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Results for “functional inference”

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PubMed1999

How tumors escape immune destruction and what we can do about it.

There is strong circumstantial evidence that tumor progression in cancer patients is controlled by the immune system. As will be detailed below, this conclusion is based on observations that tumor progression is often associated with secretion of immune suppressive factors and/or downregulation of MHC class I antigen presentation functions. The inference is that tumors must have elaborated strategies to circumvent an apparently effective immune response. Importantly, a tumor-specific immune response cannot be detected in most individuals. While this failure is in part technical, it also suggests that the magnitude of the immune responses to which tumors have to respond is low. This raises the concern, which is the underlying theme of this commentary, that a more robust immune response elicited by deliberate vaccination will exacerbate the rate of immune escape and nullify the potential benefits of immune-based therapies.

Animals↗

PubMed2003

Transient expression of Arabidopsis thaliana ascorbate peroxidase 3 in Nicotiana benthamiana plants infected with recombinant potato virus X.

We have explored the transient over-expression of Arabidopsis thaliana ascorbate peroxidase 3 (APX3) in Nicotiana benthamiana using a viral vector based on the potato virus X (PVX). Plants infected with a PVX:APX3 hybrid had a similar progression of viral particles compared to control plants infected with a PVX:GFP hybrid, indicating that infection was not affected by the over-expression of heterologous APX3. Our results also showed that in PVX:APX3-infected plants, the hybrid virus directed a high level of APX3 expression and the recombinant protein was functional, as inferred from the higher APX activity compared to mock and PVX:GFP hybrid-infected plants. The PVX recombinant expression system used is a simple and quick method for transient expression of heterologous APXs, which are expected to suffer specific processing in plant cells.

Arabidopsis↗

PubMed1980

Neuroregulatory and neuroendocrine GnRH pathways in the hypothalamus and forebrain of the baboon.

The distribution of neurons containing gonadotropin-releasing hormone (GnRH) in the baboon hypothalamus and forebrain was studied immunocytochemically by light and electron microscopy. GnRH was present in the perikarya, axonal and dendritic processes of immunoreactive neurons. Three populations of GnRH neurons could be distinguished. Most of the GnRH neurons which are assumed to directly influence the anterior pituitary were in the medial basal hypothalamus. Other cells that projected to the median eminence were found scattered throughout the hypothalamus. A second, larger population of neurons apparently was not involved with control of the anterior pituitary. These neurons were generally found within afferent and efferent pathways of the hypothalamus and forebrain, and may receive external information affecting reproduction. A few neurons projecting to the median eminence were also observed sending collaterals to other brain areas. Thus, in addition to their neuroendocrine role, these cells possibly have neuroregulatory functions. The inference is made that these bifunctional neurons, together with the widely observed GnRH-GnRH cellular interactions may help to synchronize ovulation and sexual behavior.

Animals↗

PubMed1995

Tendon biomechanical properties enhance human wrist muscle specialization.

Biomechanical properties of human wrist tendons were measured under loads predicted to be experienced by those tendons under physiological conditions. This was accomplished by measuring the architectural properties of the five prime wrist movers--extensors carpi radialis brevis (ECRB), extensor carpi radialis longus (ECRL), extensor carpi ulnaris (ECU), flexor carpi radials (FCR), flexor carpi ulnaris (FCU)--and predicting their maximum tension (P0) using a specific tension value (22.5 N cm-2. Loading the corresponding tendons to P0 resulted in significantly different strain among tendons (p < 0.01) with the largest strain observed in the FCU (3.68 +/- 0.31%) and the smallest strain observed in the ECRL (1.78 +/- 0.14%). Further, strain magnitude was significantly positively correlated with the tendon length-to-fiber length ratio of the muscle-tendon unit, a measure of the intrinsic compliance of the muscle-tendon unit. Theoretical modeling of the magnitude of muscle sarcomere shortening expected based on the measured biomechanical properties revealed a maximum sarcomere length decrease of about 0.6 micron for the FCU to a minimum of about 0.2 micron for the ECRB at P0. Thus, tendon compliance may, but does not necessarily, result in significant modification of muscle force generation. The significant variation in tendon biomechanical properties was not observed using traditional elongation-to-failure methods on the same specimens. Thus, the use of elongation-to-failure experiments for determination of tendon properties may not be reasonable when the purpose of such studies is to infer physiological function. These data indicate that muscle-tendon units show remarkable specialization and that tendon intrinsic properties accentuate the muscle architectural specialization already present.

Biomechanical Phenomena↗

PubMed1991

Vaccinia virus encodes a protein with similarity to glutaredoxins.

Recently, we have reported the complete nucleotide sequence of vaccinia virus (Goebel, S. J., Johnson, G. P., Perkus, M. E., Davis, S. W., Winslow, J. P., and Paoletti, E. 1990, Virology 179, 247-266). Approximately 2.2 kbp leftward of the large subunit of ribonucleotide reductase resides a 108-amino acid open reading frame, O2L (nt 62,851-62,528) with significant similarity to known glutaredoxins. The deduced amino acid sequence of open reading frame O2L is 28.7% identical to the yeast and Escherichia coli proteins and greater than 40% identical to various mammalian glutaredoxins. Similar patterns of hydrophobicity as well as alpha-helix and beta-sheet potentials suggest that O2L and the glutaredoxins share a similar secondary structure. Furthermore, a common function is inferred by the presence of a highly conserved redox-active site.

Amino Acid Sequence↗

PubMed1990

Evidence for a power law intensity code in the coupled cones of the turtle.

The hyperpolarizing responses to light were recorded intracellularly from red cones of the turtle, Pseudemys scripta elegans. Pairs of slit stimuli were flashed alone or together at various intensities, one slit positioned on the receptive field center and the other displaced 30 microns. The peak amplitude of the response was measured, and the results analyzed to quantify the relationship between the light intensity and the size of the neural signal evoked prior to the spatial interactions occurring in the network of coupled cones. This signal, E, was found to be described by a compressive power law, E = k.I0.5, where I is slit intensity. Evidence that the inferred excitation function describes a local mechanism independent of the slit position was obtained by measuring the response and the sensitivity receptive field profiles. The response and the sensitivity fields both decreased exponentially, but with space constants that differed by a factor of two, indicating in still another way the existence of an early square-root transformation.

Animals↗

PubMed1988

Molecular cloning and expression of the human interferon-gamma receptor.

A cDNA encoding the human interferon-gamma receptor was isolated from a lambda gt11 expression library using a polyclonal antireceptor antiserum. The gene for this receptor was identified in a cosmid library and transfected into mouse cells. The human interferon-gamma receptor expressed in mouse cells displayed the same binding properties as in human cells. However, transfected cells were not sensitive to human IFN-gamma, suggesting the need for species-specific cofactors in receptor function. As inferred from the cDNA sequence, the human interferon-gamma receptor shows no similarities to known proteins and represents a novel transmembrane receptor. It is most likely the product of a single mRNA and a gene located on chromosome 6q.

Amino Acid Sequence↗

PubMed1982

The utilization of prevailing evaluation policy in the selection of performance measures.

This study considers the problem of inferring a functional evaluation criterion from existing performance measure policies. The objective is to develop a rational basis by which to adaptively evaluate a current best set of performance measures from alternative sets. The analysis is based on a matrix approach for relating system characteristics to performance measures across a set of activities. A procedure for ranking measure combinations which are candidate implementation alternatives is devised using this matrix representation and cost information. An example illustrating the procedure is presented.

Employee Performance Appraisal↗

PubMed1989

The case against the case against group studies.

We challenge the position that only the analysis of single patients can allow us to infer normal function from impaired performance. We claim that the focus on group vs. single case studies is unprofitable and that a more useful question is how best to form abstractions of relevance to cognitive theory. In this context, we consider issues concerning the category of "agrammatism."

Aphasia↗

PubMed2005

Developing animals flout prominent assumptions of ecological physiology.

Every field of biology has its assumptions, but when they grow to be dogma, they can become constraining. This essay presents data-based challenges to several prominent assumptions of developmental physiologists. The ubiquity of allometry is such an assumption, yet animal development is characterized by rate changes that are counter to allometric predictions. Physiological complexity is assumed to increase with development, but examples are provided showing that complexity can be greatest at intermediate developmental stages. It is assumed that organs have functional equivalency in embryos and adults, yet embryonic structures can have quite different functions than inferred from adults. Another assumption challenged is the duality of neural control (typically sympathetic and parasympathetic), since one of these two regulatory mechanisms typically considerably precedes in development the appearance of the other. A final assumption challenged is the notion that divergent phylogeny creates divergent physiologies in embryos just as in adults, when in fact early in development disparate vertebrate taxa show great quantitative as well as qualitative similarity. Collectively, the inappropriateness of these prominent assumptions based on adult studies suggests that investigation of embryos, larvae and fetuses be conducted with appreciation for their potentially unique physiologies.

Anatomy, Comparative↗

PubMed2026

Endocrine-disrupting chemical-induced gene networks confer coronary heart disease risk revealed by causal inference and single-cell analyses.

BACKGROUND: Endocrine-disrupting chemicals (EDCs) are linked to coronary heart disease (CHD), but underlying mechanisms remain unclear. We aimed to identify EDC-related genes and evaluate their causal roles in CHD. METHODS: We curated EDC-related genes from a compound-gene interaction database and integrated them with CHD genome-wide association study (GWAS) summary statistics and tissue-specific expression quantitative trait loci (eQTL) data. Two-sample Mendelian randomization (MR) and Bayesian colocalization were applied to infer causality. Functional enrichment, single-cell RNA sequencing of human coronary arteries, and EDC-gene networks were further analyzed. RESULTS: After FDR correction, 39 genes were significantly associated with CHD risk via MR. Four genes-ZNF827, FCHO1, IPO9 (protective), and RPL13 (risk-increasing)-showed strong colocalization (PPH4 > 0.9). Pathway and single-cell analyses of coronary artery tissue indicated that vascular and immune pathways mediate these effects. An interaction network highlighted associations between specific EDCs and candidate genes implicated in CHD susceptibility. CONCLUSION: This integrative genomic study provides evidence that EDCs influence CHD susceptibility through distinct gene networks, revealing potential mechanisms and molecular targets for prevention and therapy.

Humans↗

PubMed2005

The coupling mechanism of P-glycoprotein involves residue L339 in the sixth membrane spanning segment.

The transmembrane (TM) domains in P-glycoprotein (P-gp) contain the drug binding sites and undergo conformational changes driven by nucleotide catalysis to effect translocation. However, our understanding of exactly which regions are involved in such events remains unclear. A site-directed labelling approach was used to attach thiol-reactive probes to cysteines introduced into transmembrane segment 6 (TM6) in order to perturb function and infer involvement of specific residues in drug binding and/or interdomain communication. Covalent attachment of coumarin-maleimide at residue 339C within TM6 resulted in impaired ATP hydrolysis by P-gp. The nature of the effect was to reduce the characteristic modulation of basal activity caused by transported substrates, modulators and the potent inhibitor XR9576. Photoaffinity labelling of P-gp with [(3)H]-azidopine indicated that residue 339C does not alter drug binding per se. However, covalent modification of this residue appears to prevent conformational changes that lead to drug stimulation of ATP hydrolysis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

Quality of life assessments in major depressive disorder: a review of the literature.

According to the DSM-IV classification, a diagnosis of Major Depressive Disorder (MDD) is possible only when there is evidence of significant inference with functioning. However, despite the high prevalence of MDD in the general population, it is uncommon for clinicians to assess overall functioning in a systematic way before making such diagnosis. An important correlate of functioning is quality of life, which is typically defined as "patients' own assessments of how they feel about what they have, how they are functioning, and their ability to derive pleasure from their life activities". In the present article, we review studies focusing on the relationship between depression and quality of life, particularly focusing on the impact of the treatment of depression on quality of life. Studies focusing on the quality of life in MDD are reviewed. Candidate studies published between 1970 and recently were initially identified by Pubmed and Ovid search cross-referencing the terms "quality of life," "psychosocial functioning" with "major depression" and "treatment." A number of studies report poorer quality of life in MDD patients compared to controls. Several studies also report an improvement in quality of life measures during various phases of treatment with antidepressants and/or psychotherapy. However, trials comparing the role of newer psychopharmacologic agents in the acute phase of treatment, and the role of newer psychotherapies in the continuation and maintenance phases of treatment in restoring psychosocial functioning and improving the quality of life in MDD are lacking. Exploring the impact of these modalities on psychosocial function and quality of life in MDD are necessary to help translate clinical response into restoration of psychosocial function and to thus further improve the standard of care.

Major Depressive Disorder↗

PubMed2006

Comparative genomics and protein domain graph analyses link ubiquitination and RNA metabolism.

The human gene parkin, known to cause familial Parkinson disease, as well as several other genes, likely involved in other neurodegenerative diseases or in cancer, encode proteins of the RBR family of ubiquitin ligases. Here, we describe the structural diversity of the RBR family in order to infer their functional roles. Of particular interest is a relationship detected between RBR-mediated ubiquitination and RNA metabolism: a few RBR proteins contain RNA binding domains and DEAH-box RNA helicase domains. Global protein domain graph analyses demonstrate that this connection is not RBR-specific, but instead many other proteins contain both ubiquitination and RNA-related domains. These proteins are present in animals, plants and fungi, suggesting that the link between these two cellular processes is ancient. Our results show that global bioinformatic approaches, involving comparative genomics and domain network analyses, may unearth novel functional relationships involving well-known and thoroughly studied groups of proteins.

Algorithms↗

PubMed2006

The role of the right superior temporal gyrus in visual search-insights from intraoperative electrical stimulation.

Intraoperative electrical stimulation in awake patients is a seminal technique during brain surgery allowing one to infer the function of brain areas by temporary inactivation. Using this technique, we found that inactivation of the middle portion of the superior temporal gyrus (STG) leads to disturbed serial exploratory visual search. The data supplement recent findings by Ellison et al. [Ellison, A., Schindler, I., Pattison, L. L., & Milner, A. D. (2004). An exploration of the role of the superior temporal gyrus in visual search and spatial perception using TMS. Brain, 127, 2307-2315] using repetitive transcranial magnetic stimulation over the STG in healthy subjects. Our data demonstrate that the STG is integral to human exploration behaviour and challenge the traditional view that only the right posterior parietal cortex is involved in the mediation of visual search processes.

Aged↗

PubMed2004

Patterns and clusters within the PSM column in TiBS, 1992-2004.

Sequence similarities among proteins can infer biological function and evolutionary relationships--a powerful approach for investigating new proteins and suggesting future experiments. The availability of public sequence databases and freely distributed tools for sequence analysis has meant that researchers from all over the world can use this approach. For the past 12 years, the Protein Sequence Motif column in TiBS has provided a platform for documenting interesting discoveries from sequence analyses. As the column comes to an end, we look at the published contributions over the years and reflect on sequence analysis through the beginning of the genomic era.

Animals↗

PubMed1977

Clofibrate effects: mitochondria vs exercise tolerance in aging hamsters.

Mitochondria in skeletal and cardiac muscle have been found to be less stable in aging hamsters, in contrast to preparations from young animals. We have found previously that clofibrate (Atromid-S) will reverse this degeneration in the older hamsters. This study examined the exercise tolerance of aged hamsters, to see if clofibrate had a parallel effect on exercise tolerance as had been shown for muscle mitochondria stability. Maximal duration of exercise for hamsters on a treadmill was measured in a control and treatment group before and after treatment with clofibrate. There was no improvement in exercise tolerance with clofibrate. We conclude that inferences of functional effects in intact animals from changes found in isolated tissue preparations should be drawn with caution.

Aging↗

PubMed2001

Hierarchical approach to predicting permeation in ion channels.

A hierarchical computational strategy combining molecular modeling, electrostatics calculations, molecular dynamics, and Brownian dynamics simulations is developed and implemented to compute electrophysiologically measurable properties of the KcsA potassium channel. Models for a series of channels with different pore sizes are developed from the known x-ray structure, using insights into the gating conformational changes as suggested by a variety of published experiments. Information on the pH dependence of the channel gating is incorporated into the calculation of potential profiles for K(+) ions inside the channel, which are then combined with K(+) ion mobilities inside the channel, as computed by molecular dynamics simulations, to provide inputs into Brownian dynamics simulations for computing ion fluxes. The open model structure has a conductance of approximately 110 pS under symmetric 250 mM K(+) conditions, in reasonable agreement with experiments for the largest conducting substate. The dimensions of this channel are consistent with electrophysiologically determined size dependence of quaternary ammonium ion blocking from the intracellular end of this channel as well as with direct structural evidence that tetrabutylammonium ions can enter into the interior cavity of the channel. Realistic values of Ussing flux ratio exponents, distribution of ions within the channel, and shapes of the current-voltage and current-concentration curves are obtained. The Brownian dynamics calculations suggest passage of ions through the selectivity filter proceeds by a "knock-off" mechanism involving three ions, as has been previously inferred from functional and structural studies of barium ion blocking. These results suggest that the present calculations capture the essential nature of K(+) ion permeation in the KcsA channel and provide a proof-of-concept for the integrated microscopic/mesoscopic multitiered approach for predicting ion channel function from structure, which can be applied to other channel structures.

Bacterial Proteins↗