RESUMEN
Antibiotic resistance (ABR) is a global public health threat. Despite the emergence of highly resistant organisms and the huge medical need for new drugs, the development of antibacterials has slowed to an unacceptable level worldwide. Numerous government and non-government agencies have called for public-private partnerships and innovative funding mechanisms to address this problem. To respond to this public health crisis, the Innovative Medicines Initiative Joint Undertaking programme has invested more than 660 million, with a goal of matched contributions from the European Commission and the European Federation of Pharmaceutical Industries and Associations, in the development of new antibacterial strategies. The New Drugs for Bad Bugs (ND4BB) programme, an Innovative Medicines Initiative, has the ultimate goal to boost the fight against ABR at every level from basic science and drug discovery, through clinical development to new business models and responsible use of antibiotics. Seven projects have been launched within the ND4BB programme to achieve this goal. Four of them will include clinical trials of new anti-infective compounds, as well as epidemiological studies on an unprecedented scale, which will increase our knowledge of ABR and specific pathogens, and improve the designs of the clinical trials with new investigational drugs. The need for rapid concerted action has driven the funding of seven topics, each of which should add significantly to progress in the fight against ABR. ND4BB unites expertise and provides a platform where the commitment and resources required by all parties are streamlined into a joint public-private partnership initiative of unprecedented scale.
Asunto(s)
Antibacterianos/aislamiento & purificación , Antibacterianos/uso terapéutico , Financiación del Capital , Descubrimiento de Drogas/organización & administración , Farmacorresistencia Bacteriana , Utilización de Medicamentos/normas , Asociación entre el Sector Público-Privado , Descubrimiento de Drogas/métodos , Europa (Continente) , HumanosRESUMEN
The global burden of antibiotic resistance is tremendous and, without new anti-infective strategies, will continue to increase in the coming decades. Despite the growing need for new antibiotics, few pharmaceutical companies today retain active antibacterial drug discovery programmes. One reason is that it is scientifically challenging to discover new antibiotics that are active against the antibiotic-resistant bacteria of current clinical concern. However, the main hurdle is diminishing economic incentives. Increased global calls to minimize the overuse of antibiotics, the cost of meeting regulatory requirements and the low prices of currently marketed antibiotics are strong deterrents to antibacterial drug development programmes. New economic models that create incentives for the discovery of new antibiotics and yet reconcile these incentives with responsible antibiotic use are long overdue. DRIVE-AB is a 9.4 million public-private consortium, funded by the EU Innovative Medicines Initiative, that aims to define a standard for the responsible use of antibiotics and to develop, test and recommend new economic models to incentivize investment in producing new anti-infective agents.
Asunto(s)
Antibacterianos/aislamiento & purificación , Descubrimiento de Drogas/economía , Descubrimiento de Drogas/métodos , Industria Farmacéutica/economía , Industria Farmacéutica/métodos , Investigación/economía , Descubrimiento de Drogas/organización & administración , Descubrimiento de Drogas/tendencias , Humanos , MotivaciónAsunto(s)
Embarazo Gemelar , Ultrasonografía Prenatal , Malformaciones de la Vena de Galeno/diagnóstico , Adulto , Diagnóstico Diferencial , Resultado Fatal , Femenino , Humanos , Recién Nacido , Masculino , Embarazo , Tercer Trimestre del Embarazo , Malformaciones de la Vena de Galeno/diagnóstico por imagenRESUMEN
We have examined the nature and localization of somatic mutations in three kappa transgenes cloned from IgG-secreting hybridomas. All of the mutations identified were single base substitutions. Mutations were localized to the variable (V) region and its flanking sequences. In every case, the nuclear matrix association region, kappa enhancer, and C gene were spared. These data indicate that the rearranged kappa gene contains the necessary sequences for targeting of the mutation process, and suggest that the observed localization of mutations to the V region reflects the inherent specificity of this mutation process.
Asunto(s)
Reordenamiento Génico/genética , Región Variable de Inmunoglobulina/genética , Mutación , Animales , Secuencia de Bases , Línea Celular , Clonación Molecular , Análisis Mutacional de ADN , Hibridomas/inmunología , Ratones , Ratones Transgénicos , Datos de Secuencia MolecularRESUMEN
NK cells demonstrate many immune functions both in vitro and in vivo, including the lysis of tumor or virus-infected cells and the rejection of bone marrow allografts. However it remains unclear whether or not all NK cells can mediate these various functions or if NK cells exist in functionally distinct subsets. We have developed a new NK-specific mAb, SW5E6, which binds to approximately 50% of murine NK cells. The 5E6 antigen identifies a distinct and stable subset of NK cells and is expressed on about one-half of fresh or rIL-2-activated murine NK cells. Both 5E6+ and 5E6- NK cells are capable of lysing YAC-1 tumor cells in vitro and in vivo. By treating animals with SW5E6, we demonstrate that the 5E6+ subset is necessary for the rejection of H-2d/Hh-1d but not H-2b/Hh-1b bone marrow cells. Thus NK cells exist as functionally separable subsets in vivo.
Asunto(s)
Trasplante de Médula Ósea , Rechazo de Injerto , Antígenos de Histocompatibilidad/inmunología , Células Asesinas Naturales/clasificación , Animales , Anticuerpos Monoclonales , Citotoxicidad Inmunológica , Citometría de Flujo , Células Asesinas Naturales/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Bazo/inmunologíaRESUMEN
In an effort to identify cis-acting elements required for targeting of the somatic hypermutation process in mice, we examined whether a T cell receptor (TCR) transgene under the control of the immunoglobulin (Ig) heavy (H) chain intron enhancer would be mutated in antigen-stimulated B cells. Hybridomas were established from splenic B cells of mice carrying two copies of the TCR transgene after hyperimmunization with phosphorylcholine keyhole limpet hemocyanin. Northern analysis revealed that all of the transgene-containing hybridomas expressed the TCR mRNA. Multiple somatic point mutations were found in seven of eight endogenous Ig VH genes examined. In contrast, 29 of 32 TCR genes examined contained no mutations. One potential mutation was seen in each of the three other TCR genes. Our data indicate that although the TCR transgene is expressed in B cells, it is not efficiently targeted by the mutator mechanism. Furthermore, the presence of an Ig H chain enhancer is itself not sufficient for targeting of the somatic hypermutation mechanism.
Asunto(s)
Mutación , Receptores de Antígenos de Linfocitos T/genética , Animales , Secuencia de Bases , Elementos de Facilitación Genéticos , Genes de Inmunoglobulinas , Cadenas Pesadas de Inmunoglobulina/genética , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Ratones Transgénicos , Datos de Secuencia MolecularRESUMEN
Immunoglobulin (Ig) genes expressed in mature B lymphocytes can undergo somatic hypermutation upon cell interaction with antigen and T cells. The mutation mechanism had previously been shown to depend upon transcription initiation, suggesting that a mutator factor was loaded on an RNA polymerase initiating at the promoter and causing mutations during elongation (Peters, A., and U. Storb. 1996. Immunity. 4:57-65). To further elucidate this process we have created an artificial substrate consisting of alternating EcoRV and PvuII restriction enzyme sites (EPS) located within the variable (V) region of an Ig transgene. This substrate can easily be assayed for the presence of mutations in DNA from transgenic lymphocytes by amplifying the EPS insert and determining by restriction enzyme digestion whether any of the restriction sites have been altered. Surprisingly, the EPS insert was mutated many times more frequently than the flanking Ig sequences. In addition there were striking differences in mutability of the different nucleotides within the restriction sites. The data favor a model of somatic hypermutation where the fine specificity of the mutations is determined by nucleotide sequence preferences of a mutator factor, and where the general site of mutagenesis is determined by the pausing of the RNA polymerase due to secondary structures within the nascent RNA.
Asunto(s)
Región Variable de Inmunoglobulina/genética , Cadenas kappa de Inmunoglobulina/genética , Mutagénesis Insercional , ARN , Animales , Secuencia de Bases , Sitios de Unión , ADN Complementario , Desoxirribonucleasas de Localización Especificada Tipo II , Región de Unión de la Inmunoglobulina/genética , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Conformación de Ácido Nucleico , ARN/química , ARN/metabolismo , TransgenesRESUMEN
The rearrangement of Ig genes is known to be regulated by the production of H and kappa L chains. To determine whether lambda L chains have a similar effect, transgenic mice were produced with a lambda 2 gene. It was necessary to include the H chain enhancer, since a lambda gene without the added enhancer did not result in transgene expression. The lambda 2 transgene with the H enhancer was expressed in lymphoid cells only. The majority of the B cells of newborn transgenic mice produced lambda, whereas kappa + cells were reduced. Concomitantly, serum levels of kappa and kappa mRNA were diminished. By 2 wk after birth the proportion of kappa-expressing cells was dramatically increased. Adults had reduced proportions of B cells that produced lambda only, but the levels of lambda were still higher than in normal littermates. Also, kappa + cells were still lower than in normal mice. Analysis of hybridomas revealed that reduction of kappa gene rearrangement was the basis for the decreased frequency of kappa + cells. Furthermore, many cells also contained an unrearranged H chain allele. It was concluded that feedback inhibition by the lambda 2 together with endogenous H protein may have inhibited recombinase activity in early pre-B cells, leading to inhibition of both H chain and kappa gene rearrangement. Thus, lambda 2 can replace kappa in a feedback complex. The levels of serum lambda 1 and, to a lesser degree, of spleen lambda 1 mRNA were reduced in the lambda 2 transgenic mice. However, the proportion of hybridomas with endogenous lambda gene rearrangement was at least as high as in normal mice. It was therefore concluded that the suppression of functional lambda 1 may be a consequence of decreased selection of endogenous lambda-producing cells because of the excess of transgenic lambda. The escape of kappa-producing cells from feedback inhibition may be the result of several mechanisms that operate to varying degrees, among them: (a) kappa rearrangement during a period in which the recombinase is still active after appearance of a lambda 2/mu stop signal; (b) a B cell lineage that is not feedback inhibited at the pre-B cell stage; (c) subthreshold levels of transgenic lambda 2 in some pre-B cells; and (d) loss of the lambda 2 transgenes in rare pre-B cells.
Asunto(s)
Reordenamiento Génico de Cadena Ligera de Linfocito B , Genes de Inmunoglobulinas , Cadenas lambda de Inmunoglobulina/genética , Terapia de Inmunosupresión , Animales , Linfocitos B/metabolismo , Hibridomas/metabolismo , Cadenas kappa de Inmunoglobulina/análisis , Cadenas lambda de Inmunoglobulina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Especificidad de Órganos , ARN Mensajero/aislamiento & purificación , Bazo , Transcripción GenéticaRESUMEN
A positive reinforcement with food produced high-voltage bursts of alpha activity over the posterior marginal gyrus in a cat deprived of food and water. This synchronization was always associated with a large (180 to 300 microvolt), positive steady potential shift comparable to that occurring during the onset of sleep. Since this shift was contingent upon the relative appropriateness and desirability of food reward, it was termed reward contingent positive variation.
Asunto(s)
Conducta Apetitiva , Corteza Cerebral/fisiología , Electrofisiología , Refuerzo en Psicología , Recompensa , Telencéfalo/fisiología , Animales , Gatos , Alimentos , Lóbulo Occipital/fisiología , Lóbulo Parietal/fisiología , SueñoRESUMEN
Ethanol multiplies miniature end-plate potential frequency independently of calcium ion concentrations and also multiplies calcium-dependent depolarization-evoked quantal release, to the same extent. This result implies a final common pathway, requiring little or no calcium, for both kinds of transmitter secretion. Chlorpromazine and hypertonicity act similarly to ethanol, but also depress depolarization-secretion coupling.
Asunto(s)
Calcio/fisiología , Etanol/farmacología , Potenciales de la Membrana/efectos de los fármacos , Unión Neuromuscular/fisiología , Neurotransmisores/metabolismo , Animales , Quelantes/farmacología , Clorpromazina/farmacología , Diafragma , Ácido Edético/farmacología , Soluciones Hipertónicas/farmacología , Técnicas In Vitro , Ratones , Unión Neuromuscular/efectos de los fármacos , Estimulación Química , SacarosaRESUMEN
We find that pADEO16, a recombinant cosmid carrying the rck gene of the Salmonella typhimurium virulence plasmid, when cloned into either rough or smooth Escherichia coli and Salmonella strains, confers high level resistance to the bactericidal activity of pooled normal human serum. The rck gene encodes a 17-kD outer membrane protein that is homologous to a family of virulence-associated outer membrane proteins, including pagC and Ail. Complement depletion, C3 and C5 binding, and membrane-bound C3 cleavage products are similar in strains with and without rck. Although a large difference in C9 binding was not seen, trypsin cleaved 55.7% of bound 125I-C9 counts from rough S. typhimurium with pADEO16, whereas only 26.4% were released from S. typhimurium with K2011, containing a mutation in rck. The majority of C9 extracted from rck strain membranes sediments at a lower molecular weight than in strains without rck, suggesting less C9 polymerization. Furthermore, SDS-PAGE analysis of gradient peak fractions indicated that the slower sedimenting C9-containing complexes in rck strains did not contain polymerized C9 typical of the tubular membrane attack complex. These results indicate that complement resistance mediated by Rck is associated with a failure to form fully polymerized tubular membrane attack complexes.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/genética , Actividad Bactericida de la Sangre , Proteínas del Sistema Complemento/fisiología , Genes Bacterianos , Plásmidos , Salmonella typhimurium/genética , Anticuerpos Monoclonales/inmunología , Autorradiografía , Centrifugación por Gradiente de Densidad , Complemento C5/metabolismo , Complemento C9/metabolismo , Complejo de Ataque a Membrana del Sistema Complemento/metabolismo , Cósmidos , Humanos , Salmonella typhimurium/patogenicidad , VirulenciaRESUMEN
The pyrrolopyrimidine U101033E is a therapeutic compound potentially useful in stroke, head injury and other oxidative stress conditions. Electron paramagnetic resonance (EPR) techniques of spin labeling and spin trapping in conjunction with measures of lipid and protein oxidation have been used to investigate the proposed antioxidant capacity of U101033E. We report potent antioxidant activity of this agent in aqueous cell-free solution as measured by spin trapping. U101033E significantly (P<0.005) reduces the formation of the EPR active spin trap N-t-butyl-alpha-phenylnitrone (PBN)-radical adduct by 17.1% at a concentration of 1 microM, four orders of magnitude less than the concentration of PBN. As measured by the decrease in signal intensity of lipid-resident nitroxide stearate spin probes, an EPR assay for lipid peroxidation, this pyrrolopyrimidine compound efficiently protected against hydroxyl radical-induced lipid peroxidation in cortical synaptosomal membranes deep within the membrane bilayer, but not closer to the membrane surface. In addition, U101033E partially prevents synaptosomal protein oxidation in the presence of Fe(II); however, U101033E demonstrates some protein oxidative effects itself. These results are supportive of the proposed role of U101033E as a lipid-specific antioxidant, especially for protection against lipid peroxidation that occurs deep within the membrane bilayer, but raise some potential concerns about the oxidative nature of this agent toward proteins.
Asunto(s)
Depuradores de Radicales Libres/farmacología , Peroxidación de Lípido/efectos de los fármacos , Pirimidinas/farmacología , Pirrolidinas/farmacología , Sinaptosomas/metabolismo , Animales , Antioxidantes , Encéfalo/metabolismo , Reactivos de Enlaces Cruzados/metabolismo , Espectroscopía de Resonancia por Spin del Electrón , Compuestos Ferrosos , Gerbillinae , Radical Hidroxilo/farmacología , Proteínas de la Membrana/metabolismo , Estructura Molecular , Nitrobencenos , Óxidos de Nitrógeno , Conformación Proteica/efectos de los fármacos , Marcadores de Spin , Sinaptosomas/efectos de los fármacosRESUMEN
PURPOSE: The primary objective was to assess the duration of grade 4 neutropenia (neutrophil count < 0.5 x 10(9)/L) after one cycle of chemotherapy with etoposide, methylprednisolone, cisplatin, and cytarabine in patients randomly assigned to receive one dose of pegfilgrastim or daily filgrastim after chemotherapy. Febrile neutropenia, neutrophil profiles, time to neutrophil recovery, pharmacokinetics, and safety were also assessed. PATIENTS AND METHODS: An open-label, randomized, phase II study was designed to compare the effects of a single subcutaneous injection of pegfilgrastim (sustained-duration filgrastim) 100 micro g/kg per chemotherapy cycle (n = 33) with daily subcutaneous injections of filgrastim 5 micro g/kg (n = 33) in patients receiving salvage chemotherapy for relapsed or refractory Hodgkin's or non-Hodgkin's lymphoma. RESULTS: The incidence of grade 4 neutropenia in the pegfilgrastim and filgrastim groups was 69% and 68%, respectively. In addition, the mean duration of grade 4 neutropenia was similar in both groups (2.8 and 2.4 days, respectively). The results for the two groups were also not significantly different for febrile neutropenia, neutrophil profile, time to neutrophil recovery, or toxicity profile. A single subcutaneous injection of pegfilgrastim 100 micro g/kg produced a sustained serum concentration relative to daily subcutaneous injections of filgrastim. Filgrastim-treated patients received a median of 11 injections per cycle. CONCLUSION: Pegfilgrastim was safe and well tolerated in this patient population. A single injection of pegfilgrastim per chemotherapy cycle provided neutrophil support with safety and efficacy similar to that provided by daily injections of filgrastim. Once-per-cycle administration of pegfilgrastim simplifies the management of neutropenia and may have important clinical benefits for patients and healthcare providers.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/análogos & derivados , Factor Estimulante de Colonias de Granulocitos/farmacología , Enfermedad de Hodgkin/tratamiento farmacológico , Linfoma no Hodgkin/tratamiento farmacológico , Neutropenia/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Esquema de Medicación , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Filgrastim , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Humanos , Inyecciones Subcutáneas , Masculino , Metilprednisolona/administración & dosificación , Metilprednisolona/efectos adversos , Persona de Mediana Edad , Neutropenia/etiología , Neutropenia/prevención & control , Polietilenglicoles , Proteínas Recombinantes , Resultado del TratamientoRESUMEN
Quantitative genetic variation in behavioral response to the odorant, benzaldehyde, was assessed among a sample of 43 X and 35 third chromosomes extracted from a natural population and substituted into a common inbred background. Significant genetic variation among chromosome lines was detected. Heritability estimates for olfactory response, however, were low, as is typical for traits under natural selection. Furthermore, the loci affecting naturally occurring variation in olfactory response to benzaldehyde were not the same in males and females, since the genetic correlation between the sexes was low and not significantly different from zero for the chromosome 3 lines. Competitive fitness, viability and fertility of the chromosome 3 lines were estimated using the balancer equilibrium technique. Genetic correlations between fitness and odor-guided behavior were not significantly different from zero, suggesting the number of loci causing variation in olfactory response is small relative to the number of loci causing variation in fitness. Since different genes affect variation in olfactory response in males and females, genetic variation for olfactory response could be maintained by genotype x sex environment interaction. This unusual genetic architecture implies that divergent evolutionary trajectories for olfactory behavior may occur in males and females.
Asunto(s)
Drosophila melanogaster/genética , Reacción de Fuga , Variación Genética , Odorantes , Animales , Benzaldehídos/química , Drosophila melanogaster/fisiología , Femenino , MasculinoRESUMEN
The nature of genetic variation for Drosophila longevity in a population of recombinant inbred lines was investigated by estimating quantitative genetic parameters and mapping quantitative trait loci (QTL) for adult life span in five environments: standard culture conditions, high and low temperature, and heat-shock and starvation stress. There was highly significant genetic variation for life span within each sex and environment. In the analysis of variance of life span pooled over sexes and environments, however, the significant genetic variation appeared in the genotype x sex and genotype x environment interaction terms. The genetic correlation of longevity across the sexes and environments was not significantly different from zero in these lines. We estimated map positions and effects of QTL affecting life span by linkage to highly polymorphic roo transposable element markers, using a multiple-trait composite interval mapping procedure. A minimum of 17 QTL were detected; all were sex and/or environment-specific. Ten of the QTL had sexually antagonistic or antagonistic pleiotropic effects in different environments. These data provide support for the pleiotropy theory of senescence and the hypothesis that variation for longevity might be maintained by opposing selection pressures in males and females and variable environments. Further work is necessary to assess the generality of these results, using different strains, to determine heterozygous effects and to map the life span QTL to the level of genetic loci.
Asunto(s)
Drosophila melanogaster/genética , Longevidad/genética , Carácter Cuantitativo Heredable , Animales , Drosophila melanogaster/fisiología , Femenino , Variación Genética , Genotipo , Masculino , FenotipoRESUMEN
Our studies with scid mice have clarified the relationship between T cells and NK cells. C.B-17 scid mice have normal frequency of transplantable NK progenitors in their bone marrow which develop into fully functional NK cells. Spleens of scid mice contain mature NK cells which are phenotypically and functionally indistinguishable from NK cells found in normal mice. These cells retain their TCR genes in germline configuration and do not transcribe the CD3 genes. Thus, NK cells are distinct from the earliest identifiable cells committed to the T-lineage. In addition to the spleen, the thymus of scid mice also contains mature NK cells. These cells constitute a small proportion of the thymus cell population and can be clearly distinguished from the majority of cells, which have the phenotype and molecular characteristics of very early T-lineage cells. There is no evidence that NK cells within the thymus are derived in situ from a common NK/T precursor. Together these data support the hypothesis that NK cells form an independent lineage.
Asunto(s)
Síndromes de Inmunodeficiencia/inmunología , Células Asesinas Naturales/inmunología , Ratones Mutantes/inmunología , Animales , Médula Ósea/patología , Síndromes de Inmunodeficiencia/patología , Células Asesinas Naturales/trasplante , Activación de Linfocitos , Ratones , Bazo/patología , Timo/citologíaRESUMEN
In the past year, the importance of secretory IgA has been emphasized as fundamental to protection against oral Salmonella infection. In several human trials, aro mutants of Salmonella typhi were highly immunogenic, but still retained the capacity to proceed beyond the gut wall after ingestion. Epitopes of Shiga toxin and influenza hemagglutinin have been expressed in Salmonella surface proteins in work aimed at the construction of hybrid vaccines. Eukaryotic cell involvement in the process of Salmonella attachment/invasion appears to be triggered by host cell phospholipase activation. Our understanding of the number and functions of Salmonella genes involved in the attachment/invasion process has increased considerably--different gene sets are required for invasion of different cell types.
Asunto(s)
Expresión Génica , Salmonella/genética , Salmonella/inmunología , Vacunas Sintéticas/administración & dosificación , Animales , Antígenos Bacterianos/genética , Biotecnología , Humanos , Inmunoglobulina A Secretora/biosíntesis , Mutación , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Salmonella/patogenicidad , Infecciones por Salmonella/prevención & control , Virulencia/genéticaRESUMEN
The effects of substerilizing doses of gamma radiation on the longevity and level of inherited sterility in the Australian moth Teia anartoides Walker were determined. Six day-old male pupae were treated with 0, 100, and 160 Gy of gamma radiation by using a 1.25 MeV Cobalt60 irradiation source. Laboratory studies of male longevity showed that radiation had little impact in adult moths of the P1, F1, and F2 generations. Inherited deleterious effects resulting from irradiation were observed in the progeny of F1 and F2 generations. Outcrosses between substerile parental males or their highly sterile male progeny to wild-type females did not affect female fecundity. However, adverse effects were observed for these crosses in the rates of successful egg hatch and postembryonic development. Fertility was always greater in out-crosses involving a P1 male than in any of the F1 out-crosses. F1 males were always more sterile than F1 females, and the level of sterility for the F1 and F2 generations was higher than that of the controls. The incidence of larval and pupal mortality was higher in the F2 than the F1 generation. A dose of 100 Gy had the highest success in inducing deleterious effects that were inherited through to the F2 generation. Our results indicated that the use of partially sterilizing doses of radiation has good potential as a selective strategy for management or eradication of T. anartoides.
Asunto(s)
Rayos gamma , Mariposas Nocturnas/efectos de la radiación , Animales , Femenino , Larva/efectos de la radiación , Masculino , Mariposas Nocturnas/crecimiento & desarrollo , Mariposas Nocturnas/fisiología , Pupa/efectos de la radiación , Reproducción/efectos de la radiaciónRESUMEN
This review describes studies on somatic hypermutation of immunoglobulin genes that were started in the mid-80s in collaboration with Ralph Brinster. Almost all of the experiments were carried out using Ig transgenes as targets for the somatic mutation mechanism. Ig transgenes can be very good targets of somatic mutation, despite many different transgene integration sites. Thus, the required cis-acting elements must be present within the approximately 10 kb of the transgene. Only the Ig variable region and its proximate flanks are mutated, not the constant region in unmanipulated sequences. Several Ig gene enhancers are permissive for somatic mutation and they do not have to be associated with the Ig promoter they normally interact with. However, the mutation process does seem to be specific for Ig genes. No mutations were found in several housekeeping genes isolated from cells that had very high levels of somatic hypermutation of their Ig genes. This suggests that the Ig enhancers provide the lg gene specificity. An exception is the Bcl-6 gene, encoding a transcription factor, which was found to be mutated in normal human memory B cells. When the transcriptional promoter that is located upstream of the variable region is duplicated upstream of the constant region, this region is mutated as well. This suggests a transcription coupled model in which a mutator factor associates with the RNA polymerase at the initiation of transcription, travels with the polymerase during elongation, and causes mutations during polymerase pausing. Our recent data with an artificial substrate for somatic mutation suggest that the mutations are increased by increased stability of the secondary structures in the nascent RNA, and the specific nucleotides that are mutated are due to preferences of a mutator factor.