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PubMedDate not supplied

Cyclosporine blood monitoring after heart transplantation: a prospective comparison of monoclonal and polyclonal radioimmunoassays.

Management of heart transplant patients who are being given cyclosporine is complicated by the variety of methods available for measuring cyclosporine levels and the current trend toward exclusive use of monoclonal assays. To facilitate clinical decisions regarding cyclosporine levels when converting from a polyclonal system to monoclonal system, 79 heart transplant patients underwent a prospective study to compare the polyclonal radioimmunoassay with the monoclonal-specific parent compound and nonspecific radioimmunoassays. Multivariable regression analyses were performed to generate best-fit equations for conversion of one assay to another. The closest correlation was noted in converting the measurement of cyclosporine parent compound with metabolites by the polyclonal method to the monoclonal method (nonspecific), R2 = 0.93. Considerable variability existed in the relationship between polyclonal and monoclonal-specific levels (R2 = 0.66) and between monoclonal-nonspecific and monoclonal-specific levels (R2 = 0.66), and both relationships were affected by hepatic function. Inferences: (1) The conversion of numeric cyclosporine levels from parent compound to parent plus metabolites is not completely predictable and must be empirically determined with the generation of appropriate regression equations. (2) Caution is advisable when a transplant team adopts a new cyclosporine assay for clinical use; formal study between existing assay methods and any newly adopted assay is warranted to prevent inadvertent underdosing or overdosing with cyclosporine.

Cyclosporine↗

PubMed1990

[Changes in the level of immunoglobulins and other serum proteins in hepatic echinococcosis].

The humoral immunity and the protein-synthesizing function of the liver of 35 patients with liver echinococcosis were studied. No humoral immunity deficit was found. Statistically significant abnormalities in a number of proteins were reduced, with evidence of reduced protein-synthesizing liver function. Inferences are made on the anesthesia, resuscitation and operative interventions, in connection with the results of the study.

Adolescent↗

PubMed1989

Alteration of neuritic cytoarchitecture in Alzheimer disease.

Individuals afflicted with Alzheimer disease (AD) demonstrate two prominent brain structural alterations: senile plaques and neurofibrillary tangles (NFT) (Selkoe, 1986). Not appreciated until recently is a third quantitatively significant structure, the dystrophic neurite. Many of these altered neurites are focally associated with amyloid deposits, and together they comprise the senile plaque. However, the great majority of the abnormal neurites in AD are independent of senile plaques (Braak, et al., 1986). Recent advances have yielded considerable information on the chemical nature of the extracellular amyloid (Kang, et al., 1987; Tanzi, et al., 1988) which comprises the central portion of the senile plaque, but there is much yet to be unraveled concerning both the nature of NFT and the relationship between senile plaques and NFT (Selkoe, 1987). While the NFT is principally comprised of 20 nm helically wound filaments, descriptively termed paired helical filaments (PHF) (Kidd, 1963; Wisniewski, et al., 1976) occasionally 12-15 nm straight filaments are also present (Perry, et al., 1987c). We have found that the predominant filaments in dystrophic neurites of AD are straight filaments which are morphologically indistinguishable from those found within NFT. The abnormal neuritic filaments and PHF share microtubule associated protein, tau, and ubiquitin immunoreactivity. The prevalence of altered neurites suggests that reorganization of neuritic cytoarchitecture in AD, as demonstrated by the formation of abnormal polymers structurally, and by inference functionally distinct from the normal cytoskeleton, may constitute a more important part of the cytopathological change of AD than previously appreciated.

Alzheimer Disease↗

PubMed1997

Chronically injured posterior cruciate ligament: magnetic resonance imaging.

Magnetic resonance imaging has been said to be highly reliable for diagnosis of acute posterior cruciate ligament insufficiency. In the present study, 13 patients whose posterior cruciate ligament insufficiency had been documented by magnetic resonance imaging within 10 weeks of the acute injury were recalled for a followup examination and magnetic resonance imaging. The followup interval ranged from 5 months to 4 years. In only 23% of the cases did the posterior cruciate ligament still appear discontinuous on followup magnetic resonance imaging. In the remaining 77%, the posterior cruciate ligament was continuous from tibia to femur, although it appeared abnormally arcuate or hyperbuckled. Conventional interpretation of these magnetic resonance images would suggest that the posterior cruciate ligament had healed. Nevertheless, by clinical examination results, these same patients all were judged to have posterior cruciate ligament insufficiency. Thus, it was concluded that although magnetic resonance imaging may be reliable for evaluation of acute posterior cruciate ligament injury, magnetic resonance imaging findings should not be used to infer functional status in chronic cases.

Chronic Disease↗

PubMed2001

Detection of haemoglobin variants and inference of their functional properties using complete oxygen dissociation curve measurements.

Complete oxygen dissociation curves for red cell suspensions of three haemoglobinopathies, namely haemoglobin (Hb) H, Hb Köln and Hb Tak/beta thalassaemia diseases, were measured using automatic recording methods. These curves were left-shifted compared with the normal red cell curve and showed a biphasic shape as a result of co-existence of the high and normal affinity haemoglobin components. Computer-assisted simulation of these biphasic curves enabled us to infer the curves for the pure abnormal haemoglobins and their fraction in the total haemoglobin of the red cell. The inferred values of fraction agreed with those determined by haemoglobin type analysis or the literature values. The curve for Hb Köln red cells deviated from the normal red cell curve in the whole range of oxygen saturation, whereas the curve for Hb H was close to the normal curve at the middle and upper portions. This difference in deviation was ascribed to a possible interaction between Hb Köln and Hb A through subunit exchange, and its absence between Hb H and Hb A. The present results indicate that measurement of the complete oxygen dissociation curve is important for the detection of non-interacting variants such as Hb H and is useful for inferring the functional properties of haemoglobin components that are not easily isolated.

Chromatography, High Pressure Liquid↗

PubMed1991

Uncritical inference making and intellectual functioning.

The relationship between uncritical inference making and intelligence has been uncertain. In the present study a group of 30 advanced undergraduate students were administered the Uncritical Inference Test and the Otis-Lennon Test of Mental Ability. A significant Pearson correlation of .52 indicates that this measure of intellectual functioning is associated with uncritical inference making. Further research needs to be conducted using standard intelligence measures of specific kinds of intellectual processes.

Adult↗

PubMed2002

Crystal structure of MJ1247 protein from M. jannaschii at 2.0 A resolution infers a molecular function of 3-hexulose-6-phosphate isomerase.

The crystal structure of the hypothetical protein MJ1247 from Methanococccus jannaschii at 2 A resolution, a detailed sequence analysis, and biochemical assays infer its molecular function to be 3-hexulose-6-phosphate isomerase (PHI). In the dissimilatory ribulose monophosphate (RuMP) cycle, ribulose-5-phosphate is coupled to formaldehyde by the 3-hexulose-6-phosphate synthase (HPS), yielding hexulose-6-phosphate, which is then isomerized to fructose-6-phosphate by the enzyme 3-hexulose-6-phosphate isomerase. MJ1247 is an alpha/beta structure consisting of a five-stranded parallel beta sheet flanked on both sides by alpha helices, forming a three-layered alpha-beta-alpha sandwich. The fold represents the nucleotide binding motif of a flavodoxin type. MJ1247 is a tetramer in the crystal and in solution and each monomer has a folding similar to the isomerase domain of glucosamine-6-phosphate synthase (GlmS).

Amino Acid Sequence↗

PubMed2005

Bayesian inference for psychometric functions.

In psychophysical studies, the psychometric function is used to model the relation between physical stimulus intensity and the observer's ability to detect or discriminate between stimuli of different intensities. In this study, we propose the use of Bayesian inference to extract the information contained in experimental data to estimate the parameters of psychometric functions. Because Bayesian inference cannot be performed analytically, we describe how a Markov chain Monte Carlo method can be used to generate samples from the posterior distribution over parameters. These samples are used to estimate Bayesian confidence intervals and other characteristics of the posterior distribution. In addition, we discuss the parameterization of psychometric functions and the role of prior distributions in the analysis. The proposed approach is exemplified using artificially generated data and in a case study for real experimental data. Furthermore, we compare our approach with traditional methods based on maximum likelihood parameter estimation combined with bootstrap techniques for confidence interval estimation and find the Bayesian approach to be superior.

Bayes Theorem↗

PubMed2004

Phydbac2: improved inference of gene function using interactive phylogenomic profiling and chromosomal location analysis.

Phydbac (phylogenomic display of bacterial genes) implemented a method of phylogenomic profiling using a distance measure based on normalized BLAST scores. This method was able to increase the predictive power of phylogenomic profiling by about 25% when compared to the classical approach based on Hamming distances. Here we present a major extension of Phydbac (named here Phydbac2), that extends both the concept and the functionality of the original web-service. While phylogenomic profiles remain the central focus of Phydbac2, it now integrates chromosomal proximity and gene fusion analyses as two additional non-similarity-based indicators for inferring pairwise gene functional relationships. Moreover, all presently available (January 2004) fully sequenced bacterial genomes and those of three lower eukaryotes are now included in the profiling process, thus increasing the initial number of reference genomes (71 in Phydbac) to 150 in Phydbac2. Using the KEGG metabolic pathway database as a benchmark, we show that the predictive power of Phydbac2 is improved by 27% over the previous version. This gain is accounted for on one hand, by the increased number of reference genomes (11%) and on the other hand, as a result of including chromosomal proximity into the distance measure (16%). The expanded functionality of Phydbac2 now allows the user to query more than 50 different genomes, including at least one member of each major bacterial group, most major pathogens and potential bio-terrorism agents. The search for co-evolving genes based on consensus profiles from multiple organisms, the display of Phydbac2 profiles side by side with COG information, the inclusion of KEGG metabolic pathway maps the production of chromosomal proximity maps, and the possibility of collecting and processing results from different Phydbac queries in a common shopping cart are the main new features of Phydbac2. The Phydbac2 web server is available at http://igs-server.cnrs-mrs.fr/phydbac/.

Artificial Gene Fusion↗

PubMed2006

Functional and evolutionary inference in gene networks: does topology matter?

The relationship between the topology of a biological network and its functional or evolutionary properties has attracted much recent interest. It has been suggested that most, if not all, biological networks are 'scale free.' That is, their connections follow power-law distributions, such that there are very few nodes with very many connections and vice versa. The number of target genes of known transcriptional regulators in the yeast, Saccharomyces cerevisiae, appears to follow such a distribution, as do other networks, such as the yeast network of protein-protein interactions. These findings have inspired attempts to draw biological inferences from general properties associated with scale-free network topology. One often cited general property is that, when compromised, highly connected nodes will tend to have a larger effect on network function than sparsely connected nodes. For example, more highly connected proteins are more likely to be lethal when knocked out. However, the correlation between lethality and connectivity is relatively weak, and some highly connected proteins can be removed without noticeable phenotypic effect. Similarly, network topology only weakly predicts the response of gene expression to environmental perturbations. Evolutionary simulations of gene-regulatory networks, presented here, suggest that such weak or non-existent correlations are to be expected, and are likely not due to inadequacy of experimental data. We argue that 'top-down' inferences of biological properties based on simple measures of network topology are of limited utility, and we present simulation results suggesting that much more detailed information about a gene's location in a regulatory network, as well as dynamic gene-expression data, are needed to make more meaningful functional and evolutionary predictions. Specifically, we find in our simulations that: (1) the relationship between a gene's connectivity and its fitness effect upon knockout depends on its equilibrium expression level; (2) correlation between connectivity and genetic variation is virtually non-existent, yet upon independent evolution of networks with identical topologies, some nodes exhibit consistently low or high polymorphism; and (3) certain genes show low polymorphism yet high divergence among independent evolutionary runs. This latter pattern is generally taken as a signature of positive selection, but in our simulations its cause is often neutral coevolution of regulatory inputs to the same gene.

Algorithms↗

PubMed1996

Brain imaging and cognitive neuroscience. Toward strong inference in attributing function to structure.

Cognitive neuroscience has emerged from the neurosciences and cognitive psychology as a scientific discipline that aims at the determination of "how brain function gives rise to mental activity" (S. M. Kosslyn & L. M. Shin, 1992, p. 146). While research in cognitive neuroscience combines many levels of neuroscientific and psychological analyses, modern imaging techniques that monitor brain activity during behavioral or cognitive operations have significantly contributed to the emergence of this discipline. The conclusions deduced from these studies are inherently localizationistic in nature; in other words, they describe cognitive functions as being localized in focal brain regions (brain activity in a defined brain region, phi, is involved in specific cognitive function, psi). A broad discussion about the virtues and limitations of such conclusions may help avoid the emergence of a mentalistic localizationism (i.e., the attribution of mentalistic concepts such as happiness, morality, or consciousness to brain structure) and illustrates the importance of a convergence with information generated by different research strategies (such as, for example, evidence generated by studies in which the effects of experimental manipulations of local neuronal processes on cognitive functions are assessed). Progress in capitalizing on brain-imaging studies to investigate questions of the form "brain structure or event phi is associated with cognitive function psi" may be impeded because of the way in which inferences are typically formulated in the brain imaging literature. A conceptual framework to advance the interpretation of data describing the relationships between cognitive phenomena and brain structure activity is provided.

Animals↗

PubMed1998

Tool use and mechanical problem solving in apraxia.

Moorlaas (1928) proposed that apraxic patients can identify objects and can remember the purpose they have been made for but do not know the way in which they must be used to achieve that purpose. Knowledge about the use of objects and tools can have two sources: It can be based on retrieval of instructions of use from semantic memory or on a direct inference of function from structure. The ability to infer function from structure enables subjects to use unfamiliar tools and to detect alternative uses of familiar tools. It is the basis of mechanical problem solving. The purpose of the present study was to analyze retrieval of instruction of use, mechanical problem solving, and actual tool use in patients with apraxia due to circumscribed lesions of the left hemisphere. For assessing mechanical problem solving we developed a test of selection and application of novel tools. Access to instruction of use was tested by pantomime of tool use. Actual tool use was examined for the same familiar tools. Forty two patients with left brain damage (LBD) and aphasia, 22 patients with right brain damage (RBD) and 22 controls were examined. Only LBD patients differed from controls on all tests. RBD patients had difficulties with the use but not with the selection of novel tools. In LBD patients there was a significant correlation between pantomime of tool use and novel tool selection but there were single cases who scored in the defective range on one of these tests and normally on the other. Analysis of LBD patients' lesions suggested that frontal lobe damage does not disturb novel tool selection. Only LBD patients who failed on pantomime of object use and on novel tool selection committed errors in actual use of familiar tools. The finding that mechanical problem solving is invariably defective in apraxic patients who commit errors with familiar tools is in good accord with clinical observations, as the gravity of their errors goes beyond what one would expect as a mere sequel of loss of access to instruction of use.

Adult↗

PubMed2005

Inferring hypotheses on functional relationships of genes: Analysis of the Arabidopsis thaliana subtilase gene family.

The gene family of subtilisin-like serine proteases (subtilases) in Arabidopsis thaliana comprises 56 members, divided into six distinct subfamilies. Whereas the members of five subfamilies are similar to pyrolysins, two genes share stronger similarity to animal kexins. Mutant screens confirmed 144 T-DNA insertion lines with knockouts for 55 out of the 56 subtilases. Apart from SDD1, none of the confirmed homozygous mutants revealed any obvious visible phenotypic alteration during growth under standard conditions. Apart from this specific case, forward genetics gave us no hints about the function of the individual 54 non-characterized subtilase genes. Therefore, the main objective of our work was to overcome the shortcomings of the forward genetic approach and to infer alternative experimental approaches by using an integrative bioinformatics and biological approach. Computational analyses based on transcriptional co-expression and co-response pattern revealed at least two expression networks, suggesting that functional redundancy may exist among subtilases with limited similarity. Furthermore, two hubs were identified, which may be involved in signalling or may represent higher-order regulatory factors involved in responses to environmental cues. A particular enrichment of co-regulated genes with metabolic functions was observed for four subtilases possibly representing late responsive elements of environmental stress. The kexin homologs show stronger associations with genes of transcriptional regulation context. Based on the analyses presented here and in accordance with previously characterized subtilases, we propose three main functions of subtilases: involvement in (i) control of development, (ii) protein turnover, and (iii) action as downstream components of signalling cascades. Supplemental material is available in the Plant Subtilase Database (PSDB) (http://csbdb.mpimp-golm.mpg.de/psdb.html), as well as from the CSB.DB (http://csbdb.mpimp-golm.mpg.de).

Animals↗

PubMed2005

Inference of protein function from protein structure.

Structural genomics has brought us three-dimensional structures of proteins with unknown functions. To shed light on such structures, we have developed ProKnow (http://www.doe-mbi.ucla.edu/Services/ProKnow/), which annotates proteins with Gene Ontology functional terms. The method extracts features from the protein such as 3D fold, sequence, motif, and functional linkages and relates them to function via the ProKnow knowledgebase of features, which links features to annotated functions via annotation profiles. Bayes' theorem is used to compute weights of the functions assigned, using likelihoods based on the extracted features. The description level of the assigned function is quantified by the ontology depth (from 1 = general to 9 = specific). Jackknife tests show approximately 89% correct assignments at ontology depth 1 and 40% at depth 9, with 93% coverage of 1507 distinct folded proteins. Overall, about 70% of the assignments were inferred correctly. This level of performance suggests that ProKnow is a useful resource in functional assessments of novel proteins.

Amino Acid Motifs↗

PubMed2002

Functional integration and inference in the brain.

Self-supervised models of how the brain represents and categorises the causes of its sensory input can be divided into two classes: those that minimise the mutual information (i.e. redundancy) among evoked responses and those that minimise the prediction error. Although these models have similar goals, the way they are attained, and the functional architectures employed, can be fundamentally different. This review describes the two classes of models and their implications for the functional anatomy of sensory cortical hierarchies in the brain. We then consider how empirical evidence can be used to disambiguate between architectures that are sufficient for perceptual learning and synthesis. Most models of representational learning require prior assumptions about the distribution of sensory causes. Using the notion of empirical Bayes, we show that these assumptions are not necessary and that priors can be learned in a hierarchical context. Furthermore, we try to show that learning can be implemented in a biologically plausible way. The main point made in this review is that backward connections, mediating internal or generative models of how sensory inputs are caused, are essential if the process generating inputs cannot be inverted. Because these processes are dynamical in nature, sensory inputs correspond to a non-invertible nonlinear convolution of causes. This enforces an explicit parameterisation of generative models (i.e. backward connections) to enable approximate recognition and suggests that feedforward architectures, on their own, are not sufficient. Moreover, nonlinearities in generative models, that induce a dependence on backward connections, require these connections to be modulatory; so that estimated causes in higher cortical levels can interact to predict responses in lower levels. This is important in relation to functional asymmetries in forward and backward connections that have been demonstrated empirically. To ascertain whether backward influences are expressed functionally requires measurements of functional integration among brain systems. This review summarises approaches to integration in terms of effective connectivity and proceeds to address the question posed by the theoretical considerations above. In short, it will be shown that functional neuroimaging can be used to test for interactions between bottom-up and top-down inputs to an area. The conclusion of these studies points toward the prevalence of top-down influences and the plausibility of generative models of sensory brain function.

Animals↗

PubMed1990

Mode of action of lithium in affective disorders. An influence on intracellular calcium functions.

The inference that lithium acts by altering intracellular calcium functions is supported by the three areas considered above. First, recent work in other laboratories has broadened the range of lithium actions on calcium-dependent physiological functions. Second, a theoretical analysis of the coupling of calcium transport to the triphosphoinositide response presents a plausible mechanism by which lithium could limit the damage caused by deficient calcium transport. Third, we have recently reported that there is a direct enhancement of the calmodulin-activated membrane-bound calcium pump in lithium-treated bipolar subjects.

Adenosine Triphosphatases↗

PubMed2005

It takes the whole brain to make a cup of coffee: the neuropsychology of naturalistic actions involving technical devices.

Left hemisphere dominance has been established for use of single familiar tools and tool/object pairs, but everyday action in natural environment frequently affords multi-step actions with more or less novel technical devices. One purpose of our study was to find out whether left hemisphere dominance extends to such naturalistic action. Another aim was to analyze the cognitive components contributing to success or failure. Patients with LBD and aphasia, patients with RBD, and healthy controls were examined on experimental tests assessing retrieval of functional knowledge from semantic memory, inference of function from structure, and solution of mechanical and non-mechanical multi-step problems, and were confronted with two naturalistic tasks involving technical devices: preparing coffee with a drip coffee maker and fixing a cassette recorder. Both patient groups were about equally impaired on both naturalistic actions. Analysis of the experimental tests and their correlations to naturalistic actions suggested that different cognitive deficits caused failure in both patient groups, and that in LBD patients there were also different causes for failure on both naturalistic actions. The main difficulty of RBD patients seemed to reside in the demand to keep track of multi-step actions. In aphasic LBD patients difficulties with making coffee but not the cassette recorder were correlated with aphasia and defective retrieval of functional knowledge from semantic memory, whereas the cassette recorder correlated more strongly with a test probing solution of multi-step mechanical problems. Inference of function from structure which had been shown to be important for use of single familiar tools or tool/objects pairs [Goldenberg, G., Hagmann, S. (1998). AT Tool use and mechanical problem solving in apraxia. Neuropsychologia, 36, 581-589] appeared to play only a subordinate role for naturalistic actions involving technical devices.

Activities of Daily Living↗

PubMed1966

An attempt to infer the electrophysiological functions of some intracellular structures in cardiac cells by an electronic analogue.

A circuit which simulates the electrical conduction characteristics of the neuron has been modified by the addition of a feedback loop to simulate the electrical properties of some of the "specialized" tissues of the mammalian heart. It is suggested that there is similar electrical feedback in the muscle cells which is responsible for their electrical properties, and possible relationships between the feedback and observed structures are discussed.

Calcium↗