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At least 523 records · Page 29Linked to original sources
PubMed1995

The role of PRP8 protein in nuclear pre-mRNA splicing in yeast.

The removal of introns from precursor messenger RNAs occurs in a large complex, the spliceosome, that contains many proteins and five small nuclear RNAs (snRNAs). The snRNAs interact with the intron-containing substrate RNA and with each other to form a dynamic network of RNA interactions that define the intron and promote splicing. There is evidence that protein splicing factors play important roles in regulating RNA interactions in the spliceosome. PRP8 is a highly conserved protein that is associated in particles with the U5 snRNA and directly binds the substrate RNA in spliceosomes. UV crosslinking has been used to map the binding sites, and shows extensive interaction between PRP8 protein and the 5' exon prior to the first step of splicing and with the 3' splice site region subsequently. It is proposed that PRP8 protein may stabilize fragile interactions between the U5 snRNA and exon sequences at the splice sites, to anchor and align them in the catalytic centre of the spliceosome.

Exons↗
PubMed2004

In silico reconstitution of Listeria propulsion exhibits nano-saltation.

To understand how the actin-polymerization-mediated movements in cells emerge from myriad individual protein-protein interactions, we developed a computational model of Listeria monocytogenes propulsion that explicitly simulates a large number of monomer-scale biochemical and mechanical interactions. The literature on actin networks and L. monocytogenes motility provides the foundation for a realistic mathematical/computer simulation, because most of the key rate constants governing actin network dynamics have been measured. We use a cluster of 80 Linux processors and our own suite of simulation and analysis software to characterize salient features of bacterial motion. Our "in silico reconstitution" produces qualitatively realistic bacterial motion with regard to speed and persistence of motion and actin tail morphology. The model also produces smaller scale emergent behavior; we demonstrate how the observed nano-saltatory motion of L. monocytogenes,in which runs punctuate pauses, can emerge from a cooperative binding and breaking of attachments between actin filaments and the bacterium. We describe our modeling methodology in detail, as it is likely to be useful for understanding any subcellular system in which the dynamics of many simple interactions lead to complex emergent behavior, e.g., lamellipodia and filopodia extension, cellular organization, and cytokinesis.

Actins↗
PubMed2005

Highly nonrandom features of synaptic connectivity in local cortical circuits.

How different is local cortical circuitry from a random network? To answer this question, we probed synaptic connections with several hundred simultaneous quadruple whole-cell recordings from layer 5 pyramidal neurons in the rat visual cortex. Analysis of this dataset revealed several nonrandom features in synaptic connectivity. We confirmed previous reports that bidirectional connections are more common than expected in a random network. We found that several highly clustered three-neuron connectivity patterns are overrepresented, suggesting that connections tend to cluster together. We also analyzed synaptic connection strength as defined by the peak excitatory postsynaptic potential amplitude. We found that the distribution of synaptic connection strength differs significantly from the Poisson distribution and can be fitted by a lognormal distribution. Such a distribution has a heavier tail and implies that synaptic weight is concentrated among few synaptic connections. In addition, the strengths of synaptic connections sharing pre- or postsynaptic neurons are correlated, implying that strong connections are even more clustered than the weak ones. Therefore, the local cortical network structure can be viewed as a skeleton of stronger connections in a sea of weaker ones. Such a skeleton is likely to play an important role in network dynamics and should be investigated further.

Animals↗
PubMed2005

Output-mode transitions are controlled by prolonged inactivation of sodium channels in pyramidal neurons of subiculum.

Transitions between different behavioral states, such as sleep or wakefulness, quiescence or attentiveness, occur in part through transitions from action potential bursting to single spiking. Cortical activity, for example, is determined in large part by the spike output mode from the thalamus, which is controlled by the gating of low-voltage-activated calcium channels. In the subiculum--the major output of the hippocampus--transitions occur from bursting in the delta-frequency band to single spiking in the theta-frequency band. We show here that these transitions are influenced strongly by the inactivation kinetics of voltage-gated sodium channels. Prolonged inactivation of sodium channels is responsible for an activity-dependent switch from bursting to single spiking, constituting a novel mechanism through which network dynamics are controlled by ion channel gating.

Adenosine Diphosphate↗
PubMed2005

The involvement of protein kinase C and actin filaments in cortical granule exocytosis in the rat.

Mammalian sperm-egg fusion results in cortical granule exocytosis (CGE) and resumption of meiosis. Studies of various exocytotic cells suggest that filamentous actin (F-actin) blocks exocytosis by excluding secretory vesicles from the plasma membrane. However, the exact function of these microfilaments, in mammalian egg CGE, is still elusive. In the present study we investigated the role of actin in the process of CGE, and the possible interaction between actin and protein kinase C (PKC), by using coimmunoprecipitation, immunohistochemistry and confocal microscopy. We identified an interaction between actin and the PKC alpha isoenzyme in non-activated metaphase II (MII) eggs and in eggs activated by phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA). F-actin was evenly distributed throughout the egg's cytosol with a marked concentration at the cortex and at the plasma membrane. A decrease in the fluorescence signal of F-actin, which represents its depolymerization/reorganization, was detected upon fertilization and upon parthenogenetic activation. Exposing the eggs to drugs that cause either polymerization or depolymerization of actin (jasplakinolide (JAS) and cytochalasin D (CD) respectively) did not induce or prevent CGE. However, CD, but not JAS, followed by a low dose of TPA doubled the percentage of eggs undergoing complete CGE, as compared with TPA alone. We further demonstrated that myristoylated alanin-rich C kinase substrate (MARCKS), a protein known to cross-link F-actin in other cell types, is expressed in rat eggs and is colocalized with actin. In view of our results, we suggest that the cytoskeletal cortex is not a mere physical barrier that blocks CGE, but rather a dynamic network that can be maneuvered towards allowing CGE by activated actin-associated proteins and/or by activated PKC.

Actin Cytoskeleton↗
PubMed2004

c-Myc as a therapeutic target in cancer.

c-Myc is frequently deregulated in human cancers. The c-Myc oncoprotein is a transcription factor, with many of its target genes encoding proteins that initiate and maintain the transformed state. c-Myc is also part of a dynamic network whose members interact selectively with one another and with various transcriptional coregulators and histone-modifying enzymes. This knowledge highlights several points that might be amenable to attack. This review summarizes progress in controlling the extent of c-Myc transcription, translation, interaction with other myc network members, DNA binding and transcriptional activation. Inhibition of c-Myc can be achieved with many of these approaches; however, clinical efficacy will likely require intervention at several levels, perhaps in combination with traditional chemotherapeutic drugs or agents that target other oncoproteins.

Animals↗
PubMed2002

DNA testing for familial hypercholesterolemia: improving disease recognition and patient care.

Cardiovascular disease is the leading cause of death worldwide and, like most chronic diseases, it has major genetic and environmental components. Among patients with coronary heart disease onset before the age of 55, about 5% of cases are attributable to heterozygous familial hypercholesterolemia (FH), a disease following autosomal dominant inheritance. About 50% of individuals with FH die before the age of 60 due to myocardial infarction. The frequency of FH is estimated to be 1 : 500. FH is related to mutations in the low-density lipoprotein (LDL)-cholesterol LDL-receptor gene and apolipoprotein B (apoB) gene. The identification of individuals with FH has been based on lipid levels and segregation of lipid levels within the family. However, phenotypes are overlapping and family history is not always informative. Therefore, a DNA-based genetic test for FH appears to offer the best alternative. The DNA test gives a simple yes/no answer. The FH test is a definitive tool for the identification of affected family members. The approach of targeted family genetic screening to find new patients is faster and more reliable compared with a biochemical form of screening. Early identification and efficient treatment of such patients is important and highly cost effective. There is evidence to suggest that the nature of the LDL-receptor (LDLR) mutation influences the degree of cholesterol lowering achieved by HMG-CoA reductase inhibitors (statins). The observed differences in the LDL-cholesterol (LDL-C) responses to these drugs among the various LDLR gene mutations are not yet completely understood. The relationships shown between LDLR mutation types and lipid levels, and the response of lipid levels to HMG-CoA reductase inhibitor treatment, will have to be investigated within the framework of pharmacogenetic studies. The variables, which are important in determining the overall atherosclerosis risk, are the result of combined activity in a dynamic network of numerous genes and environment. Candidate genes for atherosclerosis need to be further tested and validated. Future research should be directed at determining the significance of such targets, which patients with FH are at particularly high risk of premature cardiovascular disease, and which environmental factors are effective in modulating this risk. Genetics-based diagnostics will complement identification of FH while improving cardiovascular risk prediction, prevention of disease and treatment efficacy.

Animals↗
PubMed1996

Auditory cortical neurons in vitro: initial pharmacological studies.

Dissociated embryonic tissue from murine auditory cortex formed spontaneously active monolayer networks in culture that were maintained for up to 113 days in vitro (div). As a first step in determining whether neurons retain histiotypic properties, we subjected a set of 10 cultures to a sequence of 4 synaptically active substances. The test sequence consisted of 50 microM bicuculline, 10 microM strychnine, 5 microM NMDA, and 20 microM GABA. Recordings were made for 5-30 min under each condition followed by complete medium changes. Six to 14 channels with the best signal-to-noise ratios were selected for analysis that consisted of continual chart recordings of integrated burst data and further analysis of short data segments after digitizing and processing. All networks showed spontaneous activity, but had greatly varying native activity ranging from organized, quasi-periodic bursting on all channels to more complex spatio-temporal patterns with less coordination among channels. Bicuculline triggered oscillatory activity, simplified bursting, increased burst amplitude, and enhanced burst regularity among electrodes. Strychnine also changed the burst activity to a simpler pattern and enhanced the burst amplitude, indicating presence of glycine receptors in cortical tissue. Application of NMDA increased burst frequencies, but reduced burst regularity and coordination among channels. 20 microM of GABA inhibited all bursting activity in the networks. These results suggest that monolayer networks cultured on multi-electrode arrays retain some basic histiotypic pharmacological responses and may provide useful platforms for the study of network dynamics in the auditory cortex.

Animals↗
PubMed2000

Mild spherocytic hereditary elliptocytosis and altered levels of alpha- and gamma-adducins in beta-adducin-deficient mice.

The membrane skeleton, a dynamic network of proteins associated with the plasma membrane, determines the shape and mechanical properties of erythrocytes. Deficiencies or defects in membrane skeletal proteins are associated with inherited disorders of erythrocyte morphology and function. Adducin is one of the proteins localized at the spectrin-actin junction of the membrane skeleton. In this work we show that deficiency of beta-adducin produces an 80% decrease of alpha-adducin and a fourfold up-regulation of gamma-adducin in erythrocytes. beta-Adducin or any other isoform generated by translation of abnormally spliced messenger RNAs could not be detected by our antibodies either in ghosts or in cytoplasm of -/- erythrocytes. Actin levels were diminished in mutant mice, suggesting alterations in the actin-spectrin junctional complexes due to the absence of adducin. Elliptocytes, ovalocytes, and occasionally spherocytes were found in the blood film of -/- mice. Hematological values showed an increase in reticulocyte counts and mean corpuscular hemoglobin concentration, decreased mean corpuscular volume and hematocrit, and normal erythrocyte counts that, associated to splenomegaly, indicate that the mice suffer from mild anemia with compensated hemolysis. These modifications are due to a loss of membrane surface and dehydration that result in an increase in the osmotic fragility of red blood cells. The marked alteration in osmotic fragility together with the predominant presence of elliptocytes is reminiscent of the human disorder called spherocytic hereditary elliptocytosis. Our results suggest that the amount of adducin remaining in the mutant animals (presumably alphagamma adducin) could be functional and might account for the mild phenotype. (Blood. 2000;95:3978-3985)

Animals↗
PubMed2001

Precise burst synchrony in the superior colliculus of the awake cat during moving stimulus presentation.

This study aimed to characterize the synchrony that occurs between cell discharges in the superior colliculus of the awake cat. We trained cats to perform a visual fixation in the presence of a visual moving stimulus and then recorded 686 pairs of neighboring cells in the superior colliculus during task performance. A new method to assess the significance of precise discharge synchronization is described, which permits analysis of nonstationary data. Of 181 pairs with sufficient data for quantitative analysis, 125 showed a cross-correlation histogram (CCH) with features assessed as significant using this approach. CCHs frequently showed an isolated central peak (41 of 125) or a peak flanked by one or two troughs (68 of 125), and in a few cases an oscillatory pattern of approximately 65 Hz (16 of 125). This is in contrast to the oscillation frequency reported for the visual cortex and shows that oscillations in the superior colliculus probably arise from a cortex-independent mechanism. Our method also permits direct quantification of the correlation shift predictors, assessing precise time locking of spikes to the stimulus. Only 1 of 125 cross-correlation shift predictors had a significant central peak, meaning that most of the CCH features were not related to cell discharges time-locked to the stimulus presentation. Further investigation using a burst-jittering method showed that synchrony in the superior colliculus is attributable to precise synchronization of short bursts of spikes. Such synchrony could be related to the network dynamics and the common inhibitory feedback from local interneurons, which would act as temporal selectors of the cells with greatest or fastest response.

Action Potentials↗
PubMed1994

Cultural values and immigrant entrepreneurship: the Chinese in Singapore.

"It is the intent of this paper to examine the interrelationships between early socialisation into core Chinese cultural values, international migration and Chinese immigrant entrepreneurship.... It is through a developmental socialisation process by which [cultural] values are articulated in family and kin network dynamics that social organisations begin to develop and define what is popularly understood as the 'Chinese way of doing business'. We argue that among the overseas Chinese, this way of doing business must be viewed historically and developmentally, as it is intimately intertwined with transmigration experiences and their consequences in shaping values necessary for the emergence and development of entrepreneurship." (SUMMARY IN FRE AND SPA)

Asia↗
PubMedDate not supplied

[Professional image and identity in the building of nursing knowledge].

Based on a historic qualitative study, using documental analyse we searched for the dispersions in the construction of knowledge in the articles of the Anais do Congresso Brasileiro de Enfermagem, from 1977 through 1987. The dispersions emerged as categories that repeat themselves as subjects of note or as smaller punctuation. Our analyze converged into two main categories: professional image and professional identity. These categories took the shape of a complex and dynamic network, in which there were two explicit sub-categories: professional status and professional role.

Education, Nursing↗
PubMed2003

Quantitative estimate of synaptic inputs to striatal neurons during up and down states in vitro.

Up states are prolonged membrane potential depolarizations critical for synaptic integration and action potential generation in cortical and striatal neurons. They commonly result from numerous concurrent synaptic inputs, whereas neurons reside in a down state when synaptic inputs are few. By quantifying the composition, frequency, and amplitude of synaptic inputs for both states, we provide important constraints for state transitions in striatal network dynamics. Up and down states occur naturally in cortex-striatum-substantia nigra cocultures, which were used as an in vitro model in the present study. Spontaneous synaptic inputs during down states were extracted automatically in spiny projection neurons and fast spiking interneurons of the striatum using a newly developed computer algorithm. Consistent with a heterogeneous population of synaptic inputs, PSPs and PSCs showed no correlation in amplitude and rise time and occurred at relatively low frequencies of 10-40 Hz during the down state. The number of synaptic inputs during up states, estimated from the up-state charge and the unitary charge of down-state PSCs, was 217 +/- 44. Given the average up-state duration of 284 +/- 34 msec, synaptic input frequency was approximately 800 Hz during up-states for both neuronal types. Many down-state events reversed at the chloride reversal potential and were blocked by GABA(A) antagonists. The high correlation between up- and down-state reversal potential suggests that despite these drastic changes in synaptic input frequency, the ratio of inhibitory to excitatory currents is similar during both states.

Action Potentials↗
PubMed2006

[The database and its data sharing of neuropathic images].

This paper introduces the basic principle and method of establishing a database for neuropathic images, and discusses its significance and data sharing. The database is composed of three data volumes about basic knowledge for images, cranial sectional anatomy and neuropathic images. The data sharing is achieved by using a method of linking the dynamic network of neuropathic images with database of neuropathic images. There are three searching approaches: catalog searching, key words searching and code searching.

Databases, Bibliographic↗
PubMedDate not supplied

Hospital governing boards: a study of their effectiveness in relation to organizational performance.

This article describes the development and evolution of governing boards and summarizes critical findings from a research study on hospital governing boards. The purpose of the research was to examine factors that measure performance of governing boards and the relationship of governing board effectiveness to the organizational performance of hospitals. Board leaders from 64 nonprofit hospitals across the country were surveyed using the BSAQ tool, which measures board effectiveness in six areas of competency. Board competency scores of this group were compared with those of a previous group, which consisted of more than 300 nonprofit boards, and demonstrated significantly higher scores. A factor analysis conducted to compare the six competency factors between study groups revealed a strong single factor in this study. The factors that measure governing board performance were found to be consolidated into one single factor of collaborative board functioning consistent with emerging governance theory. This may support the concept of the importance of governing boards as collaborative, socially dynamic networks of leaders. The hospital performance was assessed using data from the nationally recognized program, Solucient's 100 Top Hospitals. The results demonstrate that higher performing boards did have better hospital performance in several dimensions, most notably in profitability and lower expenses. Lower expenses were related to higher scores for the BSAQ total score. Hospital profitability was positively correlated with all seven BSAQ scores. A more favorable Solucient ranking was related to hospitals that had a lower BSAQ political score. This was also found in a multiple regression model that predicted a favorable ranking when the BSAQ political score was lower. This may mean that these boards do what needs to be done to maintain excellent performance and do not let politics get in the way of their work. Although governance and its effect on hospital performance is a complex concept to study, this investigation yields findings of interest to leaders in the healthcare field.

Data Collection↗
PubMed1996

The HeLa 200 kDa U5 snRNP-specific protein and its homologue in Saccharomyces cerevisiae are members of the DEXH-box protein family of putative RNA helicases.

The primary structure of the 200 kDa protein of purified HeLa U5 snRNPs (U5-200kD) was characterized by cloning and sequencing of its cDNA. In order to confirm that U5-200kD is distinct from U5-220kD we demonstrate by protein sequencing that the human U5-specific 220 kDa protein is homologous to the yeast U5-specific protein Prp8p. A 246 kDa protein (Snu246p) homologous to U5-200kD was identified in Saccharomyces cerevisiae. Both proteins contain two conserved domains characteristic of the DEXH-box protein family of putative RNA helicases and RNA-stimulated ATPases. Antibodies raised against fusion proteins produced from fragments of the cloned mammalian cDNA interact specifically with the HeLa U5-200kD protein on Western blots and co-immunoprecipitate U5 snRNA and to a lesser extent U4 and U6 snRNAs from HeLa snRNPs. Similarly, U4, U5 and U6 snRNAs can be co-immunoprecipitated from yeast splicing extracts containing an HA-tagged derivative of Snu246p with HA-tag specific antibodies. U5-200kD and Snu246p are thus the first putative RNA helicases shown to be intrinsic components of snRNPs. Disruption of the SNU246 gene in yeast is lethal and leads to a splicing defect in vivo, indicating that the protein is essential for splicing. Anti-U5-200kD antibodies specifically block the second step of mammalian splicing in vitro, demonstrating for the first time that a DEXH-box protein is involved in mammalian splicing. We propose that U5-200kD and Snu246p promote one or more conformational changes in the dynamic network of RNA-RNA interactions in the spliceosome.

Amino Acid Sequence↗
PubMedDate not supplied

A computational model of the progression of Alzheimer's disease.

Computational modeling allows analysis of the role of network dynamics in the initiation and progression of neuropathology in Alzheimer's disease. The model focuses on a final common breakdown in function, termed runaway synaptic modification. This phenomenon could account for evidence that neuropathological markers associated with neuronal death in Alzheimer's disease first appear and attain their highest concentration in subregions of the hippocampal formation, and then successively spread into the temporal lobe cortex and the cortex of the frontal and parietal lobes. The model demonstrates how the spread of neuropathology from the hippocampus into neocortical structures could result from the mechanisms of consolidation. Initial sensitivity of the hippocampus and entorhinal cortex to the neuropathological process is proposed to result from an imbalance of variables regulating the influence of synaptic transmission on synaptic modification. Memory deficits are described as due to increased interference effects on recent memory caused by runaway synaptic modification, which ultimately leads to impairments of remote and semantic memory.

Alzheimer Disease↗
PubMed2006

Network topology and the evolution of dynamics in an artificial genetic regulatory network model created by whole genome duplication and divergence.

Topological measures of large-scale complex networks are applied to a specific artificial regulatory network model created through a whole genome duplication and divergence mechanism. This class of networks share topological features with natural transcriptional regulatory networks. Specifically, these networks display scale-free and small-world topology and possess subgraph distributions similar to those of natural networks. Thus, the topologies inherent in natural networks may be in part due to their method of creation rather than being exclusively shaped by subsequent evolution under selection. The evolvability of the dynamics of these networks is also examined by evolving networks in simulation to obtain three simple types of output dynamics. The networks obtained from this process show a wide variety of topologies and numbers of genes indicating that it is relatively easy to evolve these classes of dynamics in this model.

Computational Biology↗