Search PubMed⌕ Search

Biomedical subjects

Paul Dean

Publications and source records attributed to Paul Dean.

At least 19 recordsLinked to original sources
PubMed2007

Recurrent cerebellar loops simplify adaptive control of redundant and nonlinear motor systems.

We have described elsewhere an adaptive filter model of cerebellar learning in which the cerebellar microcircuit acts to decorrelate motor commands from their sensory consequences (Dean, Porrill, & Stone, 2002). Learning stability required the cerebellar microcircuit to be embedded in a recurrent loop, and this has been shown to lead to a simple and modular adaptive control architecture when applied to the linearized 3D vestibular ocular reflex (Porrill, Dean, & Stone, 2004). Here we investigate the properties of recurrent loop connectivity in the case of redundant and nonlinear motor systems and illustrate them using the example of kinematic control of a simulated two-joint robot arm. We demonstrate that (1) the learning rule does not require unavailable motor error signals or complex neural reference structures to estimate such signals (i.e., it solves the motor error problem) and (2) control of redundant systems is not subject to the nonconvexity problem in which incorrect average motor commands are learned for end-effector positions that can be accessed in more than one arm configuration. These properties suggest a central functional role for the closed cerebellar loops, which have been shown to be ubiquitous in motor systems (e.g., Kelly & Strick, 2003).

Adaptation, Physiological↗
PubMed2006

Response linearity determined by recruitment strategy in detailed model of nictitating membrane control.

Many models of eyeblink conditioning assume that there is a simple linear relationship between the firing patterns of neurons in the interpositus nucleus and the time course of the conditioned response (CR). However, the complexities of muscle behaviour and plant dynamics call this assumption into question. We investigated the issue by implementing the most detailed model available of the rabbit nictitating membrane response (Bartha and Thompson in Biol Cybern 68:135-143, 1992a and in Biol Cybern 68:145-154, 1992b), in which each motor unit of the retractor bulbi muscle is represented by a Hill-type model, driven by a non-linear activation mechanism designed to reproduce the isometric force measurements of Lennerstrand (J Physiol 236:43-55, 1974). Globe retraction and NM extension are modelled as linked second order systems. We derived versions of the model that used a consistent set of SI units, were based on a physically realisable version of calcium kinetics, and used simulated muscle cross-bridges to produce force. All versions showed similar non-linear responses to two basic control strategies. (1) Rate-coding with no recruitment gave a sigmoidal relation between control signal and amplitude of CR, reflecting the measured relation between isometric muscle force and stimulation frequency. (2) Recruitment of similar strength motor units with no rate coding gave a sublinear relation between control signal and amplitude of CR, reflecting the increase in muscle stiffness produced by recruitment. However, the system response could be linearised by either a suitable combination of rate-coding and recruitment, or by simple recruitment of motor units in order of (exponentially) increasing strength. These plausible control strategies, either alone or in combination, would in effect present the cerebellum with the simplified virtual plant that is assumed in many models of eyeblink conditioning. Future work is therefore needed to determine the extent to which motor neuron firing is in fact linearly related to the nictitating membrane response.

Animals↗
PubMed2006

Potent diarrheagenic mechanism mediated by the cooperative action of three enteropathogenic Escherichia coli-injected effector proteins.

Enteropathogenic Escherichia coli (EPEC) induces a severe watery diarrhea responsible for several hundred thousand infant deaths each year by a process correlated with the loss (effacement) of absorptive microvilli. Effacement is linked to the locus of enterocyte effacement pathogenicity island that encodes an "injection system," "effector" proteins, and the Intimin outer membrane protein. Here, we reveal that effacement (i) is a two-step process, (ii) requires the cooperative action of three injected effectors (Map, EspF, and Tir) as well as Intimin, and (iii) leads to the retention, not release (into the extracellular milieu), of the detached microvillar material. We also discover that EPEC rapidly inactivates the sodium-d-glucose cotransporter (SGLT-1) by multiple mechanisms. Indeed, the finding that one mechanism occurs more rapidly than microvilli effacement provides a plausible explanation for the rapid onset of severe watery diarrhea, given the crucial role of SGLT-1 in the daily uptake of approximately 6 liters of fluids from the normal intestine. The importance of SGLT-1 in the disease process is supported by severe EPEC diarrheal cases being refractory to oral rehydration therapy (dependent on SGLT-1 function). Moreover, the identification of effector activities that alter microvilli structure and SGLT-1 function provides new tools for studying the underlying regulatory processes.

Adhesins, Bacterial↗
PubMed2006

The enteropathogenic Escherichia coli EspF effector molecule inhibits PI-3 kinase-mediated uptake independently of mitochondrial targeting.

Delivery of effector molecules into LMme(v) macrophages by enteropathogenic Escherichia coli, via its type three secretion system (T3SS), inhibits bacterial uptake by a phosphatidylinositol-3 (PI-3) kinase-dependent pathway. The T3SS system, encoded by the locus of enterocyte effacement (LEE) pathogenicity island, delivers LEE- and non-LEE-encoded effector proteins into host cells. Previous studies discounted essential roles for the LEE-encoded Map, EspF, Tir or Intimin proteins in this process but correlated it with loss of phosphorylation of the PI-3 kinase substrate, Akt (Celli et al., 2001, EMBO J 20: 1245-1258). Given the more recent finding that these bacterial proteins are multifunctional and can act together to subvert host cellular processes, we generated a quadruple deletion mutant (Map, Tir, EspF and Intimin deficient) to unearth any cooperativity in inhibiting uptake. The quadruple mutant was as defective as the T3SS-defective strain at preventing bacterial uptake with further studies revealing a surprising dependence on EspF but not Map, Tir or Intimin. Subversive activities previously associated with EspF are disruption of epithelial barrier function and programmed cell death, with the latter linked to EspF targeting mitochondria. Interestingly, the C-terminal domain possesses a polyproline motif associated with protein-protein interactions. We demonstrate that EspF-mediated inhibition of PI-3 kinase-dependent uptake: (i) is independent of mitochondrial targeting, (ii) requires the N-terminal domain with and (iii) the C-terminal domain is sufficient to disrupt barrier function but not inhibition of bacterial uptake. Moreover, loss of PI-3 kinase-dependent phosphorylation of Akt and gross changes in host phosphotyrosine protein profiles could not be linked to inhibition of the PI-3 kinase-dependent uptake process.

Adhesins, Bacterial↗
PubMed2005

EPEC's weapons of mass subversion.

Enteropathogenic and enterohaemorrhagic Escherichia coli are closely related enteric pathogens whose ability to cause disease in humans is linked with a capacity to deliver bacterial 'effector' proteins into host epithelia to alter cellular physiology. Although the essential role of the locus of enterocyte effacement (LEE) pathogenicity island, which encodes effector proteins and the delivery machinery, has been established, more recent studies are uncovering additional layers of complexity. This is illustrated by the emerging multifunctional nature of the effectors and their ability to work together in redundant, synergistic and antagonistic relationships. Furthermore, new virulence-associated factors are continually being uncovered that are encoded outside the LEE pathogenicity island, some of which are not injected into host cells.

Epithelial Cells↗
PubMed2005

Evidence for wide range of time scales in oculomotor plant dynamics: implications for models of eye-movement control.

Oculomotor-plant dynamics are not well characterised, despite their importance for modelling eye-movement control. We analysed the time course of the globe's return after horizontal displacements in three rhesus monkeys lightly anaesthetised with ketamine. The eye-position traces were well fitted by a sum of four exponentials (time constants 0.012, 0.099, 0.46, 7.8 s). The two long time-constant terms accounted for 25% of plant compliance, and led to a model that accounted for hitherto unexplained features of ocular motoneuron firing such as (i) hysteresis, and (ii) the inability of a 2 time-constant model to fit data for both fast and slow eye-movements.

Adaptation, Physiological↗
PubMed2005

Report on a workshop concerning the cerebellum and motor learning, held in St Louis October 2004.

A one-day meeting on the cerebellum and motor learning was held in St Louis (October 2004), to address issues arising from a previous larger meeting (Tuebingen, June 2004). The learning tasks considered were VOR adaptation, saccadic adaptation and eyeblink conditioning. A theoretical development was reported that indicated how the cerebellum could use sensory error signals for adaptive control, by decorrelating them from an efferent copy of motor commands. The main topics for discussion were the nature of the error signals actually used by the cerebellum, and the evidence for multiple sites of synaptic plasticity. Reports of studies on VOR adaptation confirmed the presence of error signals in addition to retinal slip, in particular the eye-movement related simple-spike firing of floccular PCs. This firing appears to drive synaptic plasticity in the vestibular nuclei. From a theoretical perspective, a second site of plasticity in the brainstem has two advantages: it improves the high-frequency performance of the VOR given a delayed slip signal, and it allows VOR adaptation when smooth pursuit effectively removes the retinal slip signal. In contrast, some of the physiological data reported on saccadic adaptation seemed incompatible with current theoretical ideas about error signals. However, since other reported data were broadly consistent with those ideas, an important area of experimental disagreement was identified. Furthermore, behavioural studies indicated the presence of multiple sites of plasticity, consistent with earlier lesion studies that suggested one such site within cerebellar cortex and another outside it. Data from eyeblink conditioning suggested that the predictability of the error signal was important. Related ideas have previously emerged from studies of skeletal movement, but their theoretical implications for the cerebellar algorithm have yet to be fully explored. Finally, the long-standing controversy concerning sites of plasticity in eyeblink conditioning illustrated the technical difficulties involved in tracking down such sites.

Adaptation, Physiological↗
PubMed2005

Enteropathogenic Escherichia coli (EPEC) effector-mediated suppression of antimicrobial nitric oxide production in a small intestinal epithelial model system.

In vivo studies with the mouse-specific member of the attaching and effacing (A/E) family of pathogens raised the possibility that these non-invasive enteric pathogens can specifically inhibit inducible nitric oxide synthase (iNOS) expression to prevent the production of antimicrobial nitric oxide (NO). In this study we use polarized Caco-2 cells, a model of human small intestinal epithelia, to (i) demonstrate conclusively that an A/E member, human specific enteropathogenic Escherichia coli (EPEC), can inhibit cytokine-induced iNOS expression, (ii) show that this activity is dependent on the delivery of effector molecules into host cells and (iii) investigate the mechanism of inhibition. Analysis of the level of iNOS-related mRNA, protein and NO production demonstrated that EPEC can inhibit iNOS expression at the transcriptional, by direct and indirect mechanisms, and post-transcriptional levels. This transcriptional block was linked to the failure of the iNOS-related transcriptional factor NF-kappaB, but not STAT1, to undergo phosphorylation-associated activation. A selective pressure to prevent iNOS production was evidenced by the finding that iNOS activity had a potent antimicrobial effect on adherent but not non-adherent bacteria. Moreover, given the central role NF-kappaB plays in transcribing genes associated with early host immune responses, this inhibitory mechanism presumably represents an important role in pathogenesis. Our study also provides insights into the nature of NO production in response to bacterial infection as well as the role of the locus of enterocyte effacement (LEE)-encoded effector molecules in inhibiting iNOS expression.

Bacterial Adhesion↗
PubMed2004

Recurrent cerebellar architecture solves the motor-error problem.

Current views of cerebellar function have been heavily influenced by the models of Marr and Albus, who suggested that the climbing fibre input to the cerebellum acts as a teaching signal for motor learning. It is commonly assumed that this teaching signal must be motor error (the difference between actual and correct motor command), but this approach requires complex neural structures to estimate unobservable motor error from its observed sensory consequences. We have proposed elsewhere a recurrent decorrelation control architecture in which Marr-Albus models learn without requiring motor error. Here, we prove convergence for this architecture and demonstrate important advantages for the modular control of systems with multiple degrees of freedom. These results are illustrated by modelling adaptive plant compensation for the three-dimensional vestibular ocular reflex. This provides a functional role for recurrent cerebellar connectivity, which may be a generic anatomical feature of projections between regions of cerebral and cerebellar cortex.

Cerebellum↗
PubMed2004

Consistency of Listing's law and reciprocal innervation with pseudo-inverse control of eye position in 3-D.

Pseudo-inverse kinematics, under which small movements are produced by the least possible sum square changes in motor command, has been proposed as a unifying principle for the elimination of redundancy in general biological motor control systems (Pellionsz 1984) and in particular in the oculomotor system (Daunicht 1988, 1991). We have noted elsewhere (Dean et al, 1999) that this principle is incomplete without first specifying a parameterisation of motor command space and we proposed that the relevant motor-command parameter is summed motor unit firing rate. Under this assumption we were able to show that pseudo-inverse control of the horizontal extraocular muscles is consistent with available motor pool firing rate data. In this paper we extend this result to three dimensions and six extraocular muscles, showing that pseudo-inverse control is consistent with published firing rate date for a realistic model of oculomotor kinematics. We suggest that pseudo-inverse control may represent a common currency for modular control of many degree of freedom systems while its implementation may be a consequences of the minimisation of a more ecologically relevant parameter such as post-saccadic retinal slip.

Biomechanical Phenomena↗
PubMed2004

Microbial infection causes the appearance of hemocytes with extreme spreading ability in monolayers of the tobacco hornworm Manduca sexta.

The ability to adhere to and spread on a surface is a common property of insect blood cells. Spreading on a glass surface by insect hemocytes is often used as a measure of immune fitness that can be inhibited by some insect pathogens and parasites. Here, we report that upon infection of the tobacco hornworm Manduca sexta with either a fungus (Beauveria bassiana) or a bacterium (Photorhabdus luminescens), a new type of hemocyte, not previously observed in healthy insects, was found in hemocyte monolayers. These cells have a distinctive morphology, characterised by extreme spreading ability. They achieve a diameter of up to 120 microm after 1 h on glass coverslips and are therefore extremely thin. These hyper-spreading cells first appear in fungal-infected insects prior to hyphal growth. Their numbers later fall to zero as the pathogen begins to proliferate. The same hyper-spreading cells are induced after a 24 h delay following an injection of laminarin, a source of the fungal cell wall polymer beta-1,3-glucans. Wounding, on the other hand, did not cause the appearance of hyper-spreading cells. Evidence is presented here that is consistent with these spreading cells having a role in the cellular immune response of nodule formation.

Animals↗
PubMed2004

Visual awareness and the cerebellum: possible role of decorrelation control.

The two roles in awareness most often suggested for the cerebellum are (i) keeping the details of motor skills away from forebrain computation, and (ii) signaling to the forebrain when a sensory event is not predictable from prior motor commands. However, it is unclear how current models of the cerebellum could carry out these roles. Their architecture, based on the seminal ideas of Marr and Albus, appears to need 'motor error' to learn correct motor commands. However, since motor error is the difference between the actual motor command and what the command should have been, it is a signal unavailable to the organism in principle. We propose a possible solution to this problem, termed decorrelation control, in which the cerebellum learns to decorrelate the motor command sent to the muscles from the sensory consequences of motor error. This method was tested in a linear model of oculomotor plant compensation in the vestibulo-ocular reflex. A copy of the eye-movement command was sent as mossy-fiber input to the flocculus, represented as a simple adaptive filter version of the Marr-Albus architecture. The sensory consequences of motor error were retinal slip, delivered as climbing fiber input to the flocculus. A standard anti-Hebbian learning rule was used to decorrelate the two. Simulations of the linearized problem showed the method to be effective and robust for plant compensation. Decorrelation control is thus a candidate algorithm for the basic cerebellar microcircuit, indicating how it could achieve motor learning using only signals available to the system. Such learning might then enable the cerebellum to free up visual awareness, and also, by providing a sensory signal decorrelated from motor command, supply awareness with crucial information about the external world.

Algorithms↗
PubMed2004

Intestinal barrier dysfunction by enteropathogenic Escherichia coli is mediated by two effector molecules and a bacterial surface protein.

The human intestinal pathogen, enteropathogenic Escherichia coli (EPEC), causes diarrhoeal disease by a mechanism that is dependent on the injection of effector proteins into the host cell. One effector, EspF, is reported to be required for EPEC to disrupt tight junction integrity of intestinal cells and increase the paracellular movement of molecules, which is likely to contribute to diarrhoea. Here, we show that not one but three EPEC-encoded factors play important roles in this process. Thus, the Map (Mitochondria-associated protein) effector is shown to: (i) be as essential as EspF for disrupting intestinal barrier function, (ii) be able to function independently of EspF, (iii) alter tight junction structure and (iv) mediate these effects in the absence of mitochondrial targeting. Additionally, the outer membrane protein Intimin is shown to be crucial for EspF and Map to disrupt the intestinal barrier function. This function of Intimin is completely independent of its interaction with its known receptor Tir, revealing a physiologically relevant requirement for Intimin interaction with alternative receptor(s). This work demonstrates that EPEC uses multiple multifunctional proteins to elicit specific responses in intestinal cells and that EPEC can control the activity of its injected effector molecules from its extracellular location.

Adhesins, Bacterial↗
PubMed2002

Decorrelation control by the cerebellum achieves oculomotor plant compensation in simulated vestibulo-ocular reflex.

We introduce decorrelation control as a candidate algorithm for the cerebellar microcircuit and demonstrate its utility for oculomotor plant compensation in a linear model of the vestibulo-ocular reflex (VOR). Using an adaptive-filter representation of cerebellar cortex and an anti-Hebbian learning rule, the algorithm learnt to compensate for the oculomotor plant by minimizing correlations between a predictor variable (eye-movement command) and a target variable (retinal slip), without requiring a motor-error signal. Because it also provides an estimate of the unpredicted component of the target variable, decorrelation control can simplify both motor coordination and sensory acquisition. It thus unifies motor and sensory cerebellar functions.

Algorithms↗
PubMed2002

Modulation by eicosanoid biosynthesis inhibitors of immune responses by the insect Manduca sexta to the pathogenic fungus Metarhizium anisopliae.

Metarhizium anisopliae conidia (spores) reduced weight gain and caused death when injected into Manduca sexta larvae. When the fungus was co-injected with the eicosanoid biosynthesis inhibitor dexamethasone, larval weight gain was further reduced and mortality increased. These effects were reversed when dexamethasone was given together with the eicosanoid precursor arachidonic acid (AA). Similarly, treatment with other eicosanoid biosynthesis inhibitors (esculetin, phenidone, ibuprofen, and indomethacin) with differing modes of action enhanced the reduction in weight gain caused by mycosis. Injection of M. anisopliae conidia induced nodule formation in vivo; nodule numbers were reduced by dexamethasone, and restored by AA. Incubation of hemocytes with conidia caused microaggregation of hemocytes (indicative of nodule formation) in vitro and this was inhibited by dexamethasone, suggesting that dexamethasone acts directly on hemocytes, although inhibition was only partially reversed by AA. We suggest that the M. sexta immune response to fungal pathogens is normally modulated by physiological systems that include eicosanoid biosynthesis. This is the first demonstration that the virulence of a fungal entomopathogen can be enhanced by compromising the insect host's immune system.

Animals↗
PubMed2002

Bacterial infection of a model insect: Photorhabdus luminescens and Manduca sexta.

Invertebrates, including insects, are being developed as model systems for the study of bacterial virulence. However, we understand little of the interaction between bacteria and specific invertebrate tissues or the immune system. To establish an infection model for Photorhabdus, which is released directly into the insect blood system by its nematode symbiont, we document the number and location of recoverable bacteria found during infection of Manduca sexta. After injection into the insect larva, P. luminescens multiplies in both the midgut and haemolymph, only later colonizing the fat body and the remaining tissues of the cadaver. Bacteria persist by suppressing haemocyte-mediated phagocytosis and culture supernatants grown in vitro, as well as plasma from infected insects, suppress phagocytosis of P. luminescens. Using GFP-labelled bacteria, we show that colonization of the gut begins at the anterior of the midgut and proceeds posteriorly. Within the midgut, P. luminescens occupies a specific niche between the extracellular matrix and basal membrane (lamina) of the folded midgut epithelium. Here, the bacteria express the gut-active Toxin complex A (Tca) and an RTX-like metalloprotease PrtA. This close association of the bacteria with the gut, and the production of toxins and protease, triggers a massive programmed cell death of the midgut epithelium.

Animals↗