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Results for “Driver module”

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PubMed2006

A new type of stochastic dependence revealed in gene expression data.

Modern methods of microarray data analysis are biased towards selecting those genes that display the most pronounced differential expression. The magnitude of differential expression does not necessarily indicate biological significance and other criteria are needed to supplement the information on differential expression. Three large sets of microarray data on childhood leukemia were analyzed by an original method introduced in this paper. A new type of stochastic dependence between expression levels in gene pairs was deciphered by our analysis. This modulation-like unidirectional dependence between expression signals arises when the expression of a "gene-modulator'' is stochastically proportional to that of a "gene-driver''. A total of more than 35% of all pairs formed from 12550 genes were conservatively estimated to belong to this type. There are genes that tend to form Type A relationships with the overwhelming majority of genes. However, this picture is not static: the composition of Type A gene pairs may undergo dramatic changes when comparing two phenotypes. The ability to identify genes that act as ;;modulators'' provides a potential strategy of prioritizing candidate genes.

Child↗

PubMed2026

Interplay between DNA and RNA methylation shapes cancer cell plasticity.

Cellular plasticity refers to the ability of healthy cells to shift between phenotypic states and modify their characteristics to maintain tissue homeostasis and integrity. In the tumor context, cancer stem cells (CSCs) exploit this flexibility to withstand stress, facilitate tumor dissemination, and evade therapeutic interventions. Epigenetic regulation, particularly DNA methylation at CpG sites, is recognized as a well-known driver of tumor plasticity by repressing differentiation programs through modulation of chromatin accessibility. More recently, RNA modifications (epitranscriptomics) have emerged as crucial post-transcriptional regulators of gene expression that shape RNA fate and function. Among these, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G) contribute to the regulation of cell identity by modulating stemness-differentiation balance, stress adaptation, and epithelial-to-mesenchymal transition (EMT). Notably, dysregulation of both DNA and RNA methylation signatures is frequently observed in tumors, suggesting potential functional interactions between these regulatory layers. Emerging evidence indicates that DNA CpG methylation and RNA methylation pathways may cooperate to influence stemness, survival, and EMT-associated signaling, thereby supporting CSCs' plasticity. Although the molecular mechanisms underlying this crosstalk remain incompletely understood, accumulating studies suggest that DNA and RNA methylation could converge within interconnected regulatory networks that contribute to the control of cancer cell identity. A deeper understanding of these interactions may uncover novel vulnerabilities for targeting tumor plasticity. In this review, we summarize the current knowledge on the interplay between DNA and RNA methylation in regulating tumor plasticity, highlighting emerging mechanistic insights, functional interactions, and potential implications for future epigenetic and epitranscriptomic therapeutic strategies.

Humans↗

PubMed2003

Characterization of human trophoblast as a mineralocorticoid target tissue.

In mineralocorticoid target tissues, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) confers mineralocorticoid receptor selectivity by metabolizing hormonally active cortisol to inactive cortisone, allowing aldosterone access to the receptor. This enzyme is also expressed in high abundance in fetal tissues, particularly in placental trophoblast, where a role has been proposed in regulating fetal growth and development by protecting the fetus from maternal hypercortisolaemia and modulating local glucocorticoid receptor (GR), rather than mineralocorticoid receptor-mediated responses. As such the placenta has not been considered a mineralocorticoid target tissue. We have used conventional RT-PCR and real-time quantitative RT-PCR to demonstrate that primary cultures of term human cytotrophoblast express the mineralocorticoid-responsive genes Na/K-ATPase (alpha1 and beta1 subunits), epithelial sodium channel (ENaC, alpha and gamma subunits) and the serum and glucocorticoid-inducible kinase (SGK). SGK expression was found to be rapidly and strongly induced by corticosteroids (24- and 38-fold by 10(-7) mol/l aldosterone and 10(-7) mol/l dexamethasone respectively after 1 h). Dexamethasone-, but not aldosterone-stimulated SGK induction was inhibited by GR antagonist (RU38486), confirming the presence of a functional mineralocorticoid receptor and suggesting that placental trophoblast expresses a functional mineralocorticoid receptor, which is in part responsible for the corticosteroid regulation of SGK expression. Placental 11beta-HSD2 may protect the MR in a fashion analogous to classical mineralocorticoid tissues to modulate trophoblast sodium transport.

Adult↗

PubMed2026

Meiotic Origins of Non-Mosaic Klinefelter Syndrome (47, XXY): Mechanisms, Dimorphism, and Emerging Genetic Susceptibility.

BACKGROUND: Non-mosaic Klinefelter syndrome (47,XXY) arises from sex-specific meiotic mechanisms leading to nondisjunction during gametogenesis. In maternal cases, errors occur predominantly during meiosis I, frequently involving X chromosomes that lack crossovers or exhibit crossovers outside optimal chromosomal locations; this nondisjunction is further exacerbated by advancing maternal age and the subsequent deterioration of cohesins. Conversely, paternal 47,XXY stems primarily from the failure of obligate recombination within the pseudoautosomal region, which is critical for accurate XY segregation. OBJECTIVE: Drawing on the latest literature, this review transitions from a descriptive account of non-mosaic Klinefelter syndrome (nKS) toward a comprehensive analysis of mechanistic and genomic evidence, establishing a unified framework of sex-specific meiotic vulnerability. METHODS: We synthesized recent findings from forward genetic approaches in mouse models with data from human observational and reverse-genetic studies, delineating an updated view of the established and putative mechanisms that modulate sex chromosome segregation. RESULTS: We frame XX and XY nondisjunction as a genetically modulated process rather than a purely stochastic event. The integrated evidence supports a unified framework in which maternal and paternal mechanisms converge primarily on meiotic recombination failure but differ in timing, chromosomal context, and genetic modulation. CONCLUSIONS: From a clinical standpoint, identifying the molecular drivers of sex chromosome aneuploidy will enhance genetic counseling and risk stratification. Such insights are poised to facilitate informed reproductive decision-making and timely therapeutic support, ultimately reducing the burden of nKS comorbidities and improving patients' quality of life.

aneuploidy↗

PubMed1981

Preclinical evaluation of intra-aortic balloon pumping for pediatric use.

Small intra-aortic balloons (0.75 ml to 5.0 ml) mounted on small catheters (4.0F and 5.0F) have undergone in vitro testing with the Utah Heart Driver and in vivo evaluation with 3 different pumping modules. In small animals with reduced cardiac output from acutely produced mitral regurgitation, intra-aortic balloon pumping effectively reduced aortic peak systolic pressure, lowered aortic end-diastolic pressure and reduced left atrial pressure. In addition, the Datascope system most effectively augmented diastolic pressure and increased aortic forward and negative flow as compared with 2 other pumping modules. The total system has been adequately and experimentally evaluated and is ready for clinical use in infants and small children.

Animals↗

PubMed2003

Sea breeze modulated volatilization of polycyclic aromatic hydrocarbons from the Masnou Harbor (NW Mediterranean Sea).

Harbors, marinas, and coastal environments are impacted by important pollutant loadings, particularly of polycyclic aromatic hydrocarbons (PAHs). Air-water exchange is an important process driving the environmental fate of organic pollutants in aquatic environments. However, its relevance as a factor affecting the environmental fate of pollutants from harbor sediments and waters has not been properly assessed, so far, except for few coastal environments. The objective of this study is to quantify the importance of volatilization losses of PAHs from harbor sediments and waters and to study the potential role of sea breeze as a modulator of air-water exchange in coastal environments. The results show that volatilization fluxes from a medium size marina located in the NW Mediterranean sea are relatively high in comparison to those observed in other aquatic systems, particularly for the low molecular weight (MW) compounds. This is consistent with PAHs profiles observed in harbor sediments, which are depleted by the lower MW hydrocarbons. Therefore, volatilization is an important loss of low MW PAHs such as phenanthrene, methyl phenanthrene, dibenzothiophene, etc. Indeed, these PAHs have a residence time of few days in the harbor waters and sediments. Finally, the diurnal trends in volatilization fluxes mimics that of the sea breeze influenced wind speed. These results show the important role that the diurnal sea breeze exerts on the environmental fate of pollutants such as PAHs in coastal environments as a modulator of air-water exchange and as a potential driver of transport of pollutants between adjacent coastal and terrestrial environments.

Air Pollutants↗

PubMed2006

Genomic patterns of pathogen evolution revealed by comparison of Burkholderia pseudomallei, the causative agent of melioidosis, to avirulent Burkholderia thailandensis.

BACKGROUND: The Gram-negative bacterium Burkholderia pseudomallei (Bp) is the causative agent of the human disease melioidosis. To understand the evolutionary mechanisms contributing to Bp virulence, we performed a comparative genomic analysis of Bp K96243 and B. thailandensis (Bt) E264, a closely related but avirulent relative. RESULTS: We found the Bp and Bt genomes to be broadly similar, comprising two highly syntenic chromosomes with comparable numbers of coding regions (CDs), protein family distributions, and horizontally acquired genomic islands, which we experimentally validated to be differentially present in multiple Bt isolates. By examining species-specific genomic regions, we derived molecular explanations for previously-known metabolic differences, discovered potentially new ones, and found that the acquisition of a capsular polysaccharide gene cluster in Bp, a key virulence component, is likely to have occurred non-randomly via replacement of an ancestral polysaccharide cluster. Virulence related genes, in particular members of the Type III secretion needle complex, were collectively more divergent between Bp and Bt compared to the rest of the genome, possibly contributing towards the ability of Bp to infect mammalian hosts. An analysis of pseudogenes between the two species revealed that protein inactivation events were significantly biased towards membrane-associated proteins in Bt and transcription factors in Bp. CONCLUSION: Our results suggest that a limited number of horizontal-acquisition events, coupled with the fine-scale functional modulation of existing proteins, are likely to be the major drivers underlying Bp virulence. The extensive genomic similarity between Bp and Bt suggests that, in some cases, Bt could be used as a possible model system for studying certain aspects of Bp behavior.

Burkholderia↗

PubMed2005

Drivers from the deep: the contribution of collicular input to thalamocortical processing.

A traditional view of the thalamus is that it is a relay station which receives sensory input and conveys this information to cortex. This sensory input determines most of the properties of first order thalamic neurons, and so is said to drive, rather than modulate, these neurons. This holds as a rule for first order thalamic nuclei, but in contrast, higher order thalamic nuclei receive much of their driver input back from cerebral cortex. In addition, higher order thalamic neurons receive inputs from subcortical movement-related centers. In the terminology popularized from studies of the sensory system, can we consider these ascending motor inputs to thalamus from subcortical structures to be modulators, subtly influencing the activity of their target neurons, or drivers, dictating the activity of their target neurons? This chapter summarizes relevant evidence from neuronal recording, inactivation, and stimulation of pathways projecting from the superior colliculus through thalamus to cerebral cortex. The study concludes that many inputs to the higher order nuclei of the thalamus from subcortical oculomotor areas - from the superior colliculus and probably other midbrain and pontine regions - should be regarded as motor drivers analogous to the sensory drivers at the first order thalamic nuclei. These motor drivers at the thalamus are viewed as being at the top of a series of feedback loops that provide information on impending actions, just as sensory drivers provide information about the external environment.

Action Potentials↗

PubMed2026

Scalable, open-access and multidisciplinary data integration pipeline for climate-sensitive diseases.

Climate-sensitive infectious diseases pose an important challenge for human, animal and environmental health and it has been estimated that over half of known human pathogenic diseases can be aggravated by climate change. While climatic and weather conditions are important drivers of transmission of vector-borne diseases, socio-economic, behavioural, and land-use factors as well as the interactions among them impact transmission dynamics. Analysis of drivers of climate-sensitive diseases require rapid integration of interdisciplinary data to be jointly analysed with epidemiological (including genomic and clinical) data. Current tools for the integration of multiple data sources are often limited to one data type or rely on proprietary data and software. To address this gap, we develop a scalable and open-access pipeline for the integration of multiple spatio-temporal datasets that requires only the declaration of the country and temporal range and resolution of the study. The tool is locally deployable and can easily be integrated into existing climate-disease-modelling applications. We demonstrate the utility of the tool for dengue modelling in Vietnam where epidemiological data are legally required to remain local. We include a pipeline for bias correction of climate data to enhance their quality for downstream modelling tasks. The Dengue Advanced Readiness Tools-Pipeline empowers users by simplifying complex download, correction, and aggregation steps, fostering data-driven discovery of relationships between infectious diseases and their drivers in space and time, and enhancing reproducibility in research. Additional modules and datasets can be added to the existing ones to make the pipeline extendable to use cases other than the ones presented here.

automated workflows↗

PubMed2000

Selective attention to the chemosensory modality.

Previous studies have shown that behavioral responses to auditory, visual, and tactile stimuli are modulated by expectancies regarding the likely modality of an upcoming stimulus (see Spence & Driver, 1997). In the present study, we investigated whether people can also selectively attend to the chemosensory modality (involving responses to olfactory, chemical, and painful stimuli). Participants made speeded spatial discrimination responses (left vs. right) to an unpredictable sequence of odor and tactile targets. Odor stimuli were presented to either the left or the right nostril, embedded in a birhinally applied constant airstream. Tactile stimuli were presented to the left or the right hand. On each trial, a symbolic visual cue predicted the likely modality for the upcoming target (the cue was a valid predictor of the target modality on the majority of trials). Response latencies were faster when targets were presented in the expected modality than when they were presented in the unexpected modality, showing for the first time that behavioral responses to chemosensory stimuli can be modulated by selective attention.

Attention↗

PubMed2026

Genetic diversity and molecular mechanisms in hypertrophic cardiomyopathy: toward personalized therapy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac muscle disorder, yet contemporary genomic and mechanistic research still lacks a cohesive model explaining how diverse genetic architectures give rise to heterogeneous phenotypes. This review synthesizes advances across sarcomeric and nonsarcomeric mutations, including intermediate-effect variants, polygenic modifiers, and ancestry-dependent sources of variant misclassification to elucidate how these factors govern disease penetrance and clinical expression. It critically evaluates how genetic diversity intersects with key molecular pathways, including sarcomeric hypercontractility, calcium dysregulation, mitochondrial energy deficiency, and transforming growth factor-β (TGF-β) and protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling, to drive hypertrophic and fibrotic remodeling. Emerging mechanism-based therapies, such as myosin inhibition, allele-specific silencing, clustered regularly interspaced short palindromic repeats (CRISPR)-based correction, and metabolic modulation, are examined with respect to their capacity to modify upstream molecular drivers rather than downstream hemodynamic consequences. Persistent challenges, including variants of uncertain significance classification, ancestry-biased databases, inequitable access to genetic testing, and unresolved safety concerns for gene-based therapies, are critically assessed as major barriers to precision-medicine integration. By linking genetic architecture, molecular pathogenesis, and targeted interventions, this review advances a contemporary, mechanistically grounded framework that informs both individualized management and future research directions. Future research should prioritize pathway-specific therapeutics, functional and mechanistic validation of emerging variants, deeper physiologic phenotyping to refine disease modeling, and accelerate translation throughout the continuum of HCM pathophysiology.

Humans↗

PubMed1999

Stroke treatment economic model (STEM): predicting long-term costs from functional status.

BACKGROUND AND PURPOSE: Stroke is a debilitating disease with long-term social and economic consequences. As new therapies for acute ischemic stroke are forthcoming, there is an increasing need to understand their long-term economic implications. To address this need, a stroke economic model was created. METHODS: The model consists of 3 modules. A short-term module incorporates short-term clinical trial data. A long-term module composed of several Markov submodels predicts patient transitions among various locations over time. The modules are connected via a bridge component that groups the survivors at the end of the short-term module according to their functional status and location. Examples of analyses that can be conducted with this model are provided with the use of data from 2 international trials. For illustration, UK unit costs were estimated. RESULTS: With the trial data in the short-term module, the short-term management cost is estimated to be pound8326 (US $13,649 [USD]). Hospital stay was the major cost driver. By the end of the trials, there was a pronounced difference in the distribution of patient locations between functional groups. It is predicted in the long-term module that the subsequent cost amounts to pound75 985 (124,564 USD) for a major and pound27,995 (45,893 USD) for a minor stroke. CONCLUSIONS: Linking functional recovery at the end of short-term treatment with patients' treatment and residential locations allows this model to estimate the long-term economic impact of stroke interventions. Using patient location instead of the more common natural history as the model foundation allows quantification of the long-term impact to become data driven and hence increases confidence in the results.

Cost of Illness↗

PubMed1993

Mechanism of injury from air bag deployment loads.

Loadings induced by deploying currently representative air bags were studied with driver surrogates (anesthetized swine) leaning against the system during inflation. Torso injury mechanisms were studied in a physiologic model, supported against a static steering wheel-mounted air bag system. Severe and extensive chest and abdominal injuries to the swine were observed in the tests. Loading caused by air bag deployment can occur in either of two phases. The first phase represents the initial punch out of the bag from the module; the second phase represents the membrane force of the inflating bag. Statistical analysis indicated that punch out induced injury because of the high rate of loading to the surrogate body region in direct contact with the air bag module. Membrane forces induced injury by high compression over a larger area. Punch-out loading might be reduced by allowing the bag to escape from other parts of the container not in contact with the driver during deployment. Loading by the inflating bag might be reduced by using a compliant steering system to support the module. The amount and rate of generated gas had only marginal effect on the cumulative injury. Even an inflator with inadequate gas output to protect a properly seated occupant had sufficient energy to induce severe injuries in a surrogate in contact with the inflating module. Analysis of the field relevance of the results must consider not only the injury potential given that a driver is in direct contact with the air bag module at the time of deployment, but also the expected field frequency of such an event. Analysis of the field relevance of the results must also consider the correlation of the laboratory test environment with real-world exposure.

Abdominal Injuries↗

PubMed2003

Modulation of object-based attention by spatial focus under endogenous and exogenous orienting.

In R. Egly, J. Driver, and R. D. Rafal's (1994) influential double-rectangle spatial-cuing paradigm, exogenous cues consistently induce object-based attention, whereas endogenous cues generally induce space-based attention. This difference suggests an interdependency between mode of orienting (endogenous vs exogenous) and mode of selection (object based vs space based). However, mode of orienting is generally confounded with initial focus of attention: Endogenous orienting begins with attention focused on a central cue, whereas exogenous orienting begins with attention widely spread. In this study, an attentional-focusing hypothesis is examined and supported by experiments showing that for both endogenous and exogenous cuing, object-based effects are obtained under conditions that encourage spread attention, but they are attenuated under conditions that encourage focused attention. General implications for object-based attention are discussed. ((c) 2003 APA, all rights reserved)

Adult↗

PubMed2000

Coimmunization with IFN-gamma or IL-2, but not IL-13 or IL-4 cDNA can enhance Th1-type DNA vaccine-induced immune responses in vivo.

As we explore the potential improvements to the current DNA vaccine strategies, it may be desirable to investigate methods to improve the level of resulting immune responses. One strategy is the use of cytokine cDNA as molecular adjuvants for DNA-based vaccines. Codelivery of these molecular adjuvants consisting of expression plasmid encoding for cytokines with DNA vaccine constructs is an effective method to modulate the magnitude and direction (humoral or cellular) of the immune responses. We have previously reported on the immunomodulatory effects of codelivering cDNA for interleukin-2 (IL-2) and IL-4 as molecular adjuvants for DNA-based vaccines. In this report, we extend these finding and compare the immunomodulatory effects of IL-2 and IL-4 with those of cDNA for prototypical Thl-type cytokine interferon-y (IFN-gamma) and Th2-type cytokine IL-13. We observed that distinct antigen-specific immune modulation can be achieved by the coinjection of IFN-gamma or IL-13 genes with DNA immunogen cassettes. We observed that IFN-gamma is a strong driver of Thl immune responses. Furthermore, in contrast to previous reports on their similarities in biologic activities, IL-13 and IL-4 cDNA coimmunizations modulated vaccine-induced immune responses differently in this model. Overall, these results further support the potential utility of this strategy as an important tool for the development of vaccines and immune therapies.

Adjuvants, Immunologic↗

PubMedDate not supplied

High-performance photoelastic modulator for polarization modulation spectrometer.

A high-performance photoelastic modulator (PEM) has been built. It consists of a home-made PEM head and a home-built PEM driver that is based on the principle of the phase-locked loop (PLL) (PLL PEM driver). It was installed in our new type circular dichroism (CD) spectrometer for visible light region and its performance was evaluated. With the phase angle being set exactly to zero, the PEM is found to be about eight times more efficient than commercially available one. The efficiency of PEM depends not only on the efficiency of PEM driver but also on the quality of PEM head. The latter can be estimated from admittance-parameter measurements without installing it into a spectrometer. With substituting the PLL PEM driver for a conventional one, the PEM drive voltage can be reduced from one-half to one-third and the baseline shift for air blank that is a measure of the total performance of polarization modulation spectrometers becomes quite small.

Journal Article↗

PubMed2025

Investigating the genomic landscape of mouse models of breast cancer metastasis.

Metastasis remains a major cause of cancer mortality. AbstractThis study, expanding upon previous findings in the MMTV-PyMT model, investigated four independent mouse models, representing luminal (MMTV-PyMT, MMTV-Myc), HER2-amplified (MMTV-Her2) and triple negative (C3(1)TAg) breast cancer subtypes. Consistent with previous results, limited evidence for metastasis-associated somatic point mutations was found for all models. We also found that oncogenic drivers significantly influenced the number and size of metastasis-specific copy number variations (MSCNVs), but common driver-independent MSCNVs were rare. Furthermore, analyzing a cohort with varying genetic backgrounds while maintaining a constant oncogenic driver (PyMT) revealed that genetic background profoundly impacts MSCNVs. Transcriptome analysis demonstrated that oncogenic drivers strongly shaped metastasis-specific gene expression (MSGE), with each driver exhibiting distinct expression profiles. In contrast, MSGE in the PyMT-F1 cohort was more variable across strains. Despite the diversity of MSCNV and MSGE, functional analysis revealed that both mechanisms converge on the modulation of key cellular processes, including immune responses, metabolism, and extracellular matrix interactions. These findings emphasize the complex interplay between oncogenic drivers and genetic background in shaping the genomic and transcriptional landscapes of metastatic lesions.

Journal Article↗

PubMed2002

Active tool use with the contralesional hand can reduce cross-modal extinction of touch on that hand.

After a unilateral brain lesion, patients may show cross-modal, visual-tactile extinction. Such patients may fail to report tactile stimuli on the contralesional hand when presented together with competing visual stimuli near the ipsilesional hand. In this work we tested the hypothesis that this cross-modal extinction may be reduced when a patient has used a tool with the contralesional hand to reach for objects in the ipsilesional visual field. Consistent with previous work, we hypothesize that active use of a tool may extend cross-modal interactions between visual stimuli at the tip of the tool and tactile stimuli on the hand wielding the tool. In the new situation of a tool connecting the contralesional hand with ipsilesional visual space, competition between stimuli on these opposite sides may be reduced, so that extinction decreases. We studied patient BV, who showed reliable cross-modal, visual-tactile extinction after right-hemisphere stroke. In two separate sessions we showed that prolonged tool use (10-20 min) with the contralesional hand in ipsilesional space reduced cross-modal extinction for up to 60-90 min post-training. We propose that an actively used tool may be effective in linking cross-modal stimuli presented along its extension. This can then overcome competition between stimuli presented on opposite sides of the body midline, thus modulating extinction.

Aged↗