RESUMEN
The identification of genes and interventions that slow or reverse aging is hampered by the lack of non-invasive metrics that can predict the life expectancy of pre-clinical models. Frailty Indices (FIs) in mice are composite measures of health that are cost-effective and non-invasive, but whether they can accurately predict health and lifespan is not known. Here, mouse FIs are scored longitudinally until death and machine learning is employed to develop two clocks. A random forest regression is trained on FI components for chronological age to generate the FRIGHT (Frailty Inferred Geriatric Health Timeline) clock, a strong predictor of chronological age. A second model is trained on remaining lifespan to generate the AFRAID (Analysis of Frailty and Death) clock, which accurately predicts life expectancy and the efficacy of a lifespan-extending intervention up to a year in advance. Adoption of these clocks should accelerate the identification of longevity genes and aging interventions.
Asunto(s)
Envejecimiento/fisiología , Ratones/fisiología , Envejecimiento/genética , Animales , Relojes Biológicos , Femenino , Fragilidad , Humanos , Esperanza de Vida , Aprendizaje Automático , Masculino , Ratones/genética , Ratones/crecimiento & desarrollo , Ratones Endogámicos C57BLRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMEN
Phage display antibody libraries have a proven track record for the discovery of therapeutic human antibodies, increasing the demand for large and diverse phage antibody libraries for the discovery of new therapeutics. We have constructed naïve antibody phage display libraries in both Fab and scFv formats, with each library having more than 250 billion clones that encompass the human antibody repertoire. These libraries show high fidelity in open reading frame and expression percentages, and their V-gene family distribution, VH-CDR3 length and amino acid usage mirror the natural diversity of human antibodies. Both the Fab and scFv libraries show robust sequence diversity in target-specific binders and differential V-gene usage for each target tested, supporting the use of libraries that utilize multiple display formats and V-gene utilization to maximize antibody-binding diversity. For each of the targets, clones with picomolar affinities were identified from at least one of the libraries and for the two targets assessed for activity, functional antibodies were identified from both libraries.
Asunto(s)
Técnicas de Visualización de Superficie Celular , Fragmentos Fab de Inmunoglobulinas/inmunología , Biblioteca de Péptidos , Receptor de Insulina/inmunología , Receptor TIE-2/inmunología , Anticuerpos de Cadena Única/inmunología , Secuencia de Aminoácidos , Animales , Afinidad de Anticuerpos , Especificidad de Anticuerpos , Células CHO , Cricetinae , Cricetulus , Humanos , Fragmentos Fab de Inmunoglobulinas/biosíntesis , Fragmentos Fab de Inmunoglobulinas/genética , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Sistemas de Lectura Abierta , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptor de Insulina/genética , Receptor TIE-2/genética , Anticuerpos de Cadena Única/biosíntesis , Anticuerpos de Cadena Única/genética , TransfecciónRESUMEN
There is a substantial disagreement in the existing literature regarding which hemisphere of the brain controls spatial abilities. In an attempt to resolve this dispute, we conducted a meta-analysis to decipher which hemisphere truly dominates and under what circumstances. It was found that across people and situations, the right hemisphere is the more dominant for spatial processing. However, consideration of specific moderator variables yielded a more complex picture. For example, females showed no hemisphere preference while males showed a right hemisphere advantage. Also, no hemisphere preference was indicated for spatial visualization tasks while subjects performing spatial orientation and manual manipulation tasks displayed a predictable right hemisphere preference. These findings are discussed in terms of their implications for exiting theoretical positions as well as future empirical research.