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PubMed1989

Strategies for representing metabolic pathways within biochemical systems theory: reversible pathways.

The search for systematic methods to deal with the integrated behavior of complex biochemical systems has over the past two decades led to the proposal of several theories of biochemical systems. Among the most promising is biochemical systems theory (BST). Recent comparisons of this theory with several others that have recently been proposed have demonstrated that all are variants of BST and share a common underlying formalism. Hence, the different variants can be precisely related and ranked according to their completeness and operational utility. The original and most fruitful variant within BST is based on a particular representation, called an S-system (for synergistic and saturable systems), that exhibits many advantages not found among alternative representations. Even within the preferred S-system representation there are options, depending on the method of aggregating fluxes, that become especially apparent when one considers reversible pathways. In this paper we focus on the paradigm situation and clearly distinguish the two most common strategies for generating an S-system representation. The first is called the "reversible" strategy because it involves aggregating incoming fluxes separately from outgoing fluxes for each metabolite to define a net flux that can be positive, negative, or zero. The second is the "irreversible" strategy, which involves aggregating forward and reverse fluxes through each reaction to define a net flux that is always positive. This second strategy has been used almost exclusively in all variants of BST. The principal results of detailed analyses are the following: (1) All S-system representations predict the same changes in dependent concentrations for a given change in an independent concentration. (2) The reversible strategy is superior to the irreversible on the basis of several criteria, including accuracy in predicting steady-state flux, accuracy in predicting transient responses, and robustness of representation. (3) Only the reversible strategy yields a representation that is able to capture the characteristic feature of amphibolic pathways, namely, the reversal of nets flux under physiological conditions. Finally, the results document the wide range of variation over which the S-system representation can accurately predict the behavior of intact biochemical systems and confirm similar results of earlier studies [Voit and Savageau, Biochemistry 26: 6869-6880 (1987)].

Biochemical Phenomena↗

PubMed1985

A morphological and immunocytochemical study of a distinctive variant of ductal carcinoma in-situ of the breast.

Because so-called 'carcinoid' tumour of the breast has proven to be a difficult entity to define, we studied in-situ carcinoma as there were reasons to believe that this might help clarify the complex problems involved. We studied a consecutive series of 30 cases of ductal carcinoma in-situ (DCIS) by light microscopy and silver impregnation methods and identified a relatively common endocrine variant of DCIS. This variant was studied by immunocytochemical and ultrastructural methods, using conventional DCIS as a control. Endocrine DCIS is identified by its organoid pattern, stromal 'inclusions', festooned structure and a distinctive type of polypoid invagination. It is argyrophilic and rich in neuron-specific enolase. Ultrastructurally it contains abundant dense core granules which are impregnated selectively by Grimelius' method. This tumour type frequently contains peptide hormones of the ACTH family. Three of seven cases contained cells reactive for ACTH and corticotropin-like intermediate lobe peptide CLIP or their precursor, pro-opiomelanocortin. A fourth tumour contained neurotensin, recently identified in a variety of endocrine tumours. Argyrophil invasive carcinomas are a much more heterogeneous group of tumours than argyrophil DCIS and only a minority have an endocrine structure comparable to that described here.

Adrenocorticotropic Hormone↗

PubMed2000

Warthin-like tumour of the thyroid gland: RET/PTC expression indicates it is a variant of papillary carcinoma.

AIMS: Three cases with features of so-called 'Warthin-like tumour' of the thyroid (WaLTT) are described, in order to evaluate its relationship with papillary carcinoma (PC). METHODS AND RESULTS: We performed an histological and immunohistochemical study with emphasis on RET/PTC expression. The most striking features are represented by marked lymphocytic infiltration in the stalks of papillae and by oxyphilic metaplasia of epithelium, resembling Warthin tumour of the salivary gland. In all cases, we found nuclear features reminiscent of PC. The neoplastic cells were strongly positive for Leu M1 and epithelial membrane antigen (EMA), less for thyroglobulin and negative for calcitonin. The lymphocytic infiltrate was composed of a mixed population of B and T-cells with sparse S100-positive Langerhans cells. An interesting finding was the strong positivity with the antibody against RET/PTC. CONCLUSION: All clinicopathological data along with the presence of the extensive lymphocytic infiltrate could imply a more favourable prognosis. The expression of RET/PTC fusion gene adds support to the hypothesis that this tumour is a variant of PC, probably related to the oncocytic variant of PC.

Adenolymphoma↗

PubMed1996

Mass allele detection (MAD) of rare 5-HT1A structural variants with allele-specific amplification and electrochemiluminescent detection.

A strategy is described that exploits allele-specific amplification (ASA-PCR) and electrochemiluminescence (ECL) detection technology to rapidly and cheaply screen large numbers of DNAs arranged in pooled matrices in order to identify individual nucleotide sequence variants. To demonstrate this strategy, a large genomic DNA collection was screened for two nucleotide variants in the 5-HT1A serotonin receptor gene and individual heterozygotes were identified. Conversion of two SSCP variants to allele-specific PCR polymorphisms was accomplished, and PCR product capture and ECL detection were enabled by the covalent addition of biotin to allele-specific PCR primers and ruthenium to the nonspecific PCR primer. A two-level DNA pooling strategy was used to reduce the number of individual PCR reactions required. Pooling experiments established that ASA-PCR with ECL detection is sufficiently sensitive to reproducibly detect a single specific allele in the presence of a 40-fold excess of genomic DNA from individuals negative for the specific allele. The detection sensitivity of the ECL device and the design of the pooled DNA arrays reduced the number of PCRs required to detect the rare individuals with the variant sequences by approximately 90%. This strategy is called mass allele detection (MAD).

Alleles↗

PubMed1994

Dissecting the energetics of an antibody-antigen interface by alanine shaving and molecular grafting.

Alanine-scanning mutagenesis on human growth hormone (hGH) identified 5 primary determinants (Arg 8, Asn 12, Arg 16, Asp 112, and Asp 116) for binding to a monoclonal antibody (MAb 3) (Jin L, Fendly BM, Wells JA, 1992, J Mol Biol 226:851-865). To further analyze the energetic importance of residues surrounding these five, we mutated all neighboring residues to alanine in groups of 7-16 (a procedure we call alanine shaving). Even the most extremely mutated variant, with 16 alanine substitutions, caused less than a 10-fold reduction in binding affinity to MAb3. By comparison, mutating any 1 of the 5 primary determinants to alanine caused a 6- to > 500-fold reduction in affinity. Replacing any of the 4 charged residues (Arg 8, Arg 16, Asp 112, and Asp 116) with a homologous residue (i.e., Arg to Lys or Asp to Glu) caused nearly as large a reduction in affinity as the corresponding alanine replacement. It was possible to graft the 5 primary binding determinants onto a nonbinding homologue of hGH, human placental lactogen (hPL), which has 86% sequence identity to hGH. The grafted hPL mutant bound 10-fold less tightly than hGH to MAb3 but bound as well as hGH when 2 additional framework mutations were introduced. Attempts to recover binding affinity by grafting the MAb3 epitope onto more distantly related scaffolds having a similar 4-helix bundle motif, such as human prolactin (23% sequence identity) or granulocyte colony-stimulating factor, were unsuccessful.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine↗

PubMed1998

A conserved deamidation site at Asn 2 in the catalytic subunit of mammalian cAMP-dependent protein kinase detected by capillary LC-MS and tandem mass spectrometry.

The N-terminal sequence myr-Gly-Asn is conserved among the myristoylated cAPK (protein kinase A) catalytic subunit isozymes Calpha, Cbeta, and Cgamma. By capillary LC-MS and tandem MS, we show that, in approximately one third of the Calpha and Cbeta enzyme populations from cattle, pig, rabbit, and rat striated muscle, Asn 2 is deamidated to Asp 2. This deamidation accounts for the major isoelectric variants of the cAPK C-subunits formerly called CA and CB. Deamidation also includes characteristic isoaspartate isomeric peptides from Calpha and Cbeta. Asn 2 deamidation does not occur during C-subunit preparation and is absent in recombinant myristoylated Calpha (rCalpha) from Escherichia coli. Deamidation appears to be the exclusive pathway for introduction of an acidic residue adjacent to the myristoylated N-terminal glycine, verified by the myristoylation negative phenotype of an rCalpha(Asn 2 Asp) mutant. This is the first report thus far of a naturally occurring myr-Gly-Asp sequence. Asp 2 seems to be required for the well-characterized (auto)phosphorylation of the native enzyme at Ser 10. Our results suggest that the myristoylated N terminus of cAPK is a conserved site for deamidation in vivo. Comparable myr-Gly-Asn sequences are found in several signaling proteins. This may be especially significant in view of the recent knowledge that negative charges close to myristic acid in some proteins contribute to regulating their cellular localization.

Amides↗

PubMed1979

Epidemiology of nodular paragranuloma (Hodgkin's disease with lymphocytic predominance, nodular).

The age and sex distribution and the localization of excised lymph nodes from 206 patients with a nodular variant of Hodgkin's disease with lymphocytic predominance, called "nodular paragranuloma", are presented and compared with data on other types of Hodgkin's disease. The age curve of nodular paragranuloma showed a peak in the fourth decade, which was clearly separated from the peak in the third decade exhibited by the nodular sclerosis type of Hodgkin's disease and from the peak in the sixth and seventh decades of the mixed cellularity type. The peak in the age curve of nodular paragranuloma resulted from the high frequency in men in the fourth decade; the female age curve had no peaks. The overall male-to-female ratio was 2.4:1. The age and sex distribution of diffuse paragranuloma was nearly identical to that of nodular paragranuloma, whereas the age and sex distribution of cases of the lymphocytic predominance type other than paragranuloma resembled that of the mixed cellularity type. These data indicate that the lymphocytic predominance type of Hodgkin's disease is not a uniform group and support the view that paragranuloma is a separate entity.

Adolescent↗

PubMed1979

Nodular paragranuloma and progressively transformed germinal centers. Ultrastructural and immunohistologic findings.

Ultrastructural and immunohistologic findings in a nodular variant of Hodgkin's disease with lymphocytic predominance, called nodular paragranuloma, are presented and compared with those in so-called progressively transformed germinal centers. These are large follicles with numerous lymphocytes which can be found not only in nonspecific lymphadenitis, but also in lymph nodes from patients with nodular paragranuloma. The immunoperoxidase technique was applied on paraffin sections to detect intracytoplasmic immunoglobulin and lysozyme. The so-called L & H type Sternberg-Reed cells contained IgG and one type of light chain per cell, suggesting that such cells produce immunoglobulin. The ultrastructure of the L & H type Sternberg-Reed cells favored the immunoblastic nature of these cells. It is concluded that nodular paragranuloma differs from other types of Hodgkin's disease by its localization in B-cell areas and the presence of atypical B immunoblasts.

B-Lymphocytes↗

PubMed2001

[Degenerative changes in parapharyngeal schwannoma "ancient schwannoma". Case report and review of the literature].

Schwannomas are rare, slow-growing, benign neoplasms derived from the schwann cells of the nerve sheath of peripheral nerves. Extracranial schwannomas are most frequently localized within the extremities or the head and neck region. For example, they are common in the skull base, the carotid sheath, and the parapharyngeal space. Beneath several histological variants, schwannomas showing prominent degenerative changes (so-called,,ancient schwannomas") are exceedingly rare. Histopathological features, such as degenerative changes and nuclear atypias in ancient schwannomas, may be easily confused with malignant mesenchymal neoplasm.We present the case of a 32-year-old female who required surgery for a parapharyngeal neoplasm. Histological examination revealed features of an ancient schwannoma.

Adult↗

PubMed2006

Bipolar supernumerary renal artery.

The variations of renal arteries are considered critical issues that surgeons should have thorough envision and appreciation of the condition. Variations of these vessels may influences urological, renal transplantation and laparoscopic surgeries. We present a case of bilateral accessory renal artery with a striking pre-hilar branching pattern encountered upon digital subtraction angiography (DSA) for imaging of the renal arteries of a healthy 30-year-old man, renal transplant donor. The right kidney received two renal arteries from the aorta including a main hilar and one lower polar. However, the left accessory artery while originated from the aorta, simultaneously, supplied both upper and lower renal poles following its pre-hilar division that replaced upper/apical and lower segmental arteries of the single main renal artery, respectively. The left main renal artery divided into two anterior and posterior segmental arteries. Whether this should be categorized either as an accessory hilar artery or a unique variant of renal arterial supply, the so-called bipolar supernumerary renal artery, is a matter of debate. We discuss possible embryologic origin and clinical aspects of accessory renal artery.

Adult↗

PubMed2003

Increased prevalence of platelet glycoprotein IIb/IIIa PLA2 allele in ischaemic stroke associated with large vessel pathology.

INTRODUCTION: Platelet glycoprotein IIb/IIIa is a membrane receptor with a central function in the platelet adhesion and ultimately in the thrombus formation. Two major variants of the gene encoding the IIIa subunit, called PLA1 (A1) and PLA2 (A2), have been identified in the general population. There are indications that the A2 allele can also be associated with acute thrombosis or stroke. The purpose of this study was to study the distribution of the A2 allele in different vascular subtypes of stroke disease. MATERIALS AND METHODS: A total of 638 consecutive patients were analyzed and classified as having large vessel pathology (n=168) or a small vessel infarct (n=210). Localization of the vascular occlusions was deducted from analysis of the magnetic resonance imaging (MRI) scan results in stroke patients. The remainder patients were listed into a mixed vascular pathology group (n=167). Patients with other or poorly characterized stroke etiology were excluded from the study (n=93). RESULTS: In the small vessel and mixed vascular pathology groups, the PLA2 allele frequency was similar to that in the controls. By contrast, PLA2 allele frequency was approximately two-fold higher in patients with large vessel pathology (23.3%) than in the stroke-free control subjects (11.7%, p<0.0005). Multivariate logistic regression analysis of data confirmed this association with an odds ratio (OR) of 2.9 (95% confidence interval [CI]: 1.6-4.9, p<0.0005). CONCLUSIONS: These data suggest that the PLA2 allele is more frequent in brain infarcts associated with large-vessel occlusion.

Adult↗

PubMed2003

Biology of early life stages in cephalopod molluscs.

Recent literature on embryonic and post-embryonic development, biology and behavioural ecology of juvenile cephalopods is reviewed. Emphasis is placed on biological processes. Life-history patterns and phylogenetic systematics, which are important for a proper understanding of the evolutionary history of the cephalopods, are only briefly touched upon. Egg sizes in cephalopods range from less than 1 mm to about 30 mm in diameter, so the hatchlings emerging from the largest eggs are bigger than the adults of pygmy squid, the smallest known cephalopods. Developmental durations from spawning to hatching range from a few days (for very small eggs developing at high temperatures) to one or possibly several years (for very large eggs developing at low temperatures). Such important differences notwithstanding, the morphogenetic processes are very similar in all cephalopod embryos, the major variant being the size of the so-called outer yolk sac, which may be rudimentary in extremely small embryos. Several questions concerning the timing of hatching in relation to the developmental stage attained, especially in terms of yok absorption, need clarification. These questions concern the elimination of the transient closure of the mouth, the final differentiation of digestive gland cells, and the removal of the tranquilliser effect of the perivitelline fluid necessary for the onset of the hatching behaviour. Cephalopod hatchlings are active predators. They refine their behavioural repertoires by learning from individual experience in dealing with prey and would-be predators. There is no truly larval phase, and the ecologically defined term paralarva should be used with caution. Given the considerable resource potential of cephalopods, investigations into dispersal and recruitment are of particular interest to fishery biology, but they are also important for ecological biogeography. The related studies of feeding and growth involve field sampling and tentative age determination of caught specimens, in combination with laboratory studies to test food quality, measure feeding rates, and validation of periodicities in accretional growth structures (e.g. "daily rings" in statoliths).

Animals↗

PubMedDate not supplied

[The mysteries of lipoprotein (a): a bridge between thrombosis and atheroma].

Nearly 30 years have elapsed since Berg discovered a genetic variant of low density lipoproteins (LDL) which he called lipoprotein (a), abbreviated Lp (a). Lp (a) rapidly appeared as an independent factor of atherosclerosis. Its physico-chemical characteristics are well-known, but this cannot be said of its function, its metabolism and the exact mechanism of its contribution to atherogenesis. The plasma Lp (a) concentration is determined genetically and its seems that few factors can lower it. Owing to its structural analogy with plasminogen, Lp (a) has been suspected to bind fibrin by a competitive mechanism, thereby facilitating thrombosis, a necessary step in the progression of atherosclerosis. However, these results remain controverted, and indeed there is some evidence of a possible interaction between Lp (a) and alpha-2-antiplasmin, a physiological inhibitor of fibrinolysis, an effect that would accentuate fibrinolysis. This paradoxical action of Lp (a) and the various mysteries which still shroud this lipoprotein are perhaps due to the diversity of its isotypes.

Arteriosclerosis↗

PubMedDate not supplied

Purification and biochemical properties of Pitton's type 2 beta-lactamase (SHV-1).

A five-step procedure has been developed for purifying Pitton's type 2 plasmid-mediated beta-lactamase (PIT-2, also called SHV-1) from cultures of a hyperproducing variant of an Escherichia coli K12 strain carrying the plasmid p453. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis revealed a single protein band with a molecular weight of about 27,500. The amino acid composition of the protein and the amino acid sequence of the NH2-terminal region have been determined. PIT-2 enzyme contains 272 amino acid residues with 2 cysteines. Studies of the S-carboxymethylated protein (previously reduced or unreduced) suggest that these two residues are presumably in the form of free sulphydryl groups in the native protein. Conversely, TEM-2 beta-lactamase contains 2 cysteine residues which are in the form of a disulphide bond. Comparison of PIT-2 with other beta-lactamases was made using the difference index (DI) of Metzger et al. The PIT-2 enzyme appeared more closely related to the TEM-type penicillinases (DI of 6.5).

Amino Acid Sequence↗

PubMed2001

Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13.

Congenital generalized lipodystrophy, or Berardinelli-Seip syndrome (BSCL), is a rare autosomal recessive disease characterized by a near-absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biological features include acanthosis nigricans, hyperandrogenism, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia. A locus (BSCL1) has been mapped to 9q34 with evidence of heterogeneity. Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway). We identified a new disease locus, designated BSCL2, within the 2.5-Mb interval flanked by markers D11S4076 and D11S480 on chromosome 11q13. Analysis of 20 additional families of various ethnic origins led to the identification of 11 families in which the disease cosegregates with the 11q13 locus; the remaining families provide confirmation of linkage to 9q34. Sequence analysis of genes located in the 11q13 interval disclosed mutations in a gene homologous to the murine guanine nucleotide-binding protein (G protein), gamma3-linked gene (Gng3lg) in all BSCL2-linked families. BSCL2 is most highly expressed in brain and testis and encodes a protein (which we have called seipin) of unknown function. Most of the variants are null mutations and probably result in a severe disruption of the protein. These findings are of general importance for understanding the molecular mechanisms underlying regulation of body fat distribution and insulin resistance.

Acanthosis Nigricans↗

PubMed2026

Mechanism of age-related accumulation of mtDNA mutations in human blood.

Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.

Humans↗

PubMed1997

Suppression of slow delayed rectifier current by a truncated isoform of KvLQT1 cloned from normal human heart.

It has been suggested that the cardiac slow delayed rectifier channel is formed by the association of two subunits: IsK (also called minK) and KvLQT1. N-terminal splice variants of the human KvLQT1 gene have been identified, but the functional roles of different KvLQT1 isoforms are not clear. Using the nested 5'-rapid amplification of cDNA ends technique, we obtained a truncated isoform of KvLQT1 (termed tKvLQT1) that lacks the N-terminal cytoplasmic domain and the initial one-third of the first transmembrane domain. The function of tKvLQT1 was tested by oocyte expression, alone or together with the full-length KvLQT1 or a human IsK clone (hIsK). tKvLQT1 alone did not generate functional channels. However, it suppressed the KvLQT1 current when coexpressed with the full-length isoform. It also suppressed the slow delayed rectifier current induced by hIsK, probably by competing with the KvLQT1 subunit endogenous to Xenopus oocytes in coassembly with the hIsK subunit. On the other hand, tKvLQT1 did not suppress the expression of Kv1.4, Kv4.3, or hERG. Using the reverse transcription-polymerase chain reaction technique, we further show that the truncated and full-length isoforms are coexpressed in different regions of human heart. Therefore, tKvLQT1 may modulate the function of IKs in human cardiac myocytes.

Amino Acid Sequence↗

PubMed2001

Alpha-fetoprotein in plasma and serum of healthy adults: preanalytical, analytical and biological sources of variation and construction of age-dependent reference intervals.

Alpha-fetoprotein (AFP) is a tumor marker for hepatomas and germ cell tumors, and the serum concentration has prognostic significance in other diseases. We examined the normal serum concentration of AFP in adults and sources of variation in the immunochemical variation of AFP. The serum concentration of the tumor marker alpha-fetoprotein (S-AFP) was log-normally distributed in 284 adult blood donors. S-AFP increased with age (p < 10(-7)), whereas no gender-related difference was found. Reference intervals (95-interpercentile) were constructed for persons < or =40 years (0.60-9.30 kIU/L) and >40 years (1.40 12.60 kIU/L). The concentration of AFP was significantly, albeit slightly, higher in serum than in plasma, whereas hemolysis, pretreatment with KCl and food intake did not influence S-AFP. S-AFP only changed 6% when measured twice 2 months apart (p=0.04). Three enzyme immunoassays, using three different anti-AFP monoclonal antibodies for detection, were compared and two assays gave S-AFP values significantly higher, 2.8% (p=0.03) and 19.0% (p<10(-4)), than the other assay. Thus, the choice of antibody may influence the result of immunochemical concentration determination. This can be explained by the existence of conformational variants of AFP with different antibody reactivities, and calls for careful standardization of monoclonal antibodies used in assays for AFP. With broad population reference ranges and slight intra-personal variation, the most effective reference range for S-AFP is previous values obtained in the same person.

Adult↗