149 research outputs found
Biocatalytic production of bicyclic β-lactams with three contiguous chiral centres using engineered crotonases
YesThere is a need to develop asymmetric routes to functionalised β-lactams, which remain the
most important group of antibacterials. Here we describe biocatalytic and protein engineering
studies concerning carbapenem biosynthesis enzymes, aiming to enable stereoselective
production of functionalised carbapenams with three contiguous chiral centres. Structurallyguided substitutions of wildtype carboxymethylproline synthases enable tuning of their C-N
and C-C bond forming capacity to produce 5-carboxymethylproline derivatives substituted at
C-4 and C-6, from amino acid aldehyde and malonyl-CoA derivatives. Use of tandem enzyme
incubations comprising an engineered carboxymethylproline synthase and an alkylmalonylCoA forming enzyme (i.e. malonyl-CoA synthetase or crotonyl-CoA carboxylase reductase)
can improve stereocontrol and expand the product range. Some of the prepared 4,6-disubstituted-5-carboxymethylproline derivatives are converted to bicyclic β-lactams by carbapenam synthetase catalysis. The results illustrate the utility of tandem enzyme systems
involving engineered crotonases for asymmetric bicyclic β-lactam synthesis
The Pioneer Anomaly
Radio-metric Doppler tracking data received from the Pioneer 10 and 11
spacecraft from heliocentric distances of 20-70 AU has consistently indicated
the presence of a small, anomalous, blue-shifted frequency drift uniformly
changing with a rate of ~6 x 10^{-9} Hz/s. Ultimately, the drift was
interpreted as a constant sunward deceleration of each particular spacecraft at
the level of a_P = (8.74 +/- 1.33) x 10^{-10} m/s^2. This apparent violation of
the Newton's gravitational inverse-square law has become known as the Pioneer
anomaly; the nature of this anomaly remains unexplained. In this review, we
summarize the current knowledge of the physical properties of the anomaly and
the conditions that led to its detection and characterization. We review
various mechanisms proposed to explain the anomaly and discuss the current
state of efforts to determine its nature. A comprehensive new investigation of
the anomalous behavior of the two Pioneers has begun recently. The new efforts
rely on the much-extended set of radio-metric Doppler data for both spacecraft
in conjunction with the newly available complete record of their telemetry
files and a large archive of original project documentation. As the new study
is yet to report its findings, this review provides the necessary background
for the new results to appear in the near future. In particular, we provide a
significant amount of information on the design, operations and behavior of the
two Pioneers during their entire missions, including descriptions of various
data formats and techniques used for their navigation and radio-science data
analysis. As most of this information was recovered relatively recently, it was
not used in the previous studies of the Pioneer anomaly, but it is critical for
the new investigation.Comment: 165 pages, 40 figures, 16 tables; accepted for publication in Living
Reviews in Relativit
Hawking emission from quantum gravity black holes
We address the issue of modelling quantum gravity effects in the evaporation
of higher dimensional black holes in order to go beyond the usual
semi-classical approximation. After reviewing the existing six families of
quantum gravity corrected black hole geometries, we focus our work on
non-commutative geometry inspired black holes, which encode model independent
characteristics, are unaffected by the quantum back reaction and have an
analytical form compact enough for numerical simulations. We consider the
higher dimensional, spherically symmetric case and we proceed with a complete
analysis of the brane/bulk emission for scalar fields. The key feature which
makes the evaporation of non-commutative black holes so peculiar is the
possibility of having a maximum temperature. Contrary to what happens with
classical Schwarzschild black holes, the emission is dominated by low frequency
field modes on the brane. This is a distinctive and potentially testable
signature which might disclose further features about the nature of quantum
gravity.Comment: 36 pages, 18 figures, v2: updated reference list, minor corrections,
version matching that published on JHE
Minimum length effects in black hole physics
We review the main consequences of the possible existence of a minimum
measurable length, of the order of the Planck scale, on quantum effects
occurring in black hole physics. In particular, we focus on the ensuing minimum
mass for black holes and how modified dispersion relations affect the Hawking
decay, both in four space-time dimensions and in models with extra spatial
dimensions. In the latter case, we briefly discuss possible phenomenological
signatures.Comment: 29 pages, 12 figures. To be published in "Quantum Aspects of Black
Holes", ed. X. Calmet (Springer, 2014
Asymptotically Lifshitz wormholes and black holes for Lovelock gravity in vacuum
Static asymptotically Lifshitz wormholes and black holes in vacuum are shown
to exist for a class of Lovelock theories in d=2n+1>7 dimensions, selected by
requiring that all but one of their n maximally symmetric vacua are AdS of
radius l and degenerate. The wormhole geometry is regular everywhere and
connects two Lifshitz spacetimes with a nontrivial geometry at the boundary.
The dynamical exponent z is determined by the quotient of the curvature radii
of the maximally symmetric vacua according to n(z^2-1)+1=(l/L)^2, where L
corresponds to the curvature radius of the nondegenerate vacuum. Light signals
are able to connect both asymptotic regions in finite time, and the
gravitational field pulls towards a fixed surface located at some arbitrary
proper distance to the neck. The asymptotically Lifshitz black hole possesses
the same dynamical exponent and a fixed Hawking temperature given by T=z/(2^z
pi l). Further analytic solutions, including pure Lifshitz spacetimes with a
nontrivial geometry at the spacelike boundary, and wormholes that interpolate
between asymptotically Lifshitz spacetimes with different dynamical exponents
are also found.Comment: 19 pages, 1 figur
Critical Trapped Surfaces Formation in the Collision of Ultrarelativistic Charges in (A)dS
We study the formation of marginally trapped surfaces in the head-on
collision of two ultrarelativistic charges in space-time. The metric of
ultrarelativistic charged particles in is obtained by boosting
Reissner-Nordstr\"om space-time to the speed of light. We show that
formation of trapped surfaces on the past light cone is only possible when
charge is below certain critical - situation similar to the collision of two
ultrarelativistic charges in Minkowski space-time. This critical value depends
on the energy of colliding particles and the value of a cosmological constant.
There is richer structure of critical domains in case. In this case
already for chargeless particles there is a critical value of the cosmological
constant only below which trapped surfaces formation is possible. Appearance of
arbitrary small nonzero charge significantly changes the physical picture.
Critical effect which has been observed in the neutral case does not take place
more. If the value of the charge is not very large solution to the equation on
trapped surface exists for any values of cosmological radius and energy density
of shock waves. Increasing of the charge leads to decrease of the trapped
surface area, and at some critical point the formation of trapped surfaces of
the type mentioned above becomes impossible.Comment: 30 pages, Latex, 7 figures, Refs. added and typos correcte
Changing Human Visual Field Organization from Early Visual to Extra-Occipital Cortex
BACKGROUND: The early visual areas have a clear topographic organization, such that adjacent parts of the cortical surface represent distinct yet adjacent parts of the contralateral visual field. We examined whether cortical regions outside occipital cortex show a similar organization. METHODOLOGY/PRINCIPAL FINDINGS: The BOLD responses to discrete visual field locations that varied in both polar angle and eccentricity were measured using two different tasks. As described previously, numerous occipital regions are both selective for the contralateral visual field and show topographic organization within that field. Extra-occipital regions are also selective for the contralateral visual field, but possess little (or no) topographic organization. A regional analysis demonstrates that this weak topography is not due to increased receptive field size in extra-occipital areas. CONCLUSIONS/SIGNIFICANCE: A number of extra-occipital areas are identified that are sensitive to visual field location. Neurons in these areas corresponding to different locations in the contralateral visual field do not demonstrate any regular or robust topographic organization, but appear instead to be intermixed on the cortical surface. This suggests a shift from processing that is predominately local in visual space, in occipital areas, to global, in extra-occipital areas. Global processing fits with a role for these extra-occipital areas in selecting a spatial locus for attention and/or eye-movements
A migraine variant with abdominal colic and Alice in wonderland syndrome: a case report and review
<p>Abstract</p> <p>Background</p> <p>Abdominal migraine is a commonly described migraine variant in children and young adults, but associations with Alice in Wonderland syndrome and lilliputian hallucinations are exceptional.</p> <p>Case presentation</p> <p>A 20 years-old male experienced frequent and prolonged attacks of abdominal colic associated with autonomic manifestations started at the age of ten. At the age of 17, he additionally described prolonged attacks (≥ 7 days) of distortions of shape, size or position of objects or subjects. He said "Quite suddenly, objects appear small and distant (teliopsia) or large and close (peliopsia). I feel as I am getting shorter and smaller "shrinking" and also the size of persons are not longer than my index finger (a lilliputian proportion). Sometimes I see the blind in the window or the television getting up and down, or my leg or arm is swinging. I may hear the voices of people quite loud and close or faint and far. Occasionally, I experience attacks of migrainous headache associated with eye redness, flashes of lights and a feeling of giddiness. I am always conscious to the intangible changes in myself and my environment". There is a strong family history of common migraine. Clinical examination, brain-MRI and EEG were normal. Transcranial magnetic stimulation and evoked potentials revealed enhanced cortical excitability in multiple brain regions. Treatment with valproate resulted in marked improvement of all clinical and neurophysiological abnormalities.</p> <p>Conclusions</p> <p>The association between the two migraine variants (abdominal migraine and Alice in Wonderland Syndrome) might have clinical, pathophysiological and management implications. I think this is the first description in the literature.</p
THPP target assignment reveals EchA6 as an essential fatty acid shuttle in mycobacteria
Phenotypic screens for bactericidal compounds against drug-resistant tuberculosis are beginning to yield novel inhibitors. However, reliable target identification remains challenging. Here, we show that tetrahydropyrazo[1,5-a]pyrimidine-3-carboxamide (THPP) selectively pulls down EchA6 in a stereospecific manner, instead of the previously assigned target Mycobacterium tuberculosis MmpL3. While homologous to mammalian enoyl-coenzyme A (CoA) hydratases, EchA6 is non-catalytic yet essential and binds long-chain acyl-CoAs. THPP inhibitors compete with CoA-binding, suppress mycolic acid synthesis, and are bactericidal in a mouse model of chronic tuberculosis infection. A point mutation, W133A, abrogated THPP-binding and increased both the in vitro minimum inhibitory concentration and the in vivo effective dose 99 in mice. Surprisingly, EchA6 interacts with selected enzymes of fatty acid synthase II (FAS-II) in bacterial two-hybrid assays, suggesting essentiality may be linked to feeding long-chain fatty acids to FAS-II. Finally, our data show that spontaneous resistance-conferring mutations can potentially obscure the actual target or alternative targets of small molecule inhibitors
Retinotopic Mapping of Categorical and Coordinate Spatial Relation Processing in Early Visual Cortex
Spatial relations are commonly divided in two global classes. Categorical relations concern abstract relations which define areas of spatial equivalence, whereas coordinate relations are metric and concern exact distances. Categorical and coordinate relation processing are thought to rely on at least partially separate neurocognitive mechanisms, as reflected by differential lateralization patterns, in particular in the parietal cortex. In this study we address this textbook principle from a new angle. We studied retinotopic activation in early visual cortex, as a reflection of attentional distribution, in a spatial working memory task with either a categorical or a coordinate instruction. Participants were asked to memorize a dot position, with regard to a central cross, and to indicate whether a subsequent dot position matched the first dot position, either categorically (opposite quadrant of the cross) or coordinately (same distance to the centre of the cross). BOLD responses across the retinotopic maps of V1, V2, and V3 indicate that the spatial distribution of cortical activity was different for categorical and coordinate instructions throughout the retention interval; a more local focus was found during categorical processing, whereas focus was more global for coordinate processing. This effect was strongest for V3, approached significance in V2 and was absent in V1. Furthermore, during stimulus presentation the two instructions led to different levels of activation in V3 during stimulus encoding; a stronger increase in activity was found for categorical processing. Together this is the first demonstration that instructions for specific types of spatial relations may yield distinct attentional patterns which are already reflected in activity early in the visual cortex
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