Association of large molecular weight proteasome 7 gene polymorphism with ankylosing spondylitis.
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Cysteine Endopeptidases↗
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Results for “Molecular polymorphism”
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Distribution of parvalbumin-immunoreactive cells and fibers in the monkey temporal lobe: the hippocampal formation.
The distribution of parvalbumin-immunoreactive cells and fibers in the various fields of the hippocampal formation was studied in the macaque monkey. Parvalbumin-immunoreactive neurons had aspiny or sparsely spiny dendrites that often had a beaded appearance; most resembled classically identified interneurons. Parvalbumin-immunoreactive fibers and terminals were confined to certain laminae in each field and generally had a pericellular distribution. In the dentate gyrus, there was a dense pericellular plexus of immunoreactive terminals in the granule cell layer. Except for a narrow supragranular zone, there was a marked paucity of terminals in the molecular and polymorphic cell layers. Immunoreactive neurons were mainly located immediately subjacent to the granule cell layer and comprised a variety of morphological cell types. The three fields of the hippocampus proper (CA3, CA2, and CA1) demonstrated differences in their parvalbumin staining characteristics. In CA3, there was a prominent pericellular terminal plexus in the pyramidal cell layer that was densest distally (closer to CA2). Immunoreactive cells were located either in the pyramidal cell layer, where many had a pyramidal shape and prominent apical and basal dendrites, or in stratum oriens. CA2 had a staining pattern similar to that in CA3, though both the number of labeled cells and the density of the pericellular terminal plexus were greater in CA2. In CA1, there was a markedly lower number of parvalbumin-labeled cells than in CA3 and CA2 and the cells tended to be located in the deep part of the pyramidal cell layer or in stratum oriens. The pyramidal cell layer of CA1 contained a pericellular terminal plexus that was substantially less dense than in CA3 and CA2. At the border between CA1 and the subiculum there was a marked increase in the number of parvalbumin-immunoreactive neurons. The positive cells were scattered throughout the pyramidal cell layer of the subiculum and comprised a variety of sizes and shapes. Terminal labeling was higher in the pyramidal cell layer of the subiculum than in CA1. Layer II of the presubiculum had one of the highest densities of fiber and terminal labeling in the hippocampal formation. The density of staining was lower in the superficial portion of the layer where linear cartridges of presumed axo-axonic synapses were common. A large number of parvalbumin-immunoreactive cells were scattered throughout layer II of the presubiculum; small, spherical, multipolar cells were commonly observed in layer I. The parasubiculum had a somewhat lower density of positive cells and fibers than the presubiculum.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Histoautoradiographic detection of oxytocin- and vasopressin-binding sites in the telencephalon of the rat.
Localization of oxytocin- and vasopressin-binding sites has so far been studied in the rat brain by means of film autoradiographs. The disposal of iodinated ligands with high specificity has allowed us to develop histoautoradiography on emulsion-coated sections and to reinvestigate on a microscopic scale the distribution of these sites in the telencephalon (septum, striatopallidal system, amygdala and hippocampus). This technique showed that oxytocin and vasopressin labelling presented distinct distributions and coincided with delimited zones, corresponding to anatomical subdivisions defined on cytoarchitectural and immunocytochemical bases. Vasopressin sites were seen in the dorsal and intermediate parts of the lateral septum and the juxtacapsular nucleus of the bed nucleus of the stria terminalis. Oxytocin sites were located in the ventral and intermediate parts of the lateral septum, the oval and the principal nuclei of the bed nucleus of the stria terminalis and the septofimbrial nucleus. In the striatopallidal system, vasopressin sites were found in the accumbens nucleus and the fundus striati, whereas oxytocin sites were in the accumbens nucleus, the head, and the posterolateral parts of the caudate-putamen, the striatal cell bridges, and the olfactory tubercle. In the amygdala, vasopressin sites were not found, but oxytocin sites were located in the central, medial, and basomedial nuclei. In the hippocampus, vasopressin sites were located in the dentate gyrus (polymorph and molecular layers), and oxytocin sites, in the subiculum (molecular and pyramidal layers) and in the field CA1 of Ammon's horn (lacunosum moleculare and pyramidal layers). The localization of the binding sites at the microscopic level permitted us to reinvestigate whether or not correlation existed in a same area between innervation, electrophysiological effects, and presence of binding sites.
Animals↗
Reduced nicotinamide adenine dinucleotide phosphate-diaphorase/nitric oxide synthase profiles in the human hippocampal formation and perirhinal cortex.
Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-stained profiles were evaluated throughout the human hippocampal formation (i.e., dentate gyrus, Ammon's horn, subicular complex, entorhinal cortex) and perirhinal cortex. NADPH-d staining revealed pleomorphic cells, fibers, and blood vessels. Within the entorhinal and the perirhinal cortices, darkly stained (type 1) NADPH-d pyramidal, fusiform, bipolar, and multipolar neurons with extensive dendrites were scattered mainly within deep layers and subjacent white matter. Moderately stained (type 2) NADPH-d round or oval neurons were seen mainly in layers II and III of the entorhinal and perirhinal cortices, in the dentate gyrus polymorphic layer, in the CA fields stratum pyramidal and radiatum, and in the subicular complex. The distribution of type 2 cells was more abundant in the perirhinal cortex compared to the hippocampal formation. Lightly stained (type 3) NADPH-d pyramidal and oval neurons were distributed in CA4, the entorhinal cortex medial subfields, and the amygdalohippocampal transition area. Sections concurrently stained for NADPH-d and nitric oxide synthase (NOS) revealed that all type 1 neurons coexpressed NOS, whereas types 2 and 3 were NOS immunonegative. NADPH-d fibers were heterogeneously distributed within the different regions examined and were frequently in close apposition to reactive blood vessels. The greatest concentration of fibers was in layers III and V-VI of the entorhinal and perirhinal cortices, dentate gyrus polymorphic and molecular layers, and CA1 and CA4. A band of fibers coursing within CA1 divided into dorsal and ventral bundles to reach the presubiculum and entorhinal cortex, respectively. Although the distribution of NADPH-d fibers was conserved across all ages examined (28-98 years), we observed an increase in the density of fiber staining in the aged cases. These results may be relevant to our understanding of selective vulnerability of neuronal systems within the human hippocampal formation in aging and in neurodegenerative diseases.
Adult↗
Use of antibodies against synthetic peptides for analysis of molecular multiplicity: human deoxyribonuclease I polymorphism.
Eight different antibodies were raised in rabbits and chickens by injecting them with two synthetic N- and C-peptides, which corresponded to the N- and C-terminal 15 residues of human deoxyribonuclease I (DNase I). These two peptides were used as immunogens, both free and conjugated with keyhole limpet hemocyanin (KLH). A rabbit antiserum against the C-peptide conjugated with KLH (rabbit anti-C/KLH) and two chicken antisera against the C-peptide itself (chicken anti-C) and conjugated with KLH (chicken anti-C/KLH) reacted well with purified DNase I, blotted onto a transfer membrane after isoelectric focusing in a polyacrylamide gel. A clear isoenzyme pattern identical to that detected with a rabbit antiserum against the parent enzyme (rabbit anti-DNase I) was observed. Surprisingly, the chicken anti-C antiserum was found to be a powerful and highly specific tool for the determination of urinary DNase I phenotypes (Kishi et al., Hum. Genet. 1989, 81, 295-297) and was not inferior in any respect to the rabbit anti-DNase I. These findings show that the selection of immune animal is one of the most important factors for producing an effective anti-peptide antibody. Unfortunately, the anti-peptide antisera obtained in this study neither blocked DNase I enzyme activity nor did it bind to the enzyme.
Animals↗
Binding energy analysis for wild-type and Y181C mutant HIV-1 RT/8-Cl TIBO complex structures: quantum chemical calculations based on the ONIOM method.
Two-layered and three-layered ONIOM calculations were performed to compare the binding energies of 8-Cl TIBO inhibitor when bound into the human immunodeficiency virus reverse transcriptase binding pocket and a Y181C variant. Both consisted of 20 residues within a radius of 15 A. A combination of different methods [MP2/6-31G(d), B3LYP/6-31G(d,p), and PM3] were performed to take advantage of ONIOM's layering strategy analysis. The obtained results clearly indicate that the Y181C mutation reduces the binding affinity and stability of the inhibitor by approximately 8-9 kcal/mol as obtained from different combined MO:MO methods. Analyses regarding the energetic components of the interaction and deformation energies for 8-Cl TIBO inhibitor upon binding were also examined extensively. Additional calculations involving the interaction energies between 8-Cl TIBO with individual residues surrounding the binding pocket were performed at MP2/6-31G(d,p) and B3LYP/6-31G(d,p) levels of theory to gain more insight into the energetic differences of wild-type and Y181C mutant type at the atomistic level.
Amino Acid Substitution↗
The parental origin of hydatidiform moles and blighted ova: molecular probing with hypervariable DNA polymorphisms.
The androgenetic origin of hydatidiform moles, due to a monospermic or dispermic mechanism, has been reported, and a possible pathogenetic relation with blighted ova suggested. To evaluate the origin of hydatidiform moles and their genetic relationship with blighted ova we investigated a series of samples, utilizing several hypervariable DNA polymorphisms by Southern blotting or PCR. Seven complete or partial hydatidiform mole and 49 blighted ovum cases were investigated. The results confirm the androgenetic origin of complete hydatidiform moles, which were always due in our sample to a monospermic mechanism. Our data exclude a relationship between hydatidiform moles and blighted ova, as in the latter a mixed paternal and maternal DNA contribution was always shown. A high incidence of chromosomal abnormalities in blighted ova was also found.
Blotting, Southern↗
Molecular genetics of the human major histocompatibility complex.
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Amino Acid Sequence↗
Genetic mapping and protein product diversity of the self-incompatibility locus in wild tomato (Lycopersicon peruvianum).
Phenotypic diversity of self-incompatibility (S) alleles within nine natural populations of Lycopersicon peruvianum was investigated. Only 7 incompatible responses were observed of a total of 276 unique combinations tested, on the basis of controlled pollinations, indicating the large number of alleles that exist within these populations. Molecular weight polymorphism for specific major stylar proteins observed on SDS-PAGE was also evident in two of the populations examined. Five proteins were shown to map to the S locus and to be associated with different S alleles through controlled pollinations and segregation of the proteins. Two of these S related proteins had been described previously in terms of spatial and temporal expression consistent with their involvement in self-incompatibility (Mau et al., Planta 169, 184-191, 1986). A mapping population derived from a fully compatible cross was used to establish linkage of the S locus to two DNA markers, CD15 and TG184, that lie on chromosome 1. The order of the markers and estimates of map distances are given.
Alleles↗
AMPA-selective glutamate receptor subtype immunoreactivity in the hippocampal dentate gyrus of patients with Alzheimer disease. Evidence for hippocampal plasticity.
Immunocytochemical techniques were employed in order to examine the distribution and relative intensity of immunolabeling of the alpha-amino-3-hydroxy-5-methyl-4-isoaxolepropionate (AMPA) receptor subunits GluR1 and GluR2/3 within the hippocampal formation of patients with Alzheimer disease (AD). Within sectors of the hippocampus that are particularly vulnerable to AD pathology (i.e., CA1, subiculum), we observed a variable loss of GluR1 and GluR2/3 immunolabeling correlating with the extent of cell loss and neurofibrillary pathology. In contrast, in less vulnerable sectors of the hippocampus (i.e., CA2/3, dentate gyrus), the intensity of immunolabeling was markedly increased in AD cases, particularly in the molecular and polymorphic layers of the dentate gyrus. Importantly, these latter regions correspond to termination zones of glutamatergic perforant pathway axons and mossy fiber collaterals, respectively. The increase in immunolabeling within these projection fields is hypothesized to occur in response to the deafferentation of selected glutamatergic pathways, and suggests a critical role for AMPA receptor subunits in hippocampal plasticity.
Aged↗
Microsatellites uncover extraordinary diversity in native American land races and wild populations of cultivated sunflower.
The contemporary oilseed sunflower (Helianthus annuus L.) gene pool is a product of multiple breeding and domestication bottlenecks. Despite substantial phenotypic diversity, modest differences in molecular genetic diversity have been uncovered in anciently and recently domesticated sunflowers. The paucity of molecular marker polymorphisms in early analyses led to the hypothesis of a single domestication origin. Phylogenetic analyses were performed on 47 domesticated and wild germplasm accessions using 122 microsatellite loci distributed throughout the sunflower genome. Extraordinary allelic diversity was found in the Native American land races and wild populations, and progressively less allelic diversity was found in germplasm produced by successive cycles of domestication and breeding. Of 1,341 microsatellite alleles, 489 were unique to land races, exotic domesticates and wild populations, whereas only 15 were unique to elite inbred lines. The number of taxon-specific alleles was 35-fold greater among wild populations (26.27) than elite inbred lines (0.75). Microsatellite genotyping uncovered the possibility of multiple domestication origins. Land races domesticated by Native Americans of the southwestern US (Hopi and Havasupai) formed a clade independent of land races domesticated by Native Americans of the Great Plains and eastern US (Arikara and Seneca). Predictably, domestication and breeding have ratcheted genetic diversity down in sunflower. The contemporary oilseed sunflower gene pool, while not imperiled, could profit from an infusion of novel alleles from the reservoir of latent genetic diversity present in wild populations and Native American land races.
Alleles↗
Characterization of UVC-induced DNA damage in bloodstains: forensic implications.
The ability to detect DNA polymorphisms using molecular genetic techniques has revolutionized the forensic analysis of biological evidence. DNA typing now plays a critical role within the criminal justice system, but one of the limiting factors with the technology is that DNA isolated from biological stains recovered from the crime scene is sometimes so damaged as to be intractable to analysis. Potential remedies for damaged DNA are likely to be dependent upon the precise nature of the DNA damage present in any particular sample but, unfortunately, current knowledge of the biochemical nature, and the extent, of such DNA damage in dried biological stains is rudimentary. As a model for DNA damage assessment in biological stains recovered from crime scenes, we have subjected human bloodstains and naked DNA in the hydrated and dehydrated states to varying doses of UVC radiation. It was possible to damage the DNA sufficiently in a bloodstain to cause a standard autosomal short tandem repeat (STR) profile to be lost. However, a detailed analysis of the process, based upon assays developed to detect bipyrimidine photoproducts (BPPPs), single- and double-strand breaks, and DNA-DNA crosslinks, produced some unexpected findings. Contrary to the situation with living tissues or cells in culture, the predominant UVC-induced damage to DNA in bloodstains appears not to be pyrimidine dimers. Although some evidence for the presence of BPPPs and DNA crosslinks was obtained, the major form of UVC damage causing genetic profile loss appeared to be single-strand breaks. It was not possible, however, to preclude the possibility that a combination of damage types was responsible for the profile loss observed. We demonstrate here that a significant measure of protection against UVC-mediated genetic profile loss in dried biological stain material is afforded by the dehydrated state of the DNA and, to a lesser extent, the DNA cellular milieu.
Blood Stains↗
X-ray structure determination and comparison of two crystal forms of a variant (Asn115Arg) of the alkaline protease from Bacillus alcalophilus refined at 1.85 A resolution.
The X-ray structure determination, refinement and comparison of two crystal forms of a variant (Asn115Arg) of the alkaline protease from Bacillus alcalophilus is described. Under identical conditions crystals were obtained in the orthorhombic space group P2(1)2(1)2(1) (form I) and the rhombohedral space group R32 (form II). For both space groups the structures of the protease were solved by molecular replacement and refined at 1.85 A resolution. The final R-factors are 17.9% and 17.1% for form I and form II, respectively. The root-mean-square deviation between the two forms is 0.48 A and 0.86 A for main-chain and side-chain atoms, respectively. Due to differences in crystal lattice contacts and packing, the structures of the two crystal forms differ in intermolecular interaction affecting the local conformation of three flexible polypeptide sequences (Ser50-Glu55, Ser99-Gly102, Gly258-Ser259) at the surface of the protein. While the two overall structures are very similar, the differences are significantly larger than the errors inherent in the structure determination. As expected, the differences in the temperature factors in form I and II are correlated with the solvent accessibility of the corresponding amino acid residues. In form II, two symmetry-related substrate binding sites face each other, forming a tight intermolecular interaction. Some residues contributing to this intermolecular interaction are also found to be involved in the formation of the complex between subtilisin Carlsberg and the proteinaceous inhibitor eglin C. This demonstrates that the two symmetry-related molecules interact with each other at the same molecular surface area that is used for binding of substrates and inhibitors.
Bacillus↗
Molecular karyotyping and chromosome length polymorphism in Cochliobolus sativus.
Fungi are known to have variable genomes that can generate new virulence types capable of attacking important crop plants. To assess chromosome length polymorphisms in the barley spot blotch pathogen (Cochliobolus sativus), we analyzed the karyotypes of 16 isolates using contour-clamped homogeneous electric field (CHEF) electrophoresis. The collection of isolates studied were from diverse regions of the world (USA, Canada, Japan, Brazil, Uruguay, and Poland) and included representatives comprising the three known C. sativus pathotypes of 0, 1, and 2. Under two different running conditions, the number of CHEF bands observed ranged from 8 to 13 with a size range of 0.85 to 3.80 mega-bases (Mb). Each of the 16 isolates showed a unique banding pattern, except for two North Dakota isolates ND90Pr and ND91-Bowman, which were very similar. Single-copy DNA probes, previously assigned to each of the 15 chromosomes identified in reference isolate ND93-1, were hybridized to Southern blots of CHEF-separated chromosomes and revealed highly polymorphic chromosomes among isolates. Chromosomal rearrangements (translocations, deletions, duplications) were found in several isolates. DNA markers previously found linked to VHv1, a gene in pathotype 2 isolates conferring virulence on barley cultivar Bowman, also were used as probes in hybridizations with the CHEF blots. The results showed that the chromosome carrying the virulence gene in pathotype 2 isolates is larger than its counterpart without the gene in other isolates. This suggests that the genomic region carrying the virulence locus VHv1 is unique to pathotype 2 isolates. This study provides useful information on genome structure and divergence, which is essential for advancing our understanding of the genetics and biology of C. sativus.
Ascomycota↗
Preconditioning-specific reduction of c-fos expression in hippocampal granule and pyramidal but not other forebrain neurons of ischemic brain: a quantitative immunohistochemical study.
To specify targets for an ischemic preconditioning paradigm (ischemic tolerance), c-fos expressions in ischemic (induced by 10 min bilateral carotid-occlusions subsequent to coagulation of vertebral arteries) and preconditioned rats (treated for 4 min carotid-occlusions 72 h before ischemia) were compared in 12 forebrain areas/nuclei. Fos immunostaining was applied to serial sections of the forebrain and the density (cell number/area measured) of Fos-immunopositive (Fos+) neurons, as well as their percentile changes were determined in five hippocampal and seven extrahippocampal areas/nuclei of ischemic and preconditioned rats. The ratio of counts found in ischemic over control animals showed several fold increase of Fos+ cells in the three layers (granule cell, molecular and polymorphic) of the dentate gyrus, CA3 and CA1 pyramidal neurons, as well as in thalamic and hypothalamic nuclei and limbic cortical areas. In contrast, preconditioning did not alter c-fos expressions significantly in the extrahippocampal brain areas investigated. These results strengthen the hypothesis that the hippocampal and dentate neurons are more susceptible to ischemic tolerance than cells in other brain regions. In fact stress-response and induction of ischemic tolerance in different forebrain areas can be distinguished.
Animals↗
Pathophysiological implication of the structural domains of lipoprotein(a).
Numerous epidemiological studies have shown that lipoprotein(a) (Lp(a)) is an independent risk factor for the premature development of cardiovascular disease. In spite of such evidence, the structural and functional features of this atherogenic, cholesterol-rich particle are not clearly understood. We have demonstrated the presence of two distinct structural domains in apolipoprotein(a) (apo(a)), which are linked by a flexible and accessible region located between kringles 4-4 and 4-5. We have isolated the Lp(a) particle following removal of the N-terminal domain by proteolytic cleavage; the residual particle, containing the C-terminal domain (comprising the region from Kr 4-5 to the protease domain), is linked to apo B-100 by disulphide linkage, and is termed 'mini-Lp(a)'. Mini-Lp(a) exhibited the same binding affinity to fibrin as the corresponding Lp(a). This finding indicated that the kringles responsible for fibrin binding are restricted to Kr 4-5 to Kr 4-10, an observation consistent with the failure of the N-terminal domain to bind to fibrin. N-terminal fragments of apo(a) have been detected in the urine of normal subjects, thereby indicating that part of the catabolism of Lp(a), which is largely indeterminate, could occur via the renal route.
Animals↗
Alzheimer's disease and angiogenesis.
Despite enormous investigative efforts, the pathological basis for Alzheimer's disease remains unclear. Suggested mechanisms for the disorder include cerebral hypoperfusion, inflammation, gene polymorphisms, and molecular lesions in the brain. In this Hypothesis, we argue that the vascular endothelial cell has a central role in the progressive destruction of cortical neurons in Alzheimer's disease. In Alzheimer's disease, the brain endothelium secretes the precursor substrate for the beta-amyloid plaque and a neurotoxic peptide that selectively kills cortical neurons. Large populations of endothelial cells are activated by angiogenesis due to brain hypoxia and inflammation. Results of epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs, statins, histamine H2-receptor blockers, or calcium-channel blockers seems to prevent Alzheimer's disease. We think this benefit is largely due to these drugs' ability to inhibit angiogenesis. If Alzheimer's disease is an angiogenesis-dependent disorder, then development of antiangiogenic drugs targeting the abnormal brain endothelial cell might be able to prevent and treat this disease. We suggest several laboratory and clinical approaches for testing our hypothesis.
Alzheimer Disease↗
Molecular interactions of coreceptor CD8 and MHC class I: the molecular basis for functional coordination with the T-cell receptor.
In recent years, substantial progress has been made towards understanding the molecular basis for CD8 binding to class I MHC and the coreceptor's role in cytotoxic T-cell activation. Here, we review the structural, mechanistic and functional studies that point to a model of coordination of T-cell receptor and CD8 signaling that might provide the key to cytotoxic T-cell activation.
Animals↗