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Pasadena, California. Quattro giovani scienziati di diversi campi – il fisico sperimentale Leonard Hofstadter, il fisico teorico Sheldon Cooper, l'astrofisico Rajesh Koothrappali e l'ingegnere aerospaziale Howard Wolowitz lavorano insieme al California Institute of Technology. Questi fanno amicizia con Penny, una bella ragazza di provincia col sogno di diventare attrice, venuta a vivere nell'appartamento di fronte a quello condiviso da Leonard e Sheldon.
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