Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

No abstract

Hypodontia and malformation are almost regular dental characteristics in patients suffering from ectodermal dysplasia. The distribution of absent teeth deviates remarkably from the general population. Treatment requires an interdisciplinary approach including orthodontics, prosthodontics and oral surgery.

We demonstrate the existence of generalized synchronization in systems that act as mediators between two dynamical units that, in turn, show complete synchronization with each other. These are the so-called relay systems. Specifically, we analyze the Lyapunov spectrum of the full system to elucidate when complete and generalized synchronization appear. We show that once a critical coupling strength is achieved, complete synchronization emerges between the systems to be synchronized, and at the same point, generalized synchronization with the relay system also arises. Next, we use two nonlinear measures based on the distance between phase-space neighbors to quantify the generalized synchronization in discretized time series. Finally, we experimentally show the robustness of the phenomenon and of the theoretical tools here proposed to characterize it. Synchronization is a common phenomenon in a diversity of natural and technological systems [1]. Synchrony, however, is not always achieved spontaneously, and reaching or maintaining a synchronous state often requires an external action. An elegant way to enhance synchronization is the use of relay units between the systems to be synchronized [see Fig. 1(a)]. Relay synchronization (RS) consists of achieving complete synchronization (CS) of two dynamical systems by indirect coupling through a relay unit, whose dynamics does not necessary join the synchronous state. RS is especially useful in bidirectionally coupled systems with a certain delay in the coupling line. In these cases, indeed, the coupling delay may induce instability of the synchronous state [2], which can be restored again thanks to a relay system. Lasers [3,4] and electronics circuits [5] have been the benchmark for experimental demonstration of the feasibility of RS, showing its robustness against noise or parameter mismatch. In semiconductor lasers, for instance, zero-lag synchronization between two delaycoupled oscillators can be achieved by relaying the dynamics via a third mediating element, which surprisingly lags behind the synchronized outer elements. With electronic circuits, RS has been used as a technique for transmitting and recovering encrypted messages, which can be sent bidirectionally and simultaneously [6]. Apart from its technological applications, RS has also been proposed as a possible mechanism at the basis of isochronous synchronization between distant areas of the brain [7]. Despite such evidence of RS, there are still open questions of a fundamental nature. The main issue is to characterize properly the relationship, established in RS, between the dynamics of the relay system and that of the synchronized systems. When a certain delay is introduced in the coupling lines, lag synchronization has been reported [3,4]. Nevertheless, relay units may have certain parameter mismatch [8] or even be completely different systems [5], thus having dynamics with unclear a priori relationship with the systems they are synchronizing.In this paper, we give evidence that RS in fact corresponds to t...

The dynamics of neurons is characterized by a variety of different spiking patterns in response to external stimuli. One of the most important transitions in neuronal response patterns is the transition from tonic firing to burst discharges, i.e., when the neuronal activity changes from single spikes to the grouping of spikes. An increased number of interspike-interval sequences of specific temporal correlations was detected in anticipation of temperature induced tonic-to-bursting transitions in both, experimental impulse recordings from hypothalamic brain slices and numerical simulations of a stochastic model. Analysis of the modelling data elucidates that the appearance of such patterns can be related to particular system dynamics in the vicinity of the period-doubling bifurcation. It leads to a nonlinear response on de- and hyperpolarizing perturbations introduced by noise. This explains why such particular patterns can be found as reliable precursors of the neurons' transition to burst discharges.