Genome maps across 26 human populations reveal population-specific patterns of structural variation.

Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome

An Emerging Role for Epigenetic Dysregulation in Arsenic Toxicity and Carcinogenesis

Competing Interests Declaration: The authors declare they have no competing financial interests. Abbreviations: AHCY, S-adenosylhomocysteine hydrolase; APL, acute promyelocytic leukemias; As, inorganic arsenic; AS3MT, arsenic (+3 oxidation state) methyltransferase; ChIP-on-chip, chromatin immunoprecipitation-on-chip; ChIP-seq, chromatin immunoprecipitation-sequencing; DEFB1, defensin, beta 1; DNMTs, DNA methyltransferases; H3K4me3, H3K4 tri-methylation; H3K9me2, H3K9 di-methylation; H3K27me3, H3K27 tri-methylation; HATs, histone acetyltransferases; HDACs, histon

Induction of microRNAs, mir-155, mir-222, mir-424 and mir-503, promotes monocytic differentiation through combinatorial regulation

Acute myeloid leukemia (AML) involves a block in terminal differentiation of the myeloid lineage and uncontrolled proliferation of a progenitor state. Using phorbol myristate acetate (PMA), it is possible to overcome this block in THP-1 cells (an M5-AML containing the MLL-MLLT3 fusion), resulting in differentiation to an adherent monocytic phenotype. As part of FANTOM4, we used microarrays to identify 23 microRNAs that are regulated by PMA. We identify four PMA-induced micro- RNAs (mir-155, mir-222, mir-424 and mir-503) that when overexpressed cause cell-cycle arrest and partial differentiation and when used in combination induce additional changes not seen by any individual microRNA. We further characterize these prodifferentiative microRNAs and show that mir-155 and mir-222 induce G2 arrest and apoptosis, respectively. We find mir-424 and mir-503 are derived from a polycistronic precursor mir-424-503 that is under repression by the MLL-MLLT3 leukemogenic fusion. Both of these microRNAs directly target cell-cycle regulators and induce G1 cell-cycle arrest when overexpressed in THP-1. We also find that the pro-differentiative mir-424 and mir-503 downregulate the anti-differentiative mir-9 by targeting a site in its primary transcript. Our study highlights the combinatorial effects of multiple microRNAs within cellular systems.Comment: 45 pages 5 figure

Long-range transfer of electron-phonon coupling in oxide superlattices

The electron-phonon interaction is of central importance for the electrical and thermal properties of solids, and its influence on superconductivity, colossal magnetoresistance, and other many-body phenomena in correlated-electron materials is currently the subject of intense research. However, the non-local nature of the interactions between valence electrons and lattice ions, often compounded by a plethora of vibrational modes, present formidable challenges for attempts to experimentally control and theoretically describe the physical properties of complex materials. Here we report a Raman scattering study of the lattice dynamics in superlattices of the high-temperature superconductor $\bf YBa_2 Cu_3 O_7$ and the colossal-magnetoresistance compound $\bf La_{2/3}Ca_{1/3}MnO_{3}$ that suggests a new approach to this problem. We find that a rotational mode of the MnO$_6$ octahedra in $\bf La_{2/3}Ca_{1/3}MnO_{3}$ experiences pronounced superconductivity-induced lineshape anomalies, which scale linearly with the thickness of the $\bf YBa_2 Cu_3 O_7$ layers over a remarkably long range of several tens of nanometers. The transfer of the electron-phonon coupling between superlattice layers can be understood as a consequence of long-range Coulomb forces in conjunction with an orbital reconstruction at the interface. The superlattice geometry thus provides new opportunities for controlled modification of the electron-phonon interaction in complex materials.Comment: 13 pages, 4 figures. Revised version to be published in Nature Material

PIP5KIβ Selectively Modulates Apical Endocytosis in Polarized Renal Epithelial Cells

Localized synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] at clathrin coated pits (CCPs) is crucial for the recruitment of adaptors and other components of the internalization machinery, as well as for regulating actin dynamics during endocytosis. PtdIns(4,5)P2 is synthesized from phosphatidylinositol 4-phosphate by any of three phosphatidylinositol 5-kinase type I (PIP5KI) isoforms (α, β or γ). PIP5KIβ localizes almost exclusively to the apical surface in polarized mouse cortical collecting duct cells, whereas the other isoforms have a less polarized membrane distribution. We therefore investigated the role of PIP5KI isoforms in endocytosis at the apical and basolateral domains. Endocytosis at the apical surface is known to occur more slowly than at the basolateral surface. Apical endocytosis was selectively stimulated by overexpression of PIP5KIβ whereas the other isoforms had no effect on either apical or basolateral internalization. We found no difference in the affinity for PtdIns(4,5)P2-containing liposomes of the PtdIns(4,5)P2 binding domains of epsin and Dab2, consistent with a generic effect of elevated PtdIns(4,5)P2 on apical endocytosis. Additionally, using apical total internal reflection fluorescence imaging and electron microscopy we found that cells overexpressing PIP5KIβ have fewer apical CCPs but more internalized coated structures than control cells, consistent with enhanced maturation of apical CCPs. Together, our results suggest that synthesis of PtdIns(4,5)P2 mediated by PIP5KIβ is rate limiting for apical but not basolateral endocytosis in polarized kidney cells. PtdIns(4,5)P2 may be required to overcome specific structural constraints that limit the efficiency of apical endocytosis. © 2013 Szalinski et al

Coordinated optimization of visual cortical maps (I) Symmetry-based analysis

In the primary visual cortex of primates and carnivores, functional architecture can be characterized by maps of various stimulus features such as orientation preference (OP), ocular dominance (OD), and spatial frequency. It is a long-standing question in theoretical neuroscience whether the observed maps should be interpreted as optima of a specific energy functional that summarizes the design principles of cortical functional architecture. A rigorous evaluation of this optimization hypothesis is particularly demanded by recent evidence that the functional architecture of OP columns precisely follows species invariant quantitative laws. Because it would be desirable to infer the form of such an optimization principle from the biological data, the optimization approach to explain cortical functional architecture raises the following questions: i) What are the genuine ground states of candidate energy functionals and how can they be calculated with precision and rigor? ii) How do differences in candidate optimization principles impact on the predicted map structure and conversely what can be learned about an hypothetical underlying optimization principle from observations on map structure? iii) Is there a way to analyze the coordinated organization of cortical maps predicted by optimization principles in general? To answer these questions we developed a general dynamical systems approach to the combined optimization of visual cortical maps of OP and another scalar feature such as OD or spatial frequency preference.Comment: 90 pages, 16 figure

Coverage, Continuity and Visual Cortical Architecture

The primary visual cortex of many mammals contains a continuous representation of visual space, with a roughly repetitive aperiodic map of orientation preferences superimposed. It was recently found that orientation preference maps (OPMs) obey statistical laws which are apparently invariant among species widely separated in eutherian evolution. Here, we examine whether one of the most prominent models for the optimization of cortical maps, the elastic net (EN) model, can reproduce this common design. The EN model generates representations which optimally trade of stimulus space coverage and map continuity. While this model has been used in numerous studies, no analytical results about the precise layout of the predicted OPMs have been obtained so far. We present a mathematical approach to analytically calculate the cortical representations predicted by the EN model for the joint mapping of stimulus position and orientation. We find that in all previously studied regimes, predicted OPM layouts are perfectly periodic. An unbiased search through the EN parameter space identifies a novel regime of aperiodic OPMs with pinwheel densities lower than found in experiments. In an extreme limit, aperiodic OPMs quantitatively resembling experimental observations emerge. Stabilization of these layouts results from strong nonlocal interactions rather than from a coverage-continuity-compromise. Our results demonstrate that optimization models for stimulus representations dominated by nonlocal suppressive interactions are in principle capable of correctly predicting the common OPM design. They question that visual cortical feature representations can be explained by a coverage-continuity-compromise.Comment: 100 pages, including an Appendix, 21 + 7 figure

Ecology of the Scorpion, Microtityus jaumei in Sierra de Canasta, Cuba

An assessment of the population dynamics of Microtityus jaumei Armas (Scorpiones: Buthidae) on the slopes south of Sierra de Canasta, Guantánamo Province, Cuba show an increase in activity over the year (≤ 0.05). The activity peak is related to the reproductive period from June to November. The abundance of scorpions was significantly related to density of the canopy and thickness of the substrate

Echocardiographic evaluation of mitral geometry in functional mitral regurgitation

<p>Abstract</p> <p>Objectives</p> <p>We sought to evaluate the geometric changes of the mitral leaflets, local and global LV remodeling in patients with left ventricular dysfunction and varying degrees of Functional mitral regurgitation (FMR).</p> <p>Background</p> <p>Functional mitral regurgitation (FMR) occurs as a consequence of systolic left ventricular (LV) dysfunction caused by ischemic or nonischemic cardiomyopathy. Mitral valve repair in ischemic MR is one of the most controversial topic in surgery and proper repairing requires an understanding of its mechanisms, as the exact mechanism of FMR are not well defined.</p> <p>Methods</p> <p>136 consecutive patients mean age of 55 with systolic LV dysfunction and FMR underwent complete echocardiography and after assessing MR severity, LV volumes, Ejection Fraction, LV sphericity index, C-Septal distance, Mitral valve annulus, Interpapillary distance, Tenting distance and Tenting area were obtained.</p> <p>Results</p> <p>There was significant association between MR severity and echocardiogarphic indices (all p values < 0.001). Severe MR occurred more frequently in dilated cardiomyopathy (DCM) patients compared to ischemic patients, (p < 0.001). Based on the model, only Mitral valve tenting distance (TnD) (OR = 22.11, CI 95%: 14.18 – 36.86, p < 0.001) and Interpapillary muscle distance (IPMD), (OR = 6.53, CI 95%: 2.10 – 10.23, p = 0.001) had significant associations with MR severity.</p> <p>Mitral annular dimensions and area, C-septal distance and sphericity index, although greater in patients with severe regurgitation, did not significantly contribute to FMR severity.</p> <p>Conclusion</p> <p>Degree of LV enlargement and dysfunction were not primary determinants of FMR severity, therefore local LV remodeling and mitral valve apparatus deformation are the strongest predictors of functional MR severity.</p

Positive lymph node retrieval ratio optimises patient staging in colorectal cancer

Alternative lymph node (LN) parameters have been proposed to improve staging in colorectal cancer. This study compared these alternative parameters with conventional TNM staging in predicting long-term survival in patients undergoing curative resection. A total of 295 consecutive patients (mean age 70 years; range 39–95; s.d. 10.4) underwent resection for colorectal cancer from 2001 to 2004. Age, sex, primary tumour site, TNM stage and chemotherapy/radiotherapy were recorded. Patients with colon and rectal cancers were analysed separately for LN parameters: LN total; adequate LN retrieval (⩾12) and inadequate (<12); total number of negative LN; total number of positive LN and the ratio of positive LN to total LN (pLNR). Univariate and multivariate survival analysis was performed. The median number of LN retrieved was 10 (1–57) with adequate LN retrieval in 147 cases (49.8%). For each T and N stage, inadequate LN retrieval did not adversely affect long-term survival (P>0.05). On multivariate analysis, only pLNR was an independent predictor of overall survival in both colon and rectal cancers (HR 11.65, 95% CI 5.00–27.15, P<0.001 and HR 13.40, 95% CI 3.64–49.10, P<0.001, respectively). Application of pLNR subdivided patients into four prognostic groups. Application of the pLNR improved patient stratification in colorectal cancer and should be considered in future staging systems