Targeted Deletion of a High-Affinity GATA-binding Site in the GATA-1 Promoter Leads to Selective Loss of the Eosinophil Lineage In Vivo

Transcription factor GATA-1 reprograms immature myeloid cells to three different hematopoietic lineages-erythroid cells, megakaryocytes, and eosinophils. GATA-1 is essential for maturation of erythroid and megakaryocytic precursors, as revealed by gene targeting in mice. Here we demonstrate that deletion of a high-affinity GATA-binding site in the GATA-1 promoter, an element presumed to mediate positive autoregulation of GATA-1 expression, leads to selective loss of the eosinophil lineage. These findings suggest that GATA-1 is required for specification of this lineage during hematopoietic development. Mice lacking the ability to produce eosinophils should prove useful in ascertaining the role of eosinophils in a variety of inflammatory or allergic disorders

The effect of symmetrical and asymmetrical hearing impairment on the music quality perception

The purpose of this study was to investigate the effect of symmetrical, asymmetrical and unilateral hearing impairment on music quality perception. Six validated music pieces in the categories of classical music, folk music and pop music were used to assess music quality in terms of its ‘pleasantness’, ‘naturalness’, ‘fullness’, ‘roughness’ and ‘sharpness’. 58 participants with sensorineural hearing loss [20 with unilateral hearing loss (UHL), 20 with bilateral symmetrical hearing loss (BSHL) and 18 with bilateral asymmetrical hearing loss (BAHL)] and 29 normal hearing (NH) subjects participated in the present study. Hearing impaired (HI) participants had greater difficulty in overall music quality perception than NH participants. Participants with BSHL rated music pleasantness and naturalness to be higher than participants with BAHL. Moreover, the hearing thresholds of the better ears from BSHL and BAHL participants as well as the hearing thresholds of the worse ears from BSHL participants were negatively correlated to the pleasantness and naturalness perception. HI participants rated the familiar music pieces higher than unfamiliar music pieces in the three music categories. Music quality perception in participants with hearing impairment appeared to be affected by symmetry of hearing loss, degree of hearing loss and music familiarity when they were assessed using the music quality rating test (MQRT). This indicates that binaural symmetrical hearing is important to achieve a high level of music quality perception in HI listeners. This emphasizes the importance of provision of bilateral hearing assistive devices for people with asymmetrical hearing impairment

Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide

In the 1950s the drug thalidomide administered as a sedative to pregnant women led to the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and its derivatives lenalidomide and pomalidomide (together known as Immunomodulatory Drugs: IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase and promote the ubiquitination of Ikaros/Aiolos transcription factors by CRL4CRBN. Here we present the crystal structure of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes CRBN as a CRL4CRBN substrate receptor, which enantioselectively binds IMiDs. Through an unbiased screen we identify the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4CRBN. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4CRBN when recruiting Ikaros/Aiolos for degradation. This dual activity implies that small molecules can principally modulate a ligase to up- or down-regulate the ubiquitination of proteins