Cavity master equation for the continuous time dynamics of discrete-spin models.

We present an alternate method to close the master equation representing the continuous time dynamics of interacting Ising spins. The method makes use of the theory of random point processes to derive a master equation for local conditional probabilities. We analytically test our solution studying two known cases, the dynamics of the mean-field ferromagnet and the dynamics of the one-dimensional Ising system. We present numerical results comparing our predictions with Monte Carlo simulations in three different models on random graphs with finite connectivity: the Ising ferromagnet, the random field Ising model, and the Viana-Bray spin-glass model.

Window into the complexities of chromosome interactomes.

DNA is folded into increasingly complex yet highly mobile structures to organize the chromosomes. In the interphase nucleus, chromosomes or part of the chromosomes encounter one another preferentially at the boundaries between chromosomal territories. Although this situation implies that the preferred chromosomal neighborhood is a key determinant of interactions between chromosomes, what this means in functional terms is currently not well understood. Using the H19 imprinting control region as a window, it has been demonstrated that epigenetic information of the primary chromatin fiber has dual functions. Thus, epigenetic marks not only influence the proximity between chromatin fibers but also transfer epigenetic states between chromatin fibers both in cis and in trans. High-throughput sequence and DNA fluorescence it situ hybridization (FISH) analyses reveal that these features require chromatin movements that are restricted in space and time. The mechanisms involved in the establishment of chromosome interactomes may provide insight of fundamental importance into pivotal regulatory processes in the nucleus, such as the coordination of transcriptional programs and replication timing.

Epigenetics as a first exit problem.

We develop a framework to discuss the stability of epigenetic states as first exit problems in dynamical systems with noise. We consider in particular the stability of the lysogenic state of the lambda prophage. The formalism defines a quantitative measure of robustness of inherited states.

Modeling of substance P and 5-HT induced synaptic plasticity in the lamprey spinal CPG: consequences for network pattern generation.

Consequences of synaptic plasticity in the lamprey spinal CPG are analyzed by means of simulations. This is motivated by the effects substance P (a tachykinin) and serotonin (5-hydroxytryptamin; 5-HT) have on synaptic transmission in the locomotor network. Activity-dependent synaptic depression and potentiation have recently been shown experimentally using paired intracellular recordings. Although normally activity-dependent plasticity presumably does not contribute to the patterning of network activity, this changes in the presence of the neuromodulators substance P and 5-HT, which evoke significant plasticity. Substance P can induce a faster and larger depression of inhibitory connections but potentiation of excitatory inputs, whereas 5-HT induces facilitation of both inhibitory and excitatory inputs. Changes in the amplitude of the first postsynaptic potential are also seen. These changes could thus be a potential mechanism underlying the modulatory role these substances have on the rhythmic network activity. The aim of the present study has been to implement the activity dependent synaptic depression and facilitation induced by substance P and 5-HT into two alternative models of the lamprey spinal locomotor network, one relying on reciprocal inhibition for bursting and one in which each hemicord is capable of oscillations. The consequences of the plasticity of inhibitory and excitatory connections are then explored on the network level. In the intact spinal cord, tachykinins and 5-HT, which can be endogenously released, increase and decrease the frequency of the alternating left-right burst pattern, respectively. The frequency decreasing effect of 5-HT has previously been explained based on its conductance decreasing effect on K(Ca) underlying the postspike afterhyperpolarization (AHP). The present simulations show that short-term synaptic plasticity may have strong effects on frequency regulation in the lamprey spinal CPG. In the network model relying on reciprocal inhibition, the observed effects substance P and 5-HT have on network behavior (i.e., a frequency increase and decrease respectively) can to a substantial part be explained by their effects on the total extent and time dynamics of synaptic depression and facilitation. The cellular effects of these substances will in the 5-HT case further contribute to its network effect.

Modeling postural control in the lamprey.

A phenomenological model of the mechanism of stabilization of the body orientation during locomotion (dorsal side up) in the lamprey is presented. The mathematical modeling is based on experimental results obtained during investigations of postural control in lampreys using a combined in vivo and robotics approach. The dynamics of the model agree qualitatively with the experimental data. It is shown by computer simulations that postural correction commands from reticulospinal neurons provide information sufficient to stabilize body orientation in the lamprey. The model is based on differences between the effects exerted by the vestibular apparatus on the left and the right side.

Activity-dependent modulation of adaptation produces a constant burst proportion in a model of the lamprey spinal locomotor generator.

The neuronal network underlying lamprey swimming has stimulated extensive modelling on different levels of abstraction. The lamprey swims with a burst frequency ranging from 0.3 to 8-10 Hz with a rostrocaudal lag between bursts in each segment along the spinal cord. The swimming motor pattern is characterized by a burst proportion that is independent of burst frequency and lasts around 30%-40% of the cycle duration. This also applies in preparations in which the reciprocal inhibition in the spinal cord between the left and right side is blocked. A network of coupled excitatory neurons producing hemisegmental oscillations may form the basis of the lamprey central pattern generator (CPG). Here we explored how such networks, in principle, could produce a large frequency range with a constant burst proportion. The computer simulations of the lamprey CPG use simplified, graded output units that could represent populations of neurons and that exhibit adaptation. We investigated the effect of an active modulation of the degree of adaptation of the CPG units to accomplish a constant burst proportion over the whole frequency range when, in addition, each hemisegment is assumed to be self-oscillatory. The degree of adaptation is increased with the degree of stimulation of the network. This will make the bursts terminate earlier at higher burst rates, allowing for a constant burst proportion. Without modulated adaptation the network operates in a limited range of swimming frequencies due to a progressive increase of burst duration with increasing background stimulation. By introducing a modulation of the adaptation, a broad burst frequency range can be produced. The reciprocal inhibition is thus not the primary burst terminating factor, as in many CPG models, and it is mainly responsible for producing alternation between the left and right sides. The results are compared with the Morris-Lecar oscillator model with parameters set to produce a type A and type B oscillator, in which the burst durations stay constant or increase, respectively, when the background stimulation is increased. Here as well, burst duration can be controlled by modulation of the slow variable in a similar way as above. When oscillatory hemisegmental networks are coupled together in a chain a phase lag is produced. The production of a phase lag in chains of such oscillators is compared with chains of Morris-Lecar relaxation oscillators. Models relating to the intact versus isolated spinal cord preparation are discussed, as well as the role of descending inhibition.

A longitudinal study of children with a family history of strabismus: factors determining the incidence of strabismus.

A longitudinal study of ocular refraction, position, and fixation was performed in children with a family history of strabismus. The children were examined at regular intervals between 3 months and 4 years of age, and the results are discussed in terms of changes in refraction between different ages and correlations between refraction and development of strabismus and amblyopia. Six of 34 children (17.6%) developed constant or intermittent esotropia. The strabismus was first noted between 18 and 30 months of age except in one case. All esotropic children were 4 dioptres hypermetropic or more at 6 months, and their hypermetropia remained almost unchanged through the years. Seven additional children were 4 dioptres or more hypermetropic at 6 months but did not develop a squint. In contrast to the squinting children the hypermetropia in these children changed towards emmetropia. This emmetropisation was most pronounced during the first 2 years of age. The implications of these results for an early diagnosis of strabismus amblyopia are discussed.

A multicentre study of the effect and tolerance of Ocusert-P-40.

The suitability of treatment with Ocusert-P-40, a lamellar system inserted in the eye and allowing the constant release of pilocarpine, was studied in a group of patients (age range 43-83 years) with wide-angle glaucoma. Those patients completing a 3-week trial were included in an 8 month follow-up study in which the long-term efficacy and tolerance of Ocusert were studied. Treatment was discontinued in 13 of the 42 patients in the 3-week trial owing to initial irritation and retention problems (n = 11) or unsatisfactory control of the intraocular pressure (I.O.P.) (n = 2). Of the 29 patients entering the long-term study, two were withdrawn because of tolerance problems and two as a result of unsatisfactory control of I.O.P. The 25 patients completing the study considered the Ocusert system more convenient and less liable to produce troublesome side-effects than their previous therapy. Ocusert was best tolerated by the younger patients.

Signs in the fundus oculi and arterial hypertension: unconventional assessment and significance.

Signs in the fundus oculi, long regarded as prognostic in hypertensive disease, have been shown to be subject to gross observer error and bias when assessed in conventional ways. The authors describe unconventional ways of assessing diminution of vascularity in a population sample of men aged 50 and also in a group of hospital patients.They show that a method simple enough to be learnt by a schoolboy in 20 minutes gives information that is more precise and less biased than data obtained by more conventional means. Standards can be prepared and the information is quantitative.The unconventional data are closely related to the level of hypertension. Some anomalies in the data, possible ways of improving them and ways of testing their relation to prognosis are discussed.