A nucleotide resolution map of Top2-linked DNA breaks in the yeast and human genome

DNA topoisomerases are required to resolve DNA topological stress. Despite this essential role, abortive topoisomerase activity generates aberrant protein-linked DNA breaks, jeopardising genome stability. Here, to understand the genomic distribution and mechanisms underpinning topoisomerase-induced DNA breaks, we map Top2 DNA cleavage with strand-specific nucleotide resolution across the S. cerevisiae and human genomes—and use the meiotic Spo11 protein to validate the broad applicability of this method to explore the role of diverse topoisomerase family members. Our data characterises Mre11-dependent repair in yeast and defines two strikingly different fractions of Top2 activity in humans: tightly localised CTCF-proximal, and broadly distributed transcription-proximal, the latter correlated with gene length and expression. Moreover, single nucleotide accuracy reveals the influence primary DNA sequence has upon Top2 cleavage—distinguishing sites likely to form canonical DNA double-strand breaks (DSBs) from those predisposed to form strand-biased DNA single-strand breaks (SSBs) induced by etoposide (VP16) in vivo

Semiquantum Chaos in the Double-Well

The new phenomenon of semiquantum chaos is analyzed in a classically regular double-well oscillator model. Here it arises from a doubling of the number of effectively classical degrees of freedom, which are nonlinearly coupled in a Gaussian variational approximation (TDHF) to full quantum mechanics. The resulting first-order nondissipative autonomous flow system shows energy dependent transitions between regular behavior and semiquantum chaos, which we monitor by Poincar\'e sections and a suitable frequency correlation function related to the density matrix. We discuss the general importance of this new form of deterministic chaos and point out the necessity to study open (dissipative) quantum systems, in order to observe it experimentally.Comment: LaTeX, 25 pages plus 7 postscript figures. Replaced figure 3 with a non-bitmapped versio

Evidence for shape coexistence in 98^{98}Mo

A $\gamma\gamma$ angular correlation experiment has been performed to investigate the low-energy states of the nucleus $^{98}$Mo. The new data, including spin assignments, multipole mixing ratios and lifetimes reveal evidence for shape coexistence and mixing in $^{98}$Mo, arising from a proton intruder configuration. This result is reproduced by a theoretical calculation within the proton-neutron interacting boson model with configuration mixing, based on microscopic energy density functional theory. The microscopic calculation indicates the importance of the proton particle-hole excitation across the Z=40 sub-shell closure and the subsequent mixing between spherical vibrational and the $\gamma$-soft equilibrium shapes in $^{98}$Mo.Comment: 6 pages, 5 figures, 3 tables; published in Phys. Rev.

Identification of T-cell receptor a-chain genes in the chicken

T-cell receptor (TCR) -chain (TCR) and ß-chain (TCRß) genes are well characterized in mammals, while only TCRß genes have been identified in other vertebrates. To identify avian TCR genes, we used monoclonal anti-CD3 antibodies to isolate chicken TCR for peptide sequence analysis. Degenerate oligonucleotide probes were then used to isolate a candidate TCR cDNA clone that hybridized with a 1.7-kb mRNA species present only in ß T cells and in tissues populated by these cells. Southern blot analysis revealed gene rearrangement in thymocytes and ß T-cell lines. The TCR cDNA candidate encoded an openreading frame of 275 amino acids, the predicted variable (V)-, joining (J)-, and constant (C)-region amino acid sequences of which shared 40%, 60%, and 25% homology with corresponding mammalian sequences. A single C gene and 25 V genes were identified by using region-specific probes. The V cDNA probe isolated from a Vß1+ cell line reacted with transcripts from one of five Vß2+ cell lines, suggesting shared use of V genes by Vß1+ and Vß2+ T cells and the existence of other V gene families. A genomic V sequence was flanked by classical recombination signal sequences but, unlike previously defined V genes, the leader and V region were encoded by a single exon. The data indicate evolutionary conservation of the basic TCR gene structure in birds and mammal

Characterizing Scales of Genetic Recombination and Antibiotic Resistance in Pathogenic Bacteria Using Topological Data Analysis

Pathogenic bacteria present a large disease burden on human health. Control of these pathogens is hampered by rampant lateral gene transfer, whereby pathogenic strains may acquire genes conferring resistance to common antibiotics. Here we introduce tools from topological data analysis to characterize the frequency and scale of lateral gene transfer in bacteria, focusing on a set of pathogens of significant public health relevance. As a case study, we examine the spread of antibiotic resistance in Staphylococcus aureus. Finally, we consider the possible role of the human microbiome as a reservoir for antibiotic resistance genes.Comment: 12 pages, 6 figures. To appear in AMT 2014 Special Session on Advanced Methods of Interactive Data Mining for Personalized Medicin

A study of longitudinal data examining concomitance of pain and cognition in an elderly long-term care population

Allison H Burfield1, Thomas TH Wan2, Mary Lou Sole3, James W Cooper41Gerontology Program, School of Nursing, College of Health and Human Services, University of North Carolina, Charlotte, NC, USA; 2Health Services, Administration, and Medical Education, Director, Doctoral Program in Public Affairs, Associate Dean for Research, College of Health and Public Affairs, 3College of Nursing, University of Central Florida, Orlando, FL, USA; 4College of Pharmacy, University of Georgia, Athens, GA, USAPurpose: To examine if a concomitant relationship exists between cognition and pain in an elderly population residing in long-term care.Background/significance: Prior research has found that cognitive load mediates interpretation of a stimulus. In the presence of decreased cognitive capacity as with dementia, the relationship between cognition and increasing pain is unknown in the elderly.Patients and methods: Longitudinal cohort design. Data collected from the Minimum Data Set-Resident Assessment Instrument (MDS-RAI) from the 2001–2003 annual assessments of nursing home residents. A covariance model was used to evaluate the relationship between cognition and pain at three intervals.Results: The sample included 56,494 subjects from nursing homes across the United States, with an average age of 83 ± 8.2 years. Analysis of variance scores (ANOVAs) indicated a significant effect (P < 0.01) for pain and cognition, with protected t test revealing scores decreasing significantly with these two measures. Relative stability was found for pain and cognition over time. Greater stability was found in the cognitive measure than the pain measure. Cross-legged effects observed between cognition and pain measures were inconsistent. A concomitant relationship was not found between cognition and pain. Even though the relationship was significant at the 0.01 level, the correlations were low (r ≤ 0.08), indicating a weak association between cognition and pain.Conclusion: Understanding the concomitance of pain and cognition aids in defining additional frameworks to extend models to include secondary needs, contextual factors, and resident outcomes. Cognitive decline, as with organic brain diseases, is progressive. Pain is a symptom that can be treated and reduced to improve resident quality of life. However, cognition can be used to determine the most appropriate method to assess pain in the elderly, thereby improving accuracy of pain detection in this population.Keywords: cognitive impairment, Cognitive Performance Scale (CPS), Minimum Data Set 2.

Morphologic and functional correlates of synaptic pathology in the cathepsin D knockout mouse model of congenital neuronal ceroid lipofuscinosis

Mutations in the cathepsin D (CTSD) gene cause an aggressive neurodegenerative disease (congenital neuronal ceroid lipofuscinosis) that leads to early death. Recent evidence suggests that presynaptic abnormalities play a major role in the pathogenesis of CTSD deficiencies. To identify the early events that lead to synaptic alterations, we investigated synaptic ultrastructure and function in pre-symptomatic CTSD knock-out (Ctsd(−/−)) mice. Electron microscopy revealed that there were significantly greater numbers of readily releasable synaptic vesicles present in Ctsd(−/−) mice than in wild-type control mice as early as postnatal day 16. The size of this synaptic vesicle pool continued to increase with disease progression in the hippocampus and thalamus of the Ctsd(−/−) mice. Electrophysiology revealed a markedly decreased frequency of miniature excitatory postsynaptic currents (EPSCs) with no effect on pair-pulse modulation of the evoked EPSPs in the hippocampus of Ctsd(−/−) mice. The reduced miniature EPSC frequency was observed before the appearance of epilepsy or any morphological sign of synaptic degeneration. Taken together, the data indicate that CTSD is required for normal synaptic function, and that a failure in synaptic trafficking or recycling may be an early and important pathological mechanism in Ctsd(−/−) mice; these presynaptic abnormalities may initiate synaptic degeneration in advance of subsequent neuronal loss

Equilibrium and nonequilibrium properties associated with the chiral phase transition at finite density in the Gross-Neveu Model

We study the dynamics of the chiral phase transition at finite density in the Gross-Neveu (GN) model in the leading order in large-N approximation. The phase structure of the GN model in this approximation has the property that there is a tricritical point at a fixed temperature and chemical potential separating regions where the chiral transition is first order from that where it is second order. We consider evolutions starting in local thermal and chemical equilibrium in the massless unbroken phase for conditions pertaining to traversing a first or second order phase transition. We assume boost invariant kinematics and determine the evolution of the order parameter $\sigma$, the energy density and pressure as well as the effective temperature, chemical potential and interpolating number densities as a function of the proper time $\tau$. We find that before the phase transition, the system behaves as if it were an ideal fluid in local thermal equilibrium with equation of state $p=\epsilon$. After the phase transition, the system quickly reaches its true broken symmetry vacuum value for the fermion mass and for the energy density. The single particle distribution functions for Fermions and anti-Fermions go far out of equilibrium as soon as the plasma traverses the chiral phase transition. We have also determined the spatial dependence of the "pion" Green's function $<\bar{\psi}(x) \gamma_5 \psi(x) \bar{\psi}(0) \gamma_5 \psi(0)>$ as a function of the proper time.Comment: 39 pages, 23 figure

The elevated Curie temperature and half-metallicity in the ferromagnetic semiconductor Lax_{x}Eu1−x_{1-x}O

Here we study the effect of La doping in EuO thin films using SQUID magnetometry, muon spin rotation ($\mu$SR), polarized neutron reflectivity (PNR), and density functional theory (DFT). The $\mu$SR data shows that the La$_{0.15}$Eu$_{0.85}$O is homogeneously magnetically ordered up to its elevated $T_{\rm C}$. It is concluded that bound magnetic polaron behavior does not explain the increase in $T_{\rm C}$ and an RKKY-like interaction is consistent with the $\mu$SR data. The estimation of the magnetic moment by DFT simulations concurs with the results obtained by PNR, showing a reduction of the magnetic moment per La$_{x}$Eu$_{1-x}$O for increasing lanthanum doping. This reduction of the magnetic moment is explained by the reduction of the number of Eu-4$f$ electrons present in all the magnetic interactions in EuO films. Finally, we show that an upwards shift of the Fermi energy with La or Gd doping gives rise to half-metallicity for doping levels as high as 3.2 %.Comment: 7 pages, 11 figure