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PubMed1993

Evidence for antigen driven selection in two monoclonal auto-antibodies derived from nonobese diabetic mice.

The nonobese diabetic (NOD) mouse is a model of human type I diabetes. This diabetes is due to massive infiltration of the pancreatic beta cell of islets by autoreactive T cells (insulitis) followed by the destruction of insulin-producing cells. Circulating autoantibodies are also detected, notably against glutamic acid decarboxylase, peripherin and insulin. Two monoclonal autoantibodies directed against insulin and peripherin were obtained by fusing NOD spleen and myeloma cells. We report here the nucleotide sequence of the genes encoding for the V regions of these two antibodies. Somatic mutations were identified by comparing the light chain nucleotide sequence of one of these autoantibodies with its germline counterpart precursor established from NOD mice after PCR gene amplification. The other one displays N additions on both sides of the D region. These results strongly suggest that both autoantibodies have undergone diversification, either N additions or somatic mutations, and therefore present structural features of antibodies derived from animals immunized against exogenous antigens.

Amino Acid Sequence↗
PubMed1994

Supernumerary ring chromosomes containing chromosome 17 sequences. A specific feature of dermatofibrosarcoma protuberans?

Mystery surrounds the mechanisms by which the uncommon cutaneous tumor dermatofibrosarcoma protuberans (DP) arises and progresses. A clue may be at hand in the form of extra abnormal chromosomes (one of three ring chromosomes per case with or without other chromosome abnormalities) seen in some 10 cases, including five cases in our experience. The specificity of the rings to DP would be enhanced if the rings were found to contain a contribution from a constant chromosome. We here report fluorescence in situ hybridization (FISH) results bearing on the chromosomal content of DP rings, together with clinical, pathologic, and cytogenetic documentation of our first two cases, which were briefly reported earlier, and three new DP cases. To dissect a translocation (in our 2nd case), we probed by FISH and discovered chromosome 17 sequences in the rings in all five DP cases. Nonfluorescent bands were seen on some rings painted with a whole chromosome 17 probe, indicating the presence in these rings of foreign chromosome sequences. The complexity of the rings was underscored by the detection in only one case of chromosome 17 centromeric sequences. The situation in DP seems to have parallels to that in well-differentiated liposarcoma, another tumor of intermediate malignancy with extra abnormal marker chromosome containing contributions from a constant chromosome and variable donors. In DP the supernumerary rings are clearly specific and significant.

Adult↗
PubMed1977

Obligatory free radical intermediate in the oxidative activation of the carcinogen N-hydroxy-2-acetylaminofluorene.

We have demonstrated that the nitroxyl free radical form of the carcinogen N-hydroxy-2-acetylaminofluorene (OH-AAF) is an obligatory intermediate in the cumene hydroperoxide-hematin-induced oxidative activation of this carcinogen into 2-nitrosofluorene and N-acetoxy-2-acetylaminofluorene. Both the rate of N-OH-acetylaminofluorene oxidation and the amount of its nitroxyl free radical were experimentally observed as a function of reaction time. Rate equations were derived for a model in which the nitroxyl free radical form of OH-AAF was an obligatory intermediate in the reaction. Using this theory it was possible to compute one experimental variable, the rate of OH-AAF oxidation, utilizing the other experimental variable, the amount of nitroxyl free radical present at any time during the reaction. The theory also predicts a linear relationship between the rate of OH-AAF oxidation and the square of the free radical content; and this was found to be true experimentally. The dismutation rate constant of the nitroxyl free radical of OH-AAF was found to be 2.7-10(5) M-1-s-1.

Fluorenes↗
PubMed1989

Species differences in estrogen receptors and in the response to 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure.

The acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exhibits marked interspecies variability, with the guinea-pig, rat and hamster representing the species most sensitive, intermediate and most resistant to acute toxicity. Prepubertal guinea-pigs, rats and hamsters were treated with a single intraperitoneal injection of TCDD in olive oil at doses of 4, 50 and 1500 micrograms/kg, respectively. These exposures were chosen to produce acute toxicity and all 3 species exhibited a decrease in the rate of body weight gain during the 7 days following TCDD exposure when compared with control (olive oil-treated) animals. On the 7th day after exposure, the density and affinity of 17 beta-estradiol receptors were determined in the uterus and liver of TCDD-treated and control animals. The treatment with TCDD did not alter the affinity of the receptors in these 3 species. The density of hepatic 17 beta-estradiol receptors was decreased 65% in the guinea pig and 92% in the rat following exposure to TCDD. In contrast, TCDD-treated hamsters exhibited no change in the density of hepatic 17 beta-estradiol receptors. The uterine 17 beta-estradiol receptors were increased in density by TCDD treatment in the hamster and in the rat when expressed per mg protein. Uterine wet weights in the guinea-pig and rat were also significantly decreased by TCDD treatment but were not changed in the hamster. When the Bmax for uterine 17 beta-estradiol receptors was expressed as pmol/g tissue wet weight. TCDD exposure was found to produce an 11% decrease in density in the rat, while producing a 44% increase in the hamster. In control animals, the density of uterine 17 beta-estradiol receptors correlated inversely with the lethal dose of TCDD in these 3 species (i.e., the guinea-pig has the lowest LD50 and highest density of uterine 17 beta-estradiol receptors). The different responses to TCDD in the 3 species suggest that the changes in 17 beta-estradiol receptors may be related to species-specific toxic responses associated with TCDD exposure.

Animals↗
PubMed2003

Effect of angiotensin-converting enzyme insertion/deletion polymorphism DD genotype on high-frequency heart rate variability in African Americans.

Seventy-nine African-American participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) pilot study were genotyped for the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and had spectral power of their high-frequency (HF) heart rate variability (HRV) determined by fast-Fourier transformation. HF HRV was highest in II, intermediate in ID, and lowest in DD (II vs DD, p <0.043) genotypes, thus making an association of the ACE I/D DD genotype with decreased HF HRV that is consistent with the hypothesis that the DD genotype confers susceptibility to increased cardiovascular risk. The urban African-American population we studied had a particularly high cardiovascular risk, and these findings suggest that ACE I/D genotypes may modify that risk.

Adrenergic beta-Antagonists↗
PubMed2005

Signs and symptoms in chronic heart failure: relevance of clinical trial results to point of care-data from Val-HeFT.

BACKGROUND: Clinical trials emphasize mortality and morbidity endpoints. AIMS: To bring relevance of trial results to point of care by examining the prognostic and therapeutic value of individual signs and symptoms (S&S). METHODS: We analysed data from 5010 patients with stable chronic heart failure and left ventricular dysfunction who were participants in the Val-HeFT study. Individual S&S were stratified by severity. Treatment differences between valsartan and placebo were analysed by S&S strata at baseline and endpoint by logistical regression, and an overall S&S score by ANCOVA. Hazard ratios of S&S strata were calculated for mortality and heart failure hospitalisation. Prognostic contributions of S&S to other variables were determined by multivariate analysis. RESULTS: At endpoint, there were significantly fewer valsartan and more placebo patients with severe symptoms. Over time, improvement in the S&S overall score was significantly more favourable for valsartan than placebo. S&S strata were significantly predictive of risk for hospitalisation and death. S&S were each independent and incremental predictors of mortality compared to other variables. Symptom strata separated out moderately symptomatic patients with a mortality rate which was intermediate between that for NYHA Class II and III. CONCLUSION: Risk stratification of individual S&S defined prognosis, identified patients with an intermediate mortality between Class II and III, and treatment benefits of valsartan over placebo.

Aged↗
PubMed2006

The influence of different temperature programmes on the bioremediation of polycyclic aromatic hydrocarbons (PAHs) in a coal-tar contaminated soil by in-vessel composting.

The biodegradation of 16 US. EPA-listed polycyclic aromatic hydrocarbons (sigma PAHs), with accompanying humification and microbial community structure changes during simulated in-vessel composting-bioremediation of an aged coal-tar-contaminated soil amended with green waste were studied over 56 days. The experimental design compared one constant temperature profile (TC=38 degrees C) with three variable temperature profiles (TP1, TP2 and TP3), including treatment at 70 degrees C to comply with regulatory requirements. Greatest sigma PAHs removal (75.4+/-0.1%; k(1)=0.026 day(-1), R(2)=0.98) occurred at TC=38 degrees C compared to all variable temperature profiles TP1 (62.1+/-11.0%; k(1)=0.016 day(-1), R(2)=0.93), TP2 (71.8+/-8.2%; k(1)=0.021 day(-1), R(2)=0.95) and TP3 (45.3+/-9.7%; k(1)=0.010 day(-1), R(2)=0.91). This study proved that using thermophilic temperatures (70 degrees C) towards the end of in-vessel composting processes (TP2) resulted in greater sigma PAHs removal than using other variable temperature profiles (TP1, TP3), as long as the increase was stepwise via an intermediate temperature (55 degrees C). Phospholipid fatty acid (PLFA) signatures indicated that use of thermophilic temperatures towards the end of the in-vessel composting-bioremediation (TP2) resulted in a higher fungal to bacterial PLFA ratio and a lower Gram-positive to Gram-negative (G(+)/G(-)) bacterial ratio. Fluorescence excitation-emission matrix (EEM) showed the presence of peaks typical of humic-like (Ex/Em wavelength pair approximately 340/460 nm) and fulvic-acid-like (Ex/Em wavelength pair approximately 245/460 nm) substances, indicating mineralization and/or maturation of the compost. Varying the temperature during in-vessel composting to comply with regulatory requirements for pathogen control, promoted contaminant biodegradation, microbial activity and compost maturation.

Bacteria↗
PubMed2006

Central corneal thickness and normal tension glaucoma: a cross-sectional study.

BACKGROUND: Recently published evidence has identified thinner central corneal thickness (CCT) as a strong predictive factor for the conversion from ocular hypertension (OHT) to primary open-angle glaucoma (POAG). The association between CCT and development of normal-tension glaucoma (NTG), however, is less clear. Accordingly, we designed this cross-sectional study to further explore the relationship between CCT and NTG. PATIENTS AND METHODS: All patients with a clinical diagnosis of NTG and NTG suspect (NTGS) who were seen from September 2002 through May 2003 at the Albuquerque VA Medical Center eye clinic were identified retrospectively. After eligible subjects were categorized into no, mild, moderate, and advanced visual field loss groups, analysis of variance (ANOVA) and regression analyses were used to determine group differences for several IOP variables, several systemic variables, and CCT. Additional analyses were completed after eligible subjects were recategorized into thin, intermediate, and thick CCT groups. RESULTS: Eighty-four eyes in 84 NTGS subjects and 56 eyes in 56 NTG subjects were studied. Mean CCT was significantly thicker in the no field loss group (NTGS) when compared with all 3 groups with glaucomatous visual field loss (NTG). In multivariate regression analysis, the association between CCT and the presence of NTG-related visual field loss was robust and independent. Conversely, no relationship was found between CCT and severity of NTG-related visual field loss. CONCLUSIONS: In eyes characterized by statistically normal intraocular pressure (IOP) measurements as measured by Goldmann applanation tonometry, we found a significant relationship between CCT and the presence, but not severity, of glaucomatous visual field loss. A prospective study is required to further explore and confirm these relationships.

Aged↗
PubMed1999

Synthesis and characterization of isolable thiolatocobalamin complexes relevant to coenzyme B12-dependent ribonucleoside triphosphate reductase.

The syntheses, isolation and characterization of cyclohexylthiolatocobalamin (C6H11SCbl), glutathionylcobalamin (GluSCbl), and cysteinylcobalamin (CysSCbl) are reported in 75, 55, and 65% yield, respectively. Characterization was achieved using elemental analyses, L-SIMS (liquid secondary ion mass spectrometry), UV-visible spectroscopy and, for the more stable C6H11SCbl and GluSCbl, our recently established 1H NMR method (which emphasizes the readily interpreted aromatic region of the cobalamin's 1H NMR spectrum). Preliminary evidence is presented for clean homolysis of the RS-Co bond in C6H11SCbl, GluSCbl, and CysSCbl to give RS. and .Co(II)Cbl radical pairs analogous to those that are intermediates in ribonucleoside triphosphate reductase (RTPR). A summary is provided which emphasizes the seven variables identified to date, underlying the successful syntheses and isolation of thiolatocobalamins, variables which make the one-step syntheses of RSCbls considerably more complex than they initially appear. Also briefly discussed are the analogous protein-S-Cbl complexes that are seen as side-products in RTPR, and the probability that such side-products are formed when HOCbl.HX is used as a possible 'active-site inhibitor' complex with B12-dependent enzymes.

Cobamides↗
PubMed2003

Is modularity necessary for evolvability? Remarks on the relationship between pleiotropy and evolvability.

Evolvability is the ability to respond to a selective challenge. This requires the capacity to produce the right kind of variation for selection to act upon. To understand evolvability we therefore need to understand the variational properties of biological organisms. Modularity is a variational property, which has been linked to evolvability. If different characters are able to vary independently, selection will be able to optimize each character separately without interference. But although modularity seems like a good design principle for an evolvable organism, it does not therefore follow that it is the only design that can achieve evolvability. In this essay I analyze the effects of modularity and, more generally, pleiotropy on evolvability. Although, pleiotropy causes interference between the adaptation of different characters, it also increases the variational potential of those characters. The most evolvable genetic architectures may often be those with an intermediate level of integration among characters, and in particular those where pleiotropic effects are variable and able to compensate for each other's constraints.

Adaptation, Psychological↗
PubMed1997

Three Methods to Speed up the Training of Feedforward and Feedback Perceptrons.

Training of artificial neural networks is normally a time consuming task due to iterative search imposed by the implicit nonlinearity of the network behaviour. In this work, three improvements to "batch-mode" offline training methods, gradient-based or gradient-free, are proposed. For nonlinear multilayer perceptrons (NMLP) with linear output layers, a method based on linear regression in the output layer is presented. For arbitrary NMLPs, an algorithm is developed for detecting "saturated" hidden nodes and re-activating them while transferring their contribution onto the bias node in the same layer. For state-feedback NMLPs with incomplete learning data in the state variables, a method is shown that interpolates the unknown state values to form an intermediate training set used for finding good initial weights for the final training with only the original training set. In addition, three conventional gradient-based training methods-steepest-descent gradient search, conjugate gradient, and Gauss-Newton-are compared mutually and with the above improvements on the same two example problems. Where conventional methods get stuck in bad local minima, saturation avoidance leads to satisfactory results, and the speed-up achieved by the two other improvements is about two orders of magnitude.

Journal Article↗
PubMed1981

A search for stratification-free association between plasma lipids and HLA using dizygotic twins.

A total of 71 pairs of like-sexed dizygotic twins were studied, comparing within-pair differences for plasma total, free and esterified cholesterol, and triglyceride with the number of HLA haplotypes the twins had in common. If associations are present between HLA and the blood lipids studied, the twins with no haplotypes in common would be expected to have the largest within-pair mean square, those with two in common the smallest, and those with one in common an intermediate value. No significant differences were found comparing within- pair mean squares for the variables studied.

Adolescent↗
PubMed2002

Spatial scale dictates the productivity-biodiversity relationship.

The diversity of life is heterogeneously distributed across the Earth. A primary cause for this pattern is the heterogeneity in the amount of energy, or primary productivity (the rate of carbon fixed through photosynthesis), available to the biota in a given location. But the shape of the relationship between productivity and species diversity is highly variable. In many cases, the relationship is 'hump-shaped', where diversity peaks at intermediate productivity. In other cases, diversity increases linearly with productivity. A possible reason for this discrepancy is that data are often collected at different spatial scales. If the mechanisms that determine species diversity vary with spatial scale, then so would the shape of the productivity-diversity relationship. Here, we present evidence for scale-dependent productivity-diversity patterns in ponds. When the data were viewed at a local scale (among ponds), the relationship was hump-shaped, whereas when the same data were viewed at a regional scale (among watersheds), the relationship was positively linear. This dependence on scale results because dissimilarity in local species composition within regions increased with productivity.

Animals↗
PubMed1999

Complexity- and risk-adjusted model for measuring surgical outcome.

BACKGROUND: Although currently available surgical scoring systems have good outcome predictive power, their use is often limited by complexity and their non-dynamic nature. The aim of this study was to develop and test a risk adjustment for general surgical audit which is both simple and dynamic, while preserving a high predictive power for surgical morbidity. METHODS: Twelve easily measured, well defined prognostic variables for morbidity were identified from the Otago Surgical Audit data collection form and stratified into suitable categories. Logistic regression was used to adjust for confounding between factors, identifying risk factors with the strongest prognostic value for the outcome of severe and intermediate complications. The resulting model was tested by back-validation and validation. RESULTS: The derived risk adjustment included all 12 variables. Adjusted odds ratios for all variables were markedly lower than unadjusted values. After logistic regression, the strongest predictors of postoperative morbidity were duration of operation, operation category, inpatient status and organ system in which the procedure was carried out. The area under the receiver operating characteristic curve was 0.86. CONCLUSION: A simple dynamic model for surgical morbidity has been developed which is comparable to previously published surgical scoring systems in terms of predictive power. This risk adjustment tool can be incorporated into the existing audit system, enabling comparison of surgical unit performance.

Adolescent↗
PubMed2005

Ab initio calculation of (2+1) resonance enhanced multiphoton ionization spectra and lifetimes of the (D,3)2Sigma- states of OH and OD.

High-level ab initio potential-energy curves and transition dipole moments for the OH X 2Pi, 2 2Pi, 1 2Sigma-, D 2Sigma-, 3 2Sigma-, A 2Sigma+, B 2Sigma+, 1 2Delta, 1 4Sigma-, and 1 4Pi states are computed. The results are used to estimate the (2+1) resonance enhanced multiphoton ionization spectrum for the (D,3)2Sigma-(upsilon')<--2hnuX 2Piupsilon") transitions, which are compared with experiments by Greenslade et al. [see M. E. Greenslade, M. I. Lester, D. C. Radenovic, J. A. van Roij, and D. H. Parker, J. Chem. Phys. 123, 074309 (2005), preceeding paper]. We use the discrete variable representation-absorbing boundary condition method to incorporate the effect of the dissociative intermediate 1 2Sigma- state. We obtain qualitative agreement with experiment for the line strengths. Radiative and predissociative decay rates of the Rydberg (D,3)2Sigma- states of OH and OD were computed, including spin-orbit coupling effects and the effect of spin-electronic and gyroscopic coupling. We show that the lifetime of the Rydberg 2Sigma- states for rotationally cold molecules is limited mainly by predissociation caused by spin-orbit coupling.

Journal Article↗
PubMed1982

DNA rearrangements in MPC-11 immunoglobulin heavy chain class-switch variants.

Immunoglobulin heavy chain class switching has been observed in vitro. In the IgG2b-producing MPC-11 mouse myeloma cell line, IgG2a-producing cells arise at a high frequency. In some cases, switch variants producing normal-sized (Mr 55,000) gamma 2a heavy chains have arisen spontaneously from a mutagen-induced "intermediate" (ICR 9.7.1) that produces an unusually large (Mr 75,000) heavy chain. Other switch variants have been isolated directly from the parent cell line. The expressed and unexpressed gamma 2b genes of MPC-11 can be distinguished in restriction endonuclease digests of total genomic DNA so that DNA rearrangements detected in MPC-11 variants can be directly associated with one or the other of these two genes. We describe here DNA rearrangements occurring on the expressed heavy chain chromosome of several MPC-11 gamma 2a switch variants and on the expressed chromosome of the ICR 9.7.1 intermediate. Our data indicate that all of these variants express the parental heavy chain variable region (VH) gene, supporting previous protein studies. We provide mapping data for the expressed gene of both ICR 9.7.1 and one of the IgG2a-producing variant cell lines (ICR 9.9.2.1) derived from it and discuss the advantages of an in vitro switching system for examining the dynamics of the immunoglobulin heavy chain class switch.

Animals↗
PubMed1986

Two types of immunoglobulin-negative Abelson murine leukemia virus-transformed cells: implications for B-lymphocyte differentiation.

Both alleles of immunoglobulin (Ig) heavy-chain joining region (JH) genes in three Ig-negative Abelson murine leukemia virus (Ab-MuLV)-transformed cell lines were characterized by DNA cloning and nucleotide sequence determination. These studies unambiguously identified two distinct types of Ig-negative B-lineage cells. The first type of cell (e.g., R8) is an "immature pre-B cell," and it contains at least one intermediate recombinant structure containing heavy-chain diversity (DH) and JH sequences but no variable region (VH) sequence. This type of cell, which has also been characterized by other investigators, generates mu-positive sublines during subsequent culturing of cells and represents a precursor stage to pre-B cells. The second type of cell (e.g., RAW253) is an "abortive pre-B cell," in that both JH alleles contain nonfunctional VH-DH-JH structures. The nucleotide sequence determinations in this study demonstrated that these nonfunctional V-D-J structures were generated by nonproductive somatic recombinations, involving either out-of-phase joining events, or the formation of termination codons in the DH coding sequences. The identification of abortive pre-B cells suggests that the recombinational joining of Ig VH, DH, and JH segments is not actively regulated by a putative recombinase to preserve the translational reading frame. This in turn implies that a large portion of precursor cells at the early stage of B-cell differentiation are abortive and possibly blocked to further differentiation.

Abelson murine leukemia virus↗
PubMed2004

New strategies in polypeptide and antibody synthesis: an overview.

The synthesis of radioligands can benefit considerably from optimized recombinant protein production, both on the aspect of economy of production and on the level of improving the targeting and pharmacokinetics of the ligand. This paper first describes a general production optimization strategy, and then elaborates on a protein design strategy tailored to targeting applications. Production in Escherichia coli will benefit from economy of goods and time as compared to other organisms. In order to increase the chance of finding a successful production system in this host, we have assembled a large number of expression strategies in a single, uniform expression system (FastScreen). The system allows rapid optimization of direct production of native proteins or via a fusion protein strategy with subsequent recovery of the desired protein. As an example of recombinant radioligand synthesis for improved targeting and clearing, a manifold of intermediate molecular size was synthesized by fusing one Fab and two single-chain variable fragments (scFv) antibody binding fragments into a trifunctional molecule (Tribody). Due to the use of the specific heterodimerization of the Fab chains, trispecific, bispecific, or trivalent antibody derived targeting reagents can easily be obtained. Recombinant production techniques also allow for specific incorporation of amino acids favoring a site specific labeling (labeling tags).

Antibodies, Monoclonal↗