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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 the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as [CRL4.sup.crbn]) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4cRbn. Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within [CRL4.sup.crbn] and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of [CRL4.sup.crbn]. Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to [CRL4.sup.crbn] while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins., Thalidomide (α-(N-phthalimido)glutarimide) was introduced to the market in 1954 by the company Chemie Griinenthal. Initially promoted as a sedative with anti-emetic properties (1,2), it became popular for treating 'morning sickness' [...]

The metabolically versatile soil bacterium Pseudomonas putida has to cope with numerous abiotic stresses in its habitats. The stress responses of P. putida KT2440 to 4[degrees]C, pH 4.5, 0.8 M urea, and 45 mM sodium benzoate were analyzed by determining the global mRNA expression profiles and screening for stress-intolerant non-auxotrophic Tn5 transposon mutants. In 392 regulated genes or operons, 36 gene regions were differentially expressed by more than 2.5-fold, and 32 genes in 23 operons were found to be indispensable for growth during exposure to one of the abiotic stresses. The transcriptomes of the responses to urea, benzoate, and 4[degrees]C correlated positively with each other but negatively with the transcriptome of the mineral acid response. The CbrAB sensor kinase, the cysteine synthase CysM, PcnB and VacB, which control mRNA stability, and BipA, which exerts transcript-specific translational control, were essential to cope with cold stress. The cyo operon was required to cope with acid stress. A functional PhoP, PtsP, RelA/SpoT modulon, and adhesion protein LapA were necessary for growth in the presence of urea, and the outer membrane proteins OmlA and FepA and the phosphate transporter PstBACS were indispensable for growth in the presence of benzoate. A lipid A acyltransferase (PP0063) was a mandatory component of the stress responses to cold, mineral acid, and benzoate. Adaptation of the membrane barrier, uptake of phosphate, maintenance of the intracellular pH and redox status, and translational control of metabolism are key mechanisms of the response of P. putida to abiotic stresses.

This note discusses research strategies for an investigation of urban development and planning in the Stockholm region during the period 1945-1980. The intellectual point of departure for this investigation is in polemics with traditional planning theory. As opposed to that tradition we believe that you can say very little about the role of official planning if you don't study its effects. In order to deal with this problem you have to have a clear understanding of the phenomenon of urban development. Official planning is simultaneously a part of, shaped by, and a mechanism in urban development. This proposition leads to the field of urban research, a field which internationally has undergone flourishing theoretical reorientations during the last decade. By underlining and commenting on central problems in urban research, we hope to lay foundations for a broader discussion of different strategies for approaching the study of the city under capitalism. [ABSTRACT FROM AUTHOR]

This paper introduces a series of articles which deals with social planning.