Integrated regulatory models for inference of subtype-specific susceptibilities in glioblastoma

Abstract Glioblastoma multiforme (GBM) is a highly malignant form of cancer that lacks effective treatment options or well‐defined strategies for personalized cancer therapy. The disease has been stratified into distinct molecular subtypes; however, the underlying regulatory circuitry that gives rise to such heterogeneity and its implications for therapy remain unclear. We developed a modular computational pipeline, Integrative Modeling of Transcription Regulatory Interactions for Systematic Inference of Susceptibility in Cancer (inTRINSiC), to dissect subtype‐specific regulatory programs and predict genetic dependencies in individual patient tumors. Using a multilayer network consisting of 518 transcription factors (TFs), 10,733 target genes, and a signaling layer of 3,132 proteins, we were able to accurately identify differential regulatory activity of TFs that shape subtype‐specific expression landscapes. Our models also allowed inference of mechanisms for altered TF behavior in different GBM subtypes. Most importantly, we were able to use the multilayer models to perform an in silico perturbation analysis to infer differential genetic vulnerabilities across GBM subtypes and pinpoint the MYB family member MYBL2 as a drug target specific for the Proneural subtype

Suppression of Density Fluctuations in a Quantum Degenerate Fermi Gas

We study density profiles of an ideal Fermi gas and observe Pauli suppression of density fluctuations (atom shot noise) for cold clouds deep in the quantum degenerate regime. Strong suppression is observed for probe volumes containing more than 10,000 atoms. Measuring the level of suppression provides sensitive thermometry at low temperatures. After this method of sensitive noise measurements has been validated with an ideal Fermi gas, it can now be applied to characterize phase transitions in strongly correlated many-body systems.Comment: minor edit: fixed technical problem with arxiv's processing of .eps figur

Chiral Anomaly and γ3π\gamma 3\pi

Measurement of the $\gamma 3\pi$ process has revealed a possible conflict with what should be a solid prediction generated by the chiral anomaly. We show that inclusion of appropirate energy-momentum dependence in the matrix element reduces the discrepancy.Comment: 8 page standard Latex fil

Stochastic Simulation of Process Calculi for Biology

Biological systems typically involve large numbers of components with complex, highly parallel interactions and intrinsic stochasticity. To model this complexity, numerous programming languages based on process calculi have been developed, many of which are expressive enough to generate unbounded numbers of molecular species and reactions. As a result of this expressiveness, such calculi cannot rely on standard reaction-based simulation methods, which require fixed numbers of species and reactions. Rather than implementing custom stochastic simulation algorithms for each process calculus, we propose to use a generic abstract machine that can be instantiated to a range of process calculi and a range of reaction-based simulation algorithms. The abstract machine functions as a just-in-time compiler, which dynamically updates the set of possible reactions and chooses the next reaction in an iterative cycle. In this short paper we give a brief summary of the generic abstract machine, and show how it can be instantiated with the stochastic simulation algorithm known as Gillespie's Direct Method. We also discuss the wider implications of such an abstract machine, and outline how it can be used to simulate multiple calculi simultaneously within a common framework.Comment: In Proceedings MeCBIC 2010, arXiv:1011.005

Single-cell transcriptomics to explore the immune system in health and disease

The immune system varies in cell types, states, and locations. The complex networks, interactions, and responses of immune cells produce diverse cellular ecosystems composed of multiple cell types, accompanied by genetic diversity in antigen receptors. Within this ecosystem, innate and adaptive immune cells maintain and protect tissue function, integrity, and homeostasis upon changes in functional demands and diverse insults. Characterizing this inherent complexity requires studies at single-cell resolution. Recent advances such as massively parallel single-cell RNA sequencing and sophisticated computational methods are catalyzing a revolution in our understanding of immunology. Here we provide an overview of the state of single-cell genomics methods and an outlook on the use of single-cell techniques to decipher the adaptive and innate components of immunity.National Institute of Allergy and Infectious Diseases (U.S.) (Grant U24AI118672)National Institute of Allergy and Infectious Diseases (U.S.) (Grant R24AI072073

Is telomere length socially patterned? Evidence from the West of Scotland Twenty-07 study

Lower socioeconomic status (SES) is strongly associated with an increased risk of morbidity and premature mortality, but it is not known if the same is true for telomere length, a marker often used to assess biological ageing. The West of Scotland Twenty-07 Study was used to investigate this and consists of three cohorts aged approximately 35 (N = 775), 55 (N = 866) and 75 years (N = 544) at the time of telomere length measurement. Four sets of measurements of SES were investigated: those collected contemporaneously with telomere length assessment, educational markers, SES in childhood and SES over the preceding twenty years. We found mixed evidence for an association between SES and telomere length. In 35-year-olds, many of the education and childhood SES measures were associated with telomere length, i.e. those in poorer circumstances had shorter telomeres, as was intergenerational social mobility, but not accumulated disadvantage. A crude estimate showed that, at the same chronological age, social renters, for example, were nine years (biologically) older than home owners. No consistent associations were apparent in those aged 55 or 75. There is evidence of an association between SES and telomere length, but only in younger adults and most strongly using education and childhood SES measures. These results may reflect that childhood is a sensitive period for telomere attrition. The cohort differences are possibly the result of survival bias suppressing the SES-telomere association; cohort effects with regard different experiences of SES; or telomere possibly being a less effective marker of biological ageing at older ages

Dynamical Generation of Extended Objects in a 1+11+1 Dimensional Chiral Field Theory: Non-Perturbative Dirac Operator Resolvent Analysis

We analyze the $1+1$ dimensional Nambu-Jona-Lasinio model non-perturbatively. In addition to its simple ground state saddle points, the effective action of this model has a rich collection of non-trivial saddle points in which the composite fields \sigx=\lag\bar\psi\psi\rag and \pix=\lag\bar\psi i\gam_5\psi\rag form static space dependent configurations because of non-trivial dynamics. These configurations may be viewed as one dimensional chiral bags that trap the original fermions (``quarks") into stable extended entities (``hadrons"). We provide explicit expressions for the profiles of these objects and calculate their masses. Our analysis of these saddle points is based on an explicit representation we find for the diagonal resolvent of the Dirac operator in a \{\sigx, \pix\} background which produces a prescribed number of bound states. We analyse in detail the cases of a single as well as two bound states. We find that bags that trap $N$ fermions are the most stable ones, because they release all the fermion rest mass as binding energy and become massless. Our explicit construction of the diagonal resolvent is based on elementary Sturm-Liouville theory and simple dimensional analysis and does not depend on the large $N$ approximation. These facts make it, in our view, simpler and more direct than the calculations previously done by Shei, using the inverse scattering method following Dashen, Hasslacher, and Neveu. Our method of finding such non-trivial static configurations may be applied to other $1+1$ dimensional field theories