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

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

Energy levels in polarization superlattices: a comparison of continuum strain models

A theoretical model for the energy levels in polarization superlattices is presented. The model includes the effect of strain on the local polarization-induced electric fields and the subsequent effect on the energy levels. Two continuum strain models are contrasted. One is the standard strain model derived from Hooke's law that is typically used to calculate energy levels in polarization superlattices and quantum wells. The other is a fully-coupled strain model derived from the thermodynamic equation of state for piezoelectric materials. The latter is more complete and applicable to strongly piezoelectric materials where corrections to the standard model are significant. The underlying theory has been applied to AlGaN/GaN superlattices and quantum wells. It is found that the fully-coupled strain model yields very different electric fields from the standard model. The calculated intersubband transition energies are shifted by approximately 5 -- 19 meV, depending on the structure. Thus from a device standpoint, the effect of applying the fully-coupled model produces a very measurable shift in the peak wavelength. This result has implications for the design of AlGaN/GaN optical switches.Comment: Revtex

A Qualitative Study of an Integrated Maternity, Drugs and Social Care Service for Drug-using Women

Background: The care of drug-using pregnant women is a growing health and social care concern in many countries. A specialist clinic was established offering multidisciplinary care and advice to pregnant drug users in and around Aberdeen (UK) in 1997. The majority of women stabilise and reduce their drug use. By determining the needs and views of the women more appropriate services and prevention strategies may be developed. There has been little research conducted in this area and none in Scotland. Methods: This is a qualitative study that aimed to gain an understanding of the experiences of women drug users, seeking and receiving prenatal care and drug services from a specialist clinic. Twelve women participated in semi-structured one-to-one interviews. Results: The women preferred the multidisciplinary clinic (one-stop shop) to traditional prenatal care centred within General Practice. The relationships of the clients to the range of Clinic professionals and in hospital were explored as well as attitudes to Clinic care. The study participants attributed success in reducing their drug use to the combination of different aspects of care of the multi-agency clinic, especially the high level prenatal support. It is this arrangement of all aspects of care together that seem to produce better outcomes for mother and child than single care elements delivered separately. Some women reported that their pregnancy encouraged them to rapidly detoxify due to the guilt experienced. The most important aspects of the Clinic care were found to be non-judgemental attitude of staff, consistent staff, high level of support, reliable information and multi-agency integrated care. Conclusion: There is an impetus for women drug users to change lifestyle during pregnancy. The study highlighted a need for women to have access to reliable information on the effects of drugs on the baby. Further research is required to determine whether positive outcomes related to clinic attendance in the prenatal period are sustained in the postnatal period. Early referral to a specialist clinic is of benefit to the women, as they reported to receive more appropriate care, especially in relation to their drug use. A greater awareness of needs of the pregnant drug user could help the design of more effective prevention strategies

Static stretching of the hamstring muscle for injury prevention in football codes: a systematic review

Purpose: Hamstring injuries are common among football players. There is still disagreement regarding prevention. The aim of this review is to determine whether static stretching reduces hamstring injuries in football codes. Methods: A systematic literature search was conducted on the online databases PubMed, PEDro, Cochrane, Web of Science, Bisp and Clinical Trial register. Study results were presented descriptively and the quality of the studies assessed were based on Cochrane’s ‘risk of bias’ tool. Results: The review identified 35 studies, including four analysis studies. These studies show deficiencies in the quality of study designs. Conclusion: The study protocols are varied in terms of the length of intervention and follow-up. No RCT studies are available, however, RCT studies should be conducted in the near future

Pharmacological and Toxicological Properties of the Potent Oral γ-Secretase Modulator BPN-15606.

Alzheimer's disease (AD) is characterized neuropathologically by an abundance of 1) neuritic plaques, which are primarily composed of a fibrillar 42-amino-acid amyloid-β peptide (Aβ), as well as 2) neurofibrillary tangles composed of aggregates of hyperphosporylated tau. Elevations in the concentrations of the Aβ42 peptide in the brain, as a result of either increased production or decreased clearance, are postulated to initiate and drive the AD pathologic process. We initially introduced a novel class of bridged aromatics referred tγ-secretase modulatoro as γ-secretase modulators that inhibited the production of the Aβ42 peptide and to a lesser degree the Aβ40 peptide while concomitantly increasing the production of the carboxyl-truncated Aβ38 and Aβ37 peptides. These modulators potently lower Aβ42 levels without inhibiting the γ-secretase-mediated proteolysis of Notch or causing accumulation of carboxyl-terminal fragments of APP. In this study, we report a large number of pharmacological studies and early assessment of toxicology characterizing a highly potent γ-secretase modulator (GSM), (S)-N-(1-(4-fluorophenyl)ethyl)-6-(6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl)-4-methylpyridazin-3-amine (BPN-15606). BPN-15606 displayed the ability to significantly lower Aβ42 levels in the central nervous system of rats and mice at doses as low as 5-10 mg/kg, significantly reduce Aβ neuritic plaque load in an AD transgenic mouse model, and significantly reduce levels of insoluble Aβ42 and pThr181 tau in a three-dimensional human neural cell culture model. Results from repeat-dose toxicity studies in rats and dose escalation/repeat-dose toxicity studies in nonhuman primates have designated this GSM for 28-day Investigational New Drug-enabling good laboratory practice studies and positioned it as a candidate for human clinical trials

Combinatorial Markov chains on linear extensions

We consider generalizations of Schuetzenberger's promotion operator on the set L of linear extensions of a finite poset of size n. This gives rise to a strongly connected graph on L. By assigning weights to the edges of the graph in two different ways, we study two Markov chains, both of which are irreducible. The stationary state of one gives rise to the uniform distribution, whereas the weights of the stationary state of the other has a nice product formula. This generalizes results by Hendricks on the Tsetlin library, which corresponds to the case when the poset is the anti-chain and hence L=S_n is the full symmetric group. We also provide explicit eigenvalues of the transition matrix in general when the poset is a rooted forest. This is shown by proving that the associated monoid is R-trivial and then using Steinberg's extension of Brown's theory for Markov chains on left regular bands to R-trivial monoids.Comment: 35 pages, more examples of promotion, rephrased the main theorems in terms of discrete time Markov chain

Front Propagation with Rejuvenation in Flipping Processes

We study a directed flipping process that underlies the performance of the random edge simplex algorithm. In this stochastic process, which takes place on a one-dimensional lattice whose sites may be either occupied or vacant, occupied sites become vacant at a constant rate and simultaneously cause all sites to the right to change their state. This random process exhibits rich phenomenology. First, there is a front, defined by the position of the left-most occupied site, that propagates at a nontrivial velocity. Second, the front involves a depletion zone with an excess of vacant sites. The total excess D_k increases logarithmically, D_k ~ ln k, with the distance k from the front. Third, the front exhibits rejuvenation -- young fronts are vigorous but old fronts are sluggish. We investigate these phenomena using a quasi-static approximation, direct solutions of small systems, and numerical simulations.Comment: 10 pages, 9 figures, 4 table