Polymyalgia rheumatica: the mess we are now in and what we need to do about it.
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Adrenal Cortex Hormones↗
Biomedical subjects
Bhaskar Dasgupta
Publications and source records attributed to Bhaskar Dasgupta.
The role of mutant UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 in regulating serum intact fibroblast growth factor 23 and matrix extracellular phosphoglycoprotein in heritable tumoral calcinosis.
CONTEXT: Familial tumoral calcinosis (TC) results from disruptions in phosphate metabolism and is characterized by high serum phosphate with normal or elevated 1,25 dihydroxyvitamin vitamin D concentrations and ectopic and vascular calcifications. Recessive loss-of-function mutations in UDP-N-acetyl-alpha-D-galactosamine-polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3) and fibroblast growth factor-23 (FGF23) result in TC. OBJECTIVE: The objective of the study was to determine the relationship between GALNT3 and FGF23 in familial TC. DESIGN, SETTING, AND PATIENTS: We assessed the major biochemical defects and potential genes involved in patients with TC. INTERVENTION: Combination therapy consisted of the phosphate binder Sevelamer and the carbonic anhydrase inhibitor acetazolamide. RESULTS: We report a patient homozygous for a GALNT3 exon 1 deletion, which is predicted to truncate the encoded protein. This patient had high serum FGF23 concentrations when assessed with a C-terminal FGF23 ELISA but low-normal FGF23 levels when tested with an ELISA for intact FGF23 concentrations. Matrix extracellular phosphoglycoprotein has been identified as a possible regulator of phosphate homeostasis. Serum matrix extracellular phosphoglycoprotein levels, however, were normal in the family with GALNT3-TC and a kindred with TC carrying the FGF23 S71G mutation. The tumoral masses of the patient with GALNT3-TC completely resolved after combination therapy. CONCLUSIONS: Our findings demonstrate that GALNT3 inactivation in patients with TC leads to inadequate production of biologically active FGF23 as the most likely cause of the hyperphosphatemic phenotype. Furthermore, combination therapy may be effective for reducing the tumoral burden associated with familial TC.
Amino Acid Sequence↗
Polymyalgia rheumatica and giant cell arteritis.
Polymyalgia rheumatica and giant cell arteritis are the commonest inflammatory rheumatic conditions seen in the elderly. This review focuses on the diagnostic processes and complications of disease and treatment; and the safe management of these conditions with careful consideration of balance between benefits and long-term risks of glucocorticosteroid therapy.
Aged↗
3(10)-Helix adjoining alpha-helix and beta-strand: sequence and structural features and their conservation.
Does the amino acid use at the terminal positions of an alpha-helix become altered depending on the context-more specifically, when there is an adjoining 3(10)-helix, and can a single helical cylinder encompass the resultant composite helix? An analysis of 138 and 107 cases of 3(10)-alpha and alpha-3(10) composite helices, respectively, found in known protein structures indicate that the secondary structural element occurring first imposes its characteristics on the sequence of the structural element coming next. Thus, when preceded by a 3(10)-helix, the preference of proline to occur at the N1 position of an alpha-helix is shifted to the N2 position, a typical characteristic of the C-terminal capping of the 3(10)-helix. When an alpha- or a 3(10)-helix leads into a helix of the other type, there is a bend at the junction, especially for the 3(10)-alpha composite, with the two junction residues facing inward and buried within the structure. Thus a single helical cylinder may not properly represent a composite helix, the bend providing a means for the tertiary structure to assume a globular shape, very much akin to what a proline-induced kink does to an alpha-helix. The tertiary structural context in which beta-3(10) and 3(10)-beta composites occurs can be different, causing the angle between the secondary structural elements in the two cases to be different. Composites of 3(10)-helices and beta-strands are much more conserved among members in families of homologous structures than those between two types of helices; in many of the former instances, the 3(10)-helix constitutes the loops in beta-hairpin or beta-beta-corner motifs. The overall fold of the chain may be more conserved than the actual identify of the secondary structure elements in a composite.
Amino Acid Sequence↗
Expanded turn conformations: characterization and sequence-structure correspondence in alpha-turns with implications in helix folding.
Like the beta-turns, which are characterized by a limiting distance between residues two positions apart (i, i+3), a distance criterion (involving residues at positions i and i+4) is used here to identify alpha-turns from a database of known protein structures. At least 15 classes of alpha-turns have been enumerated based on the location in the phi,psi space of the three central residues (i+1 to i+3)-one of the major being the class AAA, where the residues occupy the conventional helical backbone torsion angles. However, moving towards the C-terminal end of the turn, there is a shift in the phi,psi angles towards more negative phi, such that the electrostatic repulsion between two consecutive carbonyl oxygen atoms is reduced. Except for the last position (i+4), there is not much similarity in residue composition at different positions of hydrogen and non-hydrogen bonded AAA turns. The presence or absence of Pro at i+1 position of alpha- and beta-turns has a bearing on whether the turn is hydrogen-bonded or without a hydrogen bond. In the tertiary structure, alpha-turns are more likely to be found in beta-hairpin loops. The residue composition at the beginning of the hydrogen bonded AAA alpha-turn has similarity with type I beta-turn and N-terminal positions of helices, but the last position matches with the C-terminal capping position of helices, suggesting that the existence of a "helix cap signal" at i+4 position prevents alpha-turns from growing into helices. Our results also provide new insights into alpha-helix nucleation and folding.
Amino Acid Sequence↗
Fast optimal genome tiling with applications to microarray design and homology search.
In this paper, we consider several variations of the following basic tiling problem: given a sequence of real numbers with two size-bound parameters, we want to find a set of tiles of maximum total weight such that each tiles satisfies the size bounds. A solution to this problem is important to a number of computational biology applications such as selecting genomic DNA fragments for PCR-based amplicon microarrays and performing homology searches with long sequence queries. Our goal is to design efficient algorithms with linear or near-linear time and space in the normal range of parameter values for these problems. For this purpose, we first discuss the solution to a basic online interval maximum problem via a sliding-window approach and show how to use this solution in a nontrivial manner for many of the tiling problems introduced. We also discuss NP-hardness results and approximation algorithms for generalizing our basic tiling problem to higher dimensions. Finally, computational results from applying our tiling algorithms to genomic sequences of five model eukaryotes are reported.
Algorithms↗
Giant cell arteritis.
Giant cell arteritis is the most common vasculitis in Caucasians. The aetiology of this disease remains uncertain. This article reviews some of the recent work in epidemiology and pathology in this field, with particular regard to the immunohistochemical findings in temporal artery biopsy specimens. The possible correlation between clinical features and biopsy specimen histology is discussed, and a model of pathogenesis is presented.
Giant Cell Arteritis↗
Identification of motifs with insertions and deletions in protein sequences using self-organizing neural networks.
The problem of motif identification in protein sequences has been studied for many years in the literature. Current popular algorithms of motif identification in protein sequences face two difficulties, high computational cost and the possibility of insertions and deletions. In this paper, we provide a new strategy that solve the problem more efficiently. We develop a self-organizing neural network structure with multiple levels of subnetworks to make an intelligent classification of the subsequences obtained from protein sequences. We maintain a low computational complexity through the use of this multi-level structure so that the classification of each subsequence is performed with respect to a small subspace of the whole input space. The new definition of pairwise distance between motif patterns provided in this paper can deal with up to two insertions/deletions allowed in a motif, while other existing algorithm can only deal with one insertion or deletion. We also maintain a high reliability using our self-organizing neural network since it will grow as needed to make sure all input patterns are considered and are given the same amount of attention. Simulation results show that our algorithm significantly outperforms existing algorithms in both accuracy and reliability aspects.
Algorithms↗