Protein sectors: statistical coupling analysis versus conservation

Statistical coupling analysis (SCA) is a method for analyzing multiple sequence alignments that was used to identify groups of coevolving residues termed "sectors". The method applies spectral analysis to a matrix obtained by combining correlation information with sequence conservation. It has been asserted that the protein sectors identified by SCA are functionally significant, with different sectors controlling different biochemical properties of the protein. Here we reconsider the available experimental data and note that it involves almost exclusively proteins with a single sector. We show that in this case sequence conservation is the dominating factor in SCA, and can alone be used to make statistically equivalent functional predictions. Therefore, we suggest shifting the experimental focus to proteins for which SCA identifies several sectors. Correlations in protein alignments, which have been shown to be informative in a number of independent studies, would then be less dominated by sequence conservation.Comment: 36 pages, 17 figure

Dynamics of adaptive immunity against phage in bacterial populations

The CRISPR (clustered regularly interspaced short palindromic repeats) mechanism allows bacteria to adaptively defend against phages by acquiring short genomic sequences (spacers) that target specific sequences in the viral genome. We propose a population dynamical model where immunity can be both acquired and lost. The model predicts regimes where bacterial and phage populations can co-exist, others where the populations exhibit damped oscillations, and still others where one population is driven to extinction. Our model considers two key parameters: (1) ease of acquisition and (2) spacer effectiveness in conferring immunity. Analytical calculations and numerical simulations show that if spacers differ mainly in ease of acquisition, or if the probability of acquiring them is sufficiently high, bacteria develop a diverse population of spacers. On the other hand, if spacers differ mainly in their effectiveness, their final distribution will be highly peaked, akin to a "winner-take-all" scenario, leading to a specialized spacer distribution. Bacteria can interpolate between these limiting behaviors by actively tuning their overall acquisition probability.Comment: 17 pages, 4 Figures and Supplementary Material

Superconductors from Superstrings

We establish that in a large class of strongly coupled 3+1 dimensional N=1 quiver conformal field theories with gravity duals, adding a chemical potential for the R-charge leads to the existence of superfluid states in which a chiral primary operator of the schematic form O = \lambda\lambda + W condenses. Here \lambda is a gluino and W is the superpotential. Our argument is based on the construction of a consistent truncation of type IIB supergravity that includes a U(1) gauge field and a complex scalar.Comment: 5 pages, 2 figures; v2 improved figure, small change

Membranes with Topological Charge and AdS4/CFT3 Correspondence

If the second Betti number b_2 of a Sasaki-Einstein manifold Y^7 does not vanish, then M-theory on AdS_4 x Y^7 possesses "topological" U(1)^{b_2} gauge symmetry. The corresponding Abelian gauge fields come from three-form fluctuations with one index in AdS_4 and the other two in Y^7. We find black membrane solutions carrying one of these U(1) charges. In the zero temperature limit, our solutions interpolate between AdS_4 x Y^7 in the UV and AdS_2 x R^2 x squashed Y^7 in the IR. In fact, the AdS_2 x R^2 x squashed Y^7 background is by itself a solution of the supergravity equations of motion. These solutions do not appear to preserve any supersymmetry. We search for their possible instabilities and do not find any. We also discuss the meaning of our charged membrane backgrounds in a dual quiver Chern-Simons gauge theory with a global U(1) charge density. Finally, we present a simple analytic solution which has the same IR but different UV behavior. We reduce this solution to type IIA string theory, and perform T-duality to type IIB. The type IIB metric turns out to be a product of the squashed Y^7 and the extremal BTZ black hole. We discuss an interpretation of this type IIB background in terms of the (1+1)-dimensional CFT on D3-branes partially wrapped over the squashed Y^7.Comment: 57 pages, 7 figure

Reusability report: Prostate cancer stratification with diverse biologically-informed neural architectures

In Elmarakeby et al., "Biologically informed deep neural network for prostate cancer discovery", a feedforward neural network with biologically informed, sparse connections (P-NET) was presented to model the state of prostate cancer. We verified the reproducibility of the study conducted by Elmarakeby et al., using both their original codebase, and our own re-implementation using more up-to-date libraries. We quantified the contribution of network sparsification by Reactome biological pathways, and confirmed its importance to P-NET's superior performance. Furthermore, we explored alternative neural architectures and approaches to incorporating biological information into the networks. We experimented with three types of graph neural networks on the same training data, and investigated the clinical prediction agreement between different models. Our analyses demonstrated that deep neural networks with distinct architectures make incorrect predictions for individual patient that are persistent across different initializations of a specific neural architecture. This suggests that different neural architectures are sensitive to different aspects of the data, an important yet under-explored challenge for clinical prediction tasks.Comment: 9 pages, 3 figures. Submitted to Nature Machine Intelligenc

Emergent Quantum Near-Criticality from Baryonic Black Branes

We find new black 3-brane solutions describing the "conifold gauge theory" at nonzero temperature and baryonic chemical potential. Of particular interest is the low-temperature limit where we find a new kind of weakly curved near-horizon geometry; it is a warped product AdS_2 x R^3 x T^{1,1} with warp factors that are powers of the logarithm of the AdS radius. Thus, our solution encodes a new type of emergent quantum near-criticality. We carry out some stability checks for our solutions. We also set up a consistent ansatz for baryonic black 2-branes of M-theory that are asymptotic to AdS_4 x Q^{1,1,1}.Comment: 29 pages, 4 figures; v2 discussion of entropy revised, minor changes; v3 note added, minor improvements, version published in JHE

Rapid dissection and model-based optimization of inducible enhancers in human cells using a massively parallel reporter assay

Learning to read and write the transcriptional regulatory code is of central importance to progress in genetic analysis and engineering. Here we describe a massively parallel reporter assay (MPRA) that facilitates the systematic dissection of transcriptional regulatory elements. In MPRA, microarray-synthesized DNA regulatory elements and unique sequence tags are cloned into plasmids to generate a library of reporter constructs. These constructs are transfected into cells and tag expression is assayed by high-throughput sequencing. We apply MPRA to compare >27,000 variants of two inducible enhancers in human cells: a synthetic cAMP-regulated enhancer and the virus-inducible interferon-β enhancer. We first show that the resulting data define accurate maps of functional transcription factor binding sites in both enhancers at single-nucleotide resolution. We then use the data to train quantitative sequence-activity models (QSAMs) of the two enhancers. We show that QSAMs from two cellular states can be combined to design enhancer variants that optimize potentially conflicting objectives, such as maximizing induced activity while minimizing basal activity.National Human Genome Research Institute (U.S.) (grant R01HG004037)National Science Foundation (U.S.) ((NSF) grant PHY-0957573)National Science Foundation (U.S.) (NSF grant PHY-1022140)Broad Institut