504 research outputs found
Mutation Size Optimizes Speciation in an Evolutionary Model
The role of mutation rate in optimizing key features of evolutionary dynamics has recently been investigated in various computational models. Here, we address the related question of how maximum mutation size affects the formation of species in a simple computational evolutionary model. We find that the number of species is maximized for intermediate values of a mutation size parameter ÎĽ; the result is observed for evolving organisms on a randomly changing landscape as well as in a version of the model where negative feedback exists between the local population size and the fitness provided by the landscape. The same result is observed for various distributions of mutation values within the limits set by ÎĽ. When organisms with various values of ÎĽ compete against each other, those with intermediate ÎĽ values are found to survive. The surviving values of ÎĽ from these competition simulations, however, do not necessarily coincide with the values that maximize the number of species. These results suggest that various complex factors are involved in determining optimal mutation parameters for any population, and may also suggest approaches for building a computational bridge between the (micro) dynamics of mutations at the level of individual organisms and (macro) evolutionary dynamics at the species level
One-carbon metabolism in cancer
Cells require one-carbon units for nucleotide synthesis, methylation and reductive metabolism, and these pathways support the high proliferative rate of cancer cells. As such, anti-folates, drugs that target one-carbon metabolism, have long been used in the treatment of cancer. Amino acids, such as serine are a major one-carbon source, and cancer cells are particularly susceptible to deprivation of one-carbon units by serine restriction or inhibition of de novo serine synthesis. Recent work has also begun to decipher the specific pathways and sub-cellular compartments that are important for one-carbon metabolism in cancer cells. In this review we summarise the historical understanding of one-carbon metabolism in cancer, describe the recent findings regarding the generation and usage of one-carbon units and explore possible future therapeutics that could exploit the dependency of cancer cells on one-carbon metabolism
p16 Mutation Spectrum in the Premalignant Condition Barrett's Esophagus
Background: Mutation, promoter hypermethylation and loss of heterozygosity involving the tumor suppressor gene p16 (CDKN2a/INK4a) have been detected in a wide variety of human cancers, but much less is known concerning the frequency and spectrum of p16 mutations in premalignant conditions. Methods and Findings: We have determined the p16 mutation spectrum for a cohort of 304 patients with Barrett’s esophagus, a premalignant condition that predisposes to the development of esophageal adenocarcinoma. Forty seven mutations were detected by sequencing of p16 exon 2 in 44 BE patients (14.5%) with a mutation spectrum consistent with that caused by oxidative damage and chronic inflammation. The percentage of patients with p16 mutations increased with increasing histologic grade. In addition, samples from 3 out of 19 patients (15.8%) who underwent esophagectomy were found to have mutations. Conclusions: The results of this study suggest the environment of the esophagus in BE patients can both generate an
Valgus and varus deformity after wide-local excision, brachytherapy and external beam irradiation in two children with lower extremity synovial cell sarcoma: case report
BACKGROUND: Limb-salvage is a primary objective in the management of extremity soft-tissue sarcoma in adults and children. Wide-local excision combined with radiation therapy is effective in achieving local tumor control with acceptable morbidity and good functional outcomes for most patients. CASE PRESENTATION: Two cases of deformity after wide-local excision, brachytherapy and external beam irradiation for lower-extremity synovial cell sarcoma are presented and discussed to highlight contributing factors, time course of radiation effects and orthopedic management. In an effort to spare normal tissues from the long-term effects of radiation therapy, more focal irradiation techniques have been applied to patients with musculoskeletal tumors including brachytherapy and conformal radiation therapy. As illustrated in this report, the use of these techniques results in the asymmetric irradiation of growth plates and contributes to the development of valgus or varus deformity and leg-length discrepancies. CONCLUSIONS: Despite good functional outcomes, progressive deformity in both patients required epiphysiodesis more than 3 years after initial management. There is a dearth of information related to the effects of radiation therapy on the musculoskeletal system in children. Because limb-sparing approaches are to be highlighted in the next generation of cooperative group protocols for children with musculoskeletal tumors, documentation of the effects of surgery and radiation therapy will lead to improved decision making in the selection of the best treatment approach and in the follow-up of these patients
Search for rare quark-annihilation decays, B --> Ds(*) Phi
We report on searches for B- --> Ds- Phi and B- --> Ds*- Phi. In the context
of the Standard Model, these decays are expected to be highly suppressed since
they proceed through annihilation of the b and u-bar quarks in the B- meson.
Our results are based on 234 million Upsilon(4S) --> B Bbar decays collected
with the BABAR detector at SLAC. We find no evidence for these decays, and we
set Bayesian 90% confidence level upper limits on the branching fractions BF(B-
--> Ds- Phi) Ds*- Phi)<1.2x10^(-5). These results
are consistent with Standard Model expectations.Comment: 8 pages, 3 postscript figues, submitted to Phys. Rev. D (Rapid
Communications
Brace technology thematic series - The Sforzesco and Sibilla braces, and the SPoRT (Symmetric, Patient oriented, Rigid, Three-dimensional, active) concept
<p>Abstract</p> <p>Background</p> <p>Bracing is an effective strategy for scoliosis treatment, but there is no consensus on the best type of brace, nor on the way in which it should act on the spine to achieve good correction. The aim of this paper is to present the family of SPoRT (Symmetric, Patient-oriented, Rigid, Three-dimensional, active) braces: Sforzesco (the first introduced), Sibilla and Lapadula.</p> <p>Methods</p> <p>The Sforzesco brace was developed following specific principles of correction. Due to its overall symmetry, the brace provides space over pathological depressions and pushes over elevations. Correction is reached through construction of the envelope, pushes, escapes, stops, and drivers. The real novelty is the drivers, introduced for the first time with the Sforzesco brace; they allow to achieve the main action of the brace: a three-dimensional elongation pushing the spine in a down-up direction.</p> <p>Brace prescription is made plane by plane: frontal (on the "slopes", another novelty of this concept, i.e. the laterally flexed sections of the spine), horizontal, and sagittal. The brace is built modelling the trunk shape obtained either by a plaster cast mould or by CAD-CAM construction. Brace checking is essential, since SPoRT braces are adjustable and customisable according to each individual curve pattern.</p> <p>Treatment time and duration is individually tailored (18-23 hours per day until Risser 3, then gradual reduction). SEAS (Scientific Exercises Approach to Scoliosis) exercises are a key factor to achieve success.</p> <p>Results</p> <p>The Sforzesco brace has shown to be more effective than the Lyon brace (matched case/control), equally effective as the Risser plaster cast (prospective cohort with retrospective controls), more effective than the Risser cast + Lyon brace in treating curves over 45 degrees Cobb (prospective cohort), and is able to improve aesthetic appearance (prospective cohort).</p> <p>Conclusions</p> <p>The SPoRT concept of bracing (three-dimensional elongation pushing in a down-up direction) is different from the other corrective systems: 3-point, traction, postural, and movement-based. The Sforzesco brace, being comparable to casting, may be the best brace for the worst cases.</p
Observation and study of baryonic B decays: B -> D(*) p pbar, D(*) p pbar pi, and D(*) p pbar pi pi
We present a study of ten B-meson decays to a D(*), a proton-antiproton pair,
and a system of up to two pions using BaBar's data set of 455x10^6 BBbar pairs.
Four of the modes (B0bar -> D0 p anti-p, B0bar -> D*0 p anti-p, B0bar -> D+ p
anti-p pi-, B0bar -> D*+ p anti-p pi-) are studied with improved statistics
compared to previous measurements; six of the modes (B- -> D0 p anti-p pi-, B-
-> D*0 p anti-p pi-, B0bar -> D0 p anti-p pi- pi+, B0bar -> D*0 p anti-p pi-
pi+, B- -> D+ p anti-p pi- pi-, B- -> D*+ p anti-p pi- pi-) are first
observations. The branching fractions for 3- and 5-body decays are suppressed
compared to 4-body decays. Kinematic distributions for 3-body decays show
non-overlapping threshold enhancements in m(p anti-p) and m(D(*)0 p) in the
Dalitz plots. For 4-body decays, m(p pi-) mass projections show a narrow peak
with mass and full width of (1497.4 +- 3.0 +- 0.9) MeV/c2, and (47 +- 12 +- 4)
MeV/c2, respectively, where the first (second) errors are statistical
(systematic). For 5-body decays, mass projections are similar to phase space
expectations. All results are preliminary.Comment: 28 pages, 90 postscript figures, submitted to LP0
Evidence for the h_b(1P) meson in the decay Upsilon(3S) --> pi0 h_b(1P)
Using a sample of 122 million Upsilon(3S) events recorded with the BaBar
detector at the PEP-II asymmetric-energy e+e- collider at SLAC, we search for
the spin-singlet partner of the P-wave chi_{bJ}(1P) states in the
sequential decay Upsilon(3S) --> pi0 h_b(1P), h_b(1P) --> gamma eta_b(1S). We
observe an excess of events above background in the distribution of the recoil
mass against the pi0 at mass 9902 +/- 4(stat.) +/- 2(syst.) MeV/c^2. The width
of the observed signal is consistent with experimental resolution, and its
significance is 3.1sigma, including systematic uncertainties. We obtain the
value (4.3 +/- 1.1(stat.) +/- 0.9(syst.)) x 10^{-4} for the product branching
fraction BF(Upsilon(3S)-->pi0 h_b) x BF(h_b-->gamma eta_b).Comment: 8 pages, 4 postscript figures, submitted to Phys. Rev. D (Rapid
Communications
The c4h, tat, hppr and hppd Genes Prompted Engineering of Rosmarinic Acid Biosynthetic Pathway in Salvia miltiorrhiza Hairy Root Cultures
Rational engineering to produce biologically active plant compounds has been greatly impeded by our poor understanding of the regulatory and metabolic pathways underlying the biosynthesis of these compounds. Here we capitalized on our previously described gene-to-metabolite network in order to engineer rosmarinic acid (RA) biosynthesis pathway for the production of beneficial RA and lithospermic acid B (LAB) in Salvia miltiorrhiza hairy root cultures. Results showed their production was greatly elevated by (1) overexpression of single gene, including cinnamic acid 4-hydroxylase (c4h), tyrosine aminotransferase (tat), and 4-hydroxyphenylpyruvate reductase (hppr), (2) overexpression of both tat and hppr, and (3) suppression of 4-hydroxyphenylpyruvate dioxygenase (hppd). Co-expression of tat/hppr produced the most abundant RA (906 mg/liter) and LAB (992 mg/liter), which were 4.3 and 3.2-fold more than in their wild-type (wt) counterparts respectively. And the value of RA concentration was also higher than that reported before, that produced by means of nutrient medium optimization or elicitor treatment. It is the first report of boosting RA and LAB biosynthesis through genetic manipulation, providing an effective approach for their large-scale commercial production by using hairy root culture systems as bioreactors
Reciprocal Sign Epistasis between Frequently Experimentally Evolved Adaptive Mutations Causes a Rugged Fitness Landscape
The fitness landscape captures the relationship between genotype and evolutionary fitness and is a pervasive metaphor used to describe the possible evolutionary trajectories of adaptation. However, little is known about the actual shape of fitness landscapes, including whether valleys of low fitness create local fitness optima, acting as barriers to adaptive change. Here we provide evidence of a rugged molecular fitness landscape arising during an evolution experiment in an asexual population of Saccharomyces cerevisiae. We identify the mutations that arose during the evolution using whole-genome sequencing and use competitive fitness assays to describe the mutations individually responsible for adaptation. In addition, we find that a fitness valley between two adaptive mutations in the genes MTH1 and HXT6/HXT7 is caused by reciprocal sign epistasis, where the fitness cost of the double mutant prohibits the two mutations from being selected in the same genetic background. The constraint enforced by reciprocal sign epistasis causes the mutations to remain mutually exclusive during the experiment, even though adaptive mutations in these two genes occur several times in independent lineages during the experiment. Our results show that epistasis plays a key role during adaptation and that inter-genic interactions can act as barriers between adaptive solutions. These results also provide a new interpretation on the classic Dobzhansky-Muller model of reproductive isolation and display some surprising parallels with mutations in genes often associated with tumors
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