Enhancer mutations modulate the severity of chemotherapy-induced myelosuppression.

Non-small cell lung cancer is often diagnosed at advanced stages, and many patients are still treated with classical chemotherapy. The unselective nature of chemotherapy often results in severe myelosuppression. Previous studies showed that protein-coding mutations could not fully explain the predisposition to myelosuppression. Here, we investigate the possible role of enhancer mutations in myelosuppression susceptibility. We produced transcriptome and promoter-interaction maps (using HiCap) of three blood stem-like cell lines treated with carboplatin or gemcitabine. Taking advantage of publicly available enhancer datasets, we validated HiCap results in silico and in living cells using epigenetic CRISPR technology. We also developed a network approach for interactome analysis and detection of differentially interacting genes. Differential interaction analysis provided additional information on relevant genes and pathways for myelosuppression compared with differential gene expression analysis at the bulk level. Moreover, we showed that enhancers of differentially interacting genes are highly enriched for variants associated with differing levels of myelosuppression. Altogether, our work represents a prominent example of integrative transcriptome and gene regulatory datasets analysis for the functional annotation of noncoding mutations.

Compartment models for the electrical stimulation of retinal bipolar cells.

Bipolar cells of the retina are among the smallest neurons of the nervous system. For this reason, compared to other neurons, their delay in signaling is minimal. Additionally, the small bipolar cell surface combined with the low membrane conductance causes very little attenuation in the signal from synaptic input to the terminal. The existence of spiking bipolar cells was proven over the last two decades, but until now no complete model including all important ion channel types was published. The present study amends this and analyzes the impact of the number of model compartments on simulation accuracy. Characteristic features like membrane voltages and spike generation were tested and compared for one-, two-, four- and 117-compartment models of a macaque bipolar cell. Although results were independent of the compartment number for low membrane conductances (passive membranes), nonlinear regimes such as spiking required at least a separate axon compartment. At least a four compartment model containing the functionally different segments dendrite, soma, axon and terminal was needed for understanding signaling in spiking bipolar cells. Whereas for intracellular current application models with small numbers of compartments showed quantitatively correct results in many cases, the cell response to extracellular stimulation is sensitive to spatial variation of the electric field and accurate modeling therefore demands for a large number of short compartments even for passive membranes.

Excitation energy transport with noise and disorder in a model of the selectivity filter of an ion channel.

A selectivity filter is a gate in ion channels that is responsible for the selection and fast conduction of particular ions across the membrane (with high throughput rates of 108 ions s-1 and a high 1:104 discrimination rate between ions). It is made of four strands as the backbone, and each strand is composed of sequences of five amino acids connected by peptide units H-N-C=O in which the main molecules in the backbone that interact with ions in the filter are carbonyl (C=O) groups that mimic the transient interactions of ion with binding sites during ion conduction. It has been suggested that quantum coherence and possible emergence of resonances in the backbone carbonyl groups may play a role in mediating ion conduction and selectivity in the filter. Here, we investigate the influence of noise and disorder on the efficiency of excitation energy transfer (EET) in a linear harmonic chain of N = 5 sites with dipole-dipole couplings as a simple model for one P-loop strand of the selectivity filter backbone in biological ion channels. We include noise and disorder inherent in real biological systems by including spatial disorder in the chain, and random noise within a weak coupling quantum master equation approach. Our results show that disorder in the backbone considerably reduces EET, but the addition of noise helps to recover high EET for a wide range of system parameters. Our analysis may help for better understanding of the coordination of ions in the filter as well as the fast and efficient functioning of the selectivity filters in ion channels.

Impact of Electrode Position on the Elicitation of Sodium Spikes in Retinal Bipolar Cells.

Bipolar cells of the magnocellular pathway in the primate retina can generate action potentials because they have an axonal segment with high sodium channel density, comparable to the sodium channel band in retinal ganglion cells or pyramidal cells. The similarity between the non-human primate and the human retina is of interest for the research on retinal implants for the blind, and especially, the conditions to elicit sodium spikes in bipolar cells using extracellular stimulation. A comparison of excitation characteristics of three model neurons, a bipolar cell, a retinal ganglion cell, and a cortical pyramidal cell, demonstrates the similarities and differences regarding stimulation with microelectrodes. Moving a microelectrode parallel to the axon of a neuron commonly allows to generate spikes for every position - and this rule holds both for cathodic and anodic pulses. However, for the simulated bipolar cell anodic pulses cannot generate sodium spikes directly. Further, there is only a small region for electrode placing where extracellular cathodic stimulation causes direct spike initiation in the sodium channel band. For all other positions, a sodium spike can only be generated by antidromic current flow originating from strongly depolarized terminals.

Noise assisted excitation energy transfer in a linear model of a selectivity filter backbone strand.

In this paper, we investigate the effect of noise and disorder on the efficiency of excitation energy transfer (EET) in a N = 5 sites linear chain with 'static' dipole-dipole couplings. In fact, here, the disordered chain is a toy model for one strand of the selectivity filter backbone in ion channels. It has recently been discussed that the presence of quantum coherence in the selectivity filter is possible and can play a role in mediating ion-conduction and ion-selectivity in the selectivity filter. The question is 'how a quantum coherence can be effective in such structures while the environment of the channel is dephasing (i.e. noisy)?' Basically, we expect that the presence of the noise should have a destructive effect in the quantum transport. In fact, we show that such expectation is valid for ordered chains. However, our results indicate that introducing the dephasing in the disordered chains leads to the weakening of the localization effects, arising from the multiple back-scatterings due to the randomness, and then increases the efficiency of quantum energy transfer. Thus, the presence of noise is crucial for the enhancement of EET efficiency in disordered chains. We also show that the contribution of both classical and quantum mechanical effects are required to improve the speed of energy transfer along the chain. Our analysis may help for better understanding of fast and efficient functioning of the selectivity filters in ion channels.