RESUMEN
Cystic fibrosis (CF) is a multiorgan disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). In patients with CF, abnormalities initiate in several organs before birth. However, the long-term impact of these in utero pathologies on disease pathophysiology is unclear. To address this issue, we generated ferrets harboring a VX-770 (ivacaftor)-responsive CFTR G551D mutation. In utero VX-770 administration provided partial protection from developmental pathologies in the pancreas, intestine, and male reproductive tract. Homozygous CFTR G551D/G551D animals showed the greatest VX-770-mediated protection from these pathologies. Sustained postnatal VX-770 administration led to improved pancreatic exocrine function, glucose tolerance, growth and survival, and to reduced mucus accumulation and bacterial infections in the lung. VX-770 withdrawal at any age reestablished disease, with the most rapid onset of morbidity occurring when withdrawal was initiated during the first 2 weeks after birth. The results suggest that CFTR is important for establishing organ function early in life. Moreover, this ferret model provides proof of concept for in utero pharmacologic correction of genetic disease and offers opportunities for understanding CF pathogenesis and improving treatment.
Asunto(s)
Aminofenoles/administración & dosificación , Agonistas de los Canales de Cloruro/administración & dosificación , Fibrosis Quística/tratamiento farmacológico , Quinolonas/administración & dosificación , Animales , Animales Modificados Genéticamente , Animales Recién Nacidos , Glucemia/metabolismo , Fibrosis Quística/genética , Fibrosis Quística/fisiopatología , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Hurones , Técnicas de Sustitución del Gen , Genitales Masculinos/anomalías , Genitales Masculinos/efectos de los fármacos , Edad Gestacional , Humanos , Masculino , Mutación , Páncreas Exocrino/efectos de los fármacos , Páncreas Exocrino/patología , Páncreas Exocrino/fisiopatología , Embarazo , Infecciones del Sistema Respiratorio/etiología , Infecciones del Sistema Respiratorio/prevención & control , Investigación Biomédica TraslacionalRESUMEN
We present the design of a novel collector mirror for laser produced plasma (LPP) light sources to be used in extreme ultraviolet (EUV) lithography. The design prevents undesired infrared (IR) drive laser light, reflected from the plasma, from reaching the exit of the light source. This results in a strong purification of the EUV light, while the reflected IR light becomes refocused into the plasma for enhancing the IR-to-EUV conversion. The dual advantage of EUV purification and conversion enhancement is achieved by incorporating an IR Fresnel zone plate pattern into the EUV reflective multilayer coating of the collector mirror. Calculations using Fresnel-Kirchhoff's diffraction theory for a typical collector design show that the IR light at the EUV exit is suppressed by four orders of magnitude. Simultaneously, 37% of the reflected IR light is refocused back the plasma.
RESUMEN
Plasmas, produced by a neodymium yttrium aluminum garnet (Nd:YAG) laser pulse focused on a small water droplet and used for the generation of extreme ultraviolet light, can be described by a relatively simple model due to the fact that thermodynamic equilibrium can be assumed for the most important phase. Only three time-dependent variables--radius, expansion speed, and internal energy--are needed to describe the physics of the plasma. Nevertheless, it predicts quantities such as the size and the spectrum rather well. It is expected that the theory and the model presented here can also be applied to other laser-produced plasmas.
