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  • Basal Muscle Amino Acid Kinetics and Protein Synthesis in Healthy Young and Older Men

    Abstract Full Text
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    JAMA. 2001; 286(10):1206-1212. doi: 10.1001/jama.286.10.1206
  • JAMA

    Figure: Definition of 4 Haplotype Groups by 16 Haplotypes Defined by Amino Acid Positions 11, 71, and 74 of HLA-DRB1

    The size of the filled circle representing a haplotype is proportional to its frequency in the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort; the smallest point represents frequencies below 1%. The allocation of haplotypes to groups was performed to group rare haplotypes with frequent ones having similar odds ratios. If the PAA haplotype is set as the reference, then haplotypes associated with a decreased risk to develop rheumatoid arthritis are represented below the dashed line, whereas haplotypes associated with an increased risk are above it. Of the 1846 patients from the BRAGGSS cohort presented in Table 1, 1819 had nonmissing genotypes at the 3 positions used to construct the haplotypes. Group 1 comprises 894 heterozygote patients (1 copy of a group 1 haplotype; eg, VKA or VRA) and 314 homozygote patients (2 copies of VKA or 2 copies of VRA, 1 copy of VKA and VRA). Group 2 comprises 594 heterozygote patients and 46 homozygote patients. Group 3 comprises 715 heterozygote patients and 80 homozygote patients. Group 4 comprises 480 heterozygote patients and 37 homozygote patients. The haplotype frequency presented was calculated as: (No. of heterozygote carriers + 2 × No. of homozygote carriers)/(2 × 1819). The nomenclature for haplotype names is presented in Table 4.
  • JAMA

    Figure: Linear Correlation Between Odds Ratios (ORs) for Rheumatoid Arthritis (RA) Susceptibility and ORs for Severity of RA From Univariable Analysis

    The reference group for every amino acid comprised noncarriers of that specific amino acid. Similar results were obtained for RA severity (instead of inflammatory polyarthritis [IP]) vs anticitrullinated protein antibody–positive RA. The orange line in the top 2 panels was fitted by linear regression. Horizontal and vertical error bars indicate 95% CIs. Ala indicates alanine; Arg, arginine; Asp, aspartic acid; Gln, glutamine; Glu, glutamic acid; Gly, glycine; Leu, leucine; Lys, lysine; Pro, proline; Ser, serine; Val, valine. More information appears in eTable 4 in Supplement 1 and in Raychaudhuri et al.
  • JAMA

    Figure 3. Pedigree Structures and Clinical Features of Additional Families With SCN5A Mutations

    Haplotypes at the chromosome 3p locus where SCN5A is located are shown. Each shaded haplotype defines a chromosomal segment that harbors a mutant SCN5A gene. In 2 families, point mutations caused amino acid substitutions: D1595H in DC-30 and T220I in DC-31. In DC-26, the insertion of 2 bases in the mutant gene results in a truncated protein that terminates in a string of 18 anomalous amino acids (fs851 [frameshift at amino acid 851]; Figure 2C). In DC-96, neither of the proband’s parents and none of her 7 siblings had cardiac disease. The haplotypes she inherited from her father (dark blue) and mother (light purple) are also inherited by other siblings, yet she is the only family member with a mutation in SCN5A. These findings indicate that the point mutation, R814W, arose as a spontaneous, or de novo, event on either the paternal or maternal chromosome. SVT indicates supraventricular tachycardia.
  • JAMA

    Figure 6. Mutations at the Dihydropteroate Synthase (DHPS) Active Site

    Diagram of the Pneumocystis carinii DHPS enzyme shows position of key amino acids involved in binding 7,8-dihydropterin-pyrophosphate (DHPPP), para-aminobenzoic acid (pABA), and sulfonamides (sulfa) based on homology to the known crystal structure of the Escherichia coli enzyme. Two commonly seen mutations that may be associated with resistance are Thr55Ala and Pro57Ser.
  • JAMA

    Figure 1. KCNH2 Isoforms and Molecular Position of the HERG1b R25W Mutation

    HERG1a and HERG1b are 2 isoforms encoded by KCNH2 alternatively spliced transcripts (KCNH2 [1a] and KCNH2 [1b]). The shaded regions of the exons represent the amino acid coding region of the gene that is initiated by the ATG start codon. Full-length KCNH2 contains 15 exons. The alternatively spliced gene transcript KCNH2 has an alternate exon 1 (labeled 1b). KCNH2 (1b) does not include the first 5 exons of the full-length transcript but includes identical exons 6 through 15 that are present in the full-length transcript (KCNH2). The 2 isoforms differ only by their N-termini; HERG1b has a 56 amino acid residue N-terminus in which the first 36 residues have a unique sequence (single letter amino acid abbreviations), whereas HERG1a has a longer (396 residue) N-terminus, with the rest of the protein identical in both splice isoforms. The DNA sequence chromatogram illustrates the heterozygous c.73 C>T nucleotide substitution that results in the substitution of an arginine (R) for a tryptophan (W) at amino acid residue 25 encoded by alternate exon 1b. CNBD indicates cyclic nucleotide-binding domain; PAC, PAS-associated C-terminal; and PAS, Per-ARNT-Sim.
  • JAMA

    Figure 1. Tissue Engineering of Cartilage

    After 2 weeks of culture, cartilage cells seeded onto a scaffold have synthesized a biomechanically stable cartilage-like extracellular matrix containing phenotypically specific aggregating proteoglycans (A, toluidine blue stain) and type II collagen fibrils (B, immunohistochemical stain). The scaffold material is a recently discovered self-assembling gel made from repeating sequences of the amino acids lysine, leucine, and aspartic acid. This biomaterial can be used simultaneously as a cell-supporting structure for gene delivery to the cells.
  • JAMA

    Figure 2.KCNQ1 Genetic Variants and Molecular Position of the KV7.1 Mutations A283T and R397W

    Depicted are the novel p.A283T mutation, located between the S5 transmembrane spanning domain and the pore region (between S5 and S6 of the channel), and the mutation p.R397W, located in the C-terminal region following S6 of the protein. The DNA sequence chromatograms indicate the nucleotide changes corresponding to each mutation (c.847 G>A, p.A283T; c.1189 C>T, p.R397W). In the case of c.847 G>A, both black (G) and green (A) peaks are present at the same position indicating heterozygosity at nucleotide position 847, which predicts substitution of alanine (A) for threonine (T) at amino acid position 283 in the KV7.1 protein. The c.1189 C>T mutation (superimposed blue and red peaks) predicts substitution of arginine (R) for tryptophan (W) at amino acid position 397 in KV7.1
  • JAMA

    Figure: New Compound Inhibits Elusive Protein Behind Many Cancers

    A mutant form of the K-Ras protein is a powerful driver of cancer. A potentially therapeutic compound binds in a pocket of this protein, irreversibly attaches to the mutated amino acid—a cysteine (yellow) that had been substituted for a glycine—and destabilizes the interaction between K-Ras and guanosine triphosphate. This keeps the protein in an inactive state, preferentially binding to guanosine diphosphate (GDP).
  • JAMA

    Figure 3. Transcription and Translation

    During transcription, the DNA double helix is split apart, and RNA polymerase synthesizes messenger RNA (mRNA) using one DNA strand as a template. Sections of the primary mRNA transcript, called introns, are spliced out to form the mature mRNA, which moves into the cytoplasm. The ribosome uses the mRNA sequence to build the protein. A specific sequence of 3 bases codes for each amino acid, which is delivered to the ribosome by transfer RNA. UTR indicates untranslated region.
  • JAMA

    Figure 1. Pedigree Structure and Clinical Features of Index Family With SCN5A Mutation

    Phenotypic traits are variably expressed, designated by shaded quadrants within pedigree symbols. Genotypes for closely spaced DNA markers are shown as numbers, representing different lengths of short tandem repeat marker alleles that distinguish the paternally and maternally inherited chromosomal region. Markers are located within the previously reported disease gene locus on chromosome 3p22-p25. The distance of each marker from the p-arm telomere is indicated by Mb (megabase). The 4 central markers (5-4-5-2) within the shaded chromosome segment define a haplotype, a group of alleles inherited as a unit, common to all family members with cardiac disease. Recombination events indicate that the disease-causing gene resides between markers D3S3727 and D3S3559. SCN5A, located at 38.6-Mb, was investigated as a candidate gene. A point mutation in SCN5A that alters a single amino acid, D1275N, was identified in all affected family members. Mutation-carrier status is indicated by letter symbols for the amino acid at position 1275: aspartic acid (D) in the normal protein and asparagine (N) in the mutant protein. Amino acids shown in parentheses were inferred, together with their corresponding haplotypes. SVT indicates supraventricular tachycardia.
  • JAMA

    Figure 2. Identification of SCN5A Mutations and Localization of Cardiac Sodium Channel Defects

    A, Heteroduplex mutation scans of exons comprising the entire coding region of SCN5A were performed by denaturing high-performance liquid chromatography (DHPLC). Heterozygous variation in DNA sequence was detected in exons 6, 16, 17, 21, and 27 for the 5 family probands in Figure 1 and Figure 3. In contrast to normal exons generating single peaks on chromatographic profiles, exons harboring mutations had anomalous profiles characterized by 2 peaks. B, To determine if detected variations were benign or pathogenic, genomic DNA sequencing was performed. In 4 of the exons (exons 6, 16, 21, and 27), mutations were discovered in 1 copy of the gene, resulting in amino acid substitutions. In the remaining exon (exon 17), insertion of 2 bases disrupts the coding sequence (only the mutant gene is shown). C, Regions in the cardiac sodium channel protein altered by mutations were aligned with protein sequences of other human and nonhuman sodium channels. The 4 missense mutations alter highly conserved amino acids as indicated by vertical boxes wherein identical amino acids are designated by dots. The frameshift mutation creates a series of 18 anomalous amino acids, shown by the horizontal box in the fs851 panel, and an early stop codon, designated by an asterisk. D, Two-dimensional schematic of SCN5A, demonstrating the predicted transmembrane topology. SCN5A is a monomeric channel composed of 4 repeat domains (DI-DIV), each with 5 homologous hydrophobic transmembrane segments (S1-S3, S5, and S6) and 1 positively charged voltage-sensing segment (S4). Mutations map to all 4 domains, altering residues within membrane-spanning segments; 2 mutations occur within S4 voltage-sensing segments. The insertion or frameshift mutation severely truncates the protein by removing 13 of 24 transmembrane segments.
  • JAMA

    Figure 3. Phylogenetic Tree of Reverse Transcriptase Sequences for Patient 136 and Associated Genotypes

    All reverse transcriptase (RT) sequences from patient 136 clustered together, away from the reference sequence HXB2 and representative baseline sequences from other study patients (top). Plasma sequences are coded by visit number, with groups of 5 consecutive visits represented by a single symbol. The resting cell reservoir was sampled only at baseline. The RT region could not be amplified from the plasma of patient 140 (thus, there was no need to assess cellular reservoir virus for comparison purposes). Genetic distance from the most recent common ancestor (horizontal scale) is not greater for blip sequences. The table on the right provides the genotype for each branch of the tree (which represents all 9 study patients). Amino acid positions in RT are shown at the top of the table (protease trees are less informative because the gene is smaller and more conserved [thus, these trees are not provided herein]; however, the protease trees showed no evidence for evolution during blips and no new drug resistance mutations). The sequence of the reference isolate HXB2 is indicated under the amino acid numbers. Positions associated with resistance to the drugs the patient was taking (zidovudine, lamivudine, and efavirenz) are shown in color. Representative polymorphisms (amino acid substitutions not associated with drug resistance that distinguish this patient’s virus population from other isolates) are also shown. No resistance mutations were detected in this patient. The L→M and L→V substitutions at position 210 are not associated with significant resistance to zidovudine. There were no missing data for this analysis except as indicated above. AA indicates amino acid; AZT, zidovudine; EFV, efavirenz; HIV, human immunodeficiency virus; 3TC, lamivudine.
  • JAMA

    Figure: Antiretroviral Drug Resistance Testing in Adults With HIV Infection Implications for Clinical Management

    Figure 1.—The most common human immunodeficiency virus 1 mutations selected by protease inhibitors (A), and nucleoside and nonnucleoside reverse transcriptase inhibitors (B). For each amino acid residue listed, the letter above the listing indicates the amino acid associated with the wild-type virus. The italicized letter below the residue indicates the substitution that confers drug resistance. The drug-selected mutations are categorized as "primary" (black bars) or "secondary" (white bars). (The black-and-white bar indicates a mutation selected in vitro, but rarely seen in specimens from patients in whom therapy fails.) Primary mutations generally decrease inhibitor binding and are the first mutations selected. For indinavir, the mutations listed as primary may not be the first mutations selected, but they are selected in most patients' isolates in combination with other mutations. For zalcitabine, all mutations are listed as secondary because of inadequate clinical data to determine a common initial mutation. For nevirapine and delavirdine, each mutation can occur as either an initial or subsequent mutation and affect inhibitor binding. The asterisk indicates that the mutation has been reported in vitro, but relevance for clinical drug failure is uncertain. Amino acid abbreviations are as follows: A, alanine; C, cysteine; D, aspartate; E, glutamate; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; Y, tyrosine. Multinucleoside resistance viruses have phenotypic resistance to most nucleoside reverse transcriptase inhibitors. Current listings are also available at or at
  • JAMA

    Figure 2. Cell Death Pathway of Nitric Oxide (NO), Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH), and Siah1

    Nitric oxide, a gaseous messenger released in response to cell death stimuli, is produced by the action of nitric oxide synthase (NOS), which uses the amino acid arginine as a substrate. Nitric oxide nitrosylates GAPDH at sulfur residues, and the S-nitrosylated GAPDH binds to and stabilizes the cell death protein Siah1, after which the GAPDH-Siah1 complex enters the nucleus and promotes cell death. Molecules that disrupt the GAPDH-Siah1 interaction, such as deprenyl and TCH346, may prove useful in blocking cell death. NADP indicates nicotinamide adenine dinucleotide phosphate; NADPH, reduced NADP.
  • JAMA

    Figure. Most Common Mutations in HIV-1 Genes Conferring Drug Resistance

    For each amino acid residue, the letter above indicates the amino acid associated with wild-type virus; the italicized letters below, substitutions that confer viral resistance. Primary mutations (black bars) generally cause decreased inhibitor binding and are the first mutations selected. Secondary mutations (white bars) also contribute to drug resistance and should be considered as evidence of resistance, although they may have less direct effect on inhibitor binding in vitro than primary mutations. The mutation selected in vitro (black-and-white bar) is rarely seen in patients having treatment failure. For indinavir, the mutations listed as primary may not be the first mutations selected, but they are selected in most patient isolates in combination with other mutations. For zalcitabine, all mutations are listed as primary because of inadequate clinical data to determine the most frequent initial mutation. Amino acid abbreviations are: A, alanine; C, cysteine; D, aspartate; E, glutamate; F, phenylalanine; G, glycine; H, histidine; I, isoleucine; K, lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q, glutamine; R, arginine; S, serine; T, threonine; V, valine; W, tryptophan; Y, tyrosine. Multinucleoside resistance mutational patterns A and B each cause resistance to zidovudine, stavudine, lamivudine, didanosine, zalcitabine, and abacavir. Current listings are also available at*Mutations selected by protease inhibitors in gag cleavage sites are not listed because their contribution to resistance is not fully defined.† A preliminary report identifies mutations E44D and V118I as conferring moderately reduced (about 10-fold) susceptibility to lamivudine with uncertain clinical significance. This contrasts with the greater than 100-fold reduced susceptibility to lamivudine conferred by M184V or M184I, which is associated with virologic rebound.‡ The mutations listed for zidovudine above contribute to reduced susceptibility to abacavir in vitro and in vivo and are listed as secondary, even though they may be present before abacavir is introduced. They have also been reported to be uncommonly selected by stavudine plus didanosine even in the absence of prior zidovudine exposure. Phenotypic resistance of these mutations to stavudine or didanosine in vitro was not identified. The clinical significance of these mutations and of V75T on in vivo response to stavudine is not known.§ Several insertions of 2 amino acids have been reported following T69S (or rarely T69A), including Ser-Ser; Ser-Gly; Ser-Ala; Glu-Ala; and Thr-Ser.∥ For nevirapine or delavirdine, each mutation can occur as an initial or subsequent mutation and affect inhibitor binding.
  • JAMA

    Figure 3. Locations of Mutations on the 3-Dimensional Structure of Neuraminidase

    Three-dimensional structure of the complex between influenza virus B/Beijing/1/87 neuraminidase and zanamivir (Molecular Modeling DataBase Identifier: 10147; Protein DataBank Identifier: 1A4G). The locations of the neuraminidase mutations* identified in the present study (aspartic acid 198 [Asp198], isoleucine 222 [Ile222], serine 250 [Ser250], and glycine 402 [Gly402]) that are associated with decreased drug sensitivity are marked in yellow. These mutations are located at or near the sialidase active site, where neuraminidase inhibitors bind. (See online interactive neuraminidase model at *Amino acids are numbered according to the N2 NA numbering system. Corresponding influenza virus B/Beijing/1/87 positions are Asp196, Ile220, Ser248, and Gly406; for currently circulating type B viruses, Asp197, Ile221, Ser249, and Gly407, respectively.
  • JAMA

    Figure: Effect of Maternal Smoking During Pregnancy on Newborn Pulmonary Function as Modulated by Maternal α5 Genotype (rs16969968)

    Newborns whose mothers were homozygous for the risk allele in which amino acid 398 of the α5 nicotinic acetylcholine receptor is changed from Asp to Asn showed the largest decrease in ratio of time to peak tidal expiratory flow to expiratory time (TPTEF:TE) comparing placebo with vitamin C treatment. Data markers indicate means; error bars, 95% confidence intervals. Asp/Asp indicates mothers homozygous for nonrisk allele; Asp/Asn, heterozygous mothers; Asn/Asn, mothers homozygous for risk allele. P values comparing TPTEF:TE values from newborns of mothers randomized to receive vitamin C vs placebo are .02 for mothers of all genotypes, .32 for Asp/Asp, .07 for Asp/Asn, and <.001 for Asn/Asn. P values are from linear mixed models (used to allow for unequal variance), adjusting for gestational age at randomization (≤16 vs >16 weeks), birthweight, and gestational age younger than 37 weeks and allowing for different SDs within each genotype.
  • JAMA

    Figure: The HNF-1A Protein With a Heat Map of Diabetes-Associated Mutations

    The dimerization, DNA binding, and transactivation domains of the HNF-1A protein are highlighted. The position of the p.E508K mutation is shown as well as a common variant (p.I27L), MODY3 mutations studied (p.P112L, p.R229Q, p.P379fsdelCT, p.P447L, p.Q466X), and a rare variant associated with type 2 diabetes (p.M490T). The overlaid heat map illustrates how many of the amino acid residues of each HNF-1A domain have been reported to be mutated and hence due to the monogenic diabetes form MODY3. Domain areas in red have a higher concentration of reported mutations than areas in orange and green. Pseudo POU indicates protein domain that includes short sequence motifs similar to regions in the POU family of transcriptional activators; Homeo, protein homeodomain that binds DNA in a sequence-specific manner.