Concise Asymmetric Synthesis and Pharmacological Characterization of All Stereoisomers of Glutamate Transporter Inhibitor TFB-TBOA and Synthesis of EAAT Photoaffinity Probes

Glutamate is the major excitatory neurotransmitter in the mammalian brain. Its rapid clearance after the release into the synaptic cleft is vital in order to avoid toxic effects and is ensured by several transmembrane transport proteins, so-called excitatory amino acid transporters (EAATs). Impairment of glutamate removal has been linked to several neurodegenerative diseases and EAATs have therefore received increased attention as therapeutic targets. O-benzylated L-threo-β-hydroxyaspartate derivatives have been developed previously as highly potent inhibitors of EAATs with TFB-TBOA ((2S,3S)-2-amino-3-((3-(4-(trifluoromethyl)benzamido)benzyl)oxy)succinic acid) standing out as low-nanomolar inhibitor. We report the stereoselective synthesis of all four stereoisomers of TFB-TBOA in less than a fifth of synthetic steps than the published route. For the first time, the inhibitory activity and isoform selectivity of these TFB-TBOA enantio- and diastereomers were assessed on human glutamate transporters EAAT1-3. Furthermore, we synthesized potent photoaffinity probes based on TFB-TBOA using our novel synthetic strategy.

DNA probes for the detection of Fasciola hepatica in snails

Fasciola hepatica, also called the large liver fluke, is a trematode which can infect most mammals. Monitoring the infection rate of snails, which function as intermediate hosts and harbour larval stages of F. hepatica, is an important component of epidemiological studies on fascioliasis. For this purpose, DNA probes were generated which can be used for the detection of F. hepatica larvae in snails. Four highly repetitive DNA fragments were cloned in a plasmid vector and tested by Southern blot hybridization to the DNA of various trematodes for specificity and sensitivity. The probes Fhr-I, Fhr-II and Fhr-III hybridized only to F. hepatica DNA. Fhr-IV contained ribosomal RNA gene sequences and cross-hybridize with the DNA from various other trematode species. Squash blot analysis showed that the different probes were able to detect the parasite larvae in trematode-infected snails even as isolated single larvae. No signals were obtained in squash blots of uninfected snails. Probes Fhr-I, Fhr-II and Fhr-III are thus useful specific tools for studying the epidemiology of fascioliasis. The probe Fhr-IV, because of its broader spectrum, can be used to detect the larvae of a wide range of trematode species of waterbirds, which are the causative agents of swimmer's itch.

A novel myeloid leukemia suppressor locus at human chromosome 5q13.3

Molecular mechanisms that underlie preleukemic myelodysplasia (MDS) and acute myelogenous leukemia (AML) are poorly understood. In MDS or AML with a refractory clinical course, more than 30% of patients have acquired interstitial or complete deletions of chromosome 5. The 5q13.3 chromosomal segment is commonly lost as the result of 5q deletion. Reciprocal and unbalanced translocations of 5q13.3 can also occur as sole anomalies associated with refractory AML or MDS. This study addresses the hypothesis that a critical gene at 5q13.3 functions either as a classical tumor suppressor or as a chromosomal translocation partner and contributes to leukemogenesis. ^ Previous studies from our laboratory delineated a critical region of loss to a 2.5–3.0Mb interval at 5q13.3 between microsatellite markers D5S672 and GATA-P18104. The critical region of loss was later resolved to an interval of approximately 2Mb between the markers D5S672 and D5S2029. I, then generated a long range physical map of yeast artificial chromosomes (YACs) and developed novel sequence tagged sites (STS). To enhance the resolution of this map, bacterial artificial chromosomes (BACs) were used to construct a triply linked contig across a 1 Mb interval. These BACs were used as probes for fluorescent in situ hybridization (FISH) on an AML cell line to define the 5q13.3 critical region. A 200kb BAC, 484a9, spans the translocation breakpoint in this cell line. A novel gene, SSDP2 (single stranded DNA binding protein), is disrupted at the breakpoint because its first four exons are encoded within 140kb of BAC 484a9. This finding suggests that SSDP2 is the critical gene at 5q13.3. ^ In addition, I made an observation that deletions of chromosome 5q13 co-segregate with loss of the chromosome 17p. In some cases the deletions result from unbalanced translocations between 5q13 and 17p13. It was confirmed that the TP53 gene is deleted in patients with 17p loss, and the remaining allele harbors somatic mutation. Thus, the genetic basis for the aggressive clinical course in AML and MDS may be caused by functional cooperation between deletion or disruption of the 5q13.3 critical gene and inactivation of TP53. ^

Biogeochemistry and microbiology of groundwater during acetate and bicarbonate amendment to an alluvial aquifer

These data are from a field experiment conducted in a shallow alluvial aquifer along the Colorado River in Rifle, Colorado, USA. In this experiment, bicarbonate-promoted uranium desorption and acetate amendment were combined and compared to an acetate amendment-only experiment in the same experimental plot. Data include names and location data for boreholes, geochemical data for all the boreholes between June 1, 2010 and January 1, 2011, microarray data provided as signal to noise ratio (SNR) for individual microarray probes, microarray data provided as signal to noise ratio (SNR) by Genus.

Testing of fluorescent DC lamps for Solar Home Systems

With the advent of the Universal Technical Standard for Solar Home Systems, procedures to test the compliance of SHS fluorescent lamps with the standard have been developed. Definition of the laboratory testing procedures is a necessary step in any lamp quality assurance procedure. Particular attention has been paid to test simplicity and to affordability, in order to facilitate local application of the testing procedures, for example by the organisations which carry out electrification programmes. The set of test procedures has been applied to a representative collection of 42 lamps from many different countries, directly acquired in the current photovoltaic rural electrification market. Tests apply to: lamp resistance under normal operating conditions; lamp reliability under extreme conditions; under abnormal conditions; and lamp luminosity. Results are discussed and some recommendations for updating the relevant standard are given. The selected technical standard, together with the proposed testing procedures, form the basis of a complete quality assurance tool that can be applied locally in normal electrical laboratories. Full testing of a lamp requires less than one month, which is very reasonable on the context of quality assurance programmes

Emissions and economic costs of cycling compact fluorescent lamps with integrated ballasts

This paper proposes a way to quantify the emissions of mercury (Hg) and CO2 associated with the manufacture and operation of compact fluorescent lamps with integrated ballasts (CFLis), as well as the economic cost of using them under different operating cycles. The main purpose of this paper is to find simple criteria for reducing the polluting emissions under consideration and the economic cost of CFLi to a minimum. A lifetime model is proposed that allows the emissions and costs to be described as a function of degradation from turning CFLi on and their continuous operation. An idealized model of a CFLi is defined that combines characteristics stated by different manufacturers. In addition, two CFLi models representing poor-quality products are analyzed. It was found that the emissions and costs per unit of time of operation of the CFLi depend linearly on the number of times per unit of time it is turned on and the time of continuous operation. The optimal conditions (lowest emissions and costs) depend on the place of manufacture, the place of operation and the quality of the components of the lamp/ballast. Finally, it was also found that for each lamp, there are intervals when it is turned off during which emissions of pollutants and costs are identical regardless of how often the lamp is turned on or the time it remains on. For CO2 emissions, the lamp must be off up to 5 minutes; for the cost, up to 7 minutes and for Hg emissions, up to 43 minutes. It is advisable not to turn on a CFLi sooner than 43 minutes from the last time it was turned off.

Interference of parallel cylindrical Langmuir probes

Current to a cylindrical probe of arbitrary cross section is discussed. Previous results for circular cylinders at the high bias and moderate radius R of interest for electrodynamic bare tethers, for which space charge may be ignored over a large neighborhood of the probe, depend in separate ways on both R and perimeter p. These results are extended to a general convex cross section by introducing certain equivalent radius Req. For any concave cross section, results use a proper equivalent perimeter peq , in addition to Req. Finally, for the joint cross section of separate parallel probes, certain effective perimeter peff replaces peq. Rules to determine Req. peq. and peff are used to discuss collection interference among two or more parallel cylinders when brought from far away to contact

The orbital-motion-limited regime of cylindrical Langmuir probes

An asymptotic analysis of electron collection at high bias Fp serves to determine the domain of validity of the orbital-motion-limited regime of cylindrical Langmuir probes, which is basic for the workings of conductive bare tethers. The radius of a wire collecting OML current in an unmagnetized plasma at rest cannot exceed a value, Rmax , which is found to exhibit a minimum as a function of Fp ; atFp values of interest, Rmax is already increasing and is larger than the electron Debye length lDe . The breakdown of the regime relates to conditions far fromthe probe, at electron energies comparable to the ion thermal energy, kTi ; Rmax is found to increase with Ti . It is also found that ~1! the maximumwidth of a thin tape, if used instead of a wire, is 4Rmax ; ~2! the electron thermal gyroradius must be larger than both R and lDe for magnetic effects to be negligible; and ~3! conditions applying to the tether case are such that trapped-orbit effects are negligible.

Cylindrical Langmuir probes beyond the orbital-motion-limited regime

The current I to a cylindrical probe at rest in an unmagnetized plasma, with probe bias highly positive, is determined. The way I lags behind the orbital-motion-limited OMLcurrent, 1 OML R, as the radius R exceeds the maximum radius for the OML regime to hold, is of interest for space-tether applications. The ratio I/I OML is roughly a decreasing function of R/lD R max /lDe , which is independent of bias, with lDe the electron Debye length and Rmax /l De roughly an increasing function of the temperature ratio, Ti /Te. The dependence of current on ion energy is used to discuss the effect of probe motion through the plasma, a case applying to tethers in low orbit.

The theory of electrostatic probes in strong magnetic fields : Thesis submitted to the Faculty of The Graduate School of the University of Colorado for the Degree Doctor of Philosophy Department of Aerospace Engineering Science

A theory is developed of an electrostatic probe in a fully-ionized plasma in the presence of a strong magnetic field. The ratio of electron Larmor radius to probe transverse dimension is assumed to be small. Poisson's equation, together with kinetic equations for ions and electrons are considered. An asymptotic perturbation method of multiple scales is used by considering the characteristic lengths appearing in the problem. The leading behavior of the solution is found. The results obtained appear to apply to weaker fields also, agreeing with the solutions known in the limit of no magnetic field. The range of potentials for wich results are presented is limited. The basic effects produced by the field are a depletion of the plasma near the probe and a non-monotonic potential surrounding the probe. The ion saturation current is not changed but changes appear in both the floating potential Vf and the slope of the current-voltage diagram at Vf. The transition region extends beyond the space potential Vs,at wich point the current is largely reduced. The diagram does not have an exponential form in this region as commonly assumed. There exists saturation in electron collection. The extent to which the plasma is disturbed is determined. A cylindrical probe has no solution because of a logarithmic singularity at infinity. Extensions of the theory are considered.

Emissive Langmuir Probes in the Strong Emission Regime for the Determination of the Plasma Properties

The determination of the plasma potential Vpl of unmagnetized plasmas by using the floating potential of emissive Langmuir probes operated in the strong emission regime is investigated. The experiments evidence that, for most cases, the electron thermionic emission is orders of magnitude larger than the plasma thermal electron current. The temperature-dependent floating potentials of negatively biased Vpmenor queVpl emissive probes are in agreement with the predictions of a simple phenomenological model that considers, in addition to the plasma electrons, an ad-ditional electron group that contributes to the probe current. The latter would be constituted by a fraction of the repelled electron thermionic current, which might return back to the probe with a different energy spectrum. Its origin would be a plasma potential well formed in the plasma sheath around the probe, acting as a virtual cathode or by collisions and electron thermalization pro-cesses. These results suggest that, for probe bias voltages close to the plasma potential Vp?Vpl, two electron populations coexist, i.e., the electrons from the plasma with temperatureTeand a large group of returned thermionic electrons. These results question the theoretical possibility of measuring the electron temperature by using emissive probes biased to potentials Vp about lower equal than ?Vpl.