2,324 research outputs found
Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase
Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism
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Video Rate Molecular Imaging In Vivo with Stimulated Raman Scattering
Optical imaging in vivo with molecular specificity is important in biomedicine because of its high spatial resolution and sensitivity compared with magnetic resonance imaging. Stimulated Raman scattering (SRS) microscopy allows highly sensitive optical imaging based on vibrational spectroscopy without adding toxic or perturbative labels. However, SRS imaging in living animals and humans has not been feasible because light cannot be collected through thick tissues, and motion-blur arises from slow imaging based on backscattered light. In this work, we enable in vivo SRS imaging by substantially enhancing the collection of the backscattered signal and increasing the imaging speed by three orders of magnitude to video rate. This approach allows label-free in vivo imaging of water, lipid, and protein in skin and mapping of penetration pathways of topically applied drugs in mice and humans.Chemistry and Chemical Biolog
Cloning of potential candidates for guinea pig opioid receptors
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31190/1/0000092.pd
Topological Organization of Ventral Tegmental Area Connectivity Revealed by Viral-Genetic Dissection of Input-Output Relations
Viral-genetic tracing techniques have enabled mesoscale mapping of neuronal connectivity by teasing apart inputs to defined neuronal populations in regions with heterogeneous cell types. We previously observed input biases to output-defined ventral tegmental area dopamine (VTA-DA) neurons. Here, we further dissect connectivity in the VTA by defining input-output relations of neurochemically and output-defined neuronal populations. By expanding our analysis to include input patterns to subtypes of excitatory (vGluT2-expressing) or inhibitory (GAD2-expressing) populations, we find that the output site, rather than neurochemical phenotype, correlates with whole-brain inputs of each subpopulation. Lastly, we find that biases in input maps to different VTA neurons can be generated using publicly available whole-brain output mapping datasets. Our comprehensive dataset and detailed spatial analysis suggest that connection specificity in the VTA is largely a function of the spatial location of the cells within the VTA
Searching for network modules
When analyzing complex networks a key target is to uncover their modular
structure, which means searching for a family of modules, namely node subsets
spanning each a subnetwork more densely connected than the average. This work
proposes a novel type of objective function for graph clustering, in the form
of a multilinear polynomial whose coefficients are determined by network
topology. It may be thought of as a potential function, to be maximized, taking
its values on fuzzy clusterings or families of fuzzy subsets of nodes over
which every node distributes a unit membership. When suitably parametrized,
this potential is shown to attain its maximum when every node concentrates its
all unit membership on some module. The output thus is a partition, while the
original discrete optimization problem is turned into a continuous version
allowing to conceive alternative search strategies. The instance of the problem
being a pseudo-Boolean function assigning real-valued cluster scores to node
subsets, modularity maximization is employed to exemplify a so-called quadratic
form, in that the scores of singletons and pairs also fully determine the
scores of larger clusters, while the resulting multilinear polynomial potential
function has degree 2. After considering further quadratic instances, different
from modularity and obtained by interpreting network topology in alternative
manners, a greedy local-search strategy for the continuous framework is
analytically compared with an existing greedy agglomerative procedure for the
discrete case. Overlapping is finally discussed in terms of multiple runs, i.e.
several local searches with different initializations.Comment: 10 page
Size Dependence of Metal-Insulator Transition in Stoichiometric Fe3O4 Nanocrystals
Magnetite (Fe3O4) is one of the most actively studied materials with a famous
metal-insulator transition (MIT), so-called the Verwey transition at around 123
K. Despite the recent progress in synthesis and characterization of Fe3O4
nanocrystals (NCs), it is still an open question how the Verwey transition
changes on a nanometer scale. We herein report the systematic studies on size
dependence of the Verwey transition of stoichiometric Fe3O4 NCs. We have
successfully synthesized stoichiometric and uniform-sized Fe3O4 NCs with sizes
ranging from 5 to 100 nm. These stoichiometric Fe3O4 NCs show the Verwey
transition when they are characterized by conductance, magnetization, cryo-XRD,
and heat capacity measurements. The Verwey transition is weakly size-dependent
and becomes suppressed in NCs smaller than 20 nm before disappearing completely
for less than 6 nm, which is a clear, yet highly interesting indication of a
size effect of this well-known phenomena. Our current work will shed new light
on this ages-old problem of Verwey transition.Comment: 18 pages, 4 figures, Nano Letters (accepted
Charged hadron multiplicity fluctuations in Au+Au and Cu+Cu collisions from sqrt(s_NN) = 22.5 to 200 GeV
A comprehensive survey of event-by-event fluctuations of charged hadron
multiplicity in relativistic heavy ions is presented. The survey covers Au+Au
collisions at sqrt(s_NN) = 62.4 and 200 GeV, and Cu+Cu collisions sqrt(s_NN) =
22.5, 62.4, and 200 GeV. Fluctuations are measured as a function of collision
centrality, transverse momentum range, and charge sign. After correcting for
non-dynamical fluctuations due to fluctuations in the collision geometry within
a centrality bin, the remaining dynamical fluctuations expressed as the
variance normalized by the mean tend to decrease with increasing centrality.
The dynamical fluctuations are consistent with or below the expectation from a
superposition of participant nucleon-nucleon collisions based upon p+p data,
indicating that this dataset does not exhibit evidence of critical behavior in
terms of the compressibility of the system. An analysis of Negative Binomial
Distribution fits to the multiplicity distributions demonstrates that the heavy
ion data exhibit weak clustering properties.Comment: 464 authors from 60 institutions, 17 pages, 12 figures, 1 table.
Submitted to Physical Review C. Plain text data tables for the points plotted
in figures for this and previous PHENIX publications are (or will be)
publicly available at http://www.phenix.bnl.gov/papers.htm
Measurements of single top quark production cross sections and |Vtb| in ppbar collisions at sqrt{s}=1.96 TeV
We present measurements of production cross sections of single top quarks in
\ppbar collisions at in a data sample corresponding
to an integrated luminosity of collected by the D0 detector
at the Fermilab Tevatron Collider. We select events with an isolated electron
or muon, an imbalance in transverse energy, and two, three, or four jets, with
one or two of them containing a bottom hadron. We obtain an inclusive cross
section of \sigma({\ppbar}{\rargap}tb+X, tqb+X) = 3.43\pm^{0.73}_{0.74}\;\rm
pb and use it to extract the CKM matrix element at
the 95% C.L. We also measure \sigma({\ppbar}{\rargap}tb+X) =
0.68\pm^{0.38}_{0.35}\;\rm pb and \sigma({\ppbar}{\rargap}tqb+X) =
2.86\pm^{0.69}_{0.63}\;\rm pb when assuming, respectively, and
production rates as predicted by the standard model.Comment: 11 pages, 8 figures, submitted to Phys. Rev.
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