Model of Low-pass Filtering of Local Field Potentials in Brain Tissue

Local field potentials (LFPs) are routinely measured experimentally in brain tissue, and exhibit strong low-pass frequency filtering properties, with high frequencies (such as action potentials) being visible only at very short distances ($\approx$10~$\mu m$) from the recording electrode. Understanding this filtering is crucial to relate LFP signals with neuronal activity, but not much is known about the exact mechanisms underlying this low-pass filtering. In this paper, we investigate a possible biophysical mechanism for the low-pass filtering properties of LFPs. We investigate the propagation of electric fields and its frequency dependence close to the current source, i.e. at length scales in the order of average interneuronal distance. We take into account the presence of a high density of cellular membranes around current sources, such as glial cells. By considering them as passive cells, we show that under the influence of the electric source field, they respond by polarisation, i.e., creation of an induced field. Because of the finite velocity of ionic charge movement, this polarization will not be instantaneous. Consequently, the induced electric field will be frequency-dependent, and much reduced for high frequencies. Our model establishes that with respect to frequency attenuation properties, this situation is analogous to an equivalent RC-circuit, or better a system of coupled RC-circuits. We present a number of numerical simulations of induced electric field for biologically realistic values of parameters, and show this frequency filtering effect as well as the attenuation of extracellular potentials with distance. We suggest that induced electric fields in passive cells surrounding neurons is the physical origin of frequency filtering properties of LFPs.Comment: 10 figs, revised tex file and revised fig

AMOD: a morpholino oligonucleotide selection tool

AMOD is a web-based program that aids in the functional evaluation of nucleotide sequences through sequence characterization and antisense morpholino oligonucleotide (target site) selection. Submitted sequences are analyzed by translation initiation site prediction algorithms and sequence-to-sequence comparisons; results are used to characterize sequence features required for morpholino design. Within a defined subsequence, base composition and homodimerization values are computed for all putative morpholino oligonucleotides. Using these properties, morpholino candidates are selected and compared with genomic and transcriptome databases with the goal to identify target-specific enriched morpholinos. AMOD has been used at the University of Minnesota to design ∼200 morpholinos for a functional genomics screen in zebrafish. The AMOD web server and a tutorial are freely available to both academic and commercial users at

Novel pathogenic variant in TGFBR2 confirmed by molecular modeling is a rare cause of Loeys-Dietz syndrome

Loeys-Dietz syndrome (LDS) is a connective tissue disorder characterized by vascular findings of aneurysm and/or dissection of cerebral, thoracic, or abdominal arteries and skeletal findings. We report a case of a novel pathogenic variant in TGFBR2 and phenotype consistent with classic LDS. The proband was a 10-year-old presenting to the genetics clinic with an enlarged aortic root (Z-scores 5-6), pectus excavatum, and congenital contractures of the right 2nd and 3rd digit. Molecular testing of TGFBR2 was sent to a commercial laboratory and demonstrated a novel, likely pathogenic, variant in exon 4, c.1061T>C, p.(L354P). Molecular modeling reveals alteration of local protein structure as a result of this pathogenic variant. This pathogenic variant has not been previously reported in LDS and thus expands the pathogenic variant spectrum of this condition

3' tag digital gene expression profiling of human brain and universal reference RNA using Illumina Genome Analyzer

<p>Abstract</p> <p>Background</p> <p>Massive parallel sequencing has the potential to replace microarrays as the method for transcriptome profiling. Currently there are two protocols: full-length RNA sequencing (RNA-SEQ) and 3'-tag digital gene expression (DGE). In this preliminary effort, we evaluated the 3' DGE approach using two reference RNA samples from the MicroArray Quality Control Consortium (MAQC).</p> <p>Results</p> <p>Using Brain RNA sample from multiple runs, we demonstrated that the transcript profiles from 3' DGE were highly reproducible between technical and biological replicates from libraries constructed by the same lab and even by different labs, and between two generations of Illumina's Genome Analyzers. Approximately 65% of all sequence reads mapped to mitochondrial genes, ribosomal RNAs, and canonical transcripts. The expression profiles of brain RNA and universal human reference RNA were compared which demonstrated that DGE was also highly quantitative with excellent correlation of differential expression with quantitative real-time PCR. Furthermore, one lane of 3' DGE sequencing, using the current sequencing chemistry and image processing software, had wider dynamic range for transcriptome profiling and was able to detect lower expressed genes which are normally below the detection threshold of microarrays.</p> <p>Conclusion</p> <p>3' tag DGE profiling with massive parallel sequencing achieved high sensitivity and reproducibility for transcriptome profiling. Although it lacks the ability of detecting alternative splicing events compared to RNA-SEQ, it is much more affordable and clearly out-performed microarrays (Affymetrix) in detecting lower abundant transcripts.</p

Assessing Human Genetic Variations in Glucose Transporter SLC2A10 and Their Role in Altering Structural and Functional Properties

Purpose: Demand is increasing for clinical genomic sequencing to provide diagnoses for patients presenting phenotypes indicative of genetic diseases, but for whom routine genetic testing failed to yield a diagnosis. DNA-based testing using high-throughput technologies often identifies variants with insufficient evidence to determine whether they are disease-causal or benign, leading to categorization as variants of uncertain significance (VUS).Methods: We used molecular modeling and simulation to generate specific hypotheses for the molecular effects of variants in the human glucose transporter, GLUT10 (SLC2A10). Similar to many disease-relevant membrane proteins, no experimentally derived 3D structure exists. An atomic model was generated and used to evaluate multiple variants, including pathogenic, benign, and VUS.Results: These analyses yielded detailed mechanistic data, not currently predictable from sequence, including altered protein stability, charge distribution of ligand binding surfaces, and shifts toward or away from transport-competent conformations. Consideration of the two major conformations of GLUT10 was important as variants have conformation-specific effects. We generated detailed molecular hypotheses for the functional impact of variants in GLUT10 and propose means to determine their pathogenicity.Conclusion: The type of workflow we present here is valuable for increasing the throughput and resolution with which VUS effects can be assessed and interpreted

Effect of Non-Magnetic Impurities (Zn,Li) in a Hole Doped Spin-Fermion Model for Cuprates

The effect of adding non-magnetic impurities (NMI), such as Zn or Li, to high-Tc cuprates is studied applying Monte Carlo techniques to a spin-fermion model. It is observed that adding Li is qualitatively similar to doping with equal percentages of Sr and Zn. The mobile holes (MH) are trapped by the NMI and the system remains insulating and commensurate with antiferromagnetic (AF) correlations. This behavior persists in the region %NMI > %MH. On the other hand, when %NMI < %MH magnetic and charge incommensurabilities are observed. The vertical or horizontal hole-rich stripes, present when % NMI=0 upon hole doping, are pinned by the NMI and tend to become diagonal, surrounding finite AF domains. The %MH-%NMI plane is investigated. Good agreement with experimental results is found in the small portion of this diagram where experimental data are available. Predictions about the expected behavior in the remaining regions are made.Comment: Four pages with four figures embedded in tex

Magnetic Domains and Stripes in the Spin-Fermion Model for Cuprates

Monte Carlo simulations applied to the Spin-Fermion model for cuprates show the existence of antiferromagnetic spin domains and charge stripes upon doping. The stripes are partially filled, with a filling of approximately 1/2 hole per site, and they separate spin domains with a $\pi$ phase shift among them. The stripes observed run either along the x or y axes and they are separated by a large energy barrier. No special boundary conditions or external fields are needed to stabilize these structures at low temperatures. When magnetic incommensurate peaks are observed at momentum $\pi(1,1-\delta)$ and symmetrical points, charge incommensurate peaks appear at $(0,2 \delta)$ and symmetrical points, as experimentally observed. The strong charge fluctuations responsible for the formation of the stripes also induce a pseudogap in the density of states.Comment: Four pages with four figures embedded in tex

Anomalous electronic susceptibility in Bi2Sr2CuO6+d and comparison with other overdoped cuprates

We report magnetic susceptibility performed on overdoped Bi2Sr2CuO6+d powders as a function of oxygen doping d and temperature T. The decrease of the spin susceptibility with increasing T is confirmed. At sufficient high temperature, the spin susceptibility Chi_s presents an unusual linear temperature dependence Chi_s ~ Chi_s0 -Chi_1 T. Moreover, a linear correlation between Chi_1 and Chi_s0 for increasing hole concentration is displayed. A temperature Tchi, independent of hole doping characterizes this scaling. Comparison with other cuprates of the literature(LSCO, Tl-2201 and Bi-2212), over the same overdoped range, shows similarities with above results. These non conventional metal features will be discussed in terms of a singular narrow-band structure.Comment: 16 pages, 4 figure

Economic performance or electoral necessity? Evaluating the system of voluntary income to political parties

Whilst the public funding of political parties is the norm in western democracies, its comprehensive introduction has been resisted in Britain. Political and electoral arrangements in Britain require parties to function and campaign on a regular basis, whilst their income follows cycles largely related to general elections. This article shows that the best predictor of party income is the necessity of a well-funded general election campaign rather than party performance. As a result, income can only be controlled by parties to a limited degree, which jeopardises their ability to determine their own financial position and fulfil their functions as political parties