3,887 research outputs found
Evolutionary Multi-Objective Design of SARS-CoV-2 Protease Inhibitor Candidates
Computational drug design based on artificial intelligence is an emerging
research area. At the time of writing this paper, the world suffers from an
outbreak of the coronavirus SARS-CoV-2. A promising way to stop the virus
replication is via protease inhibition. We propose an evolutionary
multi-objective algorithm (EMOA) to design potential protease inhibitors for
SARS-CoV-2's main protease. Based on the SELFIES representation the EMOA
maximizes the binding of candidate ligands to the protein using the docking
tool QuickVina 2, while at the same time taking into account further objectives
like drug-likeliness or the fulfillment of filter constraints. The experimental
part analyzes the evolutionary process and discusses the inhibitor candidates.Comment: 15 pages, 7 figures, submitted to PPSN 202
Novel statistical approaches for non-normal censored immunological data: analysis of cytokine and gene expression data
Background: For several immune-mediated diseases, immunological analysis will become more complex in the future with datasets in which cytokine and gene expression data play a major role. These data have certain characteristics that require sophisticated statistical analysis such as strategies for non-normal distribution and censoring. Additionally, complex and multiple immunological relationships need to be adjusted for potential confounding and interaction effects.
Objective: We aimed to introduce and apply different methods for statistical analysis of non-normal censored cytokine and gene expression data. Furthermore, we assessed the performance and accuracy of a novel regression approach in order to allow adjusting for covariates and potential confounding.
Methods: For non-normally distributed censored data traditional means such as the Kaplan-Meier method or the generalized Wilcoxon test are described. In order to adjust for covariates the novel approach named Tobit regression on ranks was introduced. Its performance and accuracy for analysis of non-normal censored cytokine/gene expression data was evaluated by a simulation study and a statistical experiment applying permutation and bootstrapping.
Results: If adjustment for covariates is not necessary traditional statistical methods are adequate for non-normal censored data. Comparable with these and appropriate if additional adjustment is required, Tobit regression on ranks is a valid method. Its power, type-I error rate and accuracy were comparable to the classical Tobit regression.
Conclusion: Non-normally distributed censored immunological data require appropriate statistical methods. Tobit regression on ranks meets these requirements and can be used for adjustment for covariates and potential confounding in large and complex immunological datasets
High efficacy and low toxicity of weekly docetaxel given as first-line treatment for metastatic breast cancer
Background: Docetaxel is one of the most effective antitumor agents currently available for the treatment of metastatic breast cancer (MBC). This phase II multicenter study prospectively analyzed the efficacy and toxicity of docetaxel given on a weekly schedule as first-line treatment of metastatic breast cancer. Patients and Methods: All patients received docetaxel, 35 mg/m(2) weekly for 6 weeks, followed by 2 weeks of rest. Subsequent cycles ( 3 weeks of treatment, 2 weeks of rest) were given until a maximum of 5 cycles or disease progression. Premedication consisted of 8 mg dexamethasone intravenously 30 min prior to the infusion of docetaxel. Results: Fifty-four patients at a median age of 58 years with previously untreated MBC were included in the study. A median of 10 doses ( median cumulative dose 339 mg/m(2)) was administered ( range: 2 - 18). The overall response rate was 48.1% ( 95% CI: 34 - 61%, intent-to-treat). Median survival was 15.8 months and median time to progression was 5.9 months ( intent-to-treat). Hematological toxicity was mild with absence of neutropenia-related complications. Grade 3 neutropenia was observed in 3.7% of patients and grade 3 and 4 anemia was observed in 5.6 and 1.9% of patients, respectively. Conclusion: The weekly administration of docetaxel is highly efficient and safe as first-line treatment for MBC and may serve as an important treatment option specifically in elderly patients and patients with a reduced performance status. Copyright (C) 2005 S. Karger AG, Basel
Theoretical Constraints on the Higgs Effective Couplings
We derive constraints on the sign of couplings in an effective Higgs
Lagrangian using prime principles such as the naturalness principle, global
symmetries, and unitarity. Specifically, we study four dimension-six operators,
O_H, O_y, O_g, and O_gamma, which contribute to the production and decay of the
Higgs boson at the Large Hadron Collider (LHC), among other things. Assuming
the Higgs is a fundamental scalar, we find: 1) the coefficient of O_H is
positive except when there are triplet scalars, resulting in a reduction in the
Higgs on-shell coupling from their standard model (SM) expectations if no other
operators contribute, 2) the linear combination of O_H and O_y controlling the
overall Higgs coupling to fermion is always reduced, 3) the sign of O_g induced
by a new colored fermion is such that it interferes destructively with the SM
top contribution in the gluon fusion production of the Higgs, if the new
fermion cancels the top quadratic divergence in the Higgs mass, and 4) the
correlation between naturalness and the sign of O_gamma is similar to that of
O_g, when there is a new set of heavy electroweak gauge bosons. Next
considering a composite scalar for the Higgs, we find the reduction in the
on-shell Higgs couplings persists. If further assuming a collective breaking
mechanism as in little Higgs theories, the coefficient of O_H remains positive
even in the presence of triplet scalars. In the end, we conclude that the gluon
fusion production of the Higgs boson is reduced from the SM rate in all
composite Higgs models. Our study suggests a wealth of information could be
revealed by precise measurements of the Higgs couplings, providing strong
motivations for both improving on measurements at the LHC and building a
precision machine such as the linear collider.Comment: 37 pages, one figure; v2: improved discussion on dispersion relation
and other minor modifications; version accepted for publication
Cancer symptom awareness and barriers to symptomatic presentation in England – Are we clear on cancer?
Background: Low cancer awareness may contribute to delayed diagnosis and poor cancer survival. We aimed to quantify socio-demographic differences in cancer symptom awareness and barriers to symptomatic presentation in the English population.
Methods: Using a uniquely large data set (n=49?270), we examined the association of cancer symptom awareness and barriers to presentation with age, gender, marital status and socio-economic position (SEP), using logistic regression models to control for confounders.
Results: The youngest and oldest, the single and participants with the lowest SEP recognised the fewest cancer symptoms, and reported most barriers to presentation. Recognition of nine common cancer symptoms was significantly lower, and embarrassment, fear and difficulties in arranging transport to the doctor’s surgery were significantly more common in participants living in the most deprived areas than in the most affluent areas. Women were significantly more likely than men to both recognise common cancer symptoms and to report barriers. Women were much more likely compared with men to report that fear would put them off from going to the doctor.
Conclusions: Large and robust socio-demographic differences in recognition of some cancer symptoms, and perception of some barriers to presentation, highlight the need for targeted campaigns to encourage early presentation and improve cancer outcomes
Quantitative test of the barrier nucleosome model for statistical positioning of nucleosomes up- and downstream of transcription start sites
The positions of nucleosomes in eukaryotic genomes determine which parts of
the DNA sequence are readily accessible for regulatory proteins and which are
not. Genome-wide maps of nucleosome positions have revealed a salient pattern
around transcription start sites, involving a nucleosome-free region (NFR)
flanked by a pronounced periodic pattern in the average nucleosome density.
While the periodic pattern clearly reflects well-positioned nucleosomes, the
positioning mechanism is less clear. A recent experimental study by Mavrich et
al. argued that the pattern observed in S. cerevisiae is qualitatively
consistent with a `barrier nucleosome model', in which the oscillatory pattern
is created by the statistical positioning mechanism of Kornberg and Stryer. On
the other hand, there is clear evidence for intrinsic sequence preferences of
nucleosomes, and it is unclear to what extent these sequence preferences affect
the observed pattern. To test the barrier nucleosome model, we quantitatively
analyze yeast nucleosome positioning data both up- and downstream from NFRs.
Our analysis is based on the Tonks model of statistical physics which
quantifies the interplay between the excluded-volume interaction of nucleosomes
and their positional entropy. We find that although the typical patterns on the
two sides of the NFR are different, they are both quantitatively described by
the same physical model, with the same parameters, but different boundary
conditions. The inferred boundary conditions suggest that the first nucleosome
downstream from the NFR (the +1 nucleosome) is typically directly positioned
while the first nucleosome upstream is statistically positioned via a
nucleosome-repelling DNA region. These boundary conditions, which can be
locally encoded into the genome sequence, significantly shape the statistical
distribution of nucleosomes over a range of up to ~1000 bp to each side.Comment: includes supporting materia
Incidence and survival of childhood bone cancer in northern England and the West Midlands, 1981–2002
There is a paucity of population-based studies examining incidence and survival trends in childhood bone tumours. We used high quality data from four population-based registries in England. Incidence patterns and trends were described using Poisson regression. Survival trends were analysed using Cox regression. There were 374 cases of childhood (ages 0–14 years) bone tumours (206 osteosarcomas, 144 Ewing sarcomas, 16 chondrosarcomas, 8 other bone tumours) registered in the period 1981–2002. Overall incidence (per million person years) rates were 2.63 (95% confidence interval (CI) 2.27–2.99) for osteosarcoma, 1.90 (1.58–2.21) for Ewing sarcoma and 0.21 (0.11–0.31) for chondrosarcoma. Incidence of Ewing sarcoma declined at an average rate of 3.1% (95% CI 0.6–5.6) per annum (P=0.04), which may be due to tumour reclassification, but there was no change in osteosarcoma incidence. Survival showed marked improvement over the 20 years (1981–2000) for Ewing sarcoma (hazard ratio (HR) per annum=0.95 95% CI 0.91–0.99; P=0.02). However, no improvement was seen for osteosarcoma patients (HR per annum=1.02 95% CI 0.98–1.05; P=0.35) over this time period. Reasons for failure to improve survival including potential delays in diagnosis, accrual to trials, adherence to therapy and lack of improvement in treatment strategies all need to be considered
Simple and Realistic Composite Higgs Models in Flat Extra Dimensions
We construct new composite Higgs/gauge-Higgs unification (GHU) models in flat
space that overcome all the difficulties found in the past in attempting to
construct models of this sort. The key ingredient is the introduction of large
boundary kinetic terms for gauge (and fermion) fields. We focus our analysis on
the electroweak symmetry breaking pattern and the electroweak precision tests
and show how both are compatible with each other. Our models can be seen as
effective TeV descriptions of analogue warped models. We point out that, as far
as electroweak TeV scale physics is concerned, one can rely on simple and more
flexible flat space models rather than considering their unavoidably more
complicated warped space counterparts. The generic collider signatures of our
models are essentially undistinguishable from those expected from composite
Higgs/warped GHU models, namely a light Higgs, colored fermion resonances below
the TeV scale and sizable deviations to the Higgs and top coupling.Comment: 30 figures, 9 figures; v2: minor improvements, one reference added,
version to appear in JHE
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