639 research outputs found
A fragment merging approach towards the development of small molecule inhibitors of Mycobacterium tuberculosis EthR for use as ethionamide boosters.
With the ever-increasing instances of resistance to frontline TB drugs there is the need to develop novel strategies to fight the worldwide TB epidemic. Boosting the effect of the existing second-line antibiotic ethionamide by inhibiting the mycobacterial transcriptional repressor protein EthR is an attractive therapeutic strategy. Herein we report the use of a fragment based drug discovery approach for the structure-guided systematic merging of two fragment molecules, each binding twice to the hydrophobic cavity of EthR from M. tuberculosis. These together fill the entire binding pocket of EthR. We elaborated these fragment hits and developed small molecule inhibitors which have a 100-fold improvement of potency in vitro over the initial fragments.We also thank the Bill and Melinda Gates Foundation and the EU FP7 MM4TB Grant n°260872, the ERC-STG INTRACELLTB Grant n°260901, the Agence Nationale de la Recherche (ANR-10-EQPX-04-01), the Feder (12001407 (D-AL) Equipex Imaginex BioMed) and the Région Nord Pas de Calais, France, for providing funding to support this work.This is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C5OB02630
Non-supersymmetric heterotic model building
We investigate orbifold and smooth Calabi-Yau compactifications of the
non-supersymmetric heterotic SO(16)xSO(16) string. We focus on such Calabi-Yau
backgrounds in order to recycle commonly employed techniques, like index
theorems and cohomology theory, to determine both the fermionic and bosonic 4D
spectra. We argue that the N=0 theory never leads to tachyons on smooth
Calabi-Yaus in the large volume approximation. As twisted tachyons may arise on
certain singular orbifolds, we conjecture that such tachyonic states are lifted
in the full blow-up. We perform model searches on selected orbifold geometries.
In particular, we construct an explicit example of a Standard Model-like theory
with three generations and a single Higgs field.Comment: 1+30 pages latex, 11 tables; v2: references and minor revisions
added, matches version published in JHE
Yukawa couplings and masses of non-chiral states for the Standard Model on D6-branes on T6/Z6'
The perturbative leading order open string three-point couplings for the
Standard Model with hidden USp(6) on fractional D6-branes on T6/Z6' from
arXiv:0806.3039 [hep-th], arXiv:0910.0843 [hep-th] are computed. Physical
Yukawa couplings consisting of holomorphic Wilsonian superpotential terms times
a non-holomorphic prefactor involving the corresponding classical open string
Kaehler metrics are given, and mass terms for all non-chiral matter states are
derived. The lepton Yukawa interactions are at leading order flavour diagonal,
while the quark sector displays a more intricate pattern of mixings. While N=2
supersymmetric sectors acquire masses via only two D6-brane displacements -
which also provide the hierarchies between up- and down-type Yukawas within one
quark or lepton generation -, the remaining vector-like states receive masses
via perturbative three-point couplings to some Standard Model singlet fields
with vevs along flat directions. Couplings to the hidden sector and messengers
for supersymmetry breaking are briefly discussed.Comment: 52 pages (including 8p. appendix); 5 figures; 14 tables; v2:
discussion in section 4.1.3 extended, footnote 5 added, typos corrected,
accepted by JHE
Evaluation of acidogenesis productsâ effect on biogas production performed with metagenomics and isotopic approaches
Background: During the acetogenic step of anaerobic digestion, the products of acidogenesis are oxidized to substrates for methanogenesis: hydrogen, carbon dioxide and acetate. Acetogenesis and methanogenesis are highly interconnected processes due to the syntrophic associations between acetogenic bacteria and hydrogenotrophic methanogens, allowing the whole process to become thermodynamically favorable. The aim of this study is to determine the influence of the dominant acidic products on the metabolic pathways of methane formation and to find a core microbiome and substrate-specific species in a mixed biogas-producing system. Results: Four methane-producing microbial communities were fed with artificial media having one dominant component, respectively, lactate, butyrate, propionate and acetate, for 896Â days in 3.5-L Up-flow Anaerobic Sludge Blanket (UASB) bioreactors. All the microbial communities showed moderately different methane production and utilization of the substrates. Analyses of stable carbon isotope composition of the fermentation gas and the substrates showed differences in average values of ÎŽ13C(CH4) and ÎŽ13C(CO2) revealing that acetate and lactate strongly favored the acetotrophic pathway, while butyrate and propionate favored the hydrogenotrophic pathway of methane formation. Genome-centric metagenomic analysis recovered 234 Metagenome Assembled Genomes (MAGs), including 31 archaeal and 203 bacterial species, mostly unknown and uncultivable. MAGs accounted for 54%â67% of the entire microbial community (depending on the bioreactor) and evidenced that the microbiome is extremely complex in terms of the number of species. The core microbiome was composed of Methanothrix soehngenii (the most abundant), Methanoculleus sp., unknown Bacteroidales and Spirochaetaceae. Relative abundance analysis of all the samples revealed microbes having substrate preferences. Substrate-specific species were mostly unknown and not predominant in the microbial communities. Conclusions: In this experimental system, the dominant fermentation products subjected to methanogenesis moderately modified the final effect of bioreactor performance. At the molecular level, a different contribution of acetotrophic and hydrogenotrophic pathways for methane production, a very high level of new species recovered, and a moderate variability in microbial composition depending on substrate availability were evidenced. Propionate was not a factor ceasing methane production. All these findings are relevant because lactate, acetate, propionate and butyrate are the universal products of acidogenesis, regardless of feedstock
Precision Gauge Unification from Extra Yukawa Couplings
We investigate the impact of extra vector-like GUT multiplets on the
predicted value of the strong coupling. We find in particular that Yukawa
couplings between such extra multiplets and the MSSM Higgs doublets can resolve
the familiar two-loop discrepancy between the SUSY GUT prediction and the
measured value of alpha_3. Our analysis highlights the advantages of the
holomorphic scheme, where the perturbative running of gauge couplings is
saturated at one loop and further corrections are conveniently described in
terms of wavefunction renormalization factors. If the gauge couplings as well
as the extra Yukawas are of O(1) at the unification scale, the relevant
two-loop correction can be obtained analytically. However, the effect persists
also in the weakly-coupled domain, where possible non-perturbative corrections
at the GUT scale are under better control.Comment: 26 pages, LaTeX. v6: Important early reference adde
A Global SU(5) F-theory model with Wilson line breaking
We engineer compact SU(5) Grand Unified Theories in F-theory in which
GUT-breaking is achieved by a discrete Wilson line. Because the internal gauge
field is flat, these models avoid the high scale threshold corrections
associated with hypercharge flux. Along the way, we exemplify the
`local-to-global' approach in F-theory model building and demonstrate how the
Tate divisor formalism can be used to address several challenges of extending
local models to global ones. These include in particular the construction of
G-fluxes that extend non-inherited bundles and the engineering of U(1)
symmetries. We go beyond chirality computations and determine the precise
(charged) massless spectrum, finding exactly three families of quarks and
leptons but excessive doublet and/or triplet pairs in the Higgs sector
(depending on the example) and vector-like exotics descending from the adjoint
of SU(5)_{GUT}. Understanding why vector-like pairs persist in the Higgs sector
without an obvious symmetry to protect them may shed light on new solutions to
the mu problem in F-theory GUTs.Comment: 95 pages (71 pages + 1 Appendix); v2 references added, minor
correction
Gauged Linear Sigma Models for toroidal orbifold resolutions
Toroidal orbifolds and their resolutions are described within the framework
of (2,2) Gauged Linear Sigma Models (GLSMs). Our procedure describes two-tori
as hypersurfaces in (weighted) projective spaces. The description is chosen
such that the orbifold singularities correspond to the zeros of their
homogeneous coordinates. The individual orbifold singularities are resolved
using a GLSM guise of non-compact toric resolutions, i.e. replacing discrete
orbifold actions by Abelian worldsheet gaugings. Given that we employ the same
global coordinates for both the toroidal orbifold and its resolutions, our GLSM
formalism confirms the gluing procedure on the level of divisors discussed by
Lust et al. Using our global GLSM description we can study the moduli space of
such toroidal orbifolds as a whole. In particular, changes in topology can be
described as phase transitions of the underlying GLSM. Finally, we argue that
certain partially resolvable GLSMs, in which a certain number of fixed points
can never be resolved, might be useful for the study of mini-landscape orbifold
MSSMs.Comment: 71 pages, 2 figure
Linear Sigma Models with Torsion
Gauged linear sigma models with (0,2) supersymmetry allow a larger choice of
couplings than models with (2,2) supersymmetry. We use this freedom to find a
fully linear construction of torsional heterotic compactifications, including
models with branes. As a non-compact example, we describe a family of metrics
which correspond to deformations of the heterotic conifold by turning on
H-flux. We then describe compact models which are gauge-invariant only at the
quantum level. Our construction gives a generalization of symplectic reduction.
The resulting spaces are non-Kahler analogues of familiar toric spaces like
complex projective space. Perturbatively conformal models can be constructed by
considering intersections.Comment: 40 pages, LaTeX, 1 figure; references added; a new section on
supersymmetry added; quantization condition revisite
Light Vector Mesons in the Nuclear Medium
The light vector mesons (, , and ) were produced in
deuterium, carbon, titanium, and iron targets in a search for possible
in-medium modifications to the properties of the meson at normal nuclear
densities and zero temperature. The vector mesons were detected with the CEBAF
Large Acceptance Spectrometer (CLAS) via their decays to . The rare
leptonic decay was chosen to reduce final-state interactions. A combinatorial
background was subtracted from the invariant mass spectra using a
well-established event-mixing technique. The meson mass spectrum was
extracted after the and signals were removed in a nearly
model-independent way. Comparisons were made between the mass spectra
from the heavy targets () with the mass spectrum extracted from the
deuterium target. With respect to the -meson mass, we obtain a small
shift compatible with zero. Also, we measure widths consistent with standard
nuclear many-body effects such as collisional broadening and Fermi motion.Comment: 15 pages, 18 figures, 3 table
Modern microwave methods in solid state inorganic materials chemistry: from fundamentals to manufacturing
No abstract available
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