A Meta-Analysis on Presynaptic Changes in Alzheimer's Disease

This work was funded by TauRx Therapeutics Ltd.,SingaporePeer reviewedPublisher PD

Seismic volcanostratigraphy of the western Indian rifted margin: The pre-Deccan igneous province

The Indian Plate has been the focus of intensive research concerning the flood basalts of the Deccan Traps. Here we document a volcanostratigraphic analysis of the offshore segment of the western Indian volcanic large igneous province, between the shoreline and the first magnetic anomaly (An 28 ∼63 Ma). We have mapped the different crustal domains of the NW Indian Ocean from stretched continental crust through to oceanic crust, using seismic reflection and potential field data. Two volcanic structures, the Somnath Ridge and the Saurashtra High, are identified, extending ∼305 km NE-SW in length and 155 km NW-SE in width. These show the internal structures of buried shield volcanoes and hyaloclastic mounds, surrounded by mass-wasting deposits and volcanic sediments. The structures observed resemble seismic images from the North Atlantic and northwest Australia, as well as volcanic geometries described for Runion and Hawaii. The geometry and internal seismic facies within the volcanic basement suggest a tholeiitic composition and subaerial to shallow marine emplacement. At the scale of the western Indian Plate, the emplacement of this volcanic platform is constrained by structural lineations associated with rifting. By reviewing the volcanism in the Indian Ocean and plate reconstruction of the area, the timing of the volcanism can be associated with eruption of a pre-Deccan continental flood basalt (∼75-65.5 Ma). The volcanic platform in this study represents an addition of 19-26.5% to the known volume of the West Indian Volcanic Province. Copyright 2011 by the American Geophysical Union

Development of Human Membrane Transporters: Drug Disposition and Pharmacogenetics

Membrane transporters play an essential role in the transport of endogenous and exogenous compounds, and consequently they mediate the uptake, distribution, and excretion of many drugs. The clinical relevance of transporters in drug disposition and their effect in adults have been shown in drug–drug interaction and pharmacogenomic studies. Little is known, however, about the ontogeny of human membrane transporters and their roles in pediatric pharmacotherapy. As they are involved in the transport of endogenous substrates, growth and development may be important determinants of their expression and activity. This review presents an overview of our current knowledge on human membrane transporters in pediatric drug disposition and effect. Existing pharmacokinetic and pharmacogenetic data on membrane substrate drugs frequently used in children are presented and related, where possible, to existing ex vivo data, providing a basis for developmental patterns for individual human membrane transporters. As data for individual transporters are currently still scarce, there is a striking information gap regarding the role of human membrane transporters in drug therapy in children

Calculations of three-body observables in ^8B breakup

We discuss calculations of three-body observables for the breakup of ^8B on a ^{58}Ni target at low energy using the coupled discretised continuum channels approach. Calculations of both the angular distribution of the ^7Be fragments and their energy distributions are compared with those measured at several laboratory angles. In these observables there is interference between the breakup amplitudes from different spin-parity excitations of the projectile. The resulting angle and the energy distributions reveal the importance of the higher-order continuum state couplings for an understanding of the measurements.Comment: 22 pages (postscript), accepted in Phys. Rev.

Stimulation of the cuneiform nucleus enables training and boosts recovery after spinal cord injury

Severe spinal cord injuries result in permanent paraparesis in spite of the frequent sparing of small portions of white matter. Spared fibre tracts are often incapable of maintaining and modulating the activity of lower spinal motor centres. Effects of rehabilitative training thus remain limited. Here, we activated spared descending brainstem fibres by electrical deep brain stimulation of the cuneiform nucleus of the mesencephalic locomotor region, the main control centre for locomotion in the brainstem, in adult female Lewis rats. We show that deep brain stimulation of the cuneiform nucleus enhances the weak remaining motor drive in highly paraparetic rats with severe, incomplete spinal cord injuries and enables high-intensity locomotor training. Stimulation of the cuneiform nucleus during rehabilitative aquatraining after subchronic (n = 8 stimulated versus n = 7 unstimulated versus n = 7 untrained rats) and chronic (n = 14 stimulated versus n = 9 unstimulated versus n = 9 untrained rats) spinal cord injury re-established substantial locomotion and improved long-term recovery of motor function. We additionally identified a safety window of stimulation parameters ensuring context-specific locomotor control in intact rats (n = 18) and illustrate the importance of timing of treatment initiation after spinal cord injury (n = 14). This study highlights stimulation of the cuneiform nucleus as a highly promising therapeutic strategy to enhance motor recovery after subchronic and chronic incomplete spinal cord injury with direct clinical applicability

Upstream ORF affects MYCN translation depending on exon 1b alternative splicing

<p>Abstract</p> <p>Background</p> <p>The <it>MYCN </it>gene is transcribed into two major mRNAs: one full-length (<it>MYCN) </it>and one exon 1b-spliced (<it>MYCN</it>^{Δ1<it>b</it>}) mRNA. But nothing is known about their respective ability to translate the MYCN protein.</p> <p>Methods</p> <p>Plasmids were prepared to enable translation from the upstream (uORF) and major ORF of the two <it>MYCN </it>transcripts. Translation was studied after transfection in neuroblastoma SH-EP cell line. Impact of the upstream AUG on translation was evaluated after directed mutagenesis. Functional study with the two <it>MYCN </it>mRNAs was conducted by a cell viability assay. Existence of a new protein encoded by the <it>MYCN</it>^{Δ1<it>b </it>}uORF was explored by designing a rabbit polyclonal antibody against a specific epitope of this protein.</p> <p>Results</p> <p>Both are translated, but higher levels of protein were seen with <it>MYCN</it>^{Δ1<it>b </it>}mRNA. An upstream ORF was shown to have positive cis-regulatory activity on translation from <it>MYCN </it>but not from <it>MYCN</it>^{Δ1<it>b </it>}mRNA. In transfected SH-EP neuroblastoma cells, high MYCN dosage obtained with <it>MYCN</it>^{Δ1<it>b </it>}mRNA translation induces an antiapoptotic effect after serum deprivation that was not observed with low MYCN expression obtained with <it>MYCN </it>mRNA. Here, we showed that MYCNOT: <it>MYCN </it>Overlap Transcript, a new protein of unknown function is translated from the upstream AUG of <it>MYCN</it>^{Δ1<it>b </it>}mRNA.</p> <p>Conclusions</p> <p>Existence of upstream ORF in <it>MYCN </it>transcripts leads to a new level of MYCN regulation. The resulting MYCN dosage has a weak but significant anti-apoptotic activity after intrinsic apoptosis induction.</p

Genetics is a major determinant of expression of the human hepatic uptake transporter OATP1B1, but not of OATP1B3 and OATP2B1

Peer reviewe

Initial State Dependence of the Breakup of Weakly Bound Carbon Isotopes

The one-neutron nuclear breakup from the Carbon isotopes $^{19}$C and $^{17}$C, is calculated as an example of application of the theory of transfer to the continuum reactions in the formulation which includes spin coupling. The effect of the energy sharing between the parallel and transverse neutron momentum distributions is taken into account thus resulting in a theory which is more general than sudden eikonal approaches. Both effects are necessary to understand properly the breakup from not too weakly bound $l_i>1$ orbitals. Breakup which leaves the core into an excited state below particle threshold is also considered. The core-target interaction is treated in the smooth cut-off approximation. By comparing to presently available experimental data we show how to make some hypothesis on the quantum numbers and occupancy of the neutron initial state. Possible ambiguities in the interpretation of inclusive cross sections are discussed.Comment: 22 RevTeX pages,3 ps figures. Phys. Rev. C, accepte