bluuebunny/crossref_metadata_2025_split huggingface dataset:
Isolated 3‐methylcrotonyl‐coenzyme A carboxylase deficiency in a child with metabolic stroke
Authors: Pinto L. , Zen P. , Rosa R. , Paskulin G. , Perla A. , Barea L. , Baumgartner M. R. , Dantas M. F. , Fowler B. , Giugliani R. , Vargas C. , Wajner M. , Graziadio C. 
Published: April 2006

SummaryWe report a 3‐year‐old boy with isolated 3‐methylcrotonyl‐coenzyme A deficiency with unexpectedly severe presentation, seizures and history of cerebral ischae‐mic episode.
Manifestations of Fabry disease in placental tissue
Authors: Vedder A. C. , Strijland A. , Weerman M. A. vd Bergh , Florquin S. , Aerts J. M. F. G. , Hollak C. E. M. 
Published: April 2006

SummaryFabry disease is an X‐linked lysosomal storage disorder caused by deficiency of the lysosomal enzyme α‐galactosidase A. Manifestations of the disease in placental tissue have been reported only twice. We report for the first time on the biochemical, histological and genetic features of two cases: placenta A derived from a mother heterozygous for Fabry disease who gave birth to a hemizygous son, and placenta B obtained from a healthy mother who carried a heterozygous daughter. Biopsies of placentae A, B and of four healthy controls were taken directly after birth. Assessment of α‐galactosidase A (α‐Gal) activity was performed both in fetal leukocytes (derived from umbilical cord blood) and in the biopsy specimens. The tissue was further examined by electron microscopy, immunohistochemistry and biochemical analysis for the presence of storage material (ceramide trihexoside (CTH)). In placenta A, characteristic zebra bodies reflecting accumulated storage material were seen in all biopsies evaluated. CTH values were markedly elevated as compared to the controls and α‐Gal activity in both fetal leukocytes and placental tissue was very low. Placenta B showed no storage material at all. CTH values were within the control range. α‐Gal activity ranged from intermediate to near normal; enzyme activity in fetal leukocytes was significantly decreased. As placental tissue is mainly derived from fetal cells, we may conclude that, in a boy suffering from Fabry disease, extensive storage of CTH is already present at birth. As complications develop only around the age of 10 years, it may be not the CTH itself but secondary processes that cause cellular and organ damage.
Genetic heterogeneity of the GLDC gene in 28 unrelated patients with glycine encephalopathy
Authors: Conter C. , Rolland M. O. , Cheillan D. , Bonnet V. , Maire I. , Froissart R. 
Published: April 2006

SummaryGlycine encephalopathy, or nonketotic hyperglycinaemia (NKH; McKusick 238300) is a severe autosomal recessive disease due to a defect in the glycine cleavage system (GCS), which is a complex of four subunits: P‐, T‐, H‐ and L‐proteins. A P‐protein (glycine decarboxylase or GLDC) deficiency was reported in about 80% of NKH patients. We performed mutation analysis of the complete coding sequence of the GLDC gene in 28 unrelated patients with neonatal NKH using denaturing high‐performance liquid chromatography (DHPLC) and sequencing. Forty different gene alterations were identified, confirming the large molecular heterogeneity of the GLDC gene. Eighteen alterations were clearly disease‐causing: two large deletions, four one‐base deletions (c.28delC, c.1175delC, c.2186delC, c.2422delA), one 1‐base insertion (c.1002_1003insT), one 4‐base insertion (c.1285_1286insCAAA), one insertion/deletion (c.2153_2155delinsTCCTGGTTTA), five nonsense mutations (p.E153X, p.R236X, p.E270X, p.R337X, p.R424X) and four splice site mutations (c.861+1G > T, c.1402−1C > G, c.2316−1G > A, c.2919+1G > A). Additionally, we identified one intronic mutation outside the consensus splice sites (c.2838+5G > A) and 21 nucleotide substitutions leading to amino acid change (including three previously described mutations: p.T269M, p.R461Q, p.G771R), the pathogenicity of which should be confirmed by expression studies (p.S132W, p.Y138F, p.G171A, p.T187K, p.R212K, p.T269M, p.R373W, p.I440N, p.R461Q, p.N533Y, p.C644F, p.H651R, p.V705M, p.N732K, p.G771R, p.H775R, p.T830M, p.A841P, p.D880V, p.S957P and p.R966G). Mutation analysis allowed us to identify sequence alterations in both alleles for 19 patients and in one allele for 7 patients One patient was carrying three mutations (p.Y138F, p.T269M and p.E153X) and one patient was carrying two amino acid substitutions on the same allele (p.V705M and p.R212K) and an unidentified mutation on the other allele. No mutation could be found in two patients, suggesting possible defects in the H‐protein or gene alterations that could not be identified by our technique. The potential use of genotype determination for prenatal diagnosis is emphasized.
Cardiomyopathy in tyrosinaemia type I is common but usually benign
Authors: Arora N. , Stumper O. , Wright J. , Kelly D. A. , McKiernan P. J. 
Published: April 2006

SummaryTyrosinaemia type I (TTI) is an inherited multisystemic disorder of tyrosine metabolism. In addition to hepatic and renal involvement, cardiomyopathy is an important clinical manifestation. Objective: To evaluate the incidence and outcome of cardiomyopathy in TTI. Subjects and methods: A retrospective study was performed of 20 consecutive children with TTI (12 male, 8 female) referred to a single centre between 1986 and 2002. All were initially treated with standard dietary therapy and, since 1992, with nitisinone. The indications for orthotopic liver transplantation (LT) changed during the study. Serial echocardiography was undertaken in all subjects. Results: 9/20 (45%) children had an acute hepatic presentation. Five (25%) received dietary treatment followed by LT, and 14 (70%) were treated with nitisinone at presentation. 6/20 (30%) had cardiomyopathy at initial assessment, with interventricular septal hypertrophy being the commonest finding (5/6). Cardiomyopathy was significantly less common in those treated initially with nitisinone. After a median follow‐up of 3.6 (0.45–13.5) years, 5/6 (83%) had complete resolution of cardiomyopathy and 1/6 showed significant improvement. No child with a normal initial echocardiography subsequently developed cardiomyopathy. Conclusion: Cardiomyopathy is a common manifestation of TTI and it has a favourable long‐term outcome. Children initially treated with nitisinone are less likely to develop this complication.
Stabilization of hypoglycosylation in a patient with congenital disorder of glycosylation type Ia
Authors: Hahn S. H. , Minnich S. J. , O'Brien J. F. 
Published: April 2006

SummaryA follow‐up over 7 years on a patient with congenital disorder of glycosylation type Ia showed a significant normalization of hypoglycosylated transferrin. Isoelectric focusing for serum transferrin is a widely used screening method but there could be a limit of detection and the subtle changes can be also overlooked. Re‐test with a different method is desirable, especially when the clinical suspicion for congenital disorder of glycosylation is high.
Refining the diagnosis of mitochondrial HMG‐CoA synthase deficiency
Authors: Aledo R. , Mir C. , Dalton R. N. , Turner C. , Pié J. , Hegardt F. G. , Casals N. , Champion M. P. 
Published: April 2006

SummaryMitochondrial HMG‐CoA synthase deficiency is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies. Patients present with hypoketotic hypoglycaemia, encephalopathy and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting. The diagnosis may easily be missed as previously reported results of routine metabolic investigations, urinary organic acids and plasma acylcarnitines may be nonspecific or normal, and a high index of suspicion is required to proceed to further confirmatory tests. We describe a further acute case in which the combination of urinary organic acids, low free carnitine and changes in the plasma acylcarnitine profile on carnitine supplementation were very suggestive of a defect in ketone synthesis. The diagnosis of mitochondrial HMG‐CoA synthase deficiency was confirmed on genotyping, revealing two novel mutations: c.614G > A (R188H) and c.971T > C (M307T). A further sibling, in whom the diagnosis had not been made acutely, was also found to be affected. The possible effects of these mutations on enzyme activity are discussed.
Atypical phenotype in a boy with a maple syrup urine disease
Authors: Ben‐Omran T. I. , Blaser S. , Phillips H. , Callahan J. , Feigenbaum A. 
Published: April 2006

SummaryMaple syrup urine disease (MSUD) is a metabolic disorder due to a block in the decarboxylation step in the catabolic pathways of the branched‐chain amino acids (BCAAs). We describe an atypical presentation in an infant male. The patient presented with psychomotor retardation, profound hypotonia and elevated plasma levels of BCAAs, but no elevation of alloisoleucine. Cranial magnetic resonance imaging showed prominent diffuse CSF spaces, delayed myelin maturation and symmetrical signal abnormality within the globi pallidi, midbrain, dorsal pons and medulla. The cerebellar white matter was specifically spared. A mitochondrial disorder was suggested. After correction of feeding problems with G‐tube feeds, his high BCAAs persisted and, on fourth analysis, alloisoleucine was seen. Subsequent fibroblast enzyme and mutation analysis confirmed MSUD due to E1‐α subunit deficiency. After starting dietary treatment, there was no significant improvement in his hypotonia or his psychomotor development. However, the high signal within the globi pallidi had resolved. MSUD may have diverse clinical presentations, and should be considered in children who present with chronic psychomotor delay but no acute encephalopathic episodes. BCAA levels may not be very high, alloisoleucine may not always be detected in MSUD even with severe enzyme deficiency, and imaging may be misleading if seen in the chronic phase only.
The effect of L‐alanine therapy in a patient with adult onset glycogen storage disease type II
Authors: Mundy H. R. , Williams J. E. , Cousins A. J. , Lee P. J. 
Published: April 2006

SummaryAdult‐onset glycogen storage disease type II (GSD II) (McKusick 232300) is a progressive disabling myopathy. At present there is no treatment of proven clinical efficacy. Enzyme replacement therapy may in the future provide benefit but it will be costly and is not yet freely available. L‐Alanine, a simple and relatively cheap therapy, has been shown to reduce protein degradation in GSD II patients but has not previously been assessed for clinical benefit in a controlled study. In this study L‐alanine was assessed in a double blind, placebo‐controlled, crossover n = 1 study. Assessments consisted of spirometry, cardiopulmonary exercise testing, quality of life measurements, biochemical markers and assessment by the criterion 4‐component model of body composition. Alanine therapy was associated with a 15% gain in total body protein. However, the patient showed no functional improvement and reported feeling worse after treatment. Further controlled studies in a small group may be warranted, but not widespread use of this therapy.
D‐2‐Hydroxyglutaric aciduria: Unravelling the biochemical pathway and the genetic defect
Authors: Struys Eduard A. 
Published: April 2006

SummaryD‐2‐Hydroxyglutaric aciduria (D‐2‐HGA) is a neurometabolic inherited disorder first described in 1980. In the following years, it became clear that the clinical phenotype of the disease varies widely from severe neonatal to asymptomatic. However, the sparse biochemical knowledge made D‐2‐HGA a poorly understood disease. Much progress has been made in the last five years in various studies, revealing two human enzymes that play a role in the metabolism of D‐2‐hydroxyglutarate (D‐2‐HG): hydroxyacid‐oxoacid transhydrogenase (HOT) and D‐2‐HG dehydrogenase. HOT is expected to be responsible for the formation of D‐2‐HG, while D‐2‐HG dehydrogenase converts D‐2‐HG into 2‐ketoglutarate. We demonstrated pathogenic mutations in the D2HGD gene in patients with D‐2‐HGA, helping to unravel the primary defect causing D‐2‐HGA. However, in approximately 50% of the patients with D‐2‐HGA examined, no pathogenic mutations have yet been found.
Lipid microdomains in model and biological membranes: how strong are the connections?
Authors: Silvius John 
Published: April 2006

1. Introduction 3732. Are rafts probable? 3743. Micro-, nano- or ephemeral domains? 3754. How can we reliably assess ‘raft’ composition? 3765. Are rafts plausible? 3796. What more can model systems contribute to ‘raft’ studies? 3817. References 382The concept of ‘lipid rafts’ and related liquid-ordered membrane microdomains has attracted great attention in the field of membrane biology, both as a novel paradigm in models of membrane organization and for the potential importance of such domains in phenomena such as membrane signaling and the differential trafficking of various membrane components. Studies of biological and of model membranes have gone hand in hand in shaping our current picture of the possible organization and functions of liquid-ordered lipid microdomains in membranes. This essay discusses some important current questions concerning the existence and functional importance of lipid microdomains in mammalian cell membranes, and the potential as well as the limitations of using model systems to help to address such questions.
La structure en de quoi
Authors: LEFEUVRE FLORENCE 
Published: April 2006

Dans cet article, nous examinons la structure en de quoi + infinitif qui peut être régie par un verbe:(i) Il y a de quoi s'interroger!ou ne pas l'être:(ii) Jamais la France du très haut ne s'est aussi bien portée que sous Jospin. De quoi irriter l'ex-Premier ministreNous envisageons deux possibilités d'analyse, selon la valeur de de. Soit celui-ci est considéré comme un article partitif. Mais alors de quelle façon l'infinitif s'articulet-il à de quoi? Soit il constitue une préposition. On se rapproche alors d'énoncés tels que:(iii) Il a de qui tenirmais ici, de quoi prend une fonction inhabituelle, celle de circonstant, alors que dans un exemple tel que (iii), de qui remplit la fonction de complément essentiel indirect par rapport à l'infinitif. Dans un dernier temps, nous avons étudié les emplois en discours de cette structure, selon que la proforme quoi anaphorise ou non une structure prédicative de l'énoncé précédent et selon les infinitifs utilisés.
Conformational changes of the glucocorticoid receptor ligand binding domain induced by ligand and cofactor binding, and the location of cofactor binding sites determined by hydrogen/deuterium exchange mass spectrometry
Authors: Frego Lee , Davidson Walter 
Published: April 2006

AbstractHXMS (hydrogen/deuterium exchange mass spectrometry) of the glucocorticoid receptor ligand‐binding domain (GR LBD) complexed with the agonist dexamethasone and the antagonist RU‐486 is described. Variations in the rates of exchange were observed in regions consistent with the published crystal structures of GR LBD complexed with RU‐486 when compared with the GR dexamethasone complex. We also report the HXMS results for agonist‐bound GR LBD with the coactivator transcriptional intermediary factor 2 (TIF2) and anatagonist‐bound GR LBD with nuclear receptor corepressor (NCoR). Alterations in exchange rates observed for agonist‐bound GR LBD with TIF2 present were consistent with the published crystal structural contacts for the complex. Alterations in exchange rates observed for antagonist‐bound GR LBD with NCoR were a subset of those observed with TIF2 binding, suggesting a common or overlapping binding site for coactivator and corepressor.
New approaches to high‐throughput structure characterization of SH3 complexes: The example of Myosin‐3 and Myosin‐5 SH3 domains from S. cerevisiae
Authors: Musi Valeria , Birdsall Berry , Fernandez‐Ballester Gregorio , Guerrini Remo , Salvatori Severo , Serrano Luis , Pastore Annalisa 
Published: April 2006

AbstractSH3 domains are small protein modules that are involved in protein–protein interactions in several essential metabolic pathways. The availability of the complete genome and the limited number of clearly identifiable SH3 domains make the yeast Saccharomyces cerevisae an ideal proteomic‐based model system to investigate the structural rules dictating the SH3‐mediated protein interactions and to develop new tools to assist these studies. In the present work, we have determined the solution structure of the SH3 domain from Myo3 and modeled by homology that of the highly homologous Myo5, two myosins implicated in actin polymerization. We have then implemented an integrated approach that makes use of experimental and computational methods to characterize their binding properties. While accommodating their targets in the classical groove, the two domains have selectivity in both orientation and sequence specificity of the target peptides. From our study, we propose a consensus sequence that may provide a useful guideline to identify new natural partners and suggest a strategy of more general applicability that may be of use in other structural proteomic studies.
Expression, purification, and characterization of Thermotoga maritima membrane proteins for structure determination
Authors: Columbus Linda , Lipfert Jan , Klock Heath , Millett Ian , Doniach Sebastian , Lesley Scott A. 
Published: April 2006

AbstractStructural studies of integral membrane proteins typically rely upon detergent micelles as faithful mimics of the native lipid bilayer. Therefore, membrane protein structure determination would be greatly facilitated by biophysical techniques that are capable of evaluating and assessing the fold and oligomeric state of these proteins solubilized in detergent micelles. In this study, an approach to the characterization of detergent‐solubilized integral membrane proteins is presented. Eight Thermotoga maritima membrane proteins were screened for solubility in 11 detergents, and the resulting soluble protein–detergent complexes were characterized with small angle X‐ray scattering (SAXS), nuclear magnetic resonance (NMR) spectroscopy, circular dichroism (CD) spectroscopy, and chemical cross‐linking to evaluate the homogeneity, oligomeric state, radius of gyration, and overall fold. A new application of SAXS is presented, which does not require density matching, and NMR methods, typically used to evaluate soluble proteins, are successfully applied to detergent‐solubilized membrane proteins. Although detergents with longer alkyl chains solubilized the most proteins, further characterization indicates that some of these protein–detergent complexes are not well suited for NMR structure determination due to conformational exchange and protein oligomerization. These results emphasize the need to screen several different detergents and to characterize the protein–detergent complex in order to pursue structural studies. Finally, the physical characterization of the protein–detergent complexes indicates optimal solution conditions for further structural studies for three of the eight overexpressed membrane proteins.
Inhibition of insulin fibrillogenesis with targeted peptides
Authors: Gibson Todd J. , Murphy Regina M. 
Published: April 2006

AbstractUnder conditions of acidic pH and elevated temperature, insulin partially unfolds and aggregates into highly structured amyloid fibrils. Aggregation of insulin leads to loss of activity and can trigger an unwanted immune response. Compounds that prevent protein aggregation have been used to stabilize insulin; these compounds generally suppress aggregation only at relatively high inhibitor concentrations. For example, effective inhibition of aggregation of 0.5 mM insulin required arginine concentrations of ≥100 mM. Here, we investigate a targeted approach toward inhibiting insulin aggregation. VEALYL, corresponding to residues B12–17 of full‐length insulin, was identified as a short peptide that interacts with full‐length insulin. A hybrid peptide was synthesized that contained this binding domain and hexameric arginine; this peptide significantly reduced the rate of insulin aggregation at near‐equimolar concentrations. An effective binding domain and N‐terminal placement of the arginine hexamer were necessary for inhibitory activity. The data were analyzed using a simple two‐step model of aggregation kinetics. These results are useful not only in identifying an insulin aggregation inhibitor but also in extending a targeted protein strategy for modifying aggregation of amyloidogenic proteins.
A comparative study of available software for high‐accuracy homology modeling: From sequence alignments to structural models
Authors: Nayeem Akbar , Sitkoff Doree , Krystek Stanley 
Published: April 2006

AbstractAn open question in protein homology modeling is, how well do current modeling packages satisfy the dual criteria of quality of results and practical ease of use? To address this question objectively, we examined homology‐built models of a variety of therapeutically relevant proteins. The sequence identities across these proteins range from 19% to 76%. A novel metric, the difference alignment index (DAI), is developed to aid in quantifying the quality of local sequence alignments. The DAI is also used to construct the relative sequence alignment (RSA), a new representation of global sequence alignment that facilitates comparison of sequence alignments from different methods. Comparisons of the sequence alignments in terms of the RSA and alignment methodologies are made to better understand the advantages and caveats of each method. All sequence alignments and corresponding 3D models are compared to their respective structure‐based alignments and crystal structures. A variety of protein modeling software was used. We find that at sequence identities >40%, all packages give similar (and satisfactory) results; at lower sequence identities (<25%), the sequence alignments generated by Profit and Prime, which incorporate structural information in their sequence alignment, stand out from the rest. Moreover, the model generated by Prime in this low sequence identity region is noted to be superior to the rest. Additionally, we note that DSModeler and MOE, which generate reasonable models for sequence identities >25%, are significantly more functional and easier to use when compared with the other structure‐building software.