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PubMedDate not supplied

Crossmodal integration for perception and action.

The integration of information from different sensory modalities has many advantages for human observers, including increase of salience, resolution of perceptual ambiguities, and unified perception of objects and surroundings. Several behavioral, electrophysiological and neuroimaging data collected in various tasks, including localization and detection of spatial events, crossmodal perception of object properties and scene analysis are reviewed here. All the results highlight the multiple faces of crossmodal interactions and provide converging evidence that the brain takes advantages of spatial and temporal coincidence between spatial events in the crossmodal binding of spatial features gathered through different modalities. Furthermore, the elaboration of a multimodal percept appears to be based on an adaptive combination of the contribution of each modality, according to the intrinsic reliability of sensory cue, which itself depends on the task at hand and the kind of perceptual cues involved in sensory processing. Computational models based on bayesian sensory estimation provide valuable explanations of the way perceptual system could perform such crossmodal integration. Recent anatomical evidence suggest that crossmodal interactions affect early stages of sensory processing, and could be mediated through a dynamic recurrent network involving backprojections from multimodal areas as well as lateral connections that can modulate the activity of primary sensory cortices, though future behavioral and neurophysiological studies should allow a better understanding of the underlying mechanisms.

Animals↗

PubMed2026

Human Systems Immunology in the Omics Era: Challenges, Methods, and Emerging Directions.

The human immune system is a highly complex, dynamic, and heterogeneous network shaped by genetic, environmental, and temporal influences. Advances in high-throughput omics technologies have transformed our ability to study this complexity directly and comprehensively in human cohorts. These developments have positioned systems immunology as a powerful framework for investigating coordinated immune responses, identifying regulatory mechanisms, and linking molecular patterns to clinical phenotypes. However, the analytical challenges inherent to large-scale, multimodal datasets-including batch effects, small sample sizes, high dimensionality, and substantial interindividual heterogeneity-require rigorous study design, robust statistical modeling, and thoughtful data analysis strategies. In this review, we summarize key technological foundations enabling modern human systems immunology, outline common analytical pitfalls and effective mitigation approaches, discuss data integration concepts, and highlight emerging opportunities in the field. Together, these technological and analytical advances are redefining how immune function is measured and interpreted in real-world human biology and hold significant promise for enhancing mechanistic insight, biomarker discovery, and precision medicine across immunological diseases and interventions.

Humans↗

PubMed1995

Damage to the urinary tract secondary to irradiation.

During the past two decades highly effective multimodality therapy with surgery, chemotherapy and irradiation has been developed through consecutive national and international study protocols for childhood genitourinary cancers, the model being Wilms' tumor. These studies represent a landmark achievement in the history of pediatric oncology and mark the success of multi-institutional efforts. Now that excellent survival rates have been established, current interest is now directed primarily at examination of survivors for long-term treatment complications and minimizing the side effects while preserving treatment efficacy. Treatment sequelae may not become evident until many years after the initial diagnosis of cancer and may have adverse influences on long-term survival and/or the quality of life of former patients. With radiotherapy being a mainstay on the stage adjusted therapy of primarily Wilms' tumor and rhabdomyosarcoma, morbidity may occur as either acute or chronic with the genitourinary tract as an important adversely affected vital organ system. The effects of radiotherapy in the treatment of genitourinary childhood cancers on the urinary tract are reviewed here.

Child↗

PubMed2004

Noninvasive imaging of reporter gene expression in living subjects.

The development of noninvasive imaging technologies designed specifically for use with small animals has provided new paradigms for cancer research. Traditional molecular biology techniques are being melded with noninvasive imaging technologies to develop a new research domain, "molecular imaging." One of the most exciting advances in this research area is the adaptation and application of conventional reporter-gene imaging techniques, used extensively by cell and molecular biologists, to living animals. Using these new assays, investigators can image noninvasively, repeatedly, and quantitatively the location, magnitude, and duration of reporter-gene expression in living animals. This review will describe the instrumentation used for noninvasive imaging of reporter genes, the reporter genes developed for noninvasive imaging with radio-nuclide-based assays such as positron emission tomography, and the reporter genes used for optically based noninvasive assays using sensitive charged-coupled device cameras. Applications of noninvasive, whole-animal imaging to gene therapy for cancer, to cell-based therapy for cancer, to lymphocyte activation, to cancer progression and dissemination in engrafted models, to tumor initiation, promotion and metastasis in conditional murine models of cancer induction, and to the noninvasive monitoring of tumor responses to a variety of therapies are described. New developments in multimodality molecular imaging are discussed, and the potential utility of noninvasive reporter gene expression in the diagnosis and management of human cancer is presented.

Animals↗

PubMedDate not supplied

Realistic haptic rendering of interacting deformable objects in virtual environments.

A new computer haptics algorithm to be used in general interactive manipulations of deformable virtual objects is presented. In multimodal interactive simulations, haptic feedback computation often comes from contact forces. Subsequently, the fidelity of haptic rendering depends significantly on contact space modeling. Contact and friction laws between deformable models are often simplified in up to date methods. They do not allow a "realistic" rendering of the subtleties of contact space physical phenomena (such as slip and stick effects due to friction or mechanical coupling between contacts). In this paper, we use Signorini's contact law and Coulomb's friction law as a computer haptics basis. Real-time performance is made possible thanks to a linearization of the behavior in the contact space, formulated as the so-called Delassus operator, and iteratively solved by a Gauss-Seidel type algorithm. Dynamic deformation uses corotational global formulation to obtain the Delassus operator in which the mass and stiffness ratio are dissociated from the simulation time step. This last point is crucial to keep stable haptic feedback. This global approach has been packaged, implemented, and tested. Stable and realistic 6D haptic feedback is demonstrated through a clipping task experiment.

Algorithms↗

PubMed2006

CXCR4 inhibition synergizes with cytotoxic chemotherapy in gliomas.

PURPOSE: The chemokine receptor CXCR4 is expressed in many different cancers. In malignant brain tumors, CXCR4 signaling has been implicated in tumor growth, survival, and migration, and pharmacologic inhibition of CXCR4 results in decreased tumor growth in preclinical models. To understand how CXCR4 inhibitors may be incorporated into clinical therapy, we examined determinants of responsiveness to CXCR4 inhibition. Because optimal use of CXCR4 inhibition will likely be a part of multimodality therapy, we also investigated the efficacy of CXCR4 inhibition combined with conventional cytotoxic chemotherapy. EXPERIMENTAL DESIGN: CXCR4 protein levels and responsiveness to the CXCR4 inhibitor AMD3100 were determined in a panel of glioblastoma multiforme cell lines. The effects of AMD3100, alone or in combination with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), on cell growth were determined for several of these cell lines in vitro. We used an orthotopic model of glioblastoma multiforme to evaluate the antitumor efficacy of AMD3100 combined with BCNU in vivo. RESULTS: The level of CXCR4 protein expression in glioblastoma multiforme cells predicts the dose at which there is a response to AMD3100; cells that express higher levels of CXCR4 protein require higher doses for equivalent response. In all cell lines tested, treatment of glioblastoma multiforme cells with BCNU followed by AMD3100 results in synergistic antitumor efficacy in vitro. This synergy can also be seen in an orthotopic glioblastoma multiforme model. Treatment with subtherapeutic doses of BCNU in combination with AMD3100 results in tumor regression in vivo, and this reflects both increased apoptosis and decreased proliferation following combination therapy. CONCLUSION: These studies support testing CXCR4 inhibitors in patients with glioblastoma multiforme and establish that inhibition of CXCR4 synergizes with conventional cytotoxic therapies in a clinically relevant combinatorial strategy.

Animals↗

PubMed2002

Multisensory cues and multimodal communication in spiders: insights from video/audio playback studies.

Spiders perceive the world using multiple sensory modes, including vibration, vision, and chemical senses, for prey detection and communication. These sensory modes are used in many communication contexts, either individually or in multimodal signaling. Selection for effective signaler-receiver communication and species discrimination is especially strong for these predatory and potentially cannibalistic arthropods, resulting in the evolution of considerable diversity in signaling behaviors. In this paper, we review sensory mechanisms involved in spider signaling and present an overview of recent work done on wolf spiders (Lycosidae) that use multimodal communication (simultaneous visual and vibratory signals) in sexual signals during courtship. The relative importance of visual and vibratory signaling modes, and the use of multiple modes varies among closely related species in the genus Schizocosa, providing a model system for investigating multisensory guidance of complex behavior. Here we examine previous and current research on responses of female spiders to components of male courtship behavior, using several experimental techniques including cue isolation (single sensory modes), video/audio digitization and playback, and cue-conflict (mixed conspecific/heterospecific components) to tease apart elements of multimodal signaling.

Animal Communication↗

PubMed1990

Autoregression models of EEG. Results compared with expectations for a multilinear near-equilibrium biophysical process.

This paper considers the properties of parameters (natural frequencies and damping coefficients) obtained from segment-by-segment autoregression analysis of ECoG of rat. The use of a reference signal as control for parameter estimate errors, and multiple regression analyses indicate that the dependencies among parameters calculated from ECoG in the alert (desynchronised) state are of a form consistent with imposition of time-invariance assumptions (implicit in autoregression) on an inherently non-stationary, multimodal, linear and near-equilibrium "thermal" process.

Animals↗

PubMed2003

Bayesian integration of visual and auditory signals for spatial localization.

Human observers localize events in the world by using sensory signals from multiple modalities. We evaluated two theories of spatial localization that predict how visual and auditory information are weighted when these signals specify different locations in space. According to one theory (visual capture), the signal that is typically most reliable dominates in a winner-take-all competition, whereas the other theory (maximum-likelihood estimation) proposes that perceptual judgments are based on a weighted average of the sensory signals in proportion to each signal's relative reliability. Our results indicate that both theories are partially correct, in that relative signal reliability significantly altered judgments of spatial location, but these judgments were also characterized by an overall bias to rely on visual over auditory information. These results have important implications for the development of cue integration and for neural plasticity in the adult brain that enables humans to optimally integrate multimodal information.

Bayes Theorem↗

PubMed2006

[Is there more than one "true" theory of cognition in medicine?].

Alternative approaches such as Traditional Chinese Medicine are very popular with patients. Often, however, there is a lack of high quality studies to prove their efficacy. The question will be discussed whether different theories of cognition may coexist in medicine which are all true. Not only biological, but also psychological and social factors contribute to health and well-being. Integrative medicine should bridge the gap between mainstream evidence-based medicine and complementary methods. Shared decision making between patient and physician can help to find the optimum, often multimodal treatment strategy for each patient.

Complementary Therapies↗

PubMed2003

Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture.

BACKGROUND: The pathophysiology of cerebral ischemia is well studied in small-animal models, which offer reproducibility and control of confounding variables-factors essential to hypothesis-testing. This presentation first highlights insights into the ischemic penumbra enabled by a multimodal experimental approach; second, discusses gene expression in ischemia; and third, confronts the challenges of neuroprotectant therapy. SUMMARY OF REVIEW: The ischemic penumbra: Transient (2-hour) middle cerebral artery suture-occlusion in anesthetized rats gives rise to highly consistent neurological and histopathological sequelae. Autoradiographic local cerebral blood flow (LCBF) studies at 2 hours of occlusion define the penumbra as a region of intermediate CBF depression (20% to 40% of control) surrounding the densely ischemic core (5% to 20% of control) and constituting one half of the entire lesion. Local glucose metabolic rate in the acute penumbra is not reduced despite the critical CBF reduction, so that the penumbral metabolism/blood flow ratio is markedly elevated. In contrast, following 1 hour of recirculation, glucose metabolism throughout the previously ischemic hemisphere has become markedly depressed, and the metabolism/flow ratio has pseudonormalized. By correlating these data with histopathology using multimodal image analysis, the probability of infarction is shown to be highly determined by the degree of antecedent CBF reduction. These animal data agree strikingly with published results in patients with acute stroke studied by positron emission tomography. This remarkable correspondence belies the assertion that data from lower species may not be relevant to human stroke. Gene expression: Perfusion gradients also determine differential patterns of gene expression in ischemia. This can be demonstrated by correlating in situ hybridization autoradiographs for gene expression with autoradiographic LCBF data and histological infarct maps derived from replicate series. In other studies, DNA microarray technology is used to screen for thousands of expressed genes. In the 2-hour middle cerebral artery occlusion model with 3-hour recirculation, we have identified 28 known ischemia-hypoxia response genes that are upregulated and 6 that are downregulated, together with 35 upregulated and 41 downregulated genes newly connected with ischemia. These findings underscore the enormous complexity of ischemic biology and suggest possible novel mechanisms for future exploration. NEUROPROTECTION: A desirable neuroprotectant would, in theory, antagonize multiple injury mechanisms. We have explored 2 such therapies of particular promise. Mild brain hypothermia (32 degrees C target temperature, for 5 hours) is highly neuroprotective even when initiated at the onset of recirculation. Another highly protective agent is human albumin, administered in doses of 1.25 to 2.5 g/kg--a therapy that reduces infarct volume in this ischemia model by 60% to 65%, markedly diminishes brain swelling, and has a therapeutic window extending to 4 hours. CONCLUSION: The careful study of rodent ischemia models can yield valuable, clinically relevant insights into the pathophysiology of ischemic stroke.

Albumins↗

PubMed2006

Midbrain pathways for prepulse inhibition and startle activation in rat.

The midbrain is essential for prepulse inhibition (PPI) of the startle reflex, but the exact neural circuits for PPI are not yet determined. Electrical stimulation of the superior colliculus (SC) or pedunculopontine tegmentum was used to characterize the neurons and pathways that mediate PPI and the activation of startle that also occurs at higher currents in the same sites. Startle was inhibited by prepulses in most, but not all SC sites, with the lowest intensity sites in intermediate layers of SC. PPI latencies in SC sites were 4-6 ms longer than in inferior colliculus, intercollicular nucleus or pedunculopontine sites. Contrary to previous serial models, there must be two parallel midbrain pathways for PPI, a faster auditory pathway from inferior colliculus to pedunculopontine tegmentum, and a slower multimodal SC output for PPI. Double-pulse stimulation of SC sites shows that PPI results from direct stimulation of neurons with moderate refractory periods (0.4-1.0 ms), similar to SC neurons that mediate contraversive turning responses. By contrast, startle activation occurring at higher currents in all SC sites (even sites where PPI could not be elicited) results from stimulation of very short refractory period neurons (0.3-0.5 ms) and very long refractory period neurons (1.0-2.0 ms), with startle inhibition often found from 0.5-1.0 ms. Startle activation appears to result from stimulation of short refractory period neurons in deep SC layers that mediate fear-potentiated startle, plus long refractory period substrates in more dorsal SC sites.

Animals↗

PubMed1993

Pediatric genitourinary tumors.

During the past two decades, highly effective multimodality therapy involving surgery, chemotherapy, and radiation has been developed through consecutive national and international study protocols for childhood genitourinary cancers with the model being Wilms' tumor. These studies represent a landmark achievement in the history of pediatric oncology and mark the success of multi-institutional studies. With the excellent survival rates that have been established, current interest is now directed toward examining survivors for long-term treatment complications and minimizing the side effects while preserving treatment efficacy. In addition, new developments in the molecular biology of Wilms' tumor have made this neoplasm a model for understanding the molecular and genetic aspects of tumorigenesis. This article reviews some of the publications from 1992 on pediatric genitourinary tumors.

Child↗

PubMed1999

On the role of subthreshold dynamics in neuronal signaling.

The role of subthreshold dynamics in neuronal signaling is examined using periodic pulse train stimulation of the Fitzhugh-Nagumo (FN) model of nerve membrane excitability and results from the squid giant axon as an experimental data base. For a broad range of stimulus conditions the first pulse in a pulse train elicited an action potential, whereas all subsequent pulses elicited subthreshold responses, both in the axon and in the FN model. These results are not well described by the Hodgkin and Huxley 1952 model. Various different patterns of subthreshold responses, including chaotic dynamics, can be observed in both systems-the FN model and the axon-depending upon stimulus conditions. For some conditions action potentials are occasionally interspersed among the subthreshold events with randomly occurring interspike intervals. The randomness is directly attributable to the underlying subthreshold chaos-deterministic chaos-rather than to a stochastic noise source. We conclude that this mechanism may contribute to multimodal interspike interval histograms which have been observed from individual neurons throughout the nervous system.

Action Potentials↗

PubMed2004

The Lowbury lecture: behaviour in infection control.

The majority of healthcare-associated infections result from cross-transmission related to inappropriate patient-care practices. Improving practices frequently implies modifying healthcare workers' behaviour, a key challenge of today's infection control. To improve healthcare workers' compliance with practices, infection control should learn from the behavioural sciences. Social cognitive models can help to improve our understanding of human behaviour. Cognitive determinants that shape behaviour are acquired through the socialization process and are susceptible to change. Some models have been applied to evaluate predictors of health behaviour but, so far, none have been successfully applied to explain behaviour in the field of infection control. Successful strategies to improve infection control practices result from their multidimensional aspect. Similarly, social models that include several levels of cognitive determinants have more chance of success to explain change in behaviour. Concrete examples applied to infection control issues are presented, including special references to hand hygiene behaviour. The theory of ecological perspective, based on the idea that behaviour is viewed as being affected by and affecting multiple levels of influence, and that it both influences and is influenced by the social environment, seems promising to explain behaviour modification. Studies are needed to assess the key determinants of infection control practices and behaviour promotion among the different populations of healthcare workers, and to implement and evaluate the impact of the different components of multimodal programmes to promote optimal infection control practices.

Behavior↗

PubMed2025

Single-cell profiling of trabecular meshwork identifies mitochondrial dysfunction in a glaucoma model that is protected by vitamin B3 treatment.

Since the trabecular meshwork (TM) is central to intraocular pressure (IOP) regulation and glaucoma, a deeper understanding of its genomic landscape is needed. We present a multimodal, single-cell resolution analysis of mouse limbal cells (includes TM). In total, we sequenced 9,394 wild-type TM cell transcriptomes. We discovered three TM cell subtypes with characteristic signature genes validated by immunofluorescence on tissue sections and whole-mounts. The subtypes are robust, being detected in datasets for two diverse mouse strains and in independent data from two institutions. Results show compartmentalized enrichment of critical pathways in specific TM cell subtypes. Distinctive signatures include increased expression of genes responsible for 1) extracellular matrix structure and metabolism (TM1 subtype), 2) secreted ligand signaling to support Schlemm's canal cells (TM2), and 3) contractile and mitochondrial/metabolic activity (TM3). ATAC-sequencing data identified active transcription factors in TM cells, including LMX1B. Mutations in LMX1B cause high IOP and glaucoma. LMX1B is emerging as a key transcription factor for normal mitochondrial function and its expression is much higher in TM3 cells than other limbal cells. To understand the role of LMX1B in TM function and glaucoma, we single-cell sequenced limbal cells from Lmx1b V265D/+ mutant mice (2,491 TM cells). In V265D/+ mice, TM3 cells were uniquely affected by pronounced mitochondrial pathway changes. Mitochondria in TM cells of V265D/+ mice are swollen with a reduced cristae area, further supporting a role for mitochondrial dysfunction in the initiation of IOP elevation in these mice. Importantly, treatment with vitamin B3 (nicotinamide), to enhance mitochondrial function and metabolic resilience, significantly protected Lmx1b mutant mice from IOP elevation.

Journal Article↗

PubMed2006

A novel evolutionary drug scheduling model in cancer chemotherapy.

In this paper, we introduce a modified optimal control model of drug scheduling in cancer chemotherapy and a new adaptive elitist-population-based genetic algorithm (AEGA) to solve it. Working closely with an oncologist, we first modify the existing model, because its equation for the cumulative drug toxicity is inconsistent with medical knowledge and clinical experience. To explore multiple efficient drug scheduling policies, we propose a novel variable representation--a cycle-wise representation, and modify the elitist genetic search operators in the AEGA. The simulation results obtained by the modified model match well with the clinical treatment experiences, and can provide multiple efficient solutions for oncologists to consider. Moreover, it has been shown that the evolutionary drug scheduling approach is simple, and capable of solving complex cancer chemotherapy problems by adapting multimodal versions of evolutionary algorithms.

Algorithms↗

PubMed2005

Temporal evolution of mouse striatal gene expression following MPTP injury.

The gradual loss of striatal dopamine and dopaminergic neurons residing in the substantia nigra (SN) causes parkinsonism characterized by slow, halting movements, rigidity, and resting tremor when neuronal loss exceeds a threshold of approximately 80%. It is estimated that there is extensive compensation for several years prior to symptom onset, during which vulnerable neurons asynchronously die. Recent evidence would argue that much of the compensatory response of the nigrostriatal system is multimodal including both pre-synaptic and striatal mechanisms. Although parkinsonism may have multiple causes, the classic syndrome, Parkinson's disease (PD), is frequently modeled in small animals by repeated administration of the selective neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Because the MPTP model of PD recapitulates many of the known behavioral and pathological features of human PD, we asked whether the striatal cells of mice treated with MPTP in a semi-chronic paradigm enact a transcriptional program that would help elucidate the response to dopamine denervation. Our findings reveal a time-dependent dysregulation in the striatum of a set of genes whose products may impact both the viability and ability to communicate of dopamine neurons in the SN.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗