Evolutionary Signatures amongst Disease Genes Permit Novel Methods for Gene Prioritization and Construction of Informative Gene-Based Networks

Genes involved in the same function tend to have similar evolutionary histories, in that their rates of evolution covary over time. This coevolutionary signature, termed Evolutionary Rate Covariation (ERC), is calculated using only gene sequences from a set of closely related species and has demonstrated potential as a computational tool for inferring functional relationships between genes. To further define applications of ERC, we first established that roughly 55% of genetic diseases posses an ERC signature between their contributing genes. At a false discovery rate of 5% we report 40 such diseases including cancers, developmental disorders and mitochondrial diseases. Given these coevolutionary signatures between disease genes, we then assessed ERC's ability to prioritize known disease genes out of a list of unrelated candidates. We found that in the presence of an ERC signature, the true disease gene is effectively prioritized to the top 6% of candidates on average. We then apply this strategy to a melanoma-associated region on chromosome 1 and identify MCL1 as a potential causative gene. Furthermore, to gain global insight into disease mechanisms, we used ERC to predict molecular connections between 310 nominally distinct diseases. The resulting “disease map” network associates several diseases with related pathogenic mechanisms and unveils many novel relationships between clinically distinct diseases, such as between Hirschsprung's disease and melanoma. Taken together, these results demonstrate the utility of molecular evolution as a gene discovery platform and show that evolutionary signatures can be used to build informative gene-based networks

Heat pumping in nanomechanical systems

We propose using a phonon pumping mechanism to transfer heat from a cold to a hot body using a propagating modulation of the medium connecting the two bodies. This phonon pump can cool nanomechanical systems without the need for active feedback. We compute the lowest temperature that this refrigerator can achieve.Comment: 4 pages, 1 figure, published versio

A Bioclimatic Laboratory in Southern Ohio

Author Institution: Department of Botany and Plant Pathology, The Ohio State University, Columbus 1

Search for cold gas in z>2 damped Lyman-alpha systems: 21-cm and H_2 absorption

(Abridged) We present the results of a systematic GBT and GMRT survey for 21-cm absorption in a sample of 10 DLAs at 2<z_abs<3.4. Analysis of L-band VLBA images of the background QSOs are also presented. We detect 21-cm absorption in only one DLA (at z_abs = 3.1745 towards J1337+3152). Combining our data with the data from the literature (a sample of 28 DLAs) and assuming the measured core fraction at milliarcsecond scale to represent the gas covering factor, we find that the HI gas in DLAs at z> 2 is predominantly constituted by WNM. The detection rate of 21-cm absorption seems to be higher for systems with higher N(HI) or metallicity. However, no clear correlation is found between the integrated 21-cm optical depth (or spin temperature) and either N(HI), metallicity or velocity spread of the low ionization species. There are 13 DLAs in our sample for which high resolution optical spectra covering the expected wavelength range of H_2 absorption are available. We report the detection of H_2 molecules in the z_abs = 3.3871 21-cm absorber towards J0203+1134 (PKS 0201+113). In 8 cases, neither H_2 nor 21-cm absorption are detected. The lack of 21-cm and H_2 absorption in these systems can be explained if most of the HI in these DLAs originate from low density high temperature gas. In one case we have a DLA with 21-cm absorption not showing H_2 absorption. In two cases, both species are detected but do not originate from the same velocity component. In the remaining 2 cases 21-cm absorption is not detected despite the presence of H_2 with evidence for the presence of cold gas. All this is consistent with the idea that the H_2 components seen in DLAs are compact (with sizes of < 15 pc) and contain only a small fraction (i.e typically <10%) of the total N(HI) measured in the DLAs.Comment: Accepted for publication in MNRA

Is Bariatric Surgery an Effective Treatment for Type II Diabetic Kidney Disease?

Type II diabetic kidney disease is devastating to patients and society alike. This review will evaluate bariatric surgery as a treatment for diabetic kidney disease primarily through its ability to induce and maintain regression of type II diabetes. The review begins by outlining the global challenge of diabetic kidney disease, its link to obesity, and the comparative benefits of bariatric surgery on weight and type II diabetes. It then surveys comprehensively the relevant literature, which reports that although bariatric surgery is associated with reductions in albuminuria, its effect on harder clinical end points like progression of diabetic kidney disease is not known. The review also includes a critical assessment of the risks and costs of bariatric surgery and concludes by acknowledging the major knowledge gaps in the field and providing research strategies to overcome them. Until these knowledge gaps are filled, clinicians will be forced to rely on their own subjective judgment in determining the benefit-risk ratio of bariatric surgery for patients with diabetic kidney disease

A complete sample of 21-cm absorbers at z~1.3: Giant Metrewave Radio Telescope Survey Using MgII Systems

We present the results of a systematic Giant Metrewave Radio Telescope (GMRT) survey of 21-cm absorption in a representative and unbiased sample of 35 strong MgII systems in the redshift range: zabs~1.10-1.45, 33 of which have W_r>1 \AA. The survey using ~400hrs of telescope time has resulted in 9 new 21-cm detections and stringent 21-cm optical depth upper limits (median 3-sigma optical depth per 10 km/s of 0.017) for the remaining 26 systems. This is by far the largest number of 21-cm detections from any single survey of intervening absorbers. Prior to our survey no intervening 21-cm system was known in the above redshift range and only one system was known in the redshift range 0.7<z<1.5. We discuss the relation between the detectability of 21-cm absorption and various properties of UV absorption lines. We show that if MgII systems are selected with the following criteria, MgII doublet ratio <1.3 and W_r(MgI)/W_r(MgII)>0.3, then a detection rate of 21-cm absorption up to 90% can be achieved. We estimate n_{21}, the number per unit redshift of 21-cm absorbers with W_r(Mg(II)>W_o and integrated optical depth Tau_{21}>Tau_o and show that n_{21} decreases with increasing redshift. In particular, for W_o=1.0 \AA and Tau_o>0.3 km\s, n_{21} falls by a factor 4 from =0.5 to =1.3. The evolution seems to be stronger for stronger MgII systems. Using a subsample of systems for which high frequency VLBA images are available, we show that the effect is not related to the structure of the background radio sources and is most probably due to the evolution of the cold neutral medium filling factor in MgII systems. We find no correlation between the velocity spread of the 21-cm absorption feature and W_r(MgII) at z~1.3.Comment: 22 pages, 8 tables, 12 figures, accepted for publication in MNRA

Metallicity Evolution in the Early Universe

Observations of the damped Lya systems provide direct measurements on the chemical enrichment history of neutral gas in the early universe. In this Letter, we present new measurements for four damped Lya systems at high redshift. Combining these data with [Fe/H] values culled from the literature, we investigate the metallicity evolution of the universe from z~1.5-4.5. Contrary to our expectations and the predictions of essentially every chemical evolution model, the N(HI)-weighted mean [Fe/H] metallicity exhibits minimal evolution over this epoch. For the individual systems, we report tentative evidence for an evolution in the unweighted [Fe/H] mean and the scatter in [Fe/H] with the higher redshift systems showing lower scatter and lower typical [Fe/H] values. We also note that no damped Lya system has [Fe/H] < -2.7 dex. Finally, we discuss the potential impact of small number statistics and dust on our conclusions and consider the implications of these results on chemical evolution in the early universe.Comment: 6 pages, 2 encapsulated figures, Latex2e, uses emulateapj.sty and onecolfloat.sty. Accepted for publication in ApJ Letters: Feb 28, 200

Nucleic Acid Sequence Design via Efficient Ensemble Defect Optimization

We describe an algorithm for designing the sequence of one or more interacting nucleic acid strands intended to adopt a target secondary structure at equilibrium. Sequence design is formulated as an optimization problem with the goal of reducing the ensemble defect below a user-specified stop condition. For a candidate sequence and a given target secondary structure, the ensemble defect is the average number of incorrectly paired nucleotides at equilibrium evaluated over the ensemble of unpseudoknotted secondary structures. To reduce the computational cost of accepting or rejecting mutations to a random initial sequence, candidate mutations are evaluated on the leaf nodes of a tree-decomposition of the target structure. During leaf optimization, defect-weighted mutation sampling is used to select each candidate mutation position with probability proportional to its contribution to the ensemble defect of the leaf. As subsequences are merged moving up the tree, emergent structural defects resulting from crosstalk between sibling sequences are eliminated via reoptimization within the defective subtree starting from new random subsequences. Using a Θ(N^3) dynamic program to evaluate the ensemble defect of a target structure with N nucleotides, this hierarchical approach implies an asymptotic optimality bound on design time: for sufficiently large N, the cost of sequence design is bounded below by 4/3 the cost of a single evaluation of the ensemble defect for the full sequence. Hence, the design algorithm has time complexity Ω(N^3). For target structures containing N ∈{100,200,400,800,1600,3200} nucleotides and duplex stems ranging from 1 to 30 base pairs, RNA sequence designs at 37°C typically succeed in satisfying a stop condition with ensemble defect less than N/100. Empirically, the sequence design algorithm exhibits asymptotic optimality and the exponent in the time complexity bound is shar

Phase separation and rotor self-assembly in active particle suspensions

Adding a non-adsorbing polymer to passive colloids induces an attraction between the particles via the `depletion' mechanism. High enough polymer concentrations lead to phase separation. We combine experiments, theory and simulations to demonstrate that using active colloids (such as motile bacteria) dramatically changes the physics of such mixtures. First, significantly stronger inter-particle attraction is needed to cause phase separation. Secondly, the finite size aggregates formed at lower inter-particle attraction show unidirectional rotation. These micro-rotors demonstrate the self assembly of functional structures using active particles. The angular speed of the rotating clusters scales approximately as the inverse of their size, which may be understood theoretically by assuming that the torques exerted by the outermost bacteria in a cluster add up randomly. Our simulations suggest that both the suppression of phase separation and the self assembly of rotors are generic features of aggregating swimmers, and should therefore occur in a variety of biological and synthetic active particle systems.Comment: Main text: 6 pages, 5 figures. Supplementary information: 5 pages, 4 figures. Supplementary movies available from httP://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1116334109/-/DCSupplementa