Altered cyclic nucleotide binding and pore opening in a diseased human HCN4 channel.

A growing number of nonsynonymous mutations in the human HCN4 channel gene, the major component of the funny channel of the sinoatrial node, are associated with disease but how they impact channel structure and function, and, thus, how they result in disease, is not clear for any of them. Here, we study the S672R mutation, in the cyclic nucleotide-binding domain of the channel, which has been associated with an inherited bradycardia in an Italian family. This may be the best studied of all known mutations, yet the underlying molecular and atomistic mechanisms remain unclear and controversial.

Binding and structural asymmetry governs ligand sensitivity in a cyclic nucleotide-gated ion channel.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open more easily when cAMP or cGMP bind to a domain in the intracellular C-terminus in each of four identical subunits. How sensitivity of the channels to these ligands is determined is not well understood. Here, we apply a mathematical model, which incorporates negative cooperativity, to gating and mutagenesis data available in the literature and combine the results with binding data collected using isothermal titration calorimetry.

Association of HLA-DRB1 alleles and anti-neutrophil cytoplasmic antibodies in Han and Uyghur patients with ulcerative colitis in China.

Objective: We aimed to study the association between HLA-DRB1 alleles and anti-neutrophil cytoplasmic antibodies (ANCA) among Uyghur and Han patients with ulcerative colitis (UC) in China.

Methods: Altogether 160 UC patients and 466 healthy controls of Uyghur and Han groups residing in the Xinjiang Uyghur Autonomous Region of China were included. HLA-DRB1 variants were identified from genomic DNA using polymerase chain reaction and gene sequencing.

A computational study of spike time reliability in two types of threshold dynamics.

Spike time reliability (STR) refers to the phenomenon in which repetitive applications of a frozen copy of one stochastic signal to a neuron trigger spikes with reliable timing while a constant signal fails to do so. Observed and explored in numerous experimental and theoretical studies, STR is a complex dynamic phenomenon depending on the nature of external inputs as well as intrinsic properties of a neuron. The neuron under consideration could be either quiescent or spontaneously spiking in the absence of the external stimulus.

Difference in DRB1* gene polymorphisms between Han and Uyghur ulcerative colitis patients in China.

Aim: To evaluate the association between HLA-DRB1 alleles and Han and Uyghur ulcerative colitis (UC) patients residing in the Xinjiang Uyghur Autonomous Region of China.

Methods: In this study, 102 UC patients (53 Han including 22 men and 31 women, and 49 Uyghur patients including 25 men and 24 women; aged 48.07 ± 15.

Simple models for quorum sensing: nonlinear dynamical analysis.

Quorum sensing refers to the change in the cooperative behavior of a collection of elements in response to the change in their population size or density. This behavior can be observed in chemical and biological systems. These elements or cells are coupled via chemicals in the surrounding environment.

Characterizing mixed mode oscillations shaped by noise and bifurcation structure.

Many neuronal systems and models display a certain class of mixed mode oscillations (MMOs) consisting of periods of small amplitude oscillations interspersed with spikes. Various models with different underlying mechanisms have been proposed to generate this type of behavior. Stochastic versions of these models can produce similarly looking time series, often with noise-driven mechanisms different from those of the deterministic models.

Inferring individual rules from collective behavior.

Social organisms form striking aggregation patterns, displaying cohesion, polarization, and collective intelligence. Determining how they do so in nature is challenging; a plethora of simulation studies displaying life-like swarm behavior lack rigorous comparison with actual data because collecting field data of sufficient quality has been a bottleneck. Here, we bridge this gap by gathering and analyzing a high-quality dataset of flocking surf scoters, forming well-spaced groups of hundreds of individuals on the water surface.

An integrated model of electrical spiking, bursting, and calcium oscillations in GnRH neurons.

The plasma membrane electrical activities of neurons that secrete gonadotropin-releasing hormone (GnRH) have been studied extensively. A couple of mathematical models have been developed previously to explain different aspects of these activities. The goal of this article is to develop a single model that accounts for the previously modeled experimental results and some more recent results that have not been accounted for.

A conceptual model for milling formations in biological aggregates.

Collective behavior of swarms and flocks has been studied from several perspectives, including continuous (Eulerian) and individual-based (Lagrangian) models. Here, we use the latter approach to examine a minimal model for the formation and maintenance of group structure, with specific emphasis on a simple milling pattern in which particles follow one another around a closed circular path.We explore how rules and interactions at the level of the individuals lead to this pattern at the level of the group.

Robust synchrony and rhythmogenesis in endocrine neurons via autocrine regulations in vitro and in vivo.

Episodic pulses of gonadotropin-releasing hormone (GnRH) are essential for maintaining reproductive functions in mammals. An explanation for the origin of this rhythm remains an ultimate goal for researchers in this field. Some plausible mechanisms have been proposed among which the autocrine-regulation mechanism has been implicated by numerous experiments.

A mathematical model for the actions of activin, inhibin, and follistatin on pituitary gonadotrophs.

The timed secretion of the luteinizing hormone (LH) and follicle stimulating hormone (FSH) from pituitary gonadotrophs during the estrous cycle is crucial for normal reproductive functioning. The release of LH and FSH is stimulated by gonadotropin releasing hormone (GnRH) secreted by hypothalamic GnRH neurons. It is controlled by the frequency of the GnRH signal that varies during the estrous cycle.

Stochastic phase dynamics and noise-induced mixed-mode oscillations in coupled oscillators.

Synaptically coupled neurons show in-phase or antiphase synchrony depending on the chemical and dynamical nature of the synapse. Deterministic theory helps predict the phase differences between two phase-locked oscillators when the coupling is weak. In the presence of noise, however, deterministic theory faces difficulty when the coexistence of multiple stable oscillatory solutions occurs.

Noise-induced coherence and network oscillations in a reduced bursting model.

The dynamics of the Hindmarsh-Rose (HR) model of bursting thalamic neurons is reduced to a system of two linear differential equations that retains the subthreshold resonance properties of the HR model. Introducing a reset mechanism after a threshold crossing, we turn this system into a resonant integrate-and-fire (RIF) model. Using Monte-Carlo simulations and mathematical analysis, we examine the effects of noise and the subthreshold dynamic properties of the RIF model on the occurrence of coherence resonance (CR).

A model for the pulsatile secretion of gonadotropin-releasing hormone from synchronized hypothalamic neurons.

Cultured gonadotropin-releasing hormone (GnRH) neurons have been shown to express GnRH receptors. GnRH binding to its receptors activates three types of G-proteins at increasing doses. These G-proteins selectively activate or inhibit GnRH secretion by regulating the intracellular levels of Ca2+ and cAMP.

The influences of Ih on temporal summation in hippocampal CA1 pyramidal neurons: a modeling study.

Recent experimental and theoretical studies have found that active dendritic ionic currents can compensate for the effects of electrotonic attenuation. In particular, temporal summation, the percentage increase in peak somatic voltage responses invoked by a synaptic input train, is independent of location of the synaptic input in hippocampal CA1 pyramidal neurons under normal conditions. This independence, known as normalization of temporal summation, is destroyed when the hyperpolarization-activated current, Ih, is blocked [Magee JC (1999a), Nature Neurosci.

Clustering in small networks of excitatory neurons with heterogeneous coupling strengths.

Excitatory coupling with a slow rise time destabilizes synchrony between coupled neurons. Thus, the fully synchronous state is usually unstable in networks of excitatory neurons. Phase-clustered states, in which neurons are divided into multiple synchronized clusters, have also been found unstable in numerical studies of excitatory networks in the presence of noise.