1,988 research outputs found
Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline Derived Antitubercular Lead Compounds
Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40β
ΞΌm, one had IC50>66β
ΞΌm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets
Genomic characterization of goose parvovirus and muscovy duck parvovirus co-infection in fujian, china
Heavy fermions and two loop electroweak corrections to
Applying effective Lagrangian method and on-shell scheme, we analyze the
electroweak corrections to the rare decay from some
special two loop diagrams in which a closed heavy fermion loop is attached to
the virtual charged gauge bosons or Higgs. At the decoupling limit where the
virtual fermions in inner loop are much heavier than the electroweak scale, we
verify the final results satisfying the decoupling theorem explicitly when the
interactions among Higgs and heavy fermions do not contain the nondecoupling
couplings. Adopting the universal assumptions on the relevant couplings and
mass spectrum of new physics, we find that the relative corrections from those
two loop diagrams to the SM theoretical prediction on the branching ratio of
can reach 5% as the energy scale of new physics
GeV.Comment: 30 pages,4 figure
Emergence of scale-free close-knit friendship structure in online social networks
Despite the structural properties of online social networks have attracted
much attention, the properties of the close-knit friendship structures remain
an important question. Here, we mainly focus on how these mesoscale structures
are affected by the local and global structural properties. Analyzing the data
of four large-scale online social networks reveals several common structural
properties. It is found that not only the local structures given by the
indegree, outdegree, and reciprocal degree distributions follow a similar
scaling behavior, the mesoscale structures represented by the distributions of
close-knit friendship structures also exhibit a similar scaling law. The degree
correlation is very weak over a wide range of the degrees. We propose a simple
directed network model that captures the observed properties. The model
incorporates two mechanisms: reciprocation and preferential attachment. Through
rate equation analysis of our model, the local-scale and mesoscale structural
properties are derived. In the local-scale, the same scaling behavior of
indegree and outdegree distributions stems from indegree and outdegree of nodes
both growing as the same function of the introduction time, and the reciprocal
degree distribution also shows the same power-law due to the linear
relationship between the reciprocal degree and in/outdegree of nodes. In the
mesoscale, the distributions of four closed triples representing close-knit
friendship structures are found to exhibit identical power-laws, a behavior
attributed to the negligible degree correlations. Intriguingly, all the
power-law exponents of the distributions in the local-scale and mesoscale
depend only on one global parameter -- the mean in/outdegree, while both the
mean in/outdegree and the reciprocity together determine the ratio of the
reciprocal degree of a node to its in/outdegree.Comment: 48 pages, 34 figure
The degradation of p53 and its major E3 ligase Mdm2 is differentially dependent on the proteasomal ubiquitin receptor S5a.
p53 and its major E3 ligase Mdm2 are both ubiquitinated and targeted to the proteasome for degradation. Despite the importance of this in regulating the p53 pathway, little is known about the mechanisms of proteasomal recognition of ubiquitinated p53 and Mdm2. In this study, we show that knockdown of the proteasomal ubiquitin receptor S5a/PSMD4/Rpn10 inhibits p53 protein degradation and results in the accumulation of ubiquitinated p53. Overexpression of a dominant-negative deletion of S5a lacking its ubiquitin-interacting motifs (UIM)s, but which can be incorporated into the proteasome, also causes the stabilization of p53. Furthermore, small-interferring RNA (siRNA) rescue experiments confirm that the UIMs of S5a are required for the maintenance of low p53 levels. These observations indicate that S5a participates in the recognition of ubiquitinated p53 by the proteasome. In contrast, targeting S5a has no effect on the rate of degradation of Mdm2, indicating that proteasomal recognition of Mdm2 can be mediated by an S5a-independent pathway. S5a knockdown results in an increase in the transcriptional activity of p53. The selective stabilization of p53 and not Mdm2 provides a mechanism for p53 activation. Depletion of S5a causes a p53-dependent decrease in cell proliferation, demonstrating that p53 can have a dominant role in the response to targeting S5a. This study provides evidence for alternative pathways of proteasomal recognition of p53 and Mdm2. Differences in recognition by the proteasome could provide a means to modulate the relative stability of p53 and Mdm2 in response to cellular signals. In addition, they could be exploited for p53-activating therapies. This work shows that the degradation of proteins by the proteasome can be selectively dependent on S5a in human cells, and that this selectivity can extend to an E3 ubiquitin ligase and its substrate
Lumican Expression in Diaphragm Induced by Mechanical Ventilation
Diaphragmatic dysfunction found in the patients with acute lung injury required prolonged mechanical ventilation. Mechanical ventilation can induce production of inflammatory cytokines and excess deposition of extracellular matrix proteins via up-regulation of transforming growth factor (TGF)-Ξ²1. Lumican is known to participate in TGF-Ξ²1 signaling during wound healing. The mechanisms regulating interactions between mechanical ventilation and diaphragmatic injury are unclear. We hypothesized that diaphragmatic damage by short duration of mechanical stretch caused up-regulation of lumican that modulated TGF-Ξ²1 signaling.Male C57BL/6 mice, either wild-type or lumican-null, aged 3 months, weighing between 25 and 30 g, were exposed to normal tidal volume (10 ml/kg) or high tidal volume (30 ml/kg) mechanical ventilation with room air for 2 to 8 hours. Nonventilated mice served as control groups.High tidal volume mechanical ventilation induced interfibrillar disassembly of diaphragmatic collagen fiber, lumican activation, type I and III procollagen, fibronectin, and Ξ±-smooth muscle actin (Ξ±-SMA) mRNA, production of free radical and TGF-Ξ²1 protein, and positive staining of lumican in diaphragmatic fiber. Mechanical ventilation of lumican deficient mice attenuated diaphragmatic injury, type I and III procollagen, fibronectin, and Ξ±-SMA mRNA, and production of free radical and TGF-Ξ²1 protein. No significant diaphragmatic injury was found in mice subjected to normal tidal volume mechanical ventilation.Our data showed that high tidal volume mechanical ventilation induced TGF-Ξ²1 production, TGF-Ξ²1-inducible genes, e.g., collagen, and diaphragmatic dysfunction through activation of the lumican
Thermopower of the Correlated Narrow Gap Semiconductor FeSi and Comparison to RuSi
Iron based narrow gap semiconductors such as FeSi, FeSb2, or FeGa3 have
received a lot of attention because they exhibit a large thermopower, as well
as striking similarities to heavy fermion Kondo insulators. Many proposals have
been advanced, however, lacking quantitative methodologies applied to this
problem, a consensus remained elusive to date. Here, we employ realistic
many-body calculations to elucidate the impact of electronic correlation
effects on FeSi. Our methodology accounts for all substantial anomalies
observed in FeSi: the metallization, the lack of conservation of spectral
weight in optical spectroscopy, and the Curie susceptibility. In particular we
find a very good agreement for the anomalous thermoelectric power. Validated by
this congruence with experiment, we further discuss a new physical picture of
the microscopic nature of the insulator-to-metal crossover. Indeed, we find the
suppression of the Seebeck coefficient to be driven by correlation induced
incoherence. Finally, we compare FeSi to its iso-structural and iso-electronic
homologue RuSi, and predict that partially substituted Fe(1-x)Ru(x)Si will
exhibit an increased thermopower at intermediate temperatures.Comment: 14 pages. Proceedings of the Hvar 2011 Workshop on 'New materials for
thermoelectric applications: theory and experiment
Protein profiling in hepatocellular carcinoma by label-free quantitative proteomics in two west african populations.
Background Hepatocellular Carcinoma is the third most common cause of cancer related death worldwide, often diagnosed by measuring serum AFP; a poor performance stand-alone biomarker. With the aim of improving on this, our study focuses on plasma proteins identified by Mass Spectrometry in order to investigate and validate differences seen in the respective proteomes of controls and subjects with LC and HCC. Methods Mass Spectrometry analysis using liquid chromatography electro spray ionization quadrupole time-of-flight was conducted on 339 subjects using a pooled expression profiling approach. ELISA assays were performed on four significantly differentially expressed proteins to validate their expression profiles in subjects from the Gambia and a pilot group from Nigeria. Results from this were collated for statistical multiplexing using logistic regression analysis. Results Twenty-six proteins were identified as differentially expressed between the three subject groups. Direct measurements of four; hemopexin, alpha-1-antitrypsin, apolipoprotein A1 and complement component 3 confirmed their change in abundance in LC and HCC versus control patients. These trends were independently replicated in the pilot validation subjects from Nigeria. The statistical multiplexing of these proteins demonstrated performance comparable to or greater than ALT in identifying liver cirrhosis or carcinogenesis. This exercise also proposed preliminary cut offs with achievable sensitivity, specificity and AUC statistics greater than reported AFP averages. Conclusions The validated changes of expression in these proteins have the potential for development into high-performance tests usable in the diagnosis and or monitoring of HCC and LC patients. The identification of sustained expression trends strengthens the suggestion of these four proteins as worthy candidates for further investigation in the context of liver disease. The statistical combinations also provide a novel inroad of analyses able to propose definitive cut-offs and combinations for evaluation of performance
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