Killing two birds with one drug: a new application for HIV-1 cell entry inhibitors in the treatment of metastatic cancer.

The chemokine receptors CCR5 and CXCR4 serve as co-receptors for the human immunodeficiency virus 1 (HIV-1) and thus, are important cellular components during HIV-1 cell entry. In recent years, a new biological role for chemokine receptors has emerged in assisting the spread of primary tumors to distant secondary sites within the human body (metastasis). This review highlights some of the HIV-1 cell entry inhibitors (antagonists), which are currently in development and/or under evaluation in clinical trials, and discusses the therapeutic use of these new antagonists for the treatment of certain forms of metastatic cancer

Calmodulin Mediates Ca2+-dependent Modulation of M-type K+ Channels

To quantify the modulation of KCNQ2/3 current by [Ca2+]i and to test if calmodulin (CaM) mediates this action, simultaneous whole-cell recording and Ca2+ imaging was performed on CHO cells expressing KCNQ2/3 channels, either alone, or together with wild-type (wt) CaM, or dominant-negative (DN) CaM. We varied [Ca2+]i from <10 to >400 nM with ionomycin (5 μM) added to either a 2 mM Ca2+, or EGTA-buffered Ca2+-free, solution. Coexpression of wt CaM made KCNQ2/3 currents highly sensitive to [Ca2+]i (IC50 70 ± 20 nM, max inhibition 73%, n = 10). However, coexpression of DN CaM rendered KCNQ2/3 currents largely [Ca2+]i insensitive (max inhibition 8 ± 3%, n = 10). In cells without cotransfected CaM, the Ca2+ sensitivity was variable but generally weak. [Ca2+]i modulation of M current in superior cervical ganglion (SCG) neurons followed the same pattern as in CHO cells expressed with KCNQ2/3 and wt CaM, suggesting that endogenous M current is also highly sensitive to [Ca2+]i. Coimmunoprecipitations showed binding of CaM to KCNQ2–5 that was similar in the presence of 5 mM Ca2+ or 5 mM EGTA. Gel-shift analyses suggested Ca2+-dependent CaM binding to an “IQ-like” motif present in the carboxy terminus of KCNQ2–5. We tested whether bradykinin modulation of M current in SCG neurons uses CaM. Wt or DN CaM was exogenously expressed in SCG cells using pseudovirions or the biolistic “gene gun.” Using both methods, expression of both wt CaM and DN CaM strongly reduced bradykinin inhibition of M current, but for all groups muscarinic inhibition was unaffected. Cells expressed with wt CaM had strongly reduced tonic current amplitudes as well. We observed similar [Ca2+]i rises by bradykinin in all the groups of cells, indicating that CaM did not affect Ca2+ release from stores. We conclude that M-type currents are highly sensitive to [Ca2+]i and that calmodulin acts as their Ca2+ sensor

a new Pc-C boundary section

The widespread, terminal Ediacaran Dengying Formation (~ 551–~ 542 Ma) of South China hosts one of the most prominent negative carbonate carbon isotope excursions in Earth's history and thus bears on the correlation of the Precambrian–Cambrian boundary worldwide. The dominantly carbonate strata of the Dengying Formation are largely studied for their unique preservation of its terminal Ediacaran fauna but their geochemical context is poorly known. This study presents the first high-resolution stable isotope record (δ13C, δ18O) of calcareous siliciclastic shallow-water deposits of the Gaojiashan section (Shaanxi Province). The section includes (in ascending order) the Algal Dolomite Member, the Gaojiashan Member and the Beiwan Member of the Dengying Formation. Our data record a major δ13Ccarb negative excursion to −6 ‰ in the uppermost Gaojiashan Member which is comparable in shape and magnitude to the global Precambrian–Cambrian boundary negative δ13C excursion. Our data set is consistent with a "shallow-water anoxia" scenario which is thought to contribute to the "Cambrian explosion". The stratigraphic occurrence of Cloudina and a large negative δ13C excursion suggest that the Precambrian–Cambrian boundary is located near the top of the Gaojiashan Member and, consequently, that overlying carbonates and dolomites of the Beiwan Member are of earliest Cambrian age. Thus the Gaojiashan section may represent a new shallow-water section spanning the Precambrian–Cambrian boundary. Although bio- and chemostratigraphic data support this novel interpretation, we cannot exclude the possibility that the key excursions may represent a local perturbation indicating a restricted-basin environment

Effect of Heavy Metal Contaminated Shooting Range Soils on Mycorrhizal Colonization of Roots and Metal Uptake by Leek

We grew leek (Allium porrum) in soils of two shooting ranges heavily contaminated with heavy metals in the towns of Zuchwil and Oberuzwil in Switzerland as a bioassay to test theactivity of arbuscular mycorrhizal (AM) fungi in these soils.Soil samples were taken from (1) front of the shooting house(HOUSE), (2) the area between house and target (FIELD) and (3) the berm (BACKSTOP). Samples of Ribwort plantain (Plantagolanceolata) growing naturally within the shooting ranges werealso collected and the colonization of its roots by mycorrhizalfungi was measured. The number of AM spores in the soils wassignificantly reduced concomitant with the increase in thedegree of soil contamination with metals. In Zuchwil,mycorrhizal fungi equally colonized roots of Ribwort plantainsampled from BACKSTOP and HOUSE. In Oberuzwil, however, plantsfrom BACKSTOP had lower colonization when compared with thosesampled from HOUSE. Colonization of leek was strongly reducedin the BACKSTOP soil of Zuchwil and slightly reduced in theBACKSTOP soil of Oberuzwil when compared with plants grown inrespective HOUSE soil. Concentrations of Cd, Cr, Cu, Ni, Pb andZn in the leaves of leek grown in the BACKSTOP soil was withinthe range considered toxic for human consumption. This pointsto the high degree of bio-availability of these metal in thesesoils. Significant decrease in the number of mycorrhizal sporesin the BACKSTOP soils in Zuchwil and the low colonization ofleek roots grown in these soils point to possible changes inthe species diversity of mycorrhizal fungi in these soil

Leveraging range joins for the computation of overlap joins

Joins are essential and potentially expensive operations in database management systems. When data is associated with time periods, joins commonly include predicates that require pairs of argument tuples to overlap in order to qualify for the result. Our goal is to enable built-in systems support for such joins. In particular, we present an approach where overlap joins are formulated as unions of range joins, which are more general purpose joins compared to overlap joins, i.e., are useful in their own right, and are supported well by B+-trees. The approach is sufficiently flexible that it also supports joins with additional equality predicates, as well as open, closed, and half-open time periods over discrete and continuous domains, thus offering both generality and simplicity, which is important in a system setting. We provide both a stand-alone solution that performs on par with the state-of-the-art and a DBMS embedded solution that is able to exploit standard indexing and clearly outperforms existing DBMS solutions that depend on specialized indexing techniques. We offer both analytical and empirical evaluations of the proposals. The empirical study includes comparisons with pertinent existing proposals and offers detailed insight into the performance characteristics of the proposals

Potential for interdependent development of tRNA determinants for aminoacylation and ribosome decoding.

Although the nucleotides in tRNA required for aminoacylation are conserved in evolution, bacterial aminoacyl-transfer RNA synthetases are unable to acylate eukaryotic tRNA. The cross-species barrier may be due to the absence of eukaryote-specific domains from bacterial aminoacyl-transfer RNA synthetases. Here we show that whereas Escherichia coli CysRS cannot acylate human tRNA(Cys), the fusion of a eukaryote-specific domain of human CysRS overcomes the cross-species barrier in human tRNA(Cys). In addition to enabling recognition of the sequence differences in the tertiary core of tRNA(Cys), the fused eukaryotic domain redirects the specificity of E. coli CysRS from the A37 present in bacterial tRNA(Cys) to the G37 in mammals. Further experiments show that the accuracy of codon recognition on the ribosome was also highly sensitive to the A37G transition in tRNA(Cys). These results raise the possibility of the development of tRNA nucleotide determinants for aminoacylation being interdependent with those for ribosome decoding

Leveraging range joins for the computation of overlap joins

Joins are essential and potentially expensive operations in database management systems. When data is associated with time periods, joins commonly include predicates that require pairs of argument tuples to overlap in order to qualify for the result. Our goal is to enable built-in systems support for such joins. In particular, we present an approach where overlap joins are formulated as unions of range joins, which are more general purpose joins compared to overlap joins, i.e., are useful in their own right, and are supported well by B+-trees. The approach is sufficiently flexible that it also supports joins with additional equality predicates, as well as open, closed, and half-open time periods over discrete and continuous domains, thus offering both generality and simplicity, which is important in a system setting. We provide both a stand-alone solution that performs on par with the state-of-the-art and a DBMS embedded solution that is able to exploit standard indexing and clearly outperforms existing DBMS solutions that depend on specialized indexing techniques. We offer both analytical and empirical evaluations of the proposals. The empirical study includes comparisons with pertinent existing proposals and offers detailed insight into the performance characteristics of the proposals

Drug Delivery Micropump with Built-In Monitoring

AbstractWe report on the fabrication of the first MEMS micropump including an integrated pressure sensor. The signal of this sensor allows direct insight into the pump's operating dynamics and enables real-time self-monitoring. We demonstrate the changes in the sensor signal under different pumping conditions, including the presence of air in the pumping chamber and a downstream occlusions. Deviations from normal operating conditions create clear and characteristic deviations from the normal signal. These deviations will be exploited to detect extraordinary or faulty pumping conditions during use