1,264 research outputs found
Design, synthesis and biological characterization of novel inhibitors of CD38
Human CD38 is a novel multi-functional protein that acts not only as an antigen for B-lymphocyte activation, but also as an enzyme catalyzing the synthesis of a Ca 2+ messenger molecule, cyclic ADP-ribose, from NAD +. It is well established that this novel Ca 2+ signaling enzyme is responsible for regulating a wide range of physiological functions. Based on the crystal structure of the CD38/NAD + complex, we synthesized a series of simplified N-substituted nicotinamide derivatives (Compound1-14). A number of these compounds exhibited moderate inhibition of the NAD + utilizing activity of CD38, with Compound4 showing the highest potency. The crystal structure of CD38/Compound4 complex and computer simulation of Compound7 docking to CD38 show a significant role of the nicotinamide moiety and the distal aromatic group of the compounds for substrate recognition by the active site of CD38. Biologically, we showed that both Compounds4 and 7 effectively relaxed the agonist-induced contraction of muscle preparations from rats and guinea pigs. This study is a rational design of inhibitors for CD38 that exhibit important physiological effects, and can serve as a model for future drug development. © 2011 The Royal Society of Chemistry.postprin
Establishment of an AAV Reverse Infection-Based Array
Background: The development of a convenient high-throughput gene transduction approach is critical for biological screening. Adeno-associated virus (AAV) vectors are broadly used in gene therapy studies, yet their applications in in vitro high-throughput gene transduction are limited. Principal Findings: We established an AAV reverse infection (RI)-based method in which cells were transduced by quantified recombinant AAVs (rAAVs) pre-coated onto 96-well plates. The number of pre-coated rAAV particles and number of cells loaded per well, as well as the temperature stability of the rAAVs on the plates, were evaluated. As the first application of this method, six serotypes or hybrid serotypes of rAAVs (AAV1, AAV2, AAV5/5, AAV8, AAV25 m, AAV28 m) were compared for their transduction efficiencies using various cell lines, including BHK21, HEK293, BEAS-2BS, HeLaS3, Huh7, Hepa1-6, and A549. AAV2 and AAV1 displayed high transduction efficiency; thus, they were deemed to be suitable candidate vectors for the RI-based array. We next evaluated the impact of sodium butyrate (NaB) treatment on rAAV vectormediated reporter gene expression and found it was significantly enhanced, suggesting that our system reflected the biological response of target cells to specific treatments. Conclusions/Significance: Our study provides a novel method for establishing a highly efficient gene transduction arra
Resonances in and
A partial wave analysis is presented of and
from a sample of 58M events in the BES II detector. The
is observed clearly in both sets of data, and parameters of the
Flatt\' e formula are determined accurately: (stat)
(syst) MeV/c, MeV/c, . The data also exhibit a strong peak
centred at MeV/c. It may be fitted with and a
dominant signal made from interfering with a smaller
component. There is evidence that the signal is
resonant, from interference with . There is also a state in with MeV/c and
MeV/c; spin 0 is preferred over spin 2. This state, , is
distinct from . The data contain a strong peak due to
. A shoulder on its upper side may be fitted by interference
between and .Comment: 17 pages, 6 figures, 1 table. Submitted to Phys. Lett.
First Measurements of eta_c Decaying into K^+K^-2(pi^+pi^-) and 3(pi^+pi^-)
The decays of eta_c to K^+K^-2(pi^+pi^-) and 3(pi^+pi^-) are observed for the
first time using a sample of 5.8X10^7 J/\psi events collected by the BESII
detector. The product branching fractions are determined to be B(J/\psi-->gamma
eta_c)*B(eta_c-->K^+K^-pi^+pi^-pi^+pi^-)=(1.21+-0.32+-
0.23)X10^{-4}, and (J/\psi-->gamma eta_c)*
B(eta_c-->pi^+pi^-pi^+pi^-pi^+pi^-)= (2.59+-0.32+-0.48)X10^{-4}. The upper
limit for eta_c-->phi pi^+pi^-pi^+pi^- is also obtained as B(J/\psi-->gamma
eta_c)*B(eta_c--> phi pi^+pi^-pi^+pi^-)< 6.03 X10^{-5} at the 90% confidence
level.Comment: 11 pages, 4 figure
Role of Cajal Bodies and Nucleolus in the Maturation of the U1 snRNP in Arabidopsis
Background: The biogenesis of spliceosomal snRNPs takes place in both the cytoplasm where Sm core proteins are added and snRNAs are modified at the 59 and 39 termini and in the nucleus where snRNP-specific proteins associate. U1 snRNP consists of U1 snRNA, seven Sm proteins and three snRNP-specific proteins, U1-70K, U1A, and U1C. It has been shown previously that after import to the nucleus U2 and U4/U6 snRNP-specific proteins first appear in Cajal bodies (CB) and then in splicing speckles. In addition, in cells grown under normal conditions U2, U4, U5, and U6 snRNAs/snRNPs are abundant in CBs. Therefore, it has been proposed that the final assembly of these spliceosomal snRNPs takes place in this nuclear compartment. In contrast, U1 snRNA in both animal and plant cells has rarely been found in this nuclear compartment. Methodology/Principal Findings: Here, we analysed the subnuclear distribution of Arabidopsis U1 snRNP-specific proteins fused to GFP or mRFP in transiently transformed Arabidopsis protoplasts. Irrespective of the tag used, U1-70K was exclusively found in the nucleus, whereas U1A and U1C were equally distributed between the nucleus and the cytoplasm. In the nucleus all three proteins localised to CBs and nucleoli although to different extent. Interestingly, we also found that the appearance of the three proteins in nuclear speckles differ significantly. U1-70K was mostly found in speckles whereas U1A and U1C in,90 % of cells showed diffuse nucleoplasmic in combination with CBs and nucleolar localisation. Conclusions/Significance: Our data indicate that CBs and nucleolus are involved in the maturation of U1 snRNP. Difference
Measurement of the Branching Fraction of J/psi --> pi+ pi- pi0
Using 58 million J/psi and 14 million psi' decays obtained by the BESII
experiment, the branching fraction of J/psi --> pi+ pi- pi0 is determined. The
result is (2.10+/-0.12)X10^{-2}, which is significantly higher than previous
measurements.Comment: 9 pages, 8 figures, RevTex
First observation of psi(2S)-->K_S K_L
The decay psi(2S)-->K_S K_L is observed for the first time using psi(2S) data
collected with the Beijing Spectrometer (BESII) at the Beijing Electron
Positron Collider (BEPC); the branching ratio is determined to be
B(psi(2S)-->K_S K_L) = (5.24\pm 0.47 \pm 0.48)\times 10^{-5}. Compared with
J/psi-->K_S K_L, the psi(2S) branching ratio is enhanced relative to the
prediction of the perturbative QCD ``12%'' rule. The result, together with the
branching ratios of psi(2S) decays to other pseudoscalar meson pairs
(\pi^+\pi^- and K^+K^-), is used to investigate the relative phase between the
three-gluon and the one-photon annihilation amplitudes of psi(2S) decays.Comment: 5 pages, 4 figures, 2 tables, submitted to Phys. Rev. Let
Study of psi(2S) decays to X J/psi
Using J/psi -> mu^+ mu^- decays from a sample of approximately 4 million
psi(2S) events collected with the BESI detector, the branching fractions of
psi(2S) -> eta J/psi, pi^0 pi^0 J/psi, and anything J/psi normalized to that of
psi(2S) -> pi^+ pi^- J/psi are measured. The results are B(psi(2S) -> eta
J/psi)/B(psi(2S) -> pi^+ pi^- J/psi) = 0.098 \pm 0.005 \pm 0.010, B(psi(2S) ->
pi^0 pi^0 J/psi)/B(psi(2S) -> pi^+ pi^- J/psi) = 0.570 \pm 0.009 \pm 0.026, and
B(psi(2S) -> anything J/psi)/B(psi(2S) -> pi^+ pi^- J/psi) = 1.867 \pm 0.026
\pm 0.055.Comment: 13 pages, 8 figure
Helical Chirality: a Link between Local Interactions and Global Topology in DNA
DNA supercoiling plays a major role in many cellular functions. The global DNA conformation is however intimately linked to local DNA-DNA interactions influencing both the physical properties and the biological functions of the supercoiled molecule. Juxtaposition of DNA double helices in ubiquitous crossover arrangements participates in multiple functions such as recombination, gene regulation and DNA packaging. However, little is currently known about how the structure and stability of direct DNA-DNA interactions influence the topological state of DNA. Here, a crystallographic analysis shows that due to the intrinsic helical chirality of DNA, crossovers of opposite handedness exhibit markedly different geometries. While right-handed crossovers are self-fitted by sequence-specific groove-backbone interaction and bridging Mg2+ sites, left-handed crossovers are juxtaposed by groove-groove interaction. Our previous calculations have shown that the different geometries result in differential stabilisation in solution, in the presence of divalent cations. The present study reveals that the various topological states of the cell are associated with different inter-segmental interactions. While the unstable left-handed crossovers are exclusively formed in negatively supercoiled DNA, stable right-handed crossovers constitute the local signature of an unusual topological state in the cell, such as the positively supercoiled or relaxed DNA. These findings not only provide a simple mechanism for locally sensing the DNA topology but also lead to the prediction that, due to their different tertiary intra-molecular interactions, supercoiled molecules of opposite signs must display markedly different physical properties. Sticky inter-segmental interactions in positively supercoiled or relaxed DNA are expected to greatly slow down the slithering dynamics of DNA. We therefore suggest that the intrinsic helical chirality of DNA may have oriented the early evolutionary choices for DNA topology
Curlometer technique and applications
We review the range of applications and use of the curlometer, initially developed to analyze Cluster multi-spacecraft magnetic field data; but more recently adapted to other arrays of spacecraft flying in formation, such as MMS small-scale, 4-spacecraft configurations; THEMIS close constellations of 3–5 spacecraft, and Swarm 2–3 spacecraft configurations. Although magnetic gradients require knowledge of spacecraft separations and the magnetic field, the structure of the electric current density (for example, its relative spatial scale), and any temporal evolution, limits measurement accuracy. Nevertheless, in many magnetospheric regions the curlometer is reliable (within certain limits), particularly under conditions of time stationarity, or with supporting information on morphology (for example, when the geometry of the large scale structure is expected). A number of large-scale regions have been covered, such as: the cross-tail current sheet, ring current, the current layer at the magnetopause and field-aligned currents. Transient and smaller scale current structures (e.g., reconnected flux tube or dipolarisation fronts) and energy transfer processes. The method is able to provide estimates of single components of the vector current density, even if there are only two or three satellites flying in formation, within the current region, as can be the case when there is a highly irregular spacecraft configuration. The computation of magnetic field gradients and topology in general includes magnetic rotation analysis and various least squares approaches, as well as the curlometer, and indeed the added inclusion of plasma measurements and the extension to larger arrays of spacecraft have recently been considered
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