activation, natural killer cells, and dendritic cell presentation show promising clinical results when targeted with different nanoparticle polymer and gold materials. Following a brief discussion on immuno-oncology successes, detailed results are discussed in macrophage activation, dendritic cell presentation, and lysis of tumor cells with natural killer cells. Common targets include tumor-associated macrophages and induction of the proinflammatory phenotype, dual targeting of cell and humoral immunity with dendritic cells, and creating chimeric antigen receptors on natural killer cells. An analysis of the results shows a variety of nanoparticle synthesis methods are required depending on drug type and tissue type affected by tumors. Future research is discussed in conjunction with a brief analysis of completed clinical trial data on cancer therapies using nanoparticles to date. Although paclitaxel-loaded albumin nanoparticles are most frequently studied, academic research shows there may be additional mechanisms of action to elicit anti-tumor activity.
Asunto(s)
Inmunoterapia/métodos , Nanopartículas/uso terapéutico , Neoplasias/terapia , Antígenos de Neoplasias , Antineoplásicos/uso terapéutico , Ensayos Clínicos como Asunto , Terapia Combinada/métodos , Células Dendríticas/inmunología , Docetaxel/uso terapéutico , Doxorrubicina/uso terapéutico , Galectina 1/antagonistas & inhibidores , Oro/uso terapéutico , Humanos , Inmunidad Celular , Inmunidad Humoral , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Activación de Macrófagos , Nanopartículas/administración & dosificación , Neoplasias/inmunología , Especificidad de Órganos , Paclitaxel/uso terapéutico , Receptores Quiméricos de Antígenos/inmunologíaRESUMEN
When people suffer an embarrassing blunder, social mishap, or public failure, they often feel that their image has been severely tarnished in the eyes of others. Four studies demonstrate that these fears are commonly exaggerated. Actors who imagined committing one of several social blunders (Study 1), who experienced a public intellectual failure (Studies 2 and 3), or who were described in an embarrassing way (Study 4) anticipated being judged more harshly by others than they actually were. These exaggerated fears were produced, in part, by the actors' tendency to be inordinately focused on their misfortunes and by their resulting failure to consider the wider range of situational factors that tend to moderate onlookers' impressions. Discussion focuses on additional mechanisms that may contribute to overly pessimistic expectations as well as the role of such expectations in producing unnecessary social anxiety.
Asunto(s)
Autoimagen , Conducta Social , Percepción Social , Adulto , Femenino , Humanos , Masculino , Modelos Psicológicos , Solución de Problemas , Desempeño de Papel , Autoevaluación (Psicología)RESUMEN
People, it is hypothesized, show an asymmetry in assessing their own interpersonal and intrapersonal knowledge relative to that of their peers. Six studies suggested that people perceive their knowledge of their peers to surpass their peers' knowledge of them. Several of the studies explored sources of this perceived asymmetry, especially the conviction that while observable behaviors (e.g., interpersonal revelations or idiosyncratic word completions) are more revealing of others than self, private thoughts and feelings are more revealing of self than others. Study 2 also found that college roommates believe they know themselves better than their peers know themselves. Study 6 showed that group members display a similar bias-they believe their groups know and understand relevant out-groups better than vice versa. The relevance of such illusions of asymmetric insight for interpersonal interaction and our understanding of "naive realism" is discussed.
Asunto(s)
Cognición , Ilusiones , Relaciones Interpersonales , Percepción Social , Femenino , Humanos , Masculino , Prejuicio , Encuestas y CuestionariosRESUMEN
This research provides evidence that people overestimate the extent to which their actions and appearance are noted by others, a phenomenon dubbed the spotlight effect. In Studies 1 and 2, participants who were asked to don a T-shirt depicting either a flattering or potentially embarrassing image overestimated the number of observers who would be able to recall what was pictured on the shirt. In Study 3, participants in a group discussion overestimated how prominent their positive and negative utterances were to their fellow discussants. Studies 4 and 5 provide evidence supporting an anchoring-and-adjustment interpretation of the spotlight effect. In particular, people appear to anchor on their own rich phenomenological experience and then adjust--insufficiently--to take into account the perspective of others. The discussion focuses on the manifestations and implications of the spotlight effect across a host of everyday social phenomena.
Asunto(s)
Autoevaluación (Psicología) , Conducta Social , Percepción Social , Adolescente , Adulto , Femenino , Identidad de Género , Humanos , Masculino , Variaciones Dependientes del Observador , Autoimagen , Disposición en PsicologíaRESUMEN
Three sets of studies provide evidence for an illusion of transparency, or a tendency for people to overestimate the extent to which others can discern their internal states. People often mistakenly believe that their internal states "leak out" more than they really do. The authors attribute this bias to a tendency for people to adjust insufficiently from the "anchor" of their own phenomenological experience when attempting to take another's perspective. Evidence for this illusion is provided by showing that liars overestimate the detectability of their lies (Studies 1a, 1b, and 1c) and that people believe their feelings of disgust are more apparent than they actually are (Studies 2a and 2b). A final pair of experiments (Studies 3a and 3b) explores the implications of the illusion of transparency for people's reluctance to intervene in emergencies. All 3 sets of studies also provide evidence consistent with the proposed anchoring and adjustment interpretation.
Asunto(s)
Afecto , Actitud , Emociones , Ilusiones , Percepción Social , Estudios de Seguimiento , Humanos , Modelos Psicológicos , Distribución AleatoriaRESUMEN
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency radiation sensitivity, and cancer predisposition. A-T heterozygotes are moderately cancer prone. The A-T gene, designated ATM, was recently identified in our laboratory by positional cloning, and a partial cDNA clone was found to encode a polypeptide with a PI-3 kinase domain. We report here the molecular cloning of a cDNA contig spanning the complete open reading frame of the ATM gene. The predicted protein of 3056 amino acids shows significant sequence similarities to several large proteins in yeast, Drosophila and mammals, all of which share the PI-3 kinase domain. Many of these proteins are involved in the detection of DNA damage and the control of cell cycle progression. Mutations in their genes confer a variety of phenotypes with features similar to those observed in human A-T cells. The complete sequence of the ATM gene product provides useful clues to the function of this protein, and furthers understanding of the pleiotropic nature of the A-T mutations.
Asunto(s)
Proteínas Serina-Treonina Quinasas , Proteínas/genética , Secuencia de Aminoácidos , Animales , Proteínas de la Ataxia Telangiectasia Mutada , Secuencia de Bases , Ciclo Celular , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Clonación Molecular , Reparación del ADN , Proteínas de Unión al ADN , Humanos , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Fosfatidilinositol 3-Quinasas , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Proteínas/metabolismo , Homología de Secuencia de Aminoácido , Proteínas Supresoras de TumorRESUMEN
Mutations in the ATM gene are responsible for the multisystem disorder ataxia-telangiectasia, characterized by neurodegeneration, immune deficiency and cancer predisposition. While no alternative splicing was identified within the coding region, the first four exons of the ATM gene, which fall within the 5'untranslated region (UTR), undergo extensive alternative splicing. We identified 12 different 5'UTRs that show considerable diversity in length and sequence contents. These mRNA leaders, which range from 150 to 884 nucleotides (nt), are expected to form variable secondary structures and contain different numbers of AUG codons. The longest 5'UTR contains a total of 18 AUGs upstream of the translation start site. The 3'UTR of 3590 nt is contained within a single 3'exon. Alternative polyadenylation results in 3'UTRs of varying lengths. These structural features suggest that ATM expression might be subject to complex post-transcriptional regulation, enabling rapid modulation of ATM protein level in response to environmental stimuli or alterations in cellular physiological states.
Asunto(s)
Ataxia Telangiectasia/genética , Proteínas Serina-Treonina Quinasas , Proteínas/genética , Procesamiento Postranscripcional del ARN , Proteínas de la Ataxia Telangiectasia Mutada , Secuencia de Bases , Proteínas de Ciclo Celular , Línea Celular , ADN , Proteínas de Unión al ADN , Humanos , Células Jurkat , Masculino , Datos de Secuencia Molecular , Biosíntesis de Proteínas , Proteínas/metabolismo , ARN Mensajero/genética , Proteínas Supresoras de TumorRESUMEN
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity, and cancer predisposition. The genomic organization of the A-T gene, designated ATM, was established recently. To date, more than 100 A-T-associated mutations have been reported in the ATM gene that do not support the existence of one or several mutational hotspots. To allow genotype/phenotype correlations it will be important to find additional ATM mutations. The nature and location of the mutations will also provide insights into the molecular processes that underly the disease. To facilitate the search for ATM mutations and to establish the basis for the identification of transcriptional regulatory elements, we have sequenced and report here 184,490 bp of genomic sequence from the human 11q22-23 chromosomal region containing the entire ATM gene, spanning 146 kb, and 10 kb of the 5'-region of an adjacent gene named E14/NPAT. The latter shares a bidirectional promoter with ATM and is transcribed in the opposite direction. The entire region is transcribed to approximately 85% and translated to 5%. Genome-wide repeats were found to constitute 37.2%, with LINE (17.1%) and Alu (14.6%) being the main repetitive elements. The high representation of LINE repeats is attributable to the presence of three full-length LINE-1s, inserted in the same orientation in introns 18 and 63 as well as downstream of the ATM gene. Homology searches suggest that ATM exon 2 could have derived from a mammalian interspersed repeat (MIR). Promoter recognition algorithms identified divergent promoter elements within the CpG island, which lies between the ATM and E14/NPAT genes, and provide evidence for a putative second ATM promoter located within intron 3, immediately upstream of the first coding exon. The low G+C level (38.1%) of the ATM locus is reflected in a strongly biased codon and amino acid usage of the gene.
Asunto(s)
Ataxia Telangiectasia/genética , Proteínas de Ciclo Celular , Proteínas Nucleares , Proteínas Serina-Treonina Quinasas , Proteínas/genética , Proteínas de la Ataxia Telangiectasia Mutada , Composición de Base , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Humanos Par 11 , Clonación Molecular , Islas de CpG , Elementos Transponibles de ADN , Proteínas de Unión al ADN , Procesamiento Automatizado de Datos , Exones , Humanos , Intrones , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas , Secuencias Repetitivas de Ácidos Nucleicos , Análisis de Secuencia de ADN , Proteínas Supresoras de TumorRESUMEN
The ATM gene was recently identified and found to be responsible for the genetic disorder ataxiatelgiectasia. The major ATM transcript is 13 kb. Using long-distance PCR, we determined the genomic structure of this gene and identified all of its exon-intron boundaries. The ATM gene spans approximately 150 kb of genomic DNA and consists of 66 exons. The initiation codon falls within exon 4. The last exon is 3.8 kb and contains the stop codon and a 3'-untranslated region of about 3600 nucleotides.
Asunto(s)
Ataxia Telangiectasia/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas/genética , Ataxia Telangiectasia/genética , Proteínas de la Ataxia Telangiectasia Mutada , Secuencia de Bases , Proteínas de Ciclo Celular , ADN Complementario , Proteínas de Unión al ADN , Exones , Genoma , Humanos , Intrones , Datos de Secuencia Molecular , Proteínas Supresoras de TumorRESUMEN
The autosomal recessive disorder ataxia-telangiectasia (A-T) is genetically heterogeneous, with four complementation groups. The genes for the two major groups (ATA and ATC) have been mapped to 11q22-q23. Genetic analysis of the disease has been conducted to date using biallelic polymorphisms. We have physically mapped to this region eight new microsatellite markers that were generated by three laboratories that construct whole-genome linkage maps. These markers should be valuable for refined localization and positional cloning of the A-T genes and for diagnostic purposes. The results demonstrate the value of integrating genetic and physical maps generated by different laboratories.
Asunto(s)
Ataxia Telangiectasia/genética , Cromosomas Humanos Par 11 , Secuencia de Bases , Mapeo Cromosómico , Clonación Molecular , Cartilla de ADN/genética , ADN Satélite/genética , Marcadores Genéticos , Humanos , Datos de Secuencia MolecularRESUMEN
The locus of the autosomal recessive disorder ataxia-telangiectasia (A-T) has been assigned by linkage analysis with biallelic markers to a 4-Mb interval on chromosome 11q22-23, between GRIA4 and D11S1897. We have undertaken to saturate the A-T region with highly polymorphic microsatellite markers. To this end, we have identified seven new polymorphic CA-repeats in this region, and have mapped to it five new markers generated by Genethon and the Cooperative Human Linkage Center. These markers are in addition to 12 others that we have previously mapped or generated at the A-T locus. All 24 markers have been integrated into a high-density microsatellite map spanning some 6 Mb DNA. This map, which contains the A-T locus and flanking sequences, allows the construction of extensive, highly informative haplotypes.
Asunto(s)
Ataxia Telangiectasia/genética , Mapeo Cromosómico , ADN Satélite/genética , Secuencia de Bases , Cromosomas Humanos Par 11/genética , Cartilla de ADN/química , Marcadores Genéticos , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
A human gene encoding a putative RNA helicase, designated DDX10, was identified 400 kb telomeric to the ataxia-telangiectasia gene at chromosome 11q22-q23. The predicted amino acid sequence shows very high similarity to a subgroup of DEAD-box RNA helicases involved in ribosome biogenesis. This novel gene encodes a 3.2-kb transcript in a variety of human tissues. A processed pseudogene of DDX10 was detected at chromosome 9q21-q22. We observed a rare trinucleotide repeat length polymorphism within the coding sequence of DDX10.
Asunto(s)
Cromosomas Humanos Par 11 , ARN Nucleotidiltransferasas/genética , Secuencia de Aminoácidos , Animales , Ataxia Telangiectasia/genética , Secuencia de Bases , Línea Celular , Cromosomas Humanos Par 9 , Cricetinae , ADN Complementario , Expresión Génica , Humanos , Datos de Secuencia Molecular , Seudogenes , ARN Helicasas , Homología de Secuencia de Aminoácido , Repeticiones de TrinucleótidosRESUMEN
Ataxia-telangiectasia (A-T) is an autosomal recessive disease involving cerebellar degeneration, immunodeficiency, cancer predisposition, chromosomal instability and radiosensitivity. A-T is heterogeneous, and the majority of A-T cases are associated with two complementation groups, A and C. The ATA and ATC loci are closely linked at chromosome 11q22-q23. Recombination mapping and linkage disequilibrium analysis have confined both loci between the markers D11S1817 and D11S927, spaced approximately 3.5 Mb apart. Isolation in yeast artificial chromosomes of the genomic segment defined by these loci is essential to identify the gene or genes containing the ATA and ATC mutations. A YAC contig spanning 4.5 Mb, which includes the D11S1817-D11S927 interval, was constructed using two whole genome libraries (ICRF and St. Louis), and a chromosome 11-specific library. Construction of this contig was expedited by prior generation of a region-specific ICRF sublibrary using Alu-PCR products derived from a radiation hybrid. The contig was expanded further by screening the libraries with Alu-PCR products derived from YAC clones and with STSs from YAC ends. YAC clones were aligned by fingerprinting with moderately repetitive probes.
Asunto(s)
Ataxia Telangiectasia/genética , Cromosomas Artificiales de Levadura , Cromosomas Humanos Par 11 , Paseo de Cromosoma , Humanos , Células Híbridas/efectos de la radiación , Hibridación de Ácido Nucleico , Reacción en Cadena de la PolimerasaRESUMEN
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, ATM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a Pl 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the Pl 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the ATM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.
Asunto(s)
Ataxia Telangiectasia/metabolismo , Mutación , Proteínas Serina-Treonina Quinasas , Proteínas/genética , Secuencia de Aminoácidos , Proteínas de la Ataxia Telangiectasia Mutada , Secuencia de Bases , Proteínas de Ciclo Celular , Células Cultivadas , ADN , Análisis Mutacional de ADN , Proteínas de Unión al ADN , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa , Homología de Secuencia de Aminoácido , Proteínas Supresoras de TumorRESUMEN
Atm, the mouse homolog of the human ATM gene defective in ataxia-telangiectasia (A-T), has been identified. The entire coding sequence of the Atm transcript was cloned and found to contain an open reading frame encoding a protein of 3066 amino acids with 84% overall identity and 91% similarity to the human ATM protein. Variable levels of expression of Atm were observed in different tissues. Fluorescence in situ hybridization and linkage analysis located the Atm gene on mouse chromosome 9, band 9C, in a region homologous to the ATM region on human chromosome 11q22-q23.