In this small trial, administration of lanadelumab to patients with hereditary angioedema with C1 inhibitor deficiency reduced cleavage of high-molecular-weight kininogen and attacks of angioedema. (Funded by Dyax; ClinicalTrials.gov number, NCT02093923 .).

SF3b is a U2 snRNP-associated protein complex essential for spliceosome assembly. Although evidence that SF3b contains the spliceosomal proteins SAPs 49, 130, 145, and 155 has accumulated, a protein-mediated association between all of these proteins has yet to be directly demonstrated. Here we report the isolation of a cDNA encoding SAP 130, which completes the cloning of the putative SF3b complex proteins. Using antibodies to SAP 130 and other putative SF3b components, we showed that SAPs 130, 145, and 155 are present in a protein complex in nuclear extracts and that these proteins associate with one another in purified U2 snRNP. Moreover, SAPs 155 and 130 interact with each other (directly or indirectly) within this complex, and SAPs 49 and 145 are known to interact directly with each other. Thus, together with prior work, our studies indicate that SAPs 49, 130, 145, and 155 are indeed components of SF3b. The Saccharomyces cerevisiae homologs of SAPs 49 and 145 are encoded by essential genes. We show here that the S. cerevisiae homologs of SAPs 130 and 155 (scSAP 130/RSE1 and scSAP 155, respectively) are also essential. Recently, the SF3b proteins were found in purified U12 snRNP, which functionally substitutes for U2 snRNP in the minor spliceosome. This high level of conservation, together with the prior observation that the SF3b proteins interact with pre-mRNA very close to the branch site, suggest that the SF3b complex plays a critical role near or at the spliceosome catalytic core.Many proteins essential for spliceosome assembly and splicing have been identified, and numerous human homologs of essential yeast splicing factors are now known (for reviews, see references 19, 20, 24, and 29). Among the best characterized of these are the components of U2 snRNP (for reviews, see references 19, 20, and 29). In mammals, functional 17S U2 snRNP can be assembled from 12S U2 snRNP and two essential splicing factors, SF3a and SF3b (5, 6). SF3a has been purified to homogeneity and contains three proteins (SF3a60, SF3a66 and SF3a120) (5, 6). SF3b has been purified through multiple chromatographic steps but has not been purified to homogeneity (5, 6). The components thought to constitute SF3b were identified by comparing purified 17S U2 snRNP and the spliceosomal complex A (for reviews see references 14 and 19). The abundant proteins common to both of these complexes are referred to as SF3b 53, 120, 150, and 160 in 17S U2 snRNP and SAPs 49, 130, 145 and 155, respectively, in the spliceosome (we use the latter nomenclature here) (2,6,19). Further evidence that at least two of these proteins are components of SF3b came from the observation that SAPs 49 and 145 interact directly with each other (7). In addition, SAPs 49, 145, and 155, as well as all three SF3a subunits, can be UV cross-linked to the region surrounding the branch site in the spliceosomal complex A (11, 12). Thus, these proteins are all located next to one another in functional spliceosomal complexes, consistent with the notion that they are present in a com...

ClinicalTrials.gov identifier: NCT01923207.

No abstract

Asthma is a multifactorial disease of the airways characterized by airway inflammation, mucus hypersecretion, and airway hyperresponsiveness. Conventional MHC-class II restricted CD4 + T cells are considered a key cell in asthma pathogenesis as they have a broad T cell receptor repertoire, providing specificity and reactivity to diverse protein allergens. This notion was challenged when a study found that invariant (i) NKT cells were the predominant T cell in the lung and BAL of all asthmatic subjects studied. This finding was provocative because iNKT cells have a very limited T cell receptor repertoire and are specific for a restricted set of lipid antigens that bind to CD1d, a nonpolymorphic MHC-like molecule. However, multiple subsequent studies failed to replicate the initial study and instead found that iNKT cells are present as a small fraction of the total T cells in the asthmatic lung. Thus, we believe that while CD1d-restricted NKT cells may play a role in modulating the asthmatic phenotype, they are not the critical drivers of the asthmatic response, a role we believe is still held by conventional MHC-class II restricted CD4 + T cells.