22,163 research outputs found
A Computational Methodology to Screen Activities of Enzyme Variants
We present a fast computational method to efficiently screen enzyme activity.
In the presented method, the effect of mutations on the barrier height of an
enzyme-catalysed reaction can be computed within 24 hours on roughly 10
processors. The methodology is based on the PM6 and MOZYME methods as
implemented in MOPAC2009, and is tested on the first step of the amide
hydrolysis reaction catalyzed by Candida Antarctica lipase B (CalB) enzyme. The
barrier heights are estimated using adiabatic mapping and are shown to give
barrier heights to within 3kcal/mol of B3LYP/6-31G(d)//RHF/3-21G results for a
small model system. Relatively strict convergence criteria
(0.5kcal/(mol{\AA})), long NDDO cutoff distances within the MOZYME method
(15{\AA}) and single point evaluations using conventional PM6 are needed for
reliable results. The generation of mutant structure and subsequent setup of
the semiempirical calculations are automated so that the effect on barrier
heights can be estimated for hundreds of mutants in a matter of weeks using
high performance computing
Bayesian phylogenetic estimation of fossil ages
Recent advances have allowed for both morphological fossil evidence and
molecular sequences to be integrated into a single combined inference of
divergence dates under the rule of Bayesian probability. In particular the
fossilized birth-death tree prior and the Lewis-Mk model of discrete
morphological evolution allow for the estimation of both divergence times and
phylogenetic relationships between fossil and extant taxa. We exploit this
statistical framework to investigate the internal consistency of these models
by producing phylogenetic estimates of the age of each fossil in turn, within
two rich and well-characterized data sets of fossil and extant species
(penguins and canids). We find that the estimation accuracy of fossil ages is
generally high with credible intervals seldom excluding the true age and median
relative error in the two data sets of 5.7% and 13.2% respectively. The median
relative standard error (RSD) was 9.2% and 7.2% respectively, suggesting good
precision, although with some outliers. In fact in the two data sets we analyze
the phylogenetic estimates of fossil age is on average < 2 My from the midpoint
age of the geological strata from which it was excavated. The high level of
internal consistency found in our analyses suggests that the Bayesian
statistical model employed is an adequate fit for both the geological and
morphological data, and provides evidence from real data that the framework
used can accurately model the evolution of discrete morphological traits coded
from fossil and extant taxa. We anticipate that this approach will have diverse
applications beyond divergence time dating, including dating fossils that are
temporally unconstrained, testing of the "morphological clock", and for
uncovering potential model misspecification and/or data errors when
controversial phylogenetic hypotheses are obtained based on combined divergence
dating analyses.Comment: 28 pages, 8 figure
Bayesian total evidence dating reveals the recent crown radiation of penguins
The total-evidence approach to divergence-time dating uses molecular and
morphological data from extant and fossil species to infer phylogenetic
relationships, species divergence times, and macroevolutionary parameters in a
single coherent framework. Current model-based implementations of this approach
lack an appropriate model for the tree describing the diversification and
fossilization process and can produce estimates that lead to erroneous
conclusions. We address this shortcoming by providing a total-evidence method
implemented in a Bayesian framework. This approach uses a mechanistic tree
prior to describe the underlying diversification process that generated the
tree of extant and fossil taxa. Previous attempts to apply the total-evidence
approach have used tree priors that do not account for the possibility that
fossil samples may be direct ancestors of other samples. The fossilized
birth-death (FBD) process explicitly models the diversification, fossilization,
and sampling processes and naturally allows for sampled ancestors. This model
was recently applied to estimate divergence times based on molecular data and
fossil occurrence dates. We incorporate the FBD model and a model of
morphological trait evolution into a Bayesian total-evidence approach to dating
species phylogenies. We apply this method to extant and fossil penguins and
show that the modern penguins radiated much more recently than has been
previously estimated, with the basal divergence in the crown clade occurring at
~12.7 Ma and most splits leading to extant species occurring in the last 2
million years. Our results demonstrate that including stem-fossil diversity can
greatly improve the estimates of the divergence times of crown taxa. The method
is available in BEAST2 (v. 2.4) www.beast2.org with packages SA (v. at least
1.1.4) and morph-models (v. at least 1.0.4).Comment: 50 pages, 6 figure
Population expansion in the North African Late Pleistocene signalled by mitochondrial DNA haplogroup U6
Background
<br/>
The archaeology of North Africa remains enigmatic, with questions of population continuity versus discontinuity taking centre-stage. Debates have focused on population transitions between the bearers of the Middle Palaeolithic Aterian industry and the later Upper Palaeolithic populations of the Maghreb, as well as between the late Pleistocene and Holocene.
<br/>
Results
Improved resolution of the mitochondrial DNA (mtDNA) haplogroup U6 phylogeny, by the screening of 39 new complete sequences, has enabled us to infer a signal of moderate population expansion using Bayesian coalescent methods. To ascertain the time for this expansion, we applied both a mutation rate accounting for purifying selection and one with an internal calibration based on four approximate archaeological dates: the settlement of the Canary Islands, the settlement of Sardinia and its internal population re-expansion, and the split between haplogroups U5 and U6 around the time of the first modern human settlement of the Near East.
<br/>
Conclusions
<br/>
A Bayesian skyline plot placed the main expansion in the time frame of the Late Pleistocene, around 20 ka, and spatial smoothing techniques suggested that the most probable geographic region for this demographic event was to the west of North Africa. A comparison with U6's European sister clade, U5, revealed a stronger population expansion at around this time in Europe. Also in contrast with U5, a weak signal of a recent population expansion in the last 5,000 years was observed in North Africa, pointing to a moderate impact of the late Neolithic on the local population size of the southern Mediterranean coast
πBUSS:a parallel BEAST/BEAGLE utility for sequence simulation under complex evolutionary scenarios
Background: Simulated nucleotide or amino acid sequences are frequently used
to assess the performance of phylogenetic reconstruction methods. BEAST, a
Bayesian statistical framework that focuses on reconstructing time-calibrated
molecular evolutionary processes, supports a wide array of evolutionary models,
but lacked matching machinery for simulation of character evolution along
phylogenies.
Results: We present a flexible Monte Carlo simulation tool, called piBUSS,
that employs the BEAGLE high performance library for phylogenetic computations
within BEAST to rapidly generate large sequence alignments under complex
evolutionary models. piBUSS sports a user-friendly graphical user interface
(GUI) that allows combining a rich array of models across an arbitrary number
of partitions. A command-line interface mirrors the options available through
the GUI and facilitates scripting in large-scale simulation studies. Analogous
to BEAST model and analysis setup, more advanced simulation options are
supported through an extensible markup language (XML) specification, which in
addition to generating sequence output, also allows users to combine simulation
and analysis in a single BEAST run.
Conclusions: piBUSS offers a unique combination of flexibility and
ease-of-use for sequence simulation under realistic evolutionary scenarios.
Through different interfaces, piBUSS supports simulation studies ranging from
modest endeavors for illustrative purposes to complex and large-scale
assessments of evolutionary inference procedures. The software aims at
implementing new models and data types that are continuously being developed as
part of BEAST/BEAGLE.Comment: 13 pages, 2 figures, 1 tabl
Modeling circadian and sleep-homeostatic effects on short-term interval timing
Short-term interval timing i.e., perception and action relating to durations in the seconds range, has been suggested to display time-of-day as well as wake dependent fluctuations due to circadian and sleep-homeostatic changes to the rate at which an underlying pacemaker emits pulses; pertinent human data being relatively sparse and lacking in consistency however, the phenomenon remains elusive and its mechanism poorly understood. To better characterize the putative circadian and sleep-homeostatic effects on interval timing and to assess the ability of a pacemaker-based mechanism to account for the data, we measured timing performance in eighteen young healthy male subjects across two epochs of sustained wakefulness of 38.67 h each, conducted prior to (under entrained conditions) and following (under free-running conditions) a 28 h sleep-wake schedule, using the methods of duration estimation and duration production on target intervals of 10 and 40 s. Our findings of opposing oscillatory time courses across both epochs of sustained wakefulness that combine with increasing and, respectively, decreasing, saturating exponential change for the tasks of estimation and production are consistent with the hypothesis that a pacemaker emitting pulses at a rate controlled by the circadian oscillator and increasing with time awake determines human short-term interval timing; the duration-specificity of this pattern is interpreted as reflecting challenges to maintaining stable attention to the task that progressively increase with stimulus magnitude and thereby moderate the effects of pacemaker-rate changes on overt behavior
Robust Individual Circadian Parameter Estimation for Biosignal-based Personalisation of Cancer Chronotherapy
In cancer treatment, chemotherapy is administered according a constant
schedule. The chronotherapy approach, considering chronobiological drug
delivery, adapts the chemotherapy profile to the circadian rhythms of the human
organism. This reduces toxicity effects and at the same time enhances
efficiency of chemotherapy. To personalize cancer treatment, chemotherapy
profiles have to be further adapted to individual patients. Therefore, we
present a new model to represent cycle phenomena in circadian rhythms. The
model enables a more precise modelling of the underlying circadian rhythms. In
comparison with the standard model, our model delivers better results in all
defined quality indices. The new model can be used to adapt the chemotherapy
profile efficiently to individual patients. The adaption to individual patients
contributes to the aim of personalizing cancer therapy.Comment: Conference Biosig 2016, Berli
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