69 research outputs found

    Neural cell adhesion molecule (NCAM) association with PKCĪ²2 via Ī²I spectrin is implicated in NCAM-mediated neurite outgrowth

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    In hippocampal neurons and transfected CHO cells, neural cell adhesion molecule (NCAM) 120, NCAM140, and NCAM180 form Triton X-100ā€“insoluble complexes with Ī²I spectrin. Heteromeric spectrin (Ī±IĪ²I) binds to the intracellular domain of NCAM180, and isolated spectrin subunits bind to both NCAM180 and NCAM140, as does the Ī²I spectrin fragment encompassing second and third spectrin repeats (Ī²I2ā€“3). In NCAM120-transfected cells, Ī²I spectrin is detectable predominantly in lipid rafts. Treatment of cells with methyl-Ī²-cyclodextrin disrupts the NCAM120ā€“spectrin complex, implicating lipid rafts as a platform linking NCAM120 and spectrin. NCAM140/NCAM180ā€“Ī²I spectrin complexes do not depend on raft integrity and are located both in rafts and raft-free membrane domains. PKCĪ²2 forms detergent-insoluble complexes with NCAM140/NCAM180 and spectrin. Activation of NCAM enhances the formation of NCAM140/NCAM180ā€“spectrinā€“PKCĪ²2 complexes and results in their redistribution to lipid rafts. The complex is disrupted by the expression of dominant-negative Ī²I2ā€“3, which impairs binding of spectrin to NCAM, implicating spectrin as the bridge between PKCĪ²2 and NCAM140 or NCAM180. Redistribution of PKCĪ²2 to NCAMā€“spectrin complexes is also blocked by a specific fibroblast growth factor receptor inhibitor. Furthermore, transfection with Ī²I2ā€“3 inhibits NCAM-induced neurite outgrowth, showing that formation of the NCAMā€“spectrinā€“PKCĪ²2 complex is necessary for NCAM-mediated neurite outgrowth

    Getting It on Record: Issues and Strategies for Ethnographic Practice in Recording Studios

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    The recording studio has been somewhat neglected as a site for ethnographic fieldwork in the field of ethno-musicology and, moreover, the majority of published studies tend to overlook the specific concerns faced by the researcher within these contexts. Music recording studios can be places of creativity, artistry, and collaboration, but they often also involve challenging, intimidating, and fractious relations. Given that recording studios are, first and foremost, concerned with documenting musiciansā€™ performances, we discuss the concerns of getting studio interactions ā€œon recordā€ in terms of access, social relations, and methods of data collection. This article reflects on some of the issues we faced when conducting our fieldwork within British music recording facilities and makes suggestions based on strategies that we employed to address these issues

    Oral Abstracts 7: RA ClinicalO37.ā€ƒLong-Term Outcomes of Early RA Patients Initiated with Adalimumab Plus Methotrexate Compared with Methotrexate Alone Following a Targeted Treatment Approach

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    Background: This analysis assessed, on a group level, whether there is a long-term advantage for early RA patients treated with adalimumab (ADA) + MTX vs those initially treated with placebo (PBO) + MTX who either responded to therapy or added ADA following inadequate response (IR). Methods: OPTIMA was a 78- week, randomized, controlled trial of ADA + MTX vs PBO + MTX in MTX-naĆÆve early (<1 year) RA patients. Therapy was adjusted at week 26: ADA + MTX-responders (R) who achieved DAS28 (CRP) <3.2 at weeks 22 and 26 (Period 1, P1) were re-randomized to withdraw or continue ADA and PBO + MTX-R continued randomized therapy for 52 weeks (P2); IR-patients received open-label (OL) ADA + MTX during P2. This post hoc analysis evaluated the proportion of patients at week 78 with DAS28 (CRP) <3.2, HAQ-DI <0.5, and/or Ī”mTSS ā‰¤0.5 by initial treatment. To account for patients who withdrew ADA during P2, an equivalent proportion of R was imputed from ADA + MTX-R patients. Results: At week 26, significantly more patients had low disease activity, normal function, and/or no radiographic progression with ADA + MTX vs PBO + MTX (Table 1). Differences in clinical and functional outcomes disappeared following additional treatment, when PBO + MTX-IR (n = 348/460) switched to OL ADA + MTX. Addition of OL ADA slowed radiographic progression, but more patients who received ADA + MTX from baseline had no radiographic progression at week 78 than patients who received initial PBO + MTX. Conclusions: Early RA patients treated with PBO + MTX achieved comparable long-term clinical and functional outcomes on a group level as those who began ADA + MTX, but only when therapy was optimized by the addition of ADA in PBO + MTX-IR. Still, ADA + MTX therapy conferred a radiographic benefit although the difference did not appear to translate to an additional functional benefit. Disclosures: P.E., AbbVie, Merck, Pfizer, UCB, Roche, BMSā€”Provided Expert Advice, Undertaken Trials, AbbVieā€”AbbVie sponsored the study, contributed to its design, and participated in the collection, analysis, and interpretation of the data, and in the writing, reviewing, and approval of the final version. R.F., AbbVie, Pfizer, Merck, Roche, UCB, Celgene, Amgen, AstraZeneca, BMS, Janssen, Lilly, Novartisā€”Research Grants, Consultation Fees. S.F., AbbVieā€”Employee, Stocks. A.K., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, Pfizer, Roche, UCBā€”Research Grants, Consultation Fees. H.K., AbbVieā€”Employee, Stocks. S.R., AbbVieā€”Employee, Stocks. J.S., AbbVie, Amgen, AstraZeneca, BMS, Celgene, Centocor-Janssen, GlaxoSmithKline, Lilly, Pfizer (Wyeth), MSD (Schering-Plough), Novo-Nordisk, Roche, Sandoz, UCBā€”Research Grants, Consultation Fees. R.V., AbbVie, BMS, GlaxoSmithKline, Human Genome Sciences, Merck, Pfizer, Roche, UCB Pharmaā€”Consultation Fees, Research Support. Table 1.Week 78 clinical, functional, and radiographic outcomes in patients who received continued ADA + MTX vs those who continued PBO + MTX or added open-label ADA following an inadequate response ADA + MTX, n/N (%)a PBO + MTX, n/N (%)b Outcome Week 26 Week 52 Week 78 Week 26 Week 52 Week 78 DAS28 (CRP) <3.2 246/466 (53) 304/465 (65) 303/465 (65) 139/460 (30)*** 284/460 (62) 300/460 (65) HAQ-DI <0.5 211/466 (45) 220/466 (47) 224/466 (48) 150/460 (33)*** 203/460 (44) 208/460 (45) Ī”mTSS ā‰¤0.5 402/462 (87) 379/445 (86) 382/443 (86) 330/459 (72)*** 318/440 (72)*** 318/440 (72)*** DAS28 (CRP) <3.2 + Ī”mTSS ā‰¤0.5 216/462 (47) 260/443 (59) 266/443 (60) 112/459 (24)*** 196/440 (45) 211/440 (48)*** DAS28 (CRP) <3.2 + HAQ-DI <0.5 + Ī”mTSS ā‰¤0.5 146/462 (32) 168/443 (38) 174/443 (39) 82/459 (18)*** 120/440 (27)*** 135/440 (31)** aIncludes patients from the ADA Continuation (n = 105) and OL ADA Carry On (n = 259) arms, as well as the proportional equivalent number of responders from the ADA Withdrawal arm (n = 102). bIncludes patients from the MTX Continuation (n = 112) and Rescue ADA (n = 348) arms. Last observation carried forward: DAS28 (CRP) and HAQ-DI; Multiple imputations: Ī”mTSS. ***P < 0.001 and **iP < 0.01, respectively, for differences between initial treatments from chi-squar

    From Democratic Peace to Democratic Distinctiveness: A Critique of Democratic Exceptionalism in Peace and Conflict Studies

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    Assumption without representation: the unacknowledged abstraction from communities and social goods

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    We have not clearly acknowledged the abstraction from unpriceable ā€œsocial goodsā€ (derived from communities) which, different from private and public goods, simply disappear if it is attempted to market them. Separability from markets and economics has not been argued, much less established. Acknowledging communities would reinforce rather than undermine them, and thus facilitate the production of social goods. But it would also help economics by facilitating our understanding of ā€“ and response to ā€“ financial crises as well as environmental destruction and many social problems, and by reducing the alienation from economics often felt by students and the public

    Spectrin oligomerization is cooperatively coupled to membrane assembly: A linkage targeted by many hereditary hemolytic anemias?

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    In the erythrocyte, ankyrin is the major adapter protein linking mutation of the linker sequences that join helices C and A in repeat tetramers of band 3 to the spectrinā€“actin cytoskeleton. This linkage units that intervene between the two functional sites, mutations that involves a direct interaction between ankyrin and the 14thā€“15th repeat presumably block repeat-to-repeat transfer of conformational informaunit of b-spectrin. The spectrin cytoskeleton itself is stabilized by tion; (ii) mutations in a-spectrin repeats 4 to 6 that disrupt the ability the self-association of spectrin heterodimers into tetramers and larger of this region to trans-regulate ankyrin binding by the adjacent boligomers, a process mediated by the 17th repeat unit of b-spectrin spectrin repeats 14ā€“15; and (iii) exon-skipping mutations that shorten and a short NH2-terminal sequence in a-spectrin. The self-association a-spectrin and force repeats 4 to 6 to fall out-of-register with the of spectrin and its ankyrin-mediated membrane binding have generally ankyrin-binding motif in b-spectrin. Collectively, these results demonbeen considered independent events.We now demonstrate that spectrin strate a molecular mechanism whereby a membrane receptor can diself- association, the binding of spectrin to ankyrin, and the binding of rectly promote cytoskeletal assembly. q 2001 Academic Press ankyrin to the 43-kDa cytoplasmic domain of band 3 (cdb3) are coupled in a positively cooperative way. In solution, [125I]-labeled ankyrin was found by ND-PAGE3 to enhance the affinity of spectrin self-association by 10-fold. The reciprocal process was also true, in that spectrin tetramers and oligomers bound ankyrin with enhanced affinity relative to dimer spectrin. Saturation of the b-spectrin self-association site by INTRODUCTION an NH2-terminal 80-kDa a-spectrin peptide enhanced the affinity of spectrin dimer for ankyrin, indicating a direct relationship between ankyrin binding and the occupancy of the b-spectrin self-association During the process of erythroid maturation the cortical site. cdb3 accentuated these cooperative interactions. Several inherited spectrin mutations that cause hemolytic disease but that do not directly cytoskeleton is formed by interactions between ankyrin, destabilize the self-association or ankyrin-binding sites can be ex- band 3 (the membrane anion transporter 1, AE1), and specplained by these results. Three classes of mutations appear to disrupt trin (for reviews, see Lux and Palek, 1995; Morrow et al., cooperative coupling between self-association and ankyrin binding
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