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At least 1,279 records · Page 71Linked to original sources
PubMed2003

Molecular cloning, structure and bait region splice variants of alpha2-macroglobulin from the soft tick Ornithodoros moubata.

The sequence of a alpha(2)-macroglobulin (alpha(2)M) from the soft tick Ornithodoros moubata (TAM) was determined by cloning and sequencing of overlapping polymerase chain reaction (PCR) and rapid amplification of cDNA ends PCR products. The TAM cDNA sequence is 4,944 bp long and contains one open reading frame coding for a protein precursor composed of 1,494 amino-acid residues, including a 24-residue signal sequence. The mature protein is cleaved into two subunits similarly to the C3 and C4 components of complement and fish alpha(2)Ms. Phylogeny analysis revealed that TAM is closely related to Limulus alpha(2)M and displays the highest similarity to the partial sequence of alpha(2)M from hard tick Ixodes scapularis. The comparison of conserved cysteine residues between TAM and human and Limulus alpha(2)Ms made it possible to predict the pattern of disulfide bridges and explain the atypical molecular arrangement of TAM. Four variants of the TAM bait region differing only in a short central segment were found; our data indicate that TAM exists as a single-copy gene in the tick genome and its bait region variants likely arise by alternative splicing. TAM is produced by tick hemocytes and it is also significantly expressed in salivary glands. TAM mRNA levels were shown to be up-regulated upon blood meal.

Amino Acid Sequence↗
PubMed2001

Layered rare-earth gallium antimonides REGaSb(2) (RE = La--Nd, Sm).

The ternary rare-earth gallium antimonides, REGaSb(2) (RE = La--Nd, Sm), have been synthesized through reaction of the elements. The structures of SmGaSb(2) (orthorhombic, space group D(5)(2)-C222(1), Z = 4, a = 4.3087(5) A, b = 22.093(4) A, c = 4.3319(4) A) and NdGaSb(2) (tetragonal, space group D(19)(4h)-I4(1)/amd, Z = 8, a = 4.3486(3) A, c = 44.579(8) A) have been determined by single-crystal X-ray diffraction. The SmGaSb(2)-type structure is adopted for RE = La and Sm, whereas the NdGaSb(2)-type structure is adopted for RE = Ce--Nd. The layered SmGaSb(2) and NdGaSb(2) structures are stacking variants of each other. In both structures, two-dimensional layers of composition (2)(infinity)[GaSb] are separated from square nets of Sb atoms [Sb] by RE atoms. Alternatively, the structures may be considered as resulting from the insertion of zigzag Ga chains between (2)(infinity)[RE Sb(2)] slabs. In SmGaSb(2), all of the Ga chains are parallel and the (2)(infinity)[SmSb(2)] layers are stacked in a ZrSi(2)-type arrangement. In NdGaSb(2), the Ga chains alternate in direction, resulting in a doubling of the long axis relative to SmGaSb(2), and the (2)(infinity)[NdSb(2)] layers are stacked in a Zr(3)Al(4)Si(5)-type arrangement. Extended Hückel band structure calculations are used to explain the bonding in the [GaSb(2)](3-) substructure.

Journal Article↗
PubMed2005

Library versus library recognition and inhibition of the HIV-1 Nef allelome.

Rapid evolution of drug-resistant viruses renders essentially all small-molecule antiviral treatments ineffective. We demonstrate an in vitro library versus library approach to identify small molecules targeting a broad spectrum of HIV-1 Nef protein variants. The technique could provide more effective antiviral therapies. First, a library of clinically derived Nef allelic variants, termed an allelome, was selected for function by binding to Nef ligands p53, actin, or p56lck. Next, a library of small-molecule inhibitors challenged the Nef allelome in competition assays. In contrast to single-variant inhibition, structurally simpler molecules could better inhibit the Nef allelome. Additionally, Nef sequences selected for binding to p53 resembled sequences from patients with a rapid progression to AIDS phenotype. Thus, the allelome versus small-molecule library approach offers a route for improving antiviral drug discovery and elucidating fundamental mechanisms of viral pathogenesis and resistance.

Binding Sites↗
PubMed2002

Heritability estimates for the constitutional levels of the collectins mannan-binding lectin and lung surfactant protein D. A study of unselected like-sexed mono- and dizygotic twins at the age of 6-9 years.

The collectins mannan-binding lectin (MBL) and lung surfactant protein D (SP-D) play a significant role in innate immunity. Structural as wells as promoter variants are known for MBL and different alleles correlate with low MBL concentrations in serum and predispose to infectious diseases. Structural variants are also known for SP-D but these have not been linked to disease states. The aim of the present study was to provide heritability estimates for the constitutional levels of MBL and SP-D in children. A population of 26 monozygotic (MZ) and 36 dizygotic (DZ) like-sexed twin pairs aged 6-9 years was studied. Intraclass correlations were significantly higher in MZ than in DZ twins, indicating substantial genetic influence on both MBL and SP-D levels. Biometric model fitting showed that the estimated heritability was 0.96 (95% CI 0.92-0.97) for MBL with the presence of non-additive genetic factors and non-shared environmental factors and 0.91 (95% CI 0.83-0.95) for SP-D with additive genetic and non-shared environmental factors. The data indicate quantitatively very strong genetic dependence for the serum levels of both MBL and SP-D.

Biometry↗
PubMed1998

Structural characterization of three genetic variants of human serum albumin modified in subdomains IIB and IIIA.

Three new genetic variants of human serum albumin have been detected in Italy by routine clinical electrophoresis. Albumin Milano Slow is common in Northern Italy, while albumins Liprizzi and Trieste, which are fast migrating, are rare and local variants. Isoelectric focusing analysis of the CNBr fragments obtained from the carboxymethylated alloalbumins in all cases localized the mutation to fragment CB5 (residues 330-446). The modified CNBr fragments were isolated on a preparative scale and subjected to tryptic digestion. Sequence determination of the abnormal tryptic peptides revealed that all the variants are caused by single point mutations: Trieste, Lys359-->Asn, Milano Slow, Asp375-->His, and Liprizzi, Arg410-->Cys. These results were confirmed by sequence determination of a variant V8 peptide in the case of Trieste, and by DNA sequence analysis for the other two variants. The DNA analysis showed a G-->C transversion at nucleotide position 11969 for albumin Milano Slow, and a C-->T transition at position 13251 for Liprizzi. The latter represents a mutation at a hypermutable CpG dinucleotide site. Albumins Trieste and Milano Slow, as most of the variants thus far described, have mutations involving residues on the surface of the molecule. In contrast, albumin Liprizzi represents the first example of a mutation in the most active binding pocket of the molecule, placed in subdomain IIIA.

Amino Acid Sequence↗
PubMed2006

Dual strategies for peptidoglycan discrimination by peptidoglycan recognition proteins (PGRPs).

The innate immune system constitutes the first line of defense against microorganisms in both vertebrates and invertebrates. Although much progress has been made toward identifying key receptors and understanding their role in host defense, far less is known about how these receptors recognize microbial ligands. Such studies have been severely hampered by the need to purify ligands from microbial sources and a reliance on biological assays, rather than direct binding, to monitor recognition. We used synthetic peptidoglycan (PGN) derivatives, combined with microcalorimetry, to define the binding specificities of human and insect peptidoglycan recognition proteins (PGRPs). We demonstrate that these innate immune receptors use dual strategies to distinguish between PGNs from different bacteria: one based on the composition of the PGN peptide stem and another that senses the peptide bridge crosslinking the stems. To pinpoint the site of PGRPs that mediates discrimination, we engineered structure-based variants having altered PGN-binding properties. The plasticity of the PGRP-binding site revealed by these mutants suggests an intrinsic capacity of the innate immune system to rapidly evolve specificities to meet new microbial challenges.

Animals↗
PubMed1983

Primary structure of an amyloid prealbumin variant in familial polyneuropathy of Jewish origin.

The complete amino acid sequence of three related amyloid proteins (Mr 14,000, 10,000, and 5,000) derived from tissues of a Jewish patient who suffered from a variant of familial polyneuropathic amyloidosis was determined. The protein, which contains 127 residues, is identical to a human serum prealbumin subunit. Only one amino acid substitution, glycine for threonine, was detected at position 49, where enzymatic cleavage occurred, yielding Mr 5,000 and 10,000 fragments which represent the amino terminus (residues 1-48) and carboxyl terminus (residues 49-127) of the molecule, respectively. Thus, a prealbumin variant and its fragments constitute the amyloid fibrils in a heredofamilial amyloidosis syndrome of dominant inheritance.

Amino Acid Sequence↗
PubMed2002

Substrate-dependent competency of the catalytic triad of prolyl oligopeptidase.

Prolyl oligopeptidase, a serine peptidase unrelated to trypsin and subtilisin, is implicated in memory disorders and is an important target of drug design. The catalytic competence of the Asp(641) residue of the catalytic triad (Ser(554), Asp(641), His(680)) was studied using the D641N and D641A variants of the enzyme. Both variants displayed 3 orders of magnitude reduction in k(cat)/K(m) for benzyloxycarbonyl-Gly-Pro-2-naphthylamide. Using an octapeptide substrate, the decrease was 6 orders of magnitude, whereas with Z-Gly-Pro-4-nitrophenyl ester there was virtually no change in k(cat)/K(m). This indicates that the contribution of Asp(641) is very much dependent on the substrate-leaving group, which was not the case for the classic serine peptidase, trypsin. The rate constant for benzyloxycarbonyl-Gly-Pro-thiobenzylester conformed to this series as demonstrated by a method designed for monitoring the hydrolysis of thiolesters in the presence of thiol groups. Alkylation of His(680) with Z-Gly-Pro-CH(2)Cl was concluded with similar rate constants for wild-type and D641A variant. However, kinetic measurements with Z-Gly-Pro-OH, a product-like inhibitor, indicated that the His(680) is not accessible in the enzyme variants. Crystal structure determination of these mutants revealed subtle perturbations related to the catalytic activity. Many of these observations show differences in the catalysis between trypsin and prolyl oligopeptidase.

Animals↗
PubMed2006

Variable mannose-binding lectin expression during postoperative acute-phase response.

BACKGROUND: Low plasma concentrations and genetic polymorphisms of mannan-binding lectin (MBL) have been associated with infectious disease complications during various conditions. The present study examined the nature and expression of MBL deficiency during a surgery-induced acute-phase response. METHODS: Blood was sampled from 20 consecutive patients before and 1, 3, 5, 7, and 10 days and 6 weeks after a uniform abdominal operation (transhiatal esophagectomy). Plasma concentrations of MBL, C-reactive protein (CRP), and secretory phospholipase A2 (sPLA2) were measured. Patients were classified as low- or high-level MBL producers by their preoperative concentration (<0.5 or > or = 0.5 micrograms/mL), and were cross-verified for actual MBL deficiency by nucleotide sequencing of both the MBL promoter and exon-1 alleles. RESULTS: Baseline plasma MBL concentrations correlated with maximal postoperative plasma concentrations (r = 0.88; p < 0.0001). This was not found for CRP and sPLA2 (r = 0.19 and r = 0.08, respectively). Alleles responsible for structural MBL variants were detected in 40% of patients and were associated with significantly reduced MBL concentrations (p = 0.005). The baseline cut-off value in plasma of 0.5 micrograms/mL clearly identified individuals with variant exon-1 alleles (sensitivity 100%, specificity 83%). CONCLUSIONS: Baseline MBL plasma concentrations are predictive of MBL expression during the acute-phase response. A baseline cut-off value of 0.5 micrograms/mL can be used to identify patients with variants in the exon-1 region of the MBL gene without the need for nucleotide sequencing. Clinical studies may use this easy and quick method to identify MBL deficient patients preoperatively, as they are conditionally at risk for infectious complications.

Acute-Phase Reaction↗
PubMed1979

Population genetics of Drosophila amylase. II. Geographic patterns in D. pseudoobscura.

Morph frequencies of three related polymorphisms were determined in ten natural populations of Drosophila pseudoobscura. They are the well-known inversion polymorphism of the third chromosome and the polymorphism for alpha-amylase produced by the structural gene Amy (which resides on the third chromosome). The third polymorphism was for tissue-specific expression of Amy in adult midguts; a total of 13 different patterns of activity have been observed. The preceding paper (Powell and Lichtenfels 1979) reports evidence that the variation in Amy expression is under polygenic control. Here we show that the polymorphism for midgut patterns occurs in natural populations and is not an artifact of laboratory rearing.--From population to population, Amy allele frequencies and frequencies of inversions belonging to different phylads vary coordinately. The geographic variation in alpha-amylase midgut activity patterns is uncorrelated with that for the other two types of polymorphisms. Furthermore, no correlation was detected between activity pattern(s) and Amy genotype(s) when both were assayed in the same individual.--These results imply that whatever the evolutionary-ecological forces are that control frequencies of the structural gene variants, they are not the same factors that control the frequencies of polymorphic genetic factors responsible for the tissue-specific expression of the enzyme.

Alleles↗
PubMed1980

Developmental variation in amylase allozyme activity associated with chromosome inversions in Drosophila persimilis.

The amylase locus in Drosophila persimilis is polymorphic for allozymes, two of which show associations with naturally occurring chromosome 3 inversions. Amy1.09 occurs at high frequencies only in Whitney (WT), while the other common arrangements-Standard (ST), Klamath (KL) and Mendocino (MD)-are predominantly Amy 1.00. We have examined numerous strains, representing various electromorphs and inversions, for variation in cis-specific activity expression in both third-instar larvae and adults. Comparisons of these two life stages also allows the survey of developmental variation in amylase activities. The amount of activity variation exceeds electrophoretic variation at this locus. Moreover, this variation is largely nonrandom and reveals more genic divergence among inversions. The 1.00 allozyme of MD is more active than 1.00 KL in larvae and adults and shows a different developmental pattern. The activity of the 1.00 allozyme of KL is greater than 1.00 allozyme of ST in larvae and adults, but these two arrangements have similar developmental patterns. WT 1 with a 1.00 allele is dramatically different from the 1.00 allozymes of other arrangements in its developmental pattern. The 1.09 allozymes has high activity in WT and KL, but these arrangements differ in their developmental pattern of expression, WT being more active in adults. F2 segregational analyses are consistent with the variation being due to either structural enzyme variants or closely linked cis-acting regulatory elements. We argue that the suppression of recombination between arrangements has allowed the divergence in amylase activity among inversions.

Amylases↗
PubMed1994

Invited commentary--"molecular epidemiology": new pathway or new travelling companion?

The term "molecular epidemiology" is coming into general usage, but its implications are ambiguous. A simple definition is that it entails the inclusion in epidemiologic research of biologic measurements made at the molecular level--and is thus an extension of the increasing use of biologically based measures in epidemiologic research. "Molecular epidemiologic" measurements typically detect damaged or naturally variant molecular structures, or use immunologically based techniques to detect particular gene-product molecules. (In contrast, the measurement of biochemical concentration, such as of plasma estrogens, does not require information about molecular structure.) Molecular techniques can be used to measure exposure, early biologic response, or host characteristics that influence susceptibility. They may also elucidate mediating biologic events, and may enable differentiation of adverse health outcomes. Molecular biomarkers have been applied particularly in cancer epidemiology, to measure DNA damage, heritable genetic polymorphisms that influence susceptibility, and "cancer family" genes. Infectious disease epidemiologists use molecular measures of genetic strains of microbes, and they and cancer epidemiologists measure viral nucleic acids within host cells. The term "molecular epidemiology" may suggest the existence of a subdiscipline with substantive new research content. Molecular techniques, however, are directed principally at enhancing the measurement of exposure, effect, or susceptibility, and not at formulating new etiologic hypotheses. As techniques of refinement and elaboration, the integration of molecular measures into mainstream epidemiologic research can offer higher resolution answers in relation to disease causation.

Aflatoxin B1↗
PubMed2005

ACOG Practice Bulletin. Clinical Management Guidelines for Obstetrician-Gynecologists Number 64, July 2005 (Replaces Committee Opinion Number 238, July 2000): hemoglobinpathies in pregnancy.

The hemoglobinopathies are a heterogeneous group of single-gene disorders that include the structural hemoglobin variants and the thalassemias. More than 270 million people worldwide are heterozygous carriers of hereditary disorders of hemoglobin, and at least 300,000 affected homozygotes or compound heterozygotes are born each year (1). The purpose of this document is to review the most common hemoglobinopathies and to provide recommendations for the screening and clinical management of hemoglobinopathies during pregnancy.

Anemia, Sickle Cell↗
PubMed2007

ACOG Practice Bulletin No. 78: hemoglobinopathies in pregnancy.

The hemoglobinopathies are a heterogeneous group of single-gene disorders that includes the structural hemoglobin variants and the thalassemias. More than 270 million people worldwide are heterozygous carriers of hereditary disorders of hemoglobin, and at least 300,000 affected homozygotes or compound heterozygotes are born each year. The purpose of this document is to review the most common hemoglobinopathies and to provide recommendations for screening and clinical management of hemoglobinopathies during pregnancy.

Exchange Transfusion, Whole Blood↗
PubMed1977

Common bony densities mimicking chest disease.

Images of bony densities on routine chest radiographs may simulate intrathoracic disease processes. Such entities include images produced by normal anatomic structures, anatomic variants, and benign processes. Most commonly, chest disease was simulated by virtue of projection or poor visualization of the bony density in question on the routine chest radiograph. The true nature of the "abnormal" images produced was usually revealed by further roentgenographic evaluation using specialized radiographic technics or additional views.

Aortic Diseases↗
PubMed2026

Hidden genomic structure and widespread structural polymorphism across environmental gradients in the spiny sea star Marthasterias glacialis.

Genomic regions of reduced recombination can preserve linkage among co-adapted alleles, facilitating local adaptation despite high connectivity. Such regions-often generated by chromosomal inversions-may be especially important in highly dispersive marine taxa yet remain poorly documented in echinoderms. Here, we combined a chromosome-level reference genome with genome-wide ddRAD-seq from 296 Marthasterias glacialis individuals across 19 Atlantic-Mediterranean locations to quantify population structure and scan for recombination-suppressed haploblocks. Genome-wide neutral markers showed significant population differentiation together with evidence of high connectivity, revealed by the presence of inter-ecoregion migrants. Additionally, we identified 16 polymorphic haploblocks with patterns consistent with putative chromosomal inversions spanning 18.6% of the genome. Haploblock haplotypes were strongly environmentally and geographically structured and contained genes with key functions in stress response, osmoregulation and thermal tolerance. Haplotype distributions also paralleled previously described mitochondrial lineages despite nuclear gene flow, consistent with a model of ancient divergence followed by secondary contact. Overall, our results suggest a role for widespread structural polymorphism in adaptive differentiation in Echinodermata, providing a framework for linking echinoderm genome rearrangements to ecological divergence. Marthasterias glacialis thus emerges as a promising system to explore how structural variation contributes to adaptation and genome evolution in highly dispersive organisms.

Animals↗
PubMed1984

Genetic disorders of human haemoglobin as models for analysing gene regulation.

The genetic and acquired disorders of human haemoglobin provide a diverse group of naturally occurring models for analysing the regulation of protein synthesis. They include structural haemoglobin variants, thalassaemias, which are conditions in which there is a reduced rate of globin chain production, and hereditary persistence of foetal haemoglobin (HPFH) in which there is an inherited abnormality in the switch from foetal to adult haemoglobin synthesis. The thalassaemias result from a diverse series of cis acting lesions of the globin genes which include deletions, insertions, frame shift mutations, and point mutations involving transcription, messenger RNA processing, initiation, termination, poly A addition and globin chain stability. Many forms of HPFH are due to deletions of the beta-like gene cluster; it has been suggested that they may involve regions of the cluster which are involved in the regulation of the foetal to adult globin chain switch. So far, however, no regions of this type have been identified with certainty. The varieties of HPFH not associated with major gene deletions, or those caused by genetic determinants that are not linked to the globin gene clusters, and some of the acquired forms of alpha thalassaemia associated with mental retardation or leukaemia, may be more useful models for studying the regulation of the globin genes, particularly their developmental control.

Base Sequence↗