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At least 19 recordsLinked to original sources

PubMed2025

ProgModule: A novel computational framework to identify mutation driver modules for predicting cancer prognosis and immunotherapy response.

BACKGROUND: Cancer originates from dysregulated cell proliferation driven by driver gene mutations. Despite numerous algorithms developed to identify genomic mutational signatures, they often suffer from high computational complexity and limited clinical applicability. METHODS: Here, we presented ProgModule, an advanced computational framework designed to identify mutation driver modules for cancer prognosis and immunotherapy response prediction. In ProgModule, we introduced the Prognosis-Related Mutually Exclusive Mutation (PRMEM) score, which optimizes the balance between exclusive mutation coverage and the incorporation of mutation combination mechanisms critical for cancer prognosis. RESULTS: Applying to BLCA and HNSC cohorts, ProgModule successfully identified driver modules that stratify patients into distinct prognostic subgroups, and the combination of these modules could serve as an effective prognostic biomarker. Extending our method to diverse cancers, ProgModule presented robust prognostic performance and stability across model parameters, including stopping criteria and network topology. Moreover, our analysis suggested that driver modules can predict immunotherapeutic benefit more effectively than existing signatures. Further analyses based on published CRISPR data indicated that genes within these modules may serve as potential therapeutic targets. CONCLUSIONS: Altogether, ProgModule emerges as a powerful tool for identifying mutation driver modules as prognostic and immunotherapy response biomarkers, and genes within these modules may be used as potential therapeutic targets for cancer, offering new insights into precision oncology.

Humans↗

PubMed1998

On the actions that one nerve cell can have on another: distinguishing "drivers" from "modulators".

When one nerve cell acts on another, its postsynaptic effect can vary greatly. In sensory systems, inputs from "drivers" can be differentiated from those of "modulators." The driver can be identified as the transmitter of receptive field properties; the modulator can be identified as altering the probability of certain aspects of that transmission. Where receptive fields are not available, the distinction is more difficult and currently is undefined. We use the visual pathways, particularly the thalamic geniculate relay for which much relevant evidence is available, to explore ways in which drivers can be distinguished from modulators. The extent to which the distinction may apply first to other parts of the thalamus and then, possibly, to other parts of the brain is considered. We suggest the following distinctions: Cross-correlograms from driver inputs have sharper peaks than those from modulators; there are likely to be few drivers but many modulators for any one cell; and drivers are likely to act only through ionotropic receptors having a fast postsynaptic effect whereas modulators also are likely to activate metabotropic receptors having a slow and prolonged postsynaptic effect.

Animals↗

PubMed2005

Drivers and modulators from push-pull and balanced synaptic input.

In 1998, Sherman and Guillery proposed that there are two types of inputs to cortical neurons; drivers and modulators. These two forms of input are required to explain how, for example, sensory driven responses are controlled and modified by attention and other internally generated gating signals. One might imagine that driver signals are carried by fast ionotropic receptors, whereas modulators correspond to slower metabotropic receptors. Instead, we have proposed a novel mechanism by which both driver and modulator inputs could be carried by transmission through the same types of ionotropic receptors. In this scheme, the distinction between driver and modulator inputs is functional and changeable rather than anatomical and fixed. Driver inputs are carried by excitation and inhibition acting in a push-pull manner. This means that increases in excitation are accompanied by decreases in inhibition and vice versa. Modulators correspond to excitation and inhibition that covary so that they increase or decrease together. Theoretical and experimental work has shown that such an arrangement modulates the gain of a neuron, rather than driving it to respond. Constructing drivers and modulators in this manner allows individual excitatory synaptic inputs to play either role, and indeed to switch between roles, depending on how they are linked with inhibition.

Afferent Pathways↗

PubMed2004

Somatosensory corticothalamic projections: distinguishing drivers from modulators.

We used a juvenile mouse thalamocortical slice preparation with whole cell recording to investigate synaptic properties of corticothalamic inputs from somatosensory cortex to the ventral posterior medial and posterior medial nuclei (98 cells). We compared these data to those obtained from activating retinal and cortical inputs to the lateral geniculate nucleus (8 cells), the former representing a prototypical driver input and the latter, a typical modulator. Retinogeniculate activation evoked large, all-or-none excitatory postsynaptic potentials (EPSPs) that showed paired-pulse depression antagonized by N-methyl-d-aspartate (NMDA) and AMPA receptor blockers but with no sign of a metabotropic glutamate receptor (mGluR) component. Corticogeniculate activation evoked small, graded EPSPs showing paired-pulse facilitation, and the EPSPs showed both NMDA and AMPA receptor component plus an mGluR1 component. In the somatosensory thalamic relays, cortical stimulation elicited glutamatergic EPSPs in all thalamic cells, and these EPSPs fell into two groups. One, elicited from cortical layer 6 to cells of both nuclei, involved small, graded EPSPs with paired-pulse facilitation, and most also showed an mGluR1 component. The other, elicited from layer 5 to cells only of the posterior medial nucleus, involved large, all-or-none EPSPs with paired-pulse depression, and none showed an mGluR component. By analogy with results from the lateral geniculate nucleus, we conclude that the input from layer 6 to both nuclei acts as a modulator but that the layer 5 input to the posterior medial nucleus serves as a driver. Our data extend a common organizing principle from first-order nuclei to higher-order thalamic relays and further implicate the latter in corticocortical communication.

Animals↗

PubMed1999

Transmission beam pattern and echolocation signals of a harbor porpoise (Phocoena phocoena).

The transmission beam pattern of an echolocating harbor porpoise (Phocoena phocoena) was measured in both the vertical and horizontal planes. An array of seven Brüel and Kjaer 8103 hydrophones connected to an amplifier-line driver module was used to measure the beam patterns. The porpoise was trained to station in a hoop and echolocate a cylindrical target located at a range between 7 and 9 m while the array was located 2 m in front of the hoop. The 3-dB beamwidth in both the vertical and horizontal planes was the same at approximately 16 degrees and the beam was pointed toward the forward direction. The individual hydrophones in both the vertical and horizontal arrays measured signal waveforms that were similar throughout the 40-degree span of the array. The porpoise emitted signals with intervals that were 20 to 35 ms longer than the round trip travel time between the animal and the target. The average source level, peak frequency, and bandwidth were 157 dB, 128 kHz, and 16 kHz, respectively.

Amplifiers, Electronic↗

PubMed2006

Distribution, morphology, and synaptic targets of corticothalamic terminals in the cat lateral posterior-pulvinar complex that originate from the posteromedial lateral suprasylvian cortex.

The lateral posterior (LP) nucleus is a higher order thalamic nucleus that is believed to play a key role in the transmission of visual information between cortical areas. Two types of cortical terminals have been identified in higher order nuclei, large (type II) and smaller (type I), which have been proposed to drive and modulate, respectively, the response properties of thalamic cells (Sherman and Guillery [1998] Proc. Natl. Acad. Sci. U. S. A. 95:7121-7126). The aim of this study was to assess and compare the relative contribution of driver and modulator inputs to the LP nucleus that originate from the posteromedial part of the lateral suprasylvian cortex (PMLS) and area 17. To achieve this goal, the anterograde tracers biotinylated dextran amine (BDA) or Phaseolus vulgaris leucoagglutinin (PHAL) were injected into area 17 or PMLS. Results indicate that area 17 injections preferentially labelled large terminals, whereas PMLS injections preferentially labelled small terminals. A detailed analysis of PMLS terminal morphology revealed at least four categories of terminals: small type I terminals (57%), medium-sized to large singletons (30%), large terminals in arrangements of intermediate complexity (8%), and large terminals that form arrangements resembling rosettes (5%). Ultrastructural analysis and postembedding immunocytochemical staining for gamma-aminobutyric acid (GABA) distinguished two types of labelled PMLS terminals: small profiles with round vesicles (RS profiles) that contacted mostly non-GABAergic dendrites outside of glomeruli and large profiles with round vesicles (RL profiles) that contacted non-GABAergic dendrites (55%) and GABAergic dendritic terminals (45%) in glomeruli. RL profiles likely include singleton, intermediate, and rosette terminals, although future studies are needed to establish definitively the relationship between light microscopic morphology and ultrastructural features. All terminals types appeared to be involved in reciprocal corticothalamocortical connections as a result of an intermingling of terminals labelled by anterograde transport and cells labelled by retrograde transport. In conclusion, our results indicate that the origin of the driver inputs reaching the LP nucleus is not restricted to the primary visual cortex and that extrastriate visual areas might also contribute to the basic organization of visual receptive fields of neurons in this higher order nucleus.

Animals↗

PubMed2005

Functional impact of primary visual cortex deactivation on subcortical target structures in the thalamus and midbrain.

The functional relationships between the primary visual cortex and its major subcortical target structures have long been a subject of interest. We studied these relationships by using localized cooling deactivation to silence portions of primary visual cortex and measuring 2-deoxyglucose (2DG) uptake to assess neural activity in subcortical and midbrain targets. We focused analysis on the largest subcortical targets of primary visual cortex: the superior colliculus (SC), the dorsal lateral geniculate nucleus of the thalamus (dLGN), and the lateral division of the lateral posterior nucleus of the thalamus (LPL). We found that localized cooling of different regions of primary visual cortex caused specific decreases in 2DG uptake in target structures such that the location of 2DG decrease varied according to joint retinotopy, and the magnitude of the decreases in target structures was associated with the amount of cooled cortex. In addition, we found that the impact of cortical cooling was more profound on the SC than on the dLGN. The functional impact of cortical deactivations on the LPL was weak for small deactivations but approximated the impact on the SC when deactivations were large. We discuss these findings in terms of neural circuits and in terms of drivers and modulators.

Animals↗

PubMed2005

Thalamic relays and cortical functioning.

Studies on the visual thalamic relays, the lateral geniculate nucleus and pulvinar, provide three key properties that have dramatically changed the view that the thalamus serves as a simple relay to get information from subcortical sites to cortex. First, the retinal input, although a small minority (7%) in terms of numbers of synapses onto geniculate relay cells, dominates receptive field properties of these relay cells and strongly drives them; 93% of input thus is nonretinal and modulates the relay in dynamic and important ways related to behavioral state, including attention. We call the retinal input the driver input and the nonretinal, modulator input, and their unique morphological and functional differences allow us to recognize driver and modulator input to many other thalamic relays. Second, much of the modulation is related to control of a voltage-gated, low threshold Ca(2+) conductance that determines response properties of relay cells -burst or tonic - and this, among other things, affects the salience of information relayed. Third, the lateral geniculate nucleus and pulvinar (a massive but generally mysterious and ignored thalamic relay), are examples of two different types of relay: the LGN is a first order relay, transmitting information from a subcortical driver source (retina), while the pulvinar is mostly a higher order relay, transmitting information from a driver source emanating from layer 5 of one cortical area to another area. Higher order relays seem especially important to general corticocortical communication, and this view challenges the conventional dogma that such communication is based on direct corticocortical connections. In this sense, any new information reaching a cortical area, whether from a subcortical source or another cortical area, benefits from a thalamic relay. Other examples of first and higher order relays also exist, and generally higher order relays represent the majority of thalamus. A final property of interest emphasized in chapter 17 by Guillery (2005) is that most or all driver inputs to thalamus, whether from a subcortical source or from layer 5 of cortex, are axons that branch, with the extrathalamic branch innervating a motor or premotor region in the brainstem, or in some cases, spinal cord. This suggests that actual information relayed by thalamus to cortex is actually a copy of motor instructions (Guillery, 2005). Overall, these features of thalamic relays indicate that the thalamus not only provides a behaviorally relevant, dynamic control over the nature of information relayed, it also plays a key role in basic corticocortical communication.

Action Potentials↗

PubMed1993

Does motion-induced grouping modulate the flanker compatibility effect?: A failure to replicate Driver & Baylis.

Several experiments explored the possibility that motion-induced grouping would modulate the spatial distribution of the flanker compatibility effect (FCE). Subjects were required to make a speeded decision about a central target letter embedded in a five letter string. On each trial the identity of the near or far letters was either compatible or incompatible with the correct response while the remaining letters were neutral. In contrast to the findings of Driver & Baylis (1989), when the far distractors and the target moved together while the near distractors remained stationary, we did not find that the FCE for the far distractors was greater than the FCE for the stationary near distractors. Moreover, the pattern of response latencies in this moving condition were not different from what we observed when all letters remained stationary. Accuracy was affected, but not in the direction predicted by the view that attention is directed to perceptual groups. Modulation of the distribution of attention in response to motion-induced grouping is not a robust phenomenon. Nevertheless, a simple spotlight model of attention is challenged by demonstrations in the literature that perceptual grouping mediated by static properties such as closure, colour and good continuation strongly influence the spatial distribution of the FCE and that the allocation of attention in search is strongly influenced by stimulus motion.

Adult↗

PubMed2005

Task-dependent modulation of target-flanker lateral interactions in vision.

Visibility of a central target Gabor element often improves in the presence of collinear flankers. Such lateral interactions may reflect fundamental mechanisms underlying the perceptual integration of contours in early vision. We recently reported (Freeman, Sagi, & Driver, 2001) attentional modulation of these interactions. Here, we test whether this modulation is task dependent. Subjects had to detect a near-threshold central target while performing a secondary discrimination task on one pair of flankers that could appear with another distractor pair (one pair collinear with the target, the other orthogonal). Central target thresholds were lowered when collinear flankers were judged for the secondary task, but only when this task concerned the global spatial relationship between these flankers (discrimination of their Vernier offset or global orientation). Other secondary tasks involving discriminating the local orientations, contrasts, or colors of the relevant flanker pair produced no such attentional modulation. However, this task-dependent modulation was observed only when two flanker pairs were present, not for displays with only a single flanker pair. Top-down modulation of lateral interactions may function to select between overlapping potential contours whenever the global spatial properties of one are task relevant.

Adult↗

PubMed1986

Generalized kinetic analysis of ion-driven cotransport systems: II. Random ligand binding as a simple explanation for non-michaelian kinetics.

Solute uptake in many cells is characterized by a series of additive Michaelis-Menten functions. Several explanations for these kinetics have been advanced: unstirred layers, transport across more than one membrane, effects of solute concentration on membrane potential, numerous carrier systems. Although each of these explanations might suffice for individual cases, none provides a comprehensive basis for interpretation of the kinetics. The most common mechanism of solute absorption involves cotransport of solute with a driver ion. A model is developed in which solute and driver ion bind randomly to a membrane-bound carrier which provides a single transmembrane pathway for transport. The kinetic properties of the model are explored with particular reference to its capacity to generate additive Michaelian functions for initial rate measurements of isotopic solute influx. In accord with previous analysis of ordered binding models (Sanders, D., Hansen, U.-P., Gradmann, D., Slayman, C.L. (1984) J. Membrane Biol. 77:123), the conventional assumption that transmembrane transit rate-limits transport has not been applied. Random binding carriers can exhibit single or multiple Michaelian kinetics in response to changing substrate concentration. These kinetics include high affinity/low velocity and low affinity/high velocity phases (so-called "dual isotherms") which are commonly observed in plant cells. Other combinations of the Michaelis parameters can result in cis-(substrate) inhibition. Despite the generality of the random binding scheme and the complexity of the underlying rate equation, a number of predictive and testable features emerge. If external driver ion concentration is saturating, single Michaelian functions always result and increasing internal substrate concentration causes uncompetitive inhibition of transport. Numerical analysis of the model in conditions thought to resemble those in many experiments demonstrates that small relative differences in a few key component rate constants of the carrier reaction cycle are instrumental in generation of dual isotherms. The random binding model makes the important prediction that the contributions of the two isotherms show opposing dependence on external concentration of driver ion as this approaches saturation. In the one case in which this dependence has been examined experimentally, the model provides a good description of the data. Charge translocation characteristics of the carrier can be determined from steady-state kinetic data on the basis of the response of substrate flux to modulation of internal driver ion concentration.(ABSTRACT TRUNCATED AT 400 WORDS)

Biological Transport↗

PubMed2005

Acute effects of cigarette smoking on the heart rate variability of taxi drivers during work.

OBJECTIVES: This study attempted to clarify the acute effects of cigarette smoking on autonomic nervous function among taxi drivers under ordinary work conditions. METHODS: Holter electrocardiographic recordings from 20 healthy middle-aged taxi drivers were analyzed for the time from 0800 in the morning to 0159 at night. The amplitudes (milliseconds) of the high-frequency (HF) component and the ratio of the low-frequency component to HF (LF/HF) were calculated as changes in the R-R interval, and time-course changes were investigated by a complex demodulation method. The exact starting time of smoking was identified with the use of a specially designed cigarette lighter. The mean LF/HF and HF for 5 minutes immediately prior to smoking were calculated as the baseline, and the means for every 5 minutes up to 15 minutes were calculated. The average values of these parameters for all of the cigarette smoking within the same time span of 0800-1659 and 1700-0159 were also determined. RESULTS: The LF/HF significantly increased (P<0.05) within 5 minutes from the baseline immediately after smoking. This significant change in LF/HF was observed only at night. Although the interactive effect of the time of day on time course changes was not significant for the LF/HF or HF, the reactivity to increase LF/HF and decrease HF was more prominent at night. CONCLUSIONS: Cigarette smoking significantly increased LF/HF within 5 minutes during ordinary taxi driving. Nighttime smoking seemed to have a more potent acute effect on the cardiac modulation of taxi drivers than in the daytime. The sympathomimetic and parasympatho-withdrawal response of smoking may play an additional role in increasing cardiac risk among taxi drivers.

Adult↗

PubMed2004

Artificial neural networks and job-specific modules to assess occupational exposure.

Job-specific modules (JSMs) were used to collect information for expert retrospective exposure assessment in a community-based non-Hodgkins Lymphoma study in New South Wales, Australia. Using exposure assessment by a hygienist, artificial neural networks were developed to predict overall and intermittent benzene exposure among the module of tanker drivers. Even with a small data set (189 drivers), neural networks could assess benzene exposure with an average of 90% accuracy. By appropriate choice of cutoff (decision threshold), the neural networks could reliably reduce the expert's workload by approximately 60% by identifying negative JSMs. The use of artificial neural networks shows promise in future applications to occupational assessment by JSMs and expert assessment.

Benzene↗

PubMed2005

Thoracic Injury Investigation using PMHS in Frontal Airbag Out-of-Position Situations.

Many studies have reported multiple rib fractures sustained by an Out-of-Position (OOP) driver subjected to a frontal airbag deployment, but the injury mechanisms and thresholds remain unclear. Two successive phases occur during the bag deployment: punch-out loading of the thorax, followed by a membrane effect (Horsch et al. 1990). The aim of this study was to investigate the thoracic injuries generated by each phase separately. Tests of nine post-mortem human surrogates (PMHS) were carried out on a static test bench using a driver side airbag module described by Petit et al. (2003). The steering wheel was replaced by a plate in order to increase the loading generated by the airbag. Three loading configurations were performed: membrane only, punch-out only, and both types combined. The membrane-only tests were performed with the thorax initially positioned at 13, 78 and 128 mm from the plate in order to vary the load magnitude. The punch-out and the combined tests were performed with the thorax initially 8 mm from the module. Accelerometers and angular rate sensors were fixed on the sternum and on the first, fourth, and eighth thoracic vertebrae of the PMHS. Ribs 2 to 6 were instrumented with strain gauges. The reaction force of the bag on the plate was measured using four 2-axis load cells. Results show that both pure punch-out and pure membrane loading can result in thoracic injuries. However, the rib fracture locations seemed to differ from one type of loading to the other. Moreover, for the same initial distance between the airbag module and the thorax, the injuries were more severe in the combined effect tests than in the pure punch-out or pure membrane. The nine PMHS tests formed a matrix allowing validation of a finite element model and further analysis of thoracic injury mechanisms and thresholds.

Journal Article↗

PubMed2005

Investigation of alcohol use disorders in a group of driving-while-intoxicated offenders.

This preliminary study was carried out to investigate alcohol use disorders and personality profiles in a group of driving-while-intoxicated offenders. Thirty nine volunteer offenders were assessed by CAGE, while 21 of them were assessed by SCID-I Alcohol and Drug Use Disorders module and 14 drivers completed MMPI test. According to CAGE scores, 11 was found to have an indication of alcohol problem and 7 had clinically significant alcohol use disorder. Within 21 drivers, 4 had a DSM-IV diagnosis of alcohol abuse. Independent of their diagnosis, MMPI profiles revealed the psychopathic personality characteristics which might explain drinking while driving as a risky behaviour in this group. These results suggest that, besides legal applications, referring offenders to associated centers, in order to be evaluated and informed about alcohol use disorders, would be an important step in the prevention of recurrent alcohol impaired driving as well as alcohol related incidents.

Adult↗

PubMed2006

Activation of inward rectifier potassium channels accelerates atrial fibrillation in humans: evidence for a reentrant mechanism.

BACKGROUND: It is unclear whether atrial fibrillation (AF) drivers in humans are focal or reentrant. To test the hypothesis that functional reentry is involved in human AF maintenance, we determined the effects of adenosine infusion on local dominant frequency (DF) at different atrial sites. By increasing inward rectifier potassium channel conductance, adenosine would increase DF of reentrant drivers but decrease it in the case of a focal mechanism. METHODS AND RESULTS: Thirty-three patients were studied during AF (21 paroxysmal, 12 persistent) using recordings from each pulmonary vein-left atrial junction (PV-LAJ), high right atrium, and coronary sinus. DFs were determined during baseline and peak adenosine effect. In paroxysmal AF, adenosine increased maximal DF at each region compared with baseline (PV-LAJ, 8.03+/-2.2 versus 5.7+/-0.8; high right atrium, 7+/-2.2 versus 5.4+/-0.7; coronary sinus, 6.6+/-1.1 versus 5.3+/-0.7 Hz; P=0.001) and increased the left-to-right DF gradient (P=0.007). In contrast, in persistent AF, adenosine increased DF only in the high right atrium (8.33+/-1.1 versus 6.8+/-1.2 Hz; P=0.004). In 4 paroxysmal AF patients, real-time DF mapping of the left atrium identified the highest DF sites near the PV-LAJ, where adenosine induced an increase in DF (6.7+/-0.29 versus 4.96+/-0.26 Hz; P=0.008). Finally, simulations demonstrate that the frequency of reentrant drivers accelerates proportionally to the adenosine-modulated inward rectifier potassium current. CONCLUSIONS: Adenosine accelerates drivers and increases frequency differently in paroxysmal compared with persistent human AF. The results strongly suggest that AF is maintained by reentrant sources, most likely located at the PV-LAJ in paroxysmal AF, whereas non-PV locations are more likely in persistent AF.

Adenosine↗

PubMed2005

Controlled switching of intrinsic localized modes in a one-dimensional antiferromagnet.

Nearly-steady-state locked intrinsic localized modes (ILMs) in the quasi-1D antiferromagnet (C(2)H(5)NH(3))(2)CuCl(4) are detected via four-wave mixing emission or the uniform mode absorption. Exploiting the long-time stability of these locked ILMs, repeatable nonlinear switching is observed by varying the sample temperature, and localized modes with various amplitudes are created by modulation of the microwave driver power. This steady-state ILM locking technique could be used to produce energy localization in other atomic lattices.

Journal Article↗

PubMed2006

Importance of short-term dynamics in carbon isotope ratios of ecosystem respiration (delta13C(R)) in a Mediterranean oak woodland and linkage to environmental factors.

Temporal dynamics in carbon isotope ratios of ecosystem respiration (delta13C(R)) were evaluated on hourly, daily and annual timescales in a Mediterranean woodland. Emphasis was given to the periods of transition from wet to dry season and vice versa, when the system turns from a net carbon sink to a source. The constancy of nocturnal delta13C(R) was tested. The relationship between delta13C(R) (determined through Keeling plots) and environmental factors was evaluated through time-lag analysis. Delta13C(R) exhibited high annual variation (> 7). During the transition periods, delta13C(R) correlated significantly with factors influencing photosynthetic discrimination, soil respiration, and whole-canopy conductance. Time-lags differed between below- and above-ground variables, and between seasons. A shift in regression parameters with environmental factors indicated seasonal differences in ecosystem responsiveness (e.g. temperature acclimation). Delta13C(R) exhibited substantial nocturnal enrichment (> 4) from dusk to dawn. These data indicate pronounced short-term dynamics in delta13C(R) at hourly to daily timescales and a modulated response to environmental drivers. Substantial short-term changes in nocturnal delta13C(R) may have important implications for the sampling protocols of nocturnal Keeling plots.

Carbon Dioxide↗