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Gloria M. Culver - One of the best experts on this subject based on the ideXlab platform.
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assembly of the 30S ribosomal subunit
EcoSal Plus, 2008Co-Authors: Gloria M. Culver, Narayanaswamy KirthiAbstract:Protein synthesis involves nearly a third of the total molecules in a typical bacterial cell. Within the cell, protein synthesis is performed by the ribosomes, and research over several decades has investigated ribosomal formation, structure, and function. This review provides an overview of the current understanding of the assembly of the Escherichia coli 30S ribosomal subunit. The E. coli 30S subunit contains one rRNA molecule (16S) and 21 ribosomal proteins (r-proteins; S1 to S21). The formation of functional subunits can occur as a self-assembly process in vitro; i.e., all the information required for the formation of active ribosomes resides in the primary sequences of the r-proteins and rRNAs. In vitro reconstitution of functional 30S subunits is carried out by using a mixture of TP30, individually purified natural or recombinant r-proteins, and natural 16S rRNA. Chemical probing and primer extension analysis have been used extensively to monitor changes in the reactivities of nucleotides in 16S rRNA during the in vitro reconstitution of 30S subunits. The potential roles for r-proteins in 30S subunit assembly were determined by omitting single proteins in reconstitution experiments. The RNPs resulting from single protein omissions were examined in terms of their composition and function to determine the roles of the absent proteins. Recent developments in understanding the structure of the 30S subunit have led to speculation about roles for some of the r-proteins in assembly. The crystal structures of the 30S subunit ( 1 , 2 ) and the 70S ribosome ( 3 ) reveal details of the r-protein and rRNA interactions.
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Assembly of the 30S ribosomal subunit.
Biopolymers, 2003Co-Authors: Gloria M. CulverAbstract:Ribosomes are large macromolecular complexes responsible for cellular protein synthesis. The smallest known cytoplasmic ribosome is found in prokaryotic cells; these ribosomes are about 2.5 MDa and contain more than 4000 nucleotides of RNA and greater than 50 proteins. These components are distributed into two asymmetric subunits. Recent advances in structural studies of ribosomes and ribosomal subunits have revealed intimate details of the interactions within fully assembled particles. In contrast, many details of how these massive ribonucleoprotein complexes assemble remain elusive. The goal of this review is to discuss some crucial aspects of 30S ribosomal subunit assembly.
Antonio Laurenza - One of the best experts on this subject based on the ideXlab platform.
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analysis of falls in patients with epilepsy enrolled in the perampanel phase iii randomized double blind studies
Epilepsia, 2017Co-Authors: Ilo E Leppik, Francesco Bibbiani, Anna Patten, Betsy Williams, Haichen Yang, Sharon Zhou, Randi Fain, Antonio LaurenzaAbstract:SummaryObjective To analyze occurrence of falls among patients with partial seizures, with/without secondarily generalized seizures (SGS), and primary generalized tonic–clonic seizures (PGTCS) in the perampanel phase III clinical studies. Methods Studies 304, 305, and 306 randomized subjects (≥12 years) with drug-resistant partial seizures (with/without SGS) to perampanel 2, 4, 8, or 12 mg or placebo for double-blind treatment. The adverse event (AE) of falls was analyzed in the Safety Analysis Set (N = 1480). Study 332 randomized subjects aged ≥12 years with a diagnosis of PGTCS into perampanel 8 mg or placebo groups for double-blind treatment. In a systematic review of reported falls in the study 332 Safety Analysis Set (N = 163), falls were queried to establish whether each was seizure related; subjects with falls resulting from a seizure were not included in this analysis. Results For studies 304/305/306, treatment-emergent falls occurred in 5.1% perampanel-treated versus 3.4% placebo-treated subjects with partial seizures. Exposure-adjusted rate for falls (falls/subject-month of exposure) was greater for total perampanel than for placebo (0.0175 vs. 0.0093) and was dose related for those receiving perampanel. In subjects with SGS, incidence of treatment-emergent falls was 4.3% in perampanel and 4.0% in placebo groups. Exposure-adjusted rates were 0.0169 and 0.0097 falls per subject-month of exposure in perampanel and placebo, respectively. For study 332, 2.5% perampanel-treated and 1.2% placebo-treated subjects with PGTCS had treatment-emergent falls that were not part of a seizure. Exposure-adjusted rates were 0.0169 and 0.0032 falls per subject-month of exposure in perampanel and placebo, respectively. Significance Results of the perampanel studies suggest that patients with epilepsy should be monitored due to the common risk of falls.
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efficacy and safety of perampanel in adolescent patients with drug resistant partial seizures in three double blind placebo controlled phase iii randomized clinical studies and a combined extension study
European Journal of Paediatric Neurology, 2015Co-Authors: William Rosenfeld, Betsy Williams, Haichen Yang, Randi Fain, Dinesh Kumar, Lieven Lagae, Joan A Conry, Guntis Rozentals, Jin Zhu, Antonio LaurenzaAbstract:Abstract Objective Assess perampanel's efficacy and safety as adjunctive therapy in adolescents (ages 12–17) with drug-resistant partial seizures. Methods Adolescent patients enrolled in multinational, double-blind, placebo-controlled, phase III core studies (studies 304, 305, or 306) completed 19-week, double-blind phase (6-week titration/13-week maintenance) with once-daily perampanel or placebo. Upon completion, patients were eligible for the extension (study 307), beginning with 16-week, blinded conversion, during which placebo patients switched to perampanel. Patients then entered the open-label treatment. Results Of 1480 patients from the core studies, 143 were adolescents. Pooled adolescent data from these core studies demonstrated median percent decreases in seizure frequency for perampanel 8 mg (34.8%) and 12 mg (35.6%) were approximately twice that of placebo (18.0%). Responder rates increased with perampanel 8 mg (40.9%) and 12 mg (45.0%) versus placebo (22.2%). Adolescents receiving concomitant enzyme-inducing antiepileptic drugs (AEDs) had smaller reductions in seizure frequency (8 mg:31.6%; 12 mg:26.8%) than those taking non-inducing AEDs (8 mg:54.6%; 12 mg:52.7%). Relative to pre-perampanel baseline, seizure frequency and responder rates during the extension (Weeks 1–52) improved with perampanel. Most commonly reported adverse events in adolescents during the core studies were dizziness (20.4%), somnolence (15.3%), aggression (8.2%), decreased appetite (6.1%), and rhinitis (5.1%). Dizziness (13.2%), somnolence (11.6%), and aggression (6.6%) most often led to perampanel interruption/dose adjustment during the extension. Significance Data demonstrated adjunctive perampanel treatment in adolescents with drug-resistant partial seizures produced better seizure control versus placebo, sustained seizure frequency improvements, and a generally favorable safety profile. Results were comparable to the overall study population. Clinical Trial Registration: clinicaltrials.gov Identifiers: Study 304: NCT00699972 ; 305: NCT00699582 ; 306: NCT00700310 ; Study 307: NCT00735397 .
Narayanaswamy Kirthi - One of the best experts on this subject based on the ideXlab platform.
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assembly of the 30S ribosomal subunit
EcoSal Plus, 2008Co-Authors: Gloria M. Culver, Narayanaswamy KirthiAbstract:Protein synthesis involves nearly a third of the total molecules in a typical bacterial cell. Within the cell, protein synthesis is performed by the ribosomes, and research over several decades has investigated ribosomal formation, structure, and function. This review provides an overview of the current understanding of the assembly of the Escherichia coli 30S ribosomal subunit. The E. coli 30S subunit contains one rRNA molecule (16S) and 21 ribosomal proteins (r-proteins; S1 to S21). The formation of functional subunits can occur as a self-assembly process in vitro; i.e., all the information required for the formation of active ribosomes resides in the primary sequences of the r-proteins and rRNAs. In vitro reconstitution of functional 30S subunits is carried out by using a mixture of TP30, individually purified natural or recombinant r-proteins, and natural 16S rRNA. Chemical probing and primer extension analysis have been used extensively to monitor changes in the reactivities of nucleotides in 16S rRNA during the in vitro reconstitution of 30S subunits. The potential roles for r-proteins in 30S subunit assembly were determined by omitting single proteins in reconstitution experiments. The RNPs resulting from single protein omissions were examined in terms of their composition and function to determine the roles of the absent proteins. Recent developments in understanding the structure of the 30S subunit have led to speculation about roles for some of the r-proteins in assembly. The crystal structures of the 30S subunit ( 1 , 2 ) and the 70S ribosome ( 3 ) reveal details of the r-protein and rRNA interactions.
V Ramakrishnan - One of the best experts on this subject based on the ideXlab platform.
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structure of the 30S ribosomal subunit
Nature, 2000Co-Authors: Brian T Wimberly, William M Clemons, Andrew P Carter, Ditlev E Brodersen, Robert J Morganwarren, Thomas Hartsch, Clemens Vonrhein, V RamakrishnanAbstract:Genetic information encoded in messenger RNA is translated into protein by the ribosome, which is a large nucleoprotein complex comprising two subunits, denoted 30S and 50S in bacteria. Here we report the crystal structure of the 30S subunit from Thermus thermophilus, refined to 3 A resolution. The final atomic model rationalizes over four decades of biochemical data on the ribosome, and provides a wealth of information about RNA and protein structure, protein–RNA interactions and ribosome assembly. It is also a structural basis for analysis of the functions of the 30S subunit, such as decoding, and for understanding the action of antibiotics. The structure will facilitate the interpretation in molecular terms of lower resolution structural data on several functional states of the ribosome from electron microscopy and crystallography.
Hailong Cheng - One of the best experts on this subject based on the ideXlab platform.
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adjunctive eslicarbazepine acetate a pooled analysis of three phase iii trials
Epilepsy & Behavior, 2017Co-Authors: Victor Biton, Joanne Rogin, Gregory L Krauss, Bassel Aboukhalil, Jose Francisco Rocha, Joana Moreira, Helena Gama, Eugen Trinka, Christian E Elger, Hailong ChengAbstract:Abstract Objective To assess the safety and efficacy of once-daily (QD) adjunctive eslicarbazepine acetate (ESL). Methods This post-hoc pooled analysis of three randomized, placebo-controlled trials (2093-301, -302, -304) involved adults with refractory partial-onset seizures (POS) receiving 1–3 antiepileptic drugs (AEDs). All studies included 8-week baseline, 2-week titration, and 12-week maintenance periods. Patients were randomized equally to placebo, ESL 400 mg (studies 301, 302), 800 mg, or 1200 mg QD. The primary endpoint was standardized seizure frequency (SSF; per 4 weeks); secondary endpoints included responder rates (maintenance period), and incidence of treatment-emergent adverse events (TEAEs), TEAEs leading to discontinuation, serious AEs (SAEs), and deaths. Results The safety and efficacy analysis populations totaled 1447 and 1410 patients, respectively. SSF was significantly reduced versus placebo with ESL 800 mg (p = 0.0001) and 1200 mg (p Conclusions ESL (800 and 1200 mg QD) was effective and well tolerated as adjunctive therapy for adults with refractory POS.