218 research outputs found
Rigidity and flexibility of biological networks
The network approach became a widely used tool to understand the behaviour of
complex systems in the last decade. We start from a short description of
structural rigidity theory. A detailed account on the combinatorial rigidity
analysis of protein structures, as well as local flexibility measures of
proteins and their applications in explaining allostery and thermostability is
given. We also briefly discuss the network aspects of cytoskeletal tensegrity.
Finally, we show the importance of the balance between functional flexibility
and rigidity in protein-protein interaction, metabolic, gene regulatory and
neuronal networks. Our summary raises the possibility that the concepts of
flexibility and rigidity can be generalized to all networks.Comment: 21 pages, 4 figures, 1 tabl
Multiple Holdouts With Stability: Improving the Generalizability of Machine Learning Analyses of Brain-Behavior Relationships.
BACKGROUND:In 2009, the National Institute of Mental Health launched the Research Domain Criteria, an attempt to move beyond diagnostic categories and ground psychiatry within neurobiological constructs that combine different levels of measures (e.g., brain imaging and behavior). Statistical methods that can integrate such multimodal data, however, are often vulnerable to overfitting, poor generalization, and difficulties in interpreting the results. METHODS:We propose an innovative machine learning framework combining multiple holdouts and a stability criterion with regularized multivariate techniques, such as sparse partial least squares and kernel canonical correlation analysis, for identifying hidden dimensions of cross-modality relationships. To illustrate the approach, we investigated structural brain-behavior associations in an extensively phenotyped developmental sample of 345 participants (312 healthy and 33 with clinical depression). The brain data consisted of whole-brain voxel-based gray matter volumes, and the behavioral data included item-level self-report questionnaires and IQ and demographic measures. RESULTS:Both sparse partial least squares and kernel canonical correlation analysis captured two hidden dimensions of brain-behavior relationships: one related to age and drinking and the other one related to depression. The applied machine learning framework indicates that these results are stable and generalize well to new data. Indeed, the identified brain-behavior associations are in agreement with previous findings in the literature concerning age, alcohol use, and depression-related changes in brain volume. CONCLUSIONS:Multivariate techniques (such as sparse partial least squares and kernel canonical correlation analysis) embedded in our novel framework are promising tools to link behavior and/or symptoms to neurobiology and thus have great potential to contribute to a biologically grounded definition of psychiatric disorders
L\'evy-stable two-pion Bose-Einstein correlations in GeV AuAu collisions
We present a detailed measurement of charged two-pion correlation functions
in 0%-30% centrality GeV AuAu collisions by the
PHENIX experiment at the Relativistic Heavy Ion Collider. The data are well
described by Bose-Einstein correlation functions stemming from L\'evy-stable
source distributions. Using a fine transverse momentum binning, we extract the
correlation strength parameter , the L\'evy index of stability
and the L\'evy length scale parameter as a function of average
transverse mass of the pair . We find that the positively and the
negatively charged pion pairs yield consistent results, and their correlation
functions are represented, within uncertainties, by the same L\'evy-stable
source functions. The measurements indicate a decrease of the
strength of the correlations at low . The L\'evy length scale parameter
decreases with increasing , following a hydrodynamically
predicted type of scaling behavior. The values of the L\'evy index of stability
are found to be significantly lower than the Gaussian case of
, but also significantly larger than the conjectured value that may
characterize the critical point of a second-order quark-hadron phase
transition.Comment: 448 authors, 25 pages, 11 figures, 4 tables, 2010 data. v2 is version
accepted for publication in Phys. Rev. C. Plain text data tables for the
points plotted in figures for this and previous PHENIX publications are (or
will be) publicly available at http://www.phenix.bnl.gov/papers.htm
Characteristic mTOR activity in Hodgkin-lymphomas offers a potential therapeutic target in high risk disease – a combined tissue microarray, in vitro and in vivo study
BACKGROUND: Targeting signaling pathways is an attractive approach in many malignancies. The PI3K/Akt/mTOR pathway is activated in a number of human neoplasms, accompanied by lower overall and/or disease free survival. mTOR kinase inhibitors have been introduced in the therapy of renal cell carcinoma and mantle cell lymphoma, and several trials are currently underway. However, the pathological characterization of mTOR activity in lymphomas is still incomplete. METHODS: mTOR activity and the elements of mTOR complexes were investigated by immunohistochemistry on tissue microarrays representing different human non-Hodgkin-lymphomas (81 cases) and Hodgkin-lymphomas (87 cases). The expression of phospho-mTOR, phospho-4EBP1, phospho-p70S6K, phospho-S6, Rictor, Raptor and Bcl-2, Bcl-xL, Survivin and NF-kappaB-p50 were evaluated, and mTOR activity was statistically analyzed along with 5-year survival data. The in vitro and in vivo effect of the mTOR inhibitor rapamycin was also examined in human Hodgkin-lymphoma cell lines. RESULTS: The majority (>50%) of mantle cell lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, anaplastic large-cell lymphoma and Hodgkin-lymphoma cases showed higher mTOR activity compared to normal lymphoid tissues. Hodgkin-lymphoma was characterized by high mTOR activity in 93% of the cases, and Bcl-xL and NF-kappaB expression correlated with this mTOR activity. High mTOR activity was observed in the case of both favorable and unfavorable clinical response. Low mTOR activity was accompanied by complete remission and at least 5-year disease free survival in Hodgkin-lymphoma patients. However, statistical analysis did not identify correlation beetween mTOR activity and different clinical data of HL patients, such as survival. We also found that Rictor (mTORC2) was not overexpressed in Hodgkin-lymphoma biopsies and cell lines. Rapamycin inhibited proliferation and induced apoptosis in Hodgkin-lymphoma cells both in vitro and in vivo, moreover, it increased the apoptotic effect of chemotherapeutic agents. CONCLUSIONS: Targeting mTOR activity may be a potential therapeutic tool in lymphomas. The presence of mTOR activity probably indicates that the inclusion of mTOR inhibition in the therapy of Hodgkin-lymphomas may be feasible and beneficial, especially when standard protocols are ineffective, and it may also allow dose reduction in order to decrease late treatment toxicity. Most likely, the combination of mTOR inhibitors with other agents will offer the highest efficiency for achieving the best clinical response
Perturbation Centrality and Turbine: A Novel Centrality Measure Obtained Using a Versatile Network Dynamics Tool
Analysis of network dynamics became a focal point to understand and predict
changes of complex systems. Here we introduce Turbine, a generic framework
enabling fast simulation of any algorithmically definable dynamics on very
large networks. Using a perturbation transmission model inspired by
communicating vessels, we define a novel centrality measure: perturbation
centrality. Hubs and inter-modular nodes proved to be highly efficient in
perturbation propagation. High perturbation centrality nodes of the Met-tRNA
synthetase protein structure network were identified as amino acids involved in
intra-protein communication by earlier studies. Changes in perturbation
centralities of yeast interactome nodes upon various stresses well
recapitulated the functional changes of stressed yeast cells. The novelty and
usefulness of perturbation centrality was validated in several other model,
biological and social networks. The Turbine software and the perturbation
centrality measure may provide a large variety of novel options to assess
signaling, drug action, environmental and social interventions. The Turbine
algorithm is available at: http://www.turbine.linkgroup.huComment: 21 pages, 4 figues, 1 table, 58 references + a Supplement of 52
pages, 10 figures, 9 tables and 39 references; Turbine algorithm is available
at: http://www.turbine.linkgroup.h
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