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PubMedDate not supplied

Biochemical characterization of porphobilinogen deaminase-deficient mice during phenobarbital induction of heme synthesis and the effect of enzyme replacement.

Acute intermittent porphyria (AIP) is a genetic disorder caused by a deficiency of porphobilinogen deaminase (PBGD), the 3rd enzyme in heme synthesis. It is clinically characterized by acute attacks of neuropsychiatric symptoms and biochemically by increased urinary excretion of the porphyrin precursors porphobilinogen (PBG) and 5-aminolevulinic acid (ALA). A mouse model that is partially deficient in PBGD and biochemically mimics AIP after induction of the hepatic ALA synthase by phenobarbital was used in this study to identify the site of formation of the presumably toxic porphyrin precursors and study the effect of enzyme-replacement therapy by using recombinant human PBGD (rhPBGD). After 4 d of phenobarbital administration, high levels of PBG and ALA were found in liver, kidney, plasma, and urine of the PBGD-deficient mice. The administration of rhPBGD intravenously or subcutaneously after a 4-d phenobarbital induction was shown to lower the PBG level in plasma in a dose-dependent manner with maximal effect seen after 30 min and 2 h, respectively. Injection of rhPBGD subcutaneously twice daily during a 4-d phenobarbital induction reduced urinary PBG excretion to 25% of the levels found in PBGD-deficient mice administered with only phenobarbital. This study points to the liver as the main producer of PBG and ALA in the phenobarbital-induced PBGD-deficient mice and demonstrates efficient removal of accumulated PBG in plasma and urine by enzyme-replacement therapy.

Aminolevulinic Acid↗

PubMed1999

Anti-free prostate-specific antigen monoclonal antibody epitopes defined by mimotopes and molecular modeling.

BACKGROUND: Prostate-specific antigen (PSA) is an important marker for the diagnosis and management of prostate cancer, and the free PSA/total PSA ratio has been shown to be efficient for distinguishing prostate cancer from benign prostatic hyperplasia. We report here the characterization of seven mouse monoclonal antibodies (mAbs) and the partial localization of two conformational epitopes identified by anti-free PSA mAbs. METHODS: The mAbs were studied by competition and sandwich assays, and the epitope localization of the two anti-free PSA mAbs (6C8D8 and 5D3D11) was performed using phage displayed peptide libraries and molecular modeling. RESULTS: The seven mAbs were classified into three groups according to their recognition specificities and their ability to inhibit the enzymatic activity of PSA and the formation of PSA-alpha1-antichymotrypsin (ACT) complex. Among the anti-free PSA mAb group, 6C8D8 recognized the phage displayed peptide RKLRPHWLHFHPVAV, two parts of which presented similarities with two regions distant on the PSA sequence but joined in the tridimensional structure. mAb 5D3D11 recognized the peptide DTPYPWGWLLDEGYD, which is similar to a PSA region located on the board of the groove containing the PSA enzymatic site. Both epitopes were located in the theoretical ACT binding site described previously. Moreover, these mAbs were able to inhibit the enzymatic activity of PSA. CONCLUSIONS: These epitope localizations are in agreement with the ability of both mAbs to inhibit enzymatic activity and ACT fixation. The results presented here could bring information for the generation of clinically relevant PSA assays.

Amino Acid Sequence↗

PubMed2006

Combining visible and near-infrared spectroscopy with chemometrics to trace muscles from an autochthonous breed of pig produced in Uruguay: a feasibility study.

Visible (Vis) and near-infrared reflectance (NIR) spectroscopy combined with chemometrics was explored as a tool to trace muscles from autochthonous and crossbreed pigs from Uruguay. Muscles were sourced from two breeds, namely, the Pampa-Rocha (PR) and the Pampa-Rocha x Duroc (PRxD) crossbreed. Minced muscles were scanned in the Vis and NIR regions (400-2,500 nm) in a monochromator instrument in reflectance. Principal component analysis (PCA), discriminant partial least square regression (DPLS), linear discriminant analysis (LDA) based on PCA scores and soft independent modelling of class analogy (SIMCA) were used to identify the origin of the muscles based on Vis and NIR data. Full cross validation was used as validation method when classification models were developed. DPLS correctly classified 87% of PR and 78% of PRxD muscle samples. LDA calibration models correctly classified 87 and 67% of muscles as PR and PRxD, respectively. SIMCA correctly classified 100% of PR muscles. The results demonstrated the usefulness of Vis and NIR spectra combined with chemometrics as rapid method for authentication and identification of muscles according to the breed of pig.

Animals↗

PubMed1996

Experimental onchocercal keratitis.

In individuals with onchocerciasis, severe visual impairment (river blindness) occurs as a result of corneal inflammation induced by antigens released from dead and dying Onchocerca volvulus microfilariae. To characterize the underlying immune response, animal models have been developed that partially reproduce many of the clinical features of human onchocercal keratitis, Eric Pearlman here discusses how these studies have identified systemic and local immune responses associated with keratitis, including T helper-cell subset and cytokine responses.

Journal Article↗

PubMed1999

Frontotemporal interactions in face encoding and recognition.

Cognition may result from different patterns of neural interactions distributed across the brain. If this is true then across different cognitive tasks different functional interactions should be observed within an anatomical network. To investigate this hypothesis, a network analysis of PET data obtained from a face memory study was conducted. PET scans were obtained while subjects performed face perception, face encoding and face recognition tasks. Partial least squares (PLS) analysis of rCBF was used to identify brain regions that were engaged during these tasks, and anatomically based structural equation modeling (SEM) was used to construct functional models for matching, encoding and recognition. There was some overlap in the functional interactions observed across the three cognitive tasks. In all three tasks, there were positive interactions involving the left occipitotemporal regions. These interactions may represent the perceptual component of the three tasks. Task-specific functional interactions were also observed. During face encoding, there was a bilateral positive influence of occipitotemporal regions on medial temporal regions. In addition, there were positive interhemispheric interactions between middle temporal regions and between limbic regions during encoding. These patterns may reflect the participation of medial temporal cortex in the formation of new memories. In the face recognition task, there was a positive loop in the right hemisphere from occipital cortex to frontal cortex and back from frontal cortex to occipitotemporal cortex. In addition, there was a strong positive input into the right hippocampal region from right occipitotemporal cortex. This pattern of interaction was specific to the recognition task and might represent the process whereby the input faces are compared to the internal representation laid down during encoding, thus enabling recognition.

Adult↗

PubMed2000

A 3D-QSAR study on the structural requirements for binding to CB(1) and CB(2) cannabinoid receptors.

A 3D-QSAR study was carried out on 20 cannabinoids for which the binding affinities (K(i)) with respect to CB(1) and CB(2) receptors, determined in the same cell line, were available. For the first time three series of significantly different chemical structures such as Delta(9)-THC analogues, anandamides, and indoles were included in a single 3D-QSAR model, to obtain information on the interactions of all ligands with both CB(1) and CB(2) receptors and on their receptor selectivity. Delta(9)-THC was chosen as the structural template for alignment. The 3D-structure-activity correlation obtained by the GOLPE procedure provided a partial least squares (PLS) model with a very good predictive ability for the CB(1) receptor affinity of all compounds. The model allowed us to identify seven different regions in the space that contribute to explain the above binding affinities. External validation of the interpretation of the 3D-QSAR model was derived from a response-independent procedure such as principal components analysis (PCA). The CB(2) receptor model evidenced, besides the seven regions found for the CB(1) receptor, a new characteristic region for the CB(2) receptor. Another PCA, using 10 GRID probes, provided further evidence of receptor selectivity regions. One region opposite to the amidic NH of CB(1) selective O585 appears to be responsible for the CB(1) selectivity, while an interaction region opposite to the carbonyl of CB(2) selective JWH-015 appears to be involved in the CB(2) binding selectivity.

Arachidonic Acids↗

PubMed2004

CXCR2- and E-selectin-induced neutrophil arrest during inflammation in vivo.

The signaling events leading to the activation of integrins and firm arrest of rolling neutrophils in inflamed venules have yet to be elucidated. In vitro assays suggest that both E-selectin and chemokines can trigger arrest of rolling neutrophils, but E-selectin(-/-) mice have normal levels of adherent neutrophils in inflamed venules. To test whether chemokine-induced neutrophil arrest in vivo can be unmasked by blocking E-selectin, we investigated neutrophil adhesion in inflamed cremaster muscle venules in tumor necrosis factor (TNF)-alpha-treated CXCR2(-/-) or wild-type (WT) mice injected with E-selectin blocking monoclonal antibody (mAb) 9A9. To block chemokine receptor signaling, we investigated E-selectin(-/-) or WT mice treated with pertussis toxin (PTx) intravenously. Neutrophil adhesion was unchanged in CXCR2(-/-), E-selectin(-/-), PTx-treated WT, or mAb 9A9-treated WT mice. However, TNF-alpha-induced neutrophil adhesion was almost completely abrogated in E-selectin(-/-) mice treated with PTx and significantly reduced in CXCR2(-/-) mice treated with the E-selectin blocking mAb. In thioglycollate-induced peritonitis, PTx treatment blocked neutrophil recruitment into the peritoneum of E-selectin(-/-) mice, but had only a partial effect in WT animals. These data show that E-selectin- and chemokine-mediated arrest mechanisms are overlapping in this model and identify CXCR2 as an important neutrophil arrest chemokine in vivo.

Animals↗

PubMed2006

Scaling theory and morphometrics for a coarsening multiscale surface, via a principle of maximal dissipation.

We consider the coarsening dynamics of multiscale solutions to a dissipative singularly perturbed partial differential equation which models the evolution of a thermodynamically unstable crystalline surface. The late-time leading-order behavior of solutions is identified, through the asymptotic expansion of a maximal-dissipation principle, with a completely faceted surface governed by an intrinsic dynamical system. The properties of the resulting piecewise-affine dynamic surface predict the scaling law L(Mu) approximately t(1/3), for the growth in time of a characteristic morphological length scale L(Mu). A novel computational geometry tool which directly simulates a million-facet piecewise-affine dynamic surface is also introduced. Our computed data are consistent with the dynamic scaling hypothesis, and we report a variety of associated morphometric scaling functions.

Journal Article↗

PubMed1992

beta-Furfuryl-beta-Glucoside: An Endogenous Activator of Higher Plant UDP-Glucose:(1-3)-beta-Glucan Synthase : Biological Activity, Distribution, and in Vitro Synthesis.

In a recent paper (P Ohana, DP Delmer, JC Steffens, DE Matthews, R Mayer, M Benziman [1991] J Biol Chem 266: 13472-13475), we described the purification and structural characterization of beta-furfuryl-beta-glucoside (FG), an endogenous activator of plant UDP-glucose:(1-->3)-beta-glucan (callose) synthase. In the present report, we provide evidence that FG specifically stimulates callose synthase. The effects of FG on the kinetic properties of callose synthase were studied, and we ascertained that FG, or at least a very similar compound, is present in other plant systems. Chemically synthesized alpha-furfuryl-beta-glucoside also stimulates callose synthase, exhibiting a slightly higher K(a) of 80 micromolar, compared with 50 micromolar for FG. In addition, we have identified and partially characterized an enzyme that catalyzes the synthesis of FG using beta-furfuryl alcohol and UDP-glucose as substrates. A model for the regulation of callose synthesis in vivo, involving changes in intracellular compartmentation of FG and Ca(2+), is proposed.

Journal Article↗

PubMed2005

FINDMOL: automated identification of macromolecules in electron-density maps.

Automating the determination of novel macromolecular structures via X-ray crystallographic methods involves building a model into an electron-density map. Unfortunately, the conventional crystallographic asymmetric unit volumes are usually not well matched to the biological molecular units. In most cases, the facets of the asymmetric unit cut the molecules into a number of disconnected fragments, rendering interpretation by the crystallographer significantly more difficult. The FINDMOL algorithm is designed to quickly parse the arrangement of trace points (pseudo-atoms) derived from a skeletonized electron-density map without requiring higher level prior information such as sequence information or number of molecules in the asymmetric unit. The algorithm was tested with a variety of density-modified maps computed with medium- to low-resolution data. Typically, the resulting volume resembles the biological unit. In the remaining cases the number of disconnected fragments is very small. In all examples, secondary-structural elements such as alpha-helices or beta-sheets are easily identifiable in the defragmented arrangement. FINDMOL can greatly assist a crystallographer during manual model building or in cases where automatic model building can only build partial models owing to limitations of the data such as low resolution and/or poor phases.

Algorithms↗

PubMed2006

Polydesigns and causal inference.

In an increasingly common class of studies, the goal is to evaluate causal effects of treatments that are only partially controlled by the investigator. In such studies there are two conflicting features: (1) a model on the full cohort design and data can identify the causal effects of interest, but can be sensitive to extreme regions of that design's data, where model specification can have more impact; and (2) models on a reduced design (i.e., a subset of the full data), for example, conditional likelihood on matched subsets of data, can avoid such sensitivity, but do not generally identify the causal effects. We propose a framework to assess how inference is sensitive to designs by exploring combinations of both the full and reduced designs. We show that using such a "polydesign" framework generates a rich class of methods that can identify causal effects and that can also be more robust to model specification than methods using only the full design. We discuss implementation of polydesign methods, and provide an illustration in the evaluation of a needle exchange program.

Biometry↗

PubMed1996

Peroxidase-catalyzed generation of catechin oligomers that inhibit glucosyltransferase from Streptococcus sobrinus.

Oolong tea extract (OTE) and the purified polymeric polyphenols from OTE have been found to inhibit glucosyltransferase (GTase) of mutans streptococci. In view of the partial fermentation characteristic of oolong tea, we describe here an in vitro model reaction system to produce partially fermented products of D-(+)-catechin or green tea extract (GTE) using horseradish peroxidase. A dimeric catechin molecule was identified as dehydro-dicatechin A by instrumental analyses. The molecular size of some oligomeric catechins was estimated by the elution profile with HPLC. These catechin oligomers markedly inhibited GTase from Streptococcus sobrinus 6715. As the degree of polymerization of catechin or GTE increased, GTase was inhibited more effectively. These results suggest that polymeric polyphenols found in OTE are synthesized by partial fermentation due to oxidases/peroxidases present in tea leaves.

Bacterial Adhesion↗

PubMed1989

A dynamic model for the structure of acyl carrier protein in solution.

The determination of solution structures of proteins using two-dimensional NMR data is commonly based on the assumption that the structure can be represented by a single rigid conformer. We present here a procedure whereby this assumption can be relaxed and illustrate its application to acyl carrier protein from Escherichia coli, a small negatively charged protein with no internal disulfide bonds. The methodology rests on a model having two distinct conformers in dynamic equilibrium. Use of this two-state model results in a dramatic improvement in fit to cross-relaxation-derived distance constraints and a substantial lowering of molecular mechanics energies for individual conformers of acyl carrier protein. The two-state model retains the three-helix motif previously identified on the basis of a one-state structure, but substantial motion of loop regions and the C-terminal peptide, as well as partial disruption of the second helix, is suggested to occur. Support for the existence of these motions can be found in amide exchange rate and spin relaxation time data.

Acyl Carrier Protein↗

PubMed1978

Autoimmunity in multiple slcerosis: do we have an experimental model?

Experimental autoimmunity of the CNS has been well characterized--the antigen has been identified, effector cell specificity has been defined, and the relationship between cellular sensitization and antibody production has been partially clarified. In the guinea pig, experimental allergic encephalomyelitis (EAE) is induced by one injection of myelin basic protein in complete Freund's adjuvant (BP/CFA). If BP/CFA is preceded by repeated injections of basic protein in incomplete Freund's adjuvant (BP/IFA), EAE is not induced; the guinea pigs survive and ultimately produce antibody. Induction and prevention of EAE as well as antibody induction by this schedule are dependent on the presence of the intact encephalitogenic (T-cell) site in the polypeptide used for sensitization and preimmunization. In contrast, B cell sites (those peptide sequences which bind antibody) are independent of the T-cell site. At least 5 specific antigenic regions (B-cell sites) have been demonstrated in the BP molecule. High mycobacteria levels bypass the specificity requirement of helper T-cells but cannot bypass the specificity requirement of effector T-cells. In spite of the sophisticated immunologic techniques available, our knowledge of humoral and cellular sensitivity in multiple sclerosis (MS) patients is very limited. The experimental demonstration of an analogy between EAE and MS is weak: a) Demonstration of BP-sensitized cells or BP-specific antibodies in peripheral blood of MS patients has not been successful. b) Anti-myelin serum factors reported to be associated with both disease states (experimental autoimmunity and MS) are clearly not identical. Nevertheless, successful treatment of EAE in animals by BP/IFA injections has encouraged consideration of clinical trials to test the therapeutic value of BP injections in MS patients. If successful, the question will be answered: if unsuccessful, the dilemma still remains.

Adjuvants, Immunologic↗

PubMed1999

Differential characteristics of human 15-lipoxygenase isozymes and a novel splice variant of 15S-lipoxygenase.

The lipoxygenases (LOs) are a family of nonheme iron dioxygenases that catalyse the insertion of molecular oxygen into polyunsaturated fatty acids. Five members of this gene family have been described in man, 5-LO, 12S-LO, 12R-LO, 15-LO and 15S-LO. Using partially purified recombinant 15S-LO enzyme and cells constitutively expressing this protein, we have compared the activity, substrate specificity, kinetic characteristics and regulation of this enzyme to that previously reported for 15-LO. 15S-LO has a threefold higher Km, similar Vmax and increased specificity of oxygenation for arachidonic acid, and a similar Km but decreased Vmax for linoleic acid in comparison to 15-LO. Unlike 15-LO, 15S-LO is not suicide inactivated by the products of fatty acid oxygenation. However, in common with other LOs, 15S-LO activity is regulated through calcium-dependent association of the enzyme with the membrane fraction of cells. In addition, whilst independently cloning the recently described 15S-LO, we identified a splice variant containing an in-frame 87-bp deletion corresponding to amino acids 401-429 inclusive. Modelling of the 15S-LO and subsequent studies with partially purified recombinant protein suggest that the deleted region comprises a complete alpha-helix flanking the active site of the enzyme resulting in decreased specificity of oxygenation and affinity for fatty acid substrates. Alternative splicing of 15S-LO would therefore provide a further level of regulation of fatty acid metabolism. These results demonstrate that there are substantial differences in the enzyme characteristics and regulation of the 15-LO isozymes which may reflect differing roles for the proteins in vivo.

Amino Acid Sequence↗

PubMed1991

Patient intensity for nursing index: the measurement model.

One part of the psychometric evaluation of the Patient Intensity for Nursing Index (PINI), a new measure of nursing intensity, is reported. The PINI has four interrelated components: (a) severity of illness, (b) dependency, (c) complexity of care, and (d) time. Taken together, the 10 items that make up these four components comprise the multidimensional construct of nursing intensity. Using the factor analytic approach and a model specification search, the measurement model for the Patient Intensity for Nursing Index was identified. The structure consists of Dependency, Severity, and Complexity with time (hours of nursing care) loading on each factor. When results were cross-validated using data from four other hospitals, support emerged for a consistent pattern of factor loadings. The loadings themselves, however, are only partially invariant. Further examination of the relationship between severity and time is suggested and areas for future research are identified.

Dependency, Psychological↗

PubMed2002

Preparation of name and address data for record linkage using hidden Markov models.

BACKGROUND: Record linkage refers to the process of joining records that relate to the same entity or event in one or more data collections. In the absence of a shared, unique key, record linkage involves the comparison of ensembles of partially-identifying, non-unique data items between pairs of records. Data items with variable formats, such as names and addresses, need to be transformed and normalised in order to validly carry out these comparisons. Traditionally, deterministic rule-based data processing systems have been used to carry out this pre-processing, which is commonly referred to as "standardisation". This paper describes an alternative approach to standardisation, using a combination of lexicon-based tokenisation and probabilistic hidden Markov models (HMMs). METHODS: HMMs were trained to standardise typical Australian name and address data drawn from a range of health data collections. The accuracy of the results was compared to that produced by rule-based systems. RESULTS: Training of HMMs was found to be quick and did not require any specialised skills. For addresses, HMMs produced equal or better standardisation accuracy than a widely-used rule-based system. However, accuracy was worse when used with simpler name data. Possible reasons for this poorer performance are discussed. CONCLUSION: Lexicon-based tokenisation and HMMs provide a viable and effort-effective alternative to rule-based systems for pre-processing more complex variably formatted data such as addresses. Further work is required to improve the performance of this approach with simpler data such as names. Software which implements the methods described in this paper is freely available under an open source license for other researchers to use and improve.

Data Collection↗

PubMed2026

PLayer-FL: A Principled Approach to Personalized Layer-wise Cross-Silo Federated Learning.

Non-identically distributed data is a major challenge in Federated Learning (FL). Personalized FL tackles this by balancing local model adaptation with global model consistency. One variant, partial FL, leverages the observation that early layers learn more transferable features by federating only early layers. However, current partial FL approaches use predetermined, architecture-specific rules to select layers, limiting their applicability. We introduce Principled Layer-wise-FL (PLayer-FL), which uses a novel federation sensitivity metric to identify layers that benefit from federation. This metric, inspired by model pruning, quantifies each layer's contribution to cross-client generalization after the first training epoch, identifying a transition point in the network where the benefits of federation diminish. We first demonstrate that our federation sensitivity metric shows strong correlation with established generalization measures across diverse architectures. Next, we show that PLayer-FL outperforms existing FL algorithms on a range of tasks, also achieving more uniform performance improvements across clients.

Journal Article↗