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Results for “Partially Identified Models”

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PubMedDate not supplied

[Characteristics of protein metabolism in labyrinthine tissue].

The synthesis of total protein in organic culture of the internal ear was studied in 16-day embryo of CBA mice exposed to altering factors. The experiments showed feasibility of partial recovery for impaired metabolic processes in the labyrinth following phonophoretic introduction of mitochondrial coenzymes and inhibitors of lysosomal activity. Formation of systemic structural trace by modelling of acoustic stress and verification of protein stress agents was tested making it possible to identify an important component in dysadaption mechanism in mature CBA mice labyrinth.

Animals↗

PubMed2005

[Spatio-temporal dynamics of neuronal networks in partial epilepsy].

INTRODUCTION: The anatomo-functional organization of partial drug-resistant epilepsies is the subject of much current research aiming at better understanding these pathologies and improving their treatment. The work carried out by our team on the study of intracerebral recording falls within this category of research. The objectives are to identify the neural networks involved in the generation of paroxysmal activity and to understand their spatio-temporal dynamics, in order to be able in the long term to propose targeted therapeutic approaches likely to "control" these networks. STATE OF ART: The traditional concept of epileptic "focus" must nowadays be replaced by a more complex model taking into account potential interactions within the neural networks involved in the seizure. Indeed, during partial seizures, involved cerebral structures are the site of characteristic oscillations which may be synchronized or on the contrary transiently desynchronized. These epileptic rhythms may disturb the physiological rhythms underlying normal cognitive processes; these cognitive processes may thus be impaired in partial epilepsy, even those remote from the site of origin of the discharge. In this article we describe a model of organization of human partial seizures, through characterization of the relationships ("synchrony") between intracerebral signals recorded in the involved structures. We propose that seizures are generated in an initial network of highly epileptogenic brain structures (epileptogenic zone network, EZN) whose activity is synchronized; this activity is then transiently desynchronized with the appearance of fast oscillations. During a second ictal phase, other cortical and subcortical structures are the seat of slower rhythmic modifications that are synchronized (propagation network, PN). The emergence of a particular clinical semiology in the course of the seizure depends on these phenomena which can in certain cases "mimic" a normal cerebral process or on the contrary provoke a major rupture in normal cerebral functioning. CONCLUSIONS: These studies contribute to improvement in our knowledge of the neural networks involved in partial epilepsies. In the future, this type of research may contribute to the development of specific treatments that target certain pathophysiological mechanisms involved in seizure generation.

Brain↗

PubMed2006

Comparative QSAR modeling of CCR5 receptor binding affinity of substituted 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas.

The present QSAR study attempts to explore the structural and physicochemical requirements of substituted 1-(3,3-diphenylpropyl)-piperidinyl amides and ureas for CCR5 binding affinity using linear free energy-related (LFER) model of Hansch. QSAR models have been developed using electronic (Hammett sigma), hydrophobicity (pi), and steric (molar refractivity and STERIMOL L, B1, and B5) parameters of phenyl ring substituents of the compounds along with appropriate dummy variables. Whole molecular descriptor like partition coefficient (logP(calcd)) was also tried as an additional descriptor. Statistical techniques like stepwise regression, multiple linear regression with factor analysis as the data preprocessing step (FA-MLR), partial least squares with factor analysis as the preprocessing step (FA-PLS), principal component regression analysis (PCRA), multiple linear regression with genetic function approximation (GFA-MLR), and genetic partial least squares (G/PLS) were applied to identify the structural and physicochemical requirements for the CCR5 binding affinity. The generated equations were statistically validated using leave-one-out technique. The quality of equations obtained from stepwise regression, FA-MLR, FA-PLS, and PCRA is of acceptable statistical range (explained variance ranging from 71.9% to 80.4%, while predicted variance ranging from 67.4% to 77.0%). The GFA-derived models show high intercorrelation among predictor variables used in the equations while the G/PLS model shows lowest statistical quality among all types of models. The best models were also subjected to leave-25%-out crossvalidation.

Amides↗

PubMed2005

Hand-assisted laparoscopic partial nephrectomy in the porcine model using gelatin matrix hemostatic sealant without hilar occlusion.

BACKGROUND AND PURPOSE: Gelatin matrix hemostatic sealant (GMHS) has been used for hemostasis during partial nephrectomy with hilar clamping. The objective of this study was to determine the ability of GMHS to achieve hemostasis without hilar clamping in the porcine model. MATERIALS AND METHODS: In this feasibility study, eight farm pigs underwent a left-hand-assisted laparoscopic partial nephrectomy (HALPN). The lower fourth of the kidney was removed with cold scissors, and GMHS was applied laparoscopically. Samples were collected for measurement of serum hemoglobin (Hb) and creatinine (Cr) prior to surgery and at 4 and 30 days after HALPN. The kidneys were harvested at 30 days, and retrograde pyelograms and pathologic analysis were performed. RESULTS: Application of GMHS achieved complete hemostasis in all eight animals. The mean estimated blood loss was 40 mL, and the operating time was short (mean 92.5 minutes). In three kidneys, a significant collecting system opening was noted but not repaired. At harvest, there were no hematomas, infections, or urine leaks in any animals. In one animal, a 2-cm contained fluid collection was identified. There was no difference in the preoperative and harvest Hb (9.63 v 9.21 g/dL; P = 0.49), but there was a slight increase in Cr (1.21 v 1.46 mg/dL; P = 0.01) possibly because of the decreased renal mass after partial nephrectomy. CONCLUSION: Even without hilar occlusion, GMHS was 100% safe and effective in controlling bleeding after HALPN in the porcine model. Avoidance of hilar occlusion may reduce the risk associated with warm renal ischemia and the extra dissection required to isolate the hilum in preparation for clamping.

Animals↗

PubMed1999

The identification and characteristics of the partially dissociated states of patients with borderline personality disorder.

A developmental and structural model of borderline personality disorder is described. Partial dissociation provoked by trauma and deprivation in childhood is seen to result in the persistence of separate self states. The characteristics of these and alternations between them are seen to account for the main features of the condition. The identification and characterization of states through clinical procedures and the use of the states grid are described and case illustrations are given. The states identified by the grid method in a series of 20 borderline patients are described and classified into six groups, named abuser rage, victim rage, passive victim, ideal, coping and zombie. The clinical value and nosological implications of the model and these findings are briefly discussed.

Adult↗

PubMed2005

Endoscopic transgastric abdominal exploration and organ resection: initial experience in a porcine model.

BACKGROUND & AIMS: The evolution of flexible endoscopes and endoscopic devices has recently enabled per-oral transgastric abdominal exploration in animal models. This study was undertaken to assess the ability to systematically identify abdominopelvic organs and to determine the feasibility of organ resection via the transgastric route. METHODS: Female Yorkshire pigs were used for the study. Under general anesthesia, a gastroscope was used to place a sterile overtube into the esophagus. After antibacterial lavage, the gastric wall was incised, and a sterile dual-channel endoscope was advanced into the peritoneal cavity. Endoscopic abdominal exploration was then methodically performed in 9 animals with oophorectomy and partial hysterectomy in 6 animals. The gastric incision was closed with endoclips. Of the animals that underwent organ resection, 3 were sacrificed immediately after surgery, and the subsequent 3 survived. RESULTS: The peritoneal cavity was accessed uneventfully, and the stomach, liver, small bowel, colon, urinary bladder, uterus, fallopian tubes, and ovaries were able to be evaluated in all cases. The gallbladder could be visualized in only 5 of the 9 animals, and retroperitoneal structures could not be consistently identified. Oophorectomy with partial hysterectomy was performed in 6 animals. The 3 animals in the survival group did well for 24 hours without sequelae. CONCLUSIONS: This study shows the ability of endoscopic transgastric peritoneal exploration to successfully identify most abdominopelvic organs and demonstrates the technical feasibility of transgastric organ resection.

Abdomen↗

PubMed2004

Integrating gene expression and metabolic profiles.

Recent advances in high throughput technologies have generated an abundance of biological information, such as gene expression, protein-protein interaction, and metabolic data. These various types of data capture different aspects of the cellular response to environmental factors. Integrating data from different measurements enhances the ability of modeling frameworks to predict cellular function more accurately and can lead to a more coherent reconstruction of the underlying regulatory network structure. Different techniques, newly developed and borrowed, have been applied for the purpose of extracting this information from experimental data. In this study, we developed a framework to integrate metabolic and gene expression profiles for a hepatocellular system. Specifically, we applied genetic algorithm and partial least square analysis to identify important genes relevant to a specific cellular function. We identified genes 1) whose expression levels quantitatively predict a metabolic function and 2) that play a part in regulating a hepatocellular function and reconstructed their role in the metabolic network. The framework 1) preprocesses the gene expression data using statistical techniques, 2) selects genes using a genetic algorithm and couples them to a partial least squares analysis to predict cellular function, and 3) reconstructs, with the assistance of a literature search, the pathways that regulate cellular function, namely intracellular triglyceride and urea synthesis. This provides a framework for identifying cellular pathways that are active as a function of the environment and in turn helps to uncover the interplay between gene and metabolic networks.

Algorithms↗

PubMed2006

Predicting the prognosis of breast cancer by integrating clinical and microarray data with Bayesian networks.

MOTIVATION: Clinical data, such as patient history, laboratory analysis, ultrasound parameters--which are the basis of day-to-day clinical decision support--are often underused to guide the clinical management of cancer in the presence of microarray data. We propose a strategy based on Bayesian networks to treat clinical and microarray data on an equal footing. The main advantage of this probabilistic model is that it allows to integrate these data sources in several ways and that it allows to investigate and understand the model structure and parameters. Furthermore using the concept of a Markov Blanket we can identify all the variables that shield off the class variable from the influence of the remaining network. Therefore Bayesian networks automatically perform feature selection by identifying the (in)dependency relationships with the class variable. RESULTS: We evaluated three methods for integrating clinical and microarray data: decision integration, partial integration and full integration and used them to classify publicly available data on breast cancer patients into a poor and a good prognosis group. The partial integration method is most promising and has an independent test set area under the ROC curve of 0.845. After choosing an operating point the classification performance is better than frequently used indices.

Bayes Theorem↗

PubMed2025

Quantifying prevalence and risk factors of HIV multiple infection in Uganda from population-based deep-sequence data.

People living with HIV can acquire secondary infections through a process called superinfection, giving rise to simultaneous infection with genetically distinct variants (multiple infection). Multiple infection provides the necessary conditions for the generation of novel recombinant forms of HIV and may worsen clinical outcomes and increase the rate of transmission to HIV seronegative sexual partners. To date, studies of HIV multiple infection have relied on insensitive bulk-sequencing, labor intensive single genome amplification protocols, or deep-sequencing of short genome regions. Here, we identified multiple infections in whole-genome or near whole-genome HIV RNA deep-sequence data generated from plasma samples of 2,029 people living with viremic HIV who participated in the population-based Rakai Community Cohort Study (RCCS). We estimated individual- and population-level probabilities of being multiply infected and assessed epidemiological risk factors using the novel Bayesian deep-phylogenetic multiple infection model (deep - phyloMI) which accounts for bias due to partial sequencing success and false-negative and false-positive detection rates. We estimated that between 2010 and 2020, 4.09% (95% highest posterior density interval (HPD) 2.95%-5.45%) of RCCS participants with viremic HIV multiple infection at time of sampling. Participants living in high-HIV prevalence communities along Lake Victoria were 2.33-fold (95% HPD 1.3-3.7) more likely to harbor a multiple infection compared to individuals in lower prevalence neighboring communities. This work introduces a high-throughput surveillance framework for identifying people with multiple HIV infections and quantifying population-level prevalence and risk factors of multiple infection for clinical and epidemiological investigations.

Humans↗

PubMed2006

[QTL analysis of starch content in maize kernels using the trisomic inheritance of the endosperm model].

Two hundred and fifty-nine F2:3 families, developed from the cross between a dent corn inbred line Dan232 and a popcorn inbred line N04, were evaluated for its starch content in the replicated experiments under two environments. One hundred and eighty three pairs of SSR markers were selected to construct a genetic linkage map, covering 1,762.2 cM (centiMorgan) and on the average distance of 9.63 cM between the markers. Quantative trait loci (QTL) were identified and its effects were analyzed, using the triploid endosperm genetic model and the interval mapping method. Ten QTL, detected on chromosome 1, 3, 4, 5 and 7 respectively, were mapped in spring and in summer. All detected QTL in spring were also identified in summer. The phenotypic variation of a single QTL varied from 4.74% to 11.26%, and the total contributions of all QTL under two environments were 36.84% and 72.65%, respectively. Two QTL of all identified QTL in spring showed over-dominant effects, but additive and partially dominant in summer respectively, the amounts of other QTL showing Additive, partially dominant and over-dominant effects were 2, 1, 5 respectively. The positive alleles of three QTL were contributed by the normal corn parent Dan232, and the other positive alleles were contributed by the popcorn parent N04.

Chromosome Mapping↗

PubMed1993

Radionuclide constant pressure perfusion study on measurement of exit urine flow: experimental and preliminary clinical investigations.

To calculate exit urine flow from the renal pelvis to the bladder in hydronephrosis, a simple method, radionuclide constant pressure perfusion study, was used. The mathematical model proposed for calculation of the exit flow (F) was simple: F = (initial slope)/Do'/exp(-0.148d), where F is expressed as flow rate (ml. per minute) of infused radioactive solution into the bladder. The value of the initial slope is expressed as a count rate per minute of time-activity curve of the bladder. Do' is a count rate per ml. of infused radioactive solution, which was measured by a gamma camera in air, and d is depth (cm.) of the bladder from the body surface to the vesical mucosa. The number -0.148 indicates the effective linear attenuation coefficient of 99mtechnetium, which was determined by a phantom study. In the experimental studies calculated flow correlated well with real pump flow. In preliminary clinical studies in 16 patients (20 kidneys) who underwent nephrostomy, measurement of flow rate at steady intrapelvic pressure with no subtraction of intra-abdominal pressure in 12 of 14 nonobstructed cases demonstrated a pressure-dependent pattern in which flow increased linearly in response to the pressure increase. In 2 nonobstructed children radionuclide constant pressure perfusion study failed: 1 due to crying and 1 to unknown causes. In 2 cases of complete or equivocal obstruction by constant perfusion (Whitaker test) only minimal or no flow rate was found at the maximum intrapelvic pressure increase of 24 cm. water. The urine flow was observed only in the repeated study in 3 patients. These phenomena were assumed to be due to immature expertise in the new technique. This new technique can provide physiological measurement of the urine flow at variable levels of constant intrapelvic pressure in hydronephrotic patients, although the pressure-flow relationship for identifying partial obstruction from nonobstruction still remains to be clarified in further clinical studies.

Adolescent↗

PubMed2005

Construction of 4D-QSAR models for use in the design of novel p38-MAPK inhibitors.

The p38-mitogen-activated protein kinase (p38-MAPK) plays a key role in lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) release during the inflammatory process, emerging as an attractive target for new anti-inflammatory agents. Four-dimensional quantitative structure-activity relationship (4D-QSAR) analysis [Hopfinger et al., J. Am. Chem. Soc., 119 (1997) 10509] was applied to a series of 33 (a training set of 28 and a test set of 5) pyridinyl-imidazole and pyrimidinyl-imidazole inhibitors of p38-MAPK, with IC50 ranging from 0.11 to 2100 nM [Liverton et al., J. Med. Chem., 42 (1999) 2180]. Five thousand conformations of each analogue were sampled from a molecular dynamics simulation (MDS) during 50 ps at a constant temperature of 303 K. Each conformation was placed in a 2 angstroms grid cell lattice for each of three trial alignments. 4D-QSAR models were constructed by genetic algorithm (GA) optimization and partial least squares (PLS) fitting, and evaluated by leave-one-out cross-validation technique. In the best models, with three to six terms, the adjusted cross-validated squared correlation coefficients, Q2adj, ranged from 0.67 to 0.85. Model D (Q2adj = 0.84) was identified as the most robust model from alignment 1, and it is representative of the other best models. This model encompasses new molecular regions as containing pharmacophore sites, such as the amino-benzyl moiety of pyrimidine analogs and the N1-substituent in the imidazole ring. These regions of the ligands should be further explored to identify better anti-inflammatory inhibitors of p38-MAPK.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1985

Antigenic domains of the sperm-specific lactate dehydrogenase C4 isozyme.

Lactate dehydrogenase C4 (LDH-C4) is an antigenic protein that occurs only in spermatozoa and the mature testis. The antibody-combining sites of this enzyme were mapped by measuring the binding of anti-LDH-C4 by isolated peptides. Pure mouse LDH-C4 was digested with trypsin, and the resulting fragments were fractionated by reverse-phase high-pressure liquid chromatography. Rabbit anti-mouse LDH-C4 bound to 13 pure peptides. Amino acid compositions and partial or complete sequencing by the Edman degradation was used to identify eight of these fragments in the complete structure of the molecule. The relationship between structure and antigenicity of these peptides is discussed in detail. These data fit best to the domain model of protein antigenicity. This antigenic map of LDH-C4 will be useful in the design of a synthetic contraceptive vaccine.

Amino Acid Sequence↗

PubMed1999

Determination of protein secondary structure and solvent accessibility using site-directed fluorescence labeling. Studies of T4 lysozyme using the fluorescent probe monobromobimane.

We report an investigation of how much protein structural information could be obtained using a site-directed fluorescence labeling (SDFL) strategy. In our experiments, we used 21 consecutive single-cysteine substitution mutants in T4 lysozyme (residues T115-K135), located in a helix-turn-helix motif. The mutants were labeled with the fluorescent probe monobromobimane and subjected to an array of fluorescence measurements. Thermal stability measurements show that introduction of the label is substantially perturbing only when it is located at buried residue sites. At buried sites (solvent surface accessibility of <40 A(2)), the destabilizations are between 3 and 5.5 kcal/mol, whereas at more exposed sites, DeltaDeltaG values of < or = 1.5 kcal/mol are obtained. Of all the fluorescence parameters that were explored (excitation lambda(max), emission lambda(max), fluorescence lifetime, quantum yield, and steady-state anisotropy), the emission lambda(max) and the steady-state anisotropy values most accurately reflect the solvent surface accessibility at each site as calculated from the crystal structure of cysteine-less T4 lysozyme. The parameters we identify allow the classification of each site as buried, partially buried, or exposed. We find that the variations in these parameters as a function of residue number reflect the sequence-specific secondary structure, the determination of which is a key step for modeling a protein of unknown structure.

Bacteriophage T4↗

PubMed1998

Proteolytic activation of MST/Krs, STE20-related protein kinase, by caspase during apoptosis.

The Fas system has been extensively investigated as a model of apoptosis and the caspase cascade has been shown to be a characteristic mechanism of signaling of apoptosis. We have identified and purified a kinase that was activated after the stimulation of Fas on human thymoma-derived HPB-ALL cells. Partial amino acid sequencing of the purified kinase revealed it to be MST/Krs, member of the yeast STE20 family of protein kinases. MST/Krs was activated by proteolytic cleavage and proteolytic activation was blocked by the caspase inhibitor, Z-VAD-FK. A mutant MST with Asp-->Asn replacement at a putative caspase cleavage site was resistant to either the proteolytic cleavage or the activation of the kinase activity. These findings suggest that proteolytic activation is one activation mechanism of MST and plays a role in apoptosis.

Amino Acid Sequence↗

PubMed2003

Rapid protein fold determination using unassigned NMR data.

Experimental structure determination by x-ray crystallography and NMR spectroscopy is slow and time-consuming compared with the rate at which new protein sequences are being identified. NMR spectroscopy has the advantage of rapidly providing the structurally relevant information in the form of unassigned chemical shifts (CSs), intensities of NOESY crosspeaks [nuclear Overhauser effects (NOEs)], and residual dipolar couplings (RDCs), but use of these data are limited by the time and effort needed to assign individual resonances to specific atoms. Here, we develop a method for generating low-resolution protein structures by using unassigned NMR data that relies on the de novo protein structure prediction algorithm, rosetta [Simons, K. T., Kooperberg, C., Huang, E. & Baker, D. (1997) J. Mol. Biol. 268, 209-225] and a Monte Carlo procedure that searches for the assignment of resonances to atoms that produces the best fit of the experimental NMR data to a candidate 3D structure. A large ensemble of models is generated from sequence information alone by using rosetta, an optimal assignment is identified for each model, and the models are then ranked based on their fit with the NMR data assuming the identified assignments. The method was tested on nine protein sequences between 56 and 140 amino acids and published CS, NOE, and RDC data. The procedure yielded models with rms deviations between 3 and 6 A, and, in four of the nine cases, the partial assignments obtained by the method could be used to refine the structures to high resolution (0.6-1.8 A) by repeated cycles of structure generation guided by the partial assignments, followed by reassignment using the newly generated models.

Algorithms↗

PubMed1982

Structural genes of the mouse major urinary protein are on chromosome 4.

The major urinary proteins (MUPs) of mouse are a family of at least three major proteins which are synthesized in the liver of all strains of mice. The relative levels of synthesis of these proteins with respect to each other in the presence of testosterone is regulated by the Mup-a locus located on chromosome 4. In an effort to determine the mechanism of this regulation in molecular terms, a cDNA clone containing most of the coding region of a MUP protein has been isolated and identified by partial DNA sequence analysis. Using a combination of hybridization analysis and somatic cell genetics, the structural gene family has been unambiguously mapped to mouse chromosome 4. These data suggest that Mup-a regulation operates in a cis fashion and that models proposing trans regulation of MUP protein synthesis are unlikely.

Animals↗

PubMed1997

Value of simulated body surface potential maps as templates in localizing sites of ectopic activation for radiofrequency ablation.

Body surface potential maps recorded during catheter pace mapping can facilitate the localization of the site of origin of ventricular tachycardia. In this study, we investigated the value of a realistic computer model of the human ventricular myocardium in generating body surface potential maps as templates for identifying sites of ectopic activation. Our model features an anatomically accurate geometry and an anisotropy due to transmural fibre rotation, that were reconstructed with a spatial resolution of 0.5 mm. It simulates the electrotonic interactions of cardiac cells by solving a nonlinear parabolic partial differential equation, but it behaves as a cellular automaton when the transmembrane potential exceeds the threshold value. We successfully validated our model by comparing the simulated activation sequences--described by isochronal maps, epicardial potential maps and body surface potential maps--with the measured sequences of epicardial and body surface maps reported in the literature. By systematically pacing the left ventricular and right ventricular endocardial surfaces in our ventricular model, we generated a database of 155 QRS-integral maps, which provides a high-resolution reference frame for localizing distinct endocardial pacing sites. This database promises to be a useful tool in improving the performance of catheter pace mapping used in combination with body surface potential mapping. Overall, the results demonstrate that our computer model of the human ventricular myocardium is well suited for complementing a database of QRS-integral maps obtained during clinical pace mapping and can help enhance the efficacy of the ablative treatment of ventricular arrhythmias.

Anisotropy↗