DNA topoisomerases (topos) are essential enzymes that regulate the topological state of DNA during cellular processes such as replication, transcription, recombination, and chromatin remodeling. ...Topoisomerase I (Topo I) is a ubiquitous nuclear enzyme which catalyzes the relaxation of superhelical DNA generating a transient single strand nick in the duplex, through cycles of cleavage and religation. Topoisomerase II (Topo II) mediates the ATP-dependent induction of coordinated nicks in both strands of the DNA duplex, followed by crossing of another double strand DNA through the transiently broken duplex. Although the biological functions of Topoisomerases are important for ensuing genomic integrity, the ability to interfere with enzymes or generate enzyme-mediated damage is an effective strategy for cancer therapy and, in this connection, DNA topos (I and II) proved to be the excellent targets of clinically significant classes of anticancer drugs. Actually, specific Topo I and Topo II inhibitors reversibly trap the enzyme-DNA complexes, thus converting Topos into physiological poisons, able to produce permanent DNA damage, which triggers cell death. Given that both enzymes are good targets, it would be desirable to jointly inhibit them, but use-limiting toxicity of sequential or simultaneous combinations of topo I and II poisons include severe to life-threatening neutropenia and anemia. Furthermore, the emergence of resistance phenomena to topo I inhibitors is often accompanied by a concomitant rise in the level of topo II expression and viceversa, leading to the failure of clinical therapies. In this regard, a single compound able to inhibit both Topo I and II may present the advantage of improving antitopoisomerase activity, with reduced toxic side effects, with respect to the combination of two inhibitors. Due to the high interest in such compounds, this review represents an update of previous works dealing with the development of dual Topo I and II inhibitors as novel anti-cancer agents. The newly collected derivatives have been described focusing attention on their chemical structures and their biological profiles.
yambo is an open source project aimed at studying excited state properties of condensed matter systems from first principles using many-body methods. As input, yambo requires ground state electronic ...structure data as computed by density functional theory codes such as Quantum ESPRESSO and Abinit. yambo's capabilities include the calculation of linear response quantities (both independent-particle and including electron-hole interactions), quasi-particle corrections based on the GW formalism, optical absorption, and other spectroscopic quantities. Here we describe recent developments ranging from the inclusion of important but oft-neglected physical effects such as electron-phonon interactions to the implementation of a real-time propagation scheme for simulating linear and non-linear optical properties. Improvements to numerical algorithms and the user interface are outlined. Particular emphasis is given to the new and efficient parallel structure that makes it possible to exploit modern high performance computing architectures. Finally, we demonstrate the possibility to automate workflows by interfacing with the yambopy and AiiDA software tools.
•Recent empirical data and theory suggest the need for a new bullying definition.•We propose a theoretically-driven definition of bullying based on three elements.•Goal-directedness, power imbalance, ...and harm are the three key elements.•We discuss empirical and theoretical evidence for each of these elements.•We also discuss implications of and challenges to the new definition.
Bullying is a complex and heterogeneous phenomenon that directly affects hundreds of millions of people each year. The importance of bullying has led to research in the last two decades that has produced hundreds, if not thousands, of papers on the topic. In large part this research was stimulated by a definition provided by Olweus in 1993. That definition has proven to be tremendously useful as a starting point for research, but it was created in the absence of recent empirical and theoretical evidence. We propose an updated definition that is explicitly grounded in a unifying theory that encompasses ecological and evolutionary contexts: “bullying is aggressive goal-directed behavior that harms another individual within the context of a power imbalance”. We follow this definition with an examination of the theoretical and empirical support for each of its three elements (goal-directedness, power imbalance, and harm). We suggest that bullying measures should be based on assessments of these three elements of bullying. Our redefinition also emphasizes the importance of considering and altering the cost–benefit analysis of bullying as a cornerstone for successful interventions. Finally we address several specific potential challenges to the definition.
The early-stage density oscillations of the electronic charge in molecules irradiated by an attosecond XUV pulse takes place on femto- or subfemtosecond time scales. This ultrafast charge migration ...process is a central topic in attoscience because it dictates the relaxation pathways of the molecular structure. A predictive quantum theory of ultrafast charge migration should incorporate the atomistic details of the molecule, electronic correlations, and the multitude of ionization channels activated by the broad-bandwidth XUV pulse. We propose a first-principles nonequilibrium Green’s function method fulfilling all three requirements and apply it to a recent experiment on the photoexcited phenylalanine amino acid. Our results show that dynamical correlations are necessary for a quantitative overall agreement with the experimental data. In particular, we are able to capture the transient oscillations at frequencies 0.15 and 0.30 PHz in the hole density of the amine group as well as their suppression and the concomitant development of a new oscillation at frequency 0.25 PHz after ∼14 fs.
Background/Objectives
An increase in fat mass is accompanied by a loss of muscle mass and function in chronic kidney disease. However, no studies in haemodialysis (HD) patients have investigated the ...relationship between fat mass and sarcopenia. The primary aim of this study is to assess the prevalence of sarcopenia, while the secondary aim is to verify the association between the fat mass percentage and SARC-F and SARC-F combined with calf circumference (SARC-F+CC) in elderly HD patients.
Subjects/Methods
A cross-sectional study enrolled 96 HD older patients (male, n = 66). SARC-F ≥4 is used to define the muscle function loss, whereas SARC-F ≥6 or SARC-F ≥11 (with the calf circumference added) are the thresholds to diagnose sarcopenia. The fat mass percentage is obtained using bioelectrical impedance analysis.
Results
We found that 37.5% had a risk of muscle function loss due to SARC-F ≥4, 21.8% risk of sarcopenia using the SARC-F ≥6, and when using CC, the prevalence of risk of sarcopenia increased to 41.6% according to SARC-F+CC ≥11. In addition, there was an association between adiposity and sarcopenia for SARC-F ≥6 (OR: 1.25, p= 0.028) and SARC-F+CC ≥11 (OR: 1.25, p= 0.0003), but not with muscle function loss (SARC-F ≥4).
Conclusion
In conclusion, we found that 37.5% of HD patients had a risk of muscle function loss and 21–41% presented sarcopenia, depending on the cut-off point used. In addition, higher adiposity was associated with an increased likelihood of having sarcopenia by 25%.
Singing master Durham Hills created The Cashaway Psalmody to give as a wedding present in 1770. A collection of tenor melody parts for 152 tunes and sixty-three texts, thePsalmody is the only ...surviving tunebook from the colonial-era South and one of the oldest sacred music manuscripts from the Carolinas. It is all the more remarkable for its sophistication: no similar document of the period matches Hills's level of musical expertise, reportorial reach, and calligraphic skill.
Stephen A. Marini, discoverer ofThe Cashaway Psalmody, offers the fascinating story of the tunebook and its many meanings. From its musical, literary, and religious origins in England, he moves on to the life of Durham Hills; how Carolina communities used the book; and thePsalmody's significance in understanding how ritual song-transmitted via transatlantic music, lyrics, and sacred singing-shaped the era's development. Marini also uses close musical and textual analyses to provide a critical study that offers music historians and musicologists valuable insights on thePslamody and its period.
Meticulous in presentation and interdisciplinary in scope,The Cashaway Psalmody unlocks an important source for understanding life in the Lower South in the eighteenth century.
PDF
