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PubMed1987

Computer-graphics interpretations of residue exchanges between the alpha, beta and gamma subunits of human-liver alcohol dehydrogenase class I isozymes.

Three-dimensional models of human alcohol dehydrogenase subunits have been constructed, based on the homologous horse enzyme, with computer graphics. All types of class I subunits (alpha, beta, and gamma) and the major allelic variants (beta 1/beta 2 and gamma 1/gamma 2) have been studied. Residue differences between the E-type subunit of the horse enzyme and any of the subunits of the human isozymes occur at 64 positions, about half of which are isozyme-specific. About two thirds of the substitutions are at the surface and all differences can be accommodated in highly conserved three-dimensional structures. The model of the gamma isozyme is most similar to the crystallographically analyzed horse liver E-type alcohol dehydrogenase, and has all the functional residues identical to those of the E subunit except for one which is slightly smaller: Val-141 in the substrate pocket. The residues involved in coenzyme binding are generally conserved between the horse enzyme and the alpha, beta, and gamma types of the human enzyme. In contrast, single exchanges of these residues are the ones involved in the major allelic differences (beta 1 versus beta 2 and gamma 1 versus gamma 2), which affects the overall rate of alcohol oxidation since NADH dissociation is the rate-determining step. Residue 47 is His in beta 2 and Arg in the beta 1, gamma 1, and gamma 2 subunits, and in horse liver alcohol dehydrogenase. Both His and Arg can make a hydrogen bond to a phosphate oxygen atom of NAD; hence the lower turnover rate of beta 1 apparently derives from a charge effect. The substitution to Gly in the alpha subunit results in one less hydrogen bond in NAD binding, and consequently in rapid dissociation. This may explain why the overall rate is an order of magnitude faster than that of beta 1. The important difference between gamma 1 and gamma 2 is an exchange at position 271 from Arg to Gln which can give a hydrogen bond from Gln in gamma 2 to the adenine of NAD. The tighter binding to gamma 2 can account for the slower overall catalytic rate in this isozyme. The kinetics and interactions of cyclohexanol and benzyl alcohol with the isozymes were judged by docking experiments using an interactive fitting program.(ABSTRACT TRUNCATED AT 400 WORDS)

Alcohol Dehydrogenase↗

PubMed1979

The assessment and meaning of intraobserver error in population studies based on discontinuous cranial traits.

Intraobserver scoring precision of 50 discontinuous (discrete) cranial traits was assessed on a sample of 125 intact Iroquois crania using the square of the phi coefficient. Scoring consistency was high for most traits although several were subject to low precision (phi 2 less than 0.7). Most errors were random rather than systematic. Taken collectively the problematic traits exceeded their expected contribution to MMD coefficients among four Woodland samples from southern Ontario. A traitlist with the problematic variants excluded produced more meaningful biological relationships among the samples. Further, the % contribution of the problematic traits increased with the time interval between the scoring of the individual samples. It was suggested that intraobserver error could effectively distort the interpretation of biological relationships and that it must in part be responsible for the poor performance reported for discontinuous traits in some studies. Therefore, it was argued that the results support rather than compromise the use of discontinuous skeletal traits in population studies and that the assessment of intraobserver error should be a standard procedure of the research design.

Canada↗

PubMed2006

Cleaning of raw peptide MS/MS spectra: improved protein identification following deconvolution of multiply charged peaks, isotope clusters, and removal of background noise.

The dominant ions in MS/MS spectra of peptides, which have been fragmented by low-energy CID, are often b-, y-ions and their derivatives resulting from the cleavage of the peptide bonds. However, MS/MS spectra typically contain many more peaks. These can result not only from isotope variants and multiply charged replicates of the peptide fragmentation products but also from unknown fragmentation pathways, sample-specific or systematic chemical contaminations or from noise generated by the electronic detection system. The presence of this background complicates spectrum interpretation. Besides dramatically prolonged computation time, it can lead to incorrect protein identification, especially in the case of de novo sequencing algorithms. Here, we present an algorithm for detection and transformation of multiply charged peaks into singly charged monoisotopic peaks, removal of heavy isotope replicates, and random noise. A quantitative criterion for the recognition of some noninterpretable spectra has been derived as a byproduct. The approach is based on numerical spectral analysis and signal detection methods. The algorithm has been implemented in a stand-alone computer program called MS Cleaner that can be obtained from the authors upon request.

Adenosine Triphosphatases↗

PubMed2006

Expression of BAG-1 protein correlates with aggressive behavior of prostate cancers.

BACKGROUND: Differences in tumor behavior, ranging from indolent to aggressive, create a need for novel prognostic biomarkers. BAG-1 is a co-chaperone that regulates the activity of Hsp70, Bcl-2, Raf-1, growth factor, and steroid receptors (e.g., the Androgen Receptor). METHODS: Using immunohistochemical method, we explored BAG-1 expression in prostate cancers and its association with clinicopathological parameters. RESULTS: BAG-1 immunostaining was elevated in prostate cancer compared to normal prostatic epithelium. Higher nuclear BAG-1 in hormone-refractory (n = 34) compared to localized untreated tumors (n = 58) (P < 0.0001) suggested that upregulation of the nuclear isoform may contribute to disease progression. In 64 early-stage patients (T2N0M0) treated with external-beam irradiation, cytosolic BAG-1 correlated with higher pretreatment levels of serum Prostate specific antigen (P = 0.04) and shorter time to disease progression (P = 0.00004). CONCLUSIONS: Increased cytosolic and nuclear BAG-1 expression may denote more aggressive variants of prostate cancer.

Biomarkers, Tumor↗

PubMed1988

TAP transcription and phosphatidylinositol linkage mutants are defective in activation through the T cell receptor.

TAP is a phosphatidylinositol-anchored membrane protein that is involved in murine T lymphocyte activation. To determine the relationship between TAP and T cell receptor/CD3-mediated activation, we derived TAP expression mutants of a T-T hybridoma. Two phenotypically distinct classes of mutants were obtained. The first has a selective defect in the transcription of TAP, while the second has a defect in the biosynthesis of phosphatidylinositol-protein linkages. Both mutations affect antigen-stimulated, T cell receptor-mediated activation of the T-T hybrid. These variants have intact immune effector gene programs, as they are responsive to pharmacologic agents that mimic receptor signals. These findings support a role for phosphatidylinositol-linked cell-surface glycoproteins in physiologic T cell activation. Consistent with this interpretation, we observed similar defects in T cell responsiveness after enzymatic removal of phosphatidylinositol-linked proteins from normal T lymphocytes.

Animals↗

PubMedDate not supplied

Infection with multidrug resistant, dual-tropic HIV-1 and rapid progression to AIDS: a case report.

BACKGROUND: Rapid progression to AIDS after acute HIV-1 infection, though uncommon, has been noted, as has the transmission of multidrug resistant viruses. Here, we describe a patient in whom these two factors arose concomitantly and assess the effects. METHODS: We did a case study of a patient with HIV-1 seroconversion. We genotyped the virus and host genetic markers by PCR and nucleotide sequencing. To ascertain the drug susceptibility of our patient's HIV-1 we did phenotypic studies with the PhenoSense assay. We assessed viral coreceptor use via syncytium formation in vitro and with a modified PhenoSense assay. FINDINGS: Our patient seems to have been recently infected by a viral variant of HIV-1 resistant to multiple classes of antiretroviral drugs. Furthermore, his virus population is dual tropic for cells that express CCR5 or CXCR4 coreceptor. The infection has resulted in progression to symptomatic AIDS in 4-20 months. INTERPRETATION: The intersection of multidrug resistance and rapid development of AIDS in this patient is of concern, especially in view of his case history, which includes high-risk sexual contacts and use of metamfetamine. The public health ramifications of such a case are great.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Conformational mobility of His-64 in the Thr-200----Ser mutant of human carbonic anhydrase II.

The three-dimensional structure of the Thr-200----Ser (T200S) mutant of human carbonic anhydrase II (CAII) has been determined by X-ray crystallographic methods at 2.1-A resolution. This particular mutant of CAII exhibits CO2 hydrase activity that is comparable to that of the wild-type enzyme with a 2-fold stabilization of the E.HCO3- complex and esterase activity that is 4-fold greater than that of the wild-type enzyme. The structure of the mutant enzyme reveals no significant local changes accompanying the conservative T200S substitution, but an important nonlocal structural change is evident: the side chain of catalytic residue His-64 rotates away from the active site by 105 degrees about chi 1 and apparently displaces a water molecule. The displaced water molecule is present in the wild-type enzyme; however, the electron density into which this water is built is interpretable as an alternate conformation of His-64 with 10-20% occupancy. The rate constants for proton transfer from the zinc-water ligand to His-64 and from His-64 to bulk solvent are maintained in the T200S variant; therefore, if His-64 is conformationally mobile about chi 1 and/or chi 2 during catalysis, compensatory changes in solvent configuration must sustain efficient proton transfer.

Carbonic Anhydrases↗

PubMed2003

Demographic expansion of parasitic nematodes of livestock based on mitochondrial DNA regions that conflict with the infinite-sites model.

Mitochondrial ND4 sequences of populations of four species of parasitic nematodes of livestock were subjected to demographic analyses. Deviation from selective neutrality was detectable using the frequency spectrum of segregating sites and highly negative neutrality statistics. However, the mitochondrial data sets do not comply with the infinite-sites model that underlies these tests, and as a consequence, it was not established whether these features are solely a result of population expansion, or whether aspects of the molecular evolution of these mitochondrial regions are also involved. Coalescent analyses based on Fu's Fs neutrality test, which incorporated estimates of rate heterogeneity, the transition-transversion ratio and nucleotide bias, as well as analyses that are fairly robust to deviations from the infinite-sites model supported population expansion. Also analyses that do not depend on the infinite-sites model suggested historical population expansion of these nematodes. The very similar time since expansion, the absence of signatures of positive selection in ND4 and the logical association with human demography imply that selective sweeps of mitochondrial variants are less probable, and that expansion is the most likely scenario for the parasitic nematodes of livestock. The methods used to characterize the expansion have different assumptions and emphasize different aspects of expansions. The resulting restrictions on the interpretation of expansions are outlined.

Animals↗

PubMed2026

Uniform processing and analysis of IGVF massively parallel reporter assay data with MPRAsnakeflow.

As researchers and clinicians seek to identify human genomic alterations relevant to traits and disorders, identifying and aggregating evidence providing mechanistic support for associations between alterations and phenotypes remains challenging. In particular, the study of noncoding genomic variation remains a major challenge because of the lack of accurate functional annotation for activity in a given context and across alleles. Experimental evidence is critical for prioritizing and interpreting functional effects of genetic alterations. Massively parallel reporter assays (MPRAs) have emerged as a powerful high-throughput approach, enabling quantification of regulatory element activity and allelic effects, as well as systematic dissection of gene regulatory logic and variant effects across different contexts. However, the diversity of MPRA designs, lack of standardized formats, and many potential processing parameters hamper data integration, reproducibility, and meta-analyses across studies. To address these challenges, the Impact of Genomic Variation on Function (IGVF) Consortium established an MPRA focus group to develop community standards, including harmonized file formats, and robust analysis pipelines for a wide range of library types and experimental designs. Here, we present these formats and comprehensive computational tools, MPRAlib and MPRAsnakeflow, for uniform processing from raw sequencing reads to counts, processing, and visualization. Using diverse MPRA data sets, we investigated technical variability sources including barcode sequence bias, outlier barcodes, and delivery method (episomal vs. lentiviral). Our results establish best practices for MPRA data generation and analysis, facilitating robust, reproducible research and large-scale integration. The presented tools and standards are publicly available, providing a foundation for future collaborative efforts in regulatory genomics.

Humans↗

PubMed1980

Dextroconvexity of the mediastinum in the azygoesophageal recess: a normal CT variant in young adults.

Dextroconvexity of mediastinal contents in the azygo-esophageal recess can occur as a normal variant in young adults with relatively small anteroposterior thoracic dimensions. In older patients with a relatively larger thoracic size, the configuration of the azygo-esophageal recess is more concave. Patient age and thorax size should be considered when interpreting possible azygo-esophageal recess pathology.

Adult↗

PubMed1988

A simple pattern method for alpha 2 HS-glycoprotein typing.

An improved method for the separation of the genetic variants of the human serum alpha 2 HS-glycoprotein using isoelectric focusing in ultrathin-layer polyacrylamide gel containing carrier ampholyte pH 4 to 6.5 gradient and neuraminidase pretreated samples is described. The pattern obtained is simple, easily interpretable, and reproducible.

Blood Proteins↗

PubMed1994

Refining interpretation of MIBG scans in children.

UNLABELLED: In pediatrics, the distribution of radioiodinated metaiodobenzylguanidine (MIBG) has been studied primarily in neuroblastoma. However, normal patterns in children show a number of particularities and pitfalls related to the context of pediatric oncology which must be identified. METHODS: We report on 28 equivocal scans in 24 children. In all cases, two experienced observers judged the scans to be equivocal and the definite interpretations were confirmed by follow-up. RESULTS: Difficulties in interpreting the scans were observed at the level of the thorax (15 patients), the abdomen (5 patients), the head (4 patients) or elsewhere (4 patients). The final interpretation of the scans was attributed to an unusual physiological pattern linked to age (9 patients), tumoral context (17 patients) or artifacts (2 patients). CONCLUSIONS: A number of important physiological areas of uptake in soft tissues can lead to false-positive interpretations of normal scans, such as the physiological upper thoracic uptake which has never been previously described. Numerous technical and physiological possibilities exist and those pitfalls must be ruled out. A precise knowledge of these technical difficulties and physiological variants can reduce the number of equivocal MIBG scans.

3-Iodobenzylguanidine↗

PubMed1998

Interpretation of anatomic variations of computed tomography scans of the sinuses: a surgeon's perspective.

Four hundred computed tomography (CT) scans of patients undergoing endoscopic sinus surgery were studied with particular attention to anatomic variations. Six specific variations were identified that may predispose the surgeon to inadvertent penetration of the orbit or anterior cranial cavity. These anatomic variants are: 1. lamina papyracea lies medial to the maxillary sinus ostium; 2. maxillary sinus hypoplasia; 3. fovea ethmoidalis abnormalities, such as low or sloping fovea and encephaloceles; 4. lamina papyracea dehiscence resulting in herniation of orbital content into the ethmoids; 5. sphenoid sinus wall variations such as septa attached to the carotid covering, and penetration of the sphenoid by the internal carotid artery or optic nerve; 6. sphenoethmoid cells (Onodi cells), the most posterior ethmoid cells pneumatizing lateral and superior to the sphenoid and intimately associated with the optic nerve.

General Surgery↗

PubMed1981

[Variants of the stabilization process in the late stages of malignant schizophrenia].

Of 800 patients suffering from malignant schizophrenia for 20 years and longer a group of 94 patients showing signs of the process stabilization was selected. In a part of them (76 patients), residual positive disturbances (isolated, gradually subsiding hallucinatory manifestations not accompanied with any delusional interpretations) were noted. In the rest 18 patients, the clinical picture was characterized by personality changes according to the type of a monotonous activity or apathetic debility. Prolonged absence of positive disturbances and exacerbations in these patients suggests that the morbid process in them got stabilized (residual state). This type of the schizophrenia outcome is not an indispensable stage of the psychosis termination, and is observed rather infrequently-according to the author's data, in 2% of cases only.

Adult↗

PubMed1988

Utility of combining antigranulocyte with antileukocyte antibodies in differentiating Hodgkin's disease from non-Hodgkin's lymphoma.

The authors have reviewed their experience using the antigranulocyte marker, anti-Leu-M1, in combination with the antileukocyte marker, PD7/26, applied to paraffin sections of malignant lymphomas difficult to subclassify using morphologic criteria. The study group consisted of 73 lymphomas; 53 cases of Hodgkin's disease and 20 cases of non-Hodgkin's lymphoma. Leu-M1 was expressed by the Reed-Sternberg and Hodgkin's cells in 33 (62%) of the cases of Hodgkin's disease. The Reed-Sternberg and lymphocytic and histiocytic (L&H) cells in four cases of lymphocyte-predominant Hodgkin's disease were Leu-M1 negative. The Reed-Sternberg cells and L&H cells expressed leukocyte common antigen, utilizing the monoclonal antibody PD7/26, in seven (13%) of the 53 cases including the four cases of lymphocyte-predominant subtype (three nodular, one diffuse). The Reed-Sternberg-like cells in four (20%) of the cases of non-Hodgkin's lymphoma were stained by anti-Leu-M1 whereas, in 12 cases (60%) these cells were stained by PD7/26. The combination of anti-Leu-M1 and PD7/26 provided more useful information than that provided by anti-Leu-M1 alone by providing immunologic support for the diagnosis of lymphocyte-predominant Hodgkin's disease and by identifying cases which stained with neither antibody. The authors interpret the immunologic findings in the latter cases as equivocal. These studies were most helpful in cases with many atypical cells and provided unequivocal support for the diagnosis of Hodgkin's disease in six of 11 cases of the "syncytial variant," a form of the nodular sclerosing type characterized by cohesive aggregates of Reed-Sternberg cells and lacunar variants, not uncommonly misdiagnosed using only morphologic criteria.

Adult↗

PubMed1981

Variability of the hepatic arterial anatomy: a sonographic demonstration.

The variable origin of the hepatic arteries is well known from pathological and angiographic studies. Four main variants have been described. The common hepatic artery arising from the celiac artery is the most common type found in 70% of subjects. It can be helpful to be aware of the different patterns of hepatic artery branching in the interpretation of ultrasound examinations. This anatomy is most easily demonstrated by the use of real-time equipment.

Hepatic Artery↗

PubMed1998

The new active-coupling-pattern tilting experiment for an efficient and accurate determination of homonuclear coupling constants

A new constant-time COSY experiment which allows an efficient determination of accurate homonuclear coupling constant values is presented. Characteristic features include an improved scheme for homonuclear active-coupling-pattern tilting (ACT) and an arbitrarily scaled shift and coupling information (ASSCI) design of the F1 domain. As a result, simple and easy to interpret tilted cross-peak patterns, even for two-spin systems, are obtained with good sensitivity. The relative spacing of chemical-shift differences and coupling splittings is largely under experimental control. The effectiveness of the spectral region selective variant of the new sequence is demonstrated by a determination of the 3JHN, Halpha couplings in a peptide sample. The multiplet-selective variant is shown to produce good results with a terpene. The superiority of the new ACT scheme is additionally demonstrated by an ACT-J spectrum of the peptide. Copyright 1998 Academic Press.

Journal Article↗

PubMed1988

Structural analysis of HLA-A2.4 functional variant KNE. Implications for the mapping of HLA-A2-specific T-cell epitopes.

HLA-A2 antigens are divided into four subtypes, designated A2.1 to A2.4, by the use of cytolytic T lymphocytes (CTL). The A2.4 subtype consists of a functionally heterogeneous group of variants that are not recognized by A2.1-, A2.2-, or A2.3-specific CTL lines while it is indistinguishable from A2.1 by isoelectric focusing. The structure of an A2.4 variant expressed on donor KNE has been established by comparative peptide mapping with A2.1 and radiochemical sequencing. It was found to differ from A2.1 by a single amino acid change of Cys to Tyr at position 99. This position is only moderately polymorphic and has not previously been found to vary in any other HLA or H-2 variants. The nature of the change is compatible with its generation by one-point mutation from A2.1. The only other previously characterized A2.4 variant, CLA, differs from A2.1 by a single amino acid replacement at position 9. Both residues 9 and 99 are located in homologous positions within the alpha 1 and alpha 2 domains, respectively. The results shown contribute to the molecular interpretation of the heterogeneity of CTL recognition within the HLA-A2.4 group of antigens.

Amino Acid Sequence↗