Beyond small molecules: Targeting G-quadruplex structures with oligonucleotides and their analogues

G-Quadruplexes (G4s) are widely studied secondary DNA/RNA structures, naturally occurring when G-rich sequences are present. The strategic localization of G4s in genome areas of crucial importance, such as proto-oncogenes and telomeres, entails fundamental implications in terms of gene expression regulation and other important biological processes. Although thousands of small molecules capable to induce G4 stabilization have been reported over the past 20 years, approaches based on the hybridization of a synthetic probe, allowing sequence-specific G4-recognition and targeting are still rather limited. In this review, after introducing important general notions about G4s, we aim to list, explain and critically analyse in more detail the principal approaches available to target G4s by using oligonucleotides and synthetic analogues such as Locked Nucleic Acids (LNAs) and Peptide Nucleic Acids (PNAs), reporting on the most relevant examples described in literature to date

News from the online traveling repairman

AbstractIn the traveling repairman problem (Trp), a tour must be found through every one of a set of points (cities) in some metric space such that the weighted sum of completion times of the cities is minimized. Given a tour, the completion time of a city is the time traveled on the tour before the city is reached. In the online traveling repairman problem (OLTrp) requests for visits to cities arrive online while the repairman is traveling. We analyze the performance of algorithms for the online problem using competitive analysis, where the cost of an online algorithm is compared to that of an optimal offline algorithm.We show how to use techniques from online-scheduling to obtain a deterministic algorithm with a competitive ratio of (1+2)2<5.8285 for the OlTrp in general metric spaces. We also present a randomized algorithm which achieves a competitive ratio of 4/ln3<3.6410 against an oblivious adversary. Our results extend to the “dial-a-ride” generalization L-OlDarp of the OlTrp, where objects have to be picked up and delivered by a server. This improves upon the previously best competitive ratio of 9 for the OlTrp on the real line and, moreover, the results are valid for any metric space. For the case of the L-OlDarp our algorithms are the first competitive algorithms.We also derive the first lower bounds for the competitive ratio of randomized algorithms for the OlTrp and the L-OlDarp against an oblivious adversary. Our lower bounds are (ln16+1)/(ln16−1)>2.1282 for the L-OlDarp on the line, (4e−5)/(2e−3)>2.41041 for the L-OlDarp on general metric spaces, 2 for the OlTrp on the line, and 73 for the OlTrp on general metric spaces

Detailed Thermal Model of an Open-Drive Single-Screw Expander for ORC Applications

A comprehensive mechanistic model of an open-drive single-screw expander for waste heat recovery applications by means of an Organic Rankine Cycle (ORC) has been previously developed and validated by the authors. The model included sub-models of geometry, leakage flows, in-chamber heat transfer, simplified friction losses and a single-lumped temperature overall energy balance. Furthermore, a non-symmetric approach was also implemented to simulate the simultaneous expansion process occurring on both side of the central rotor. In this work, the mechanistic model has been extended to compute the loads on the starwheels bearings as well as the main rotor. Forces and moments analyses allowed integration of a more detailed friction loss analysis and identification of a thermal resistance network of the housing with multiple lumped temperatures. To the best of the author’s knowledge such a detailed integrated thermal model of a single-screw machine has not been reported in the available literature. The multi-lumped temperature overall energy balance (OEB) is validated with experimental data obtained from a dedicated ORC test stand. A comparison between single-lumped and multi-lumped temperature approaches on the performance predictions is provided along with a discussion about the losses distribution inside the machine

Semantics in the wild : a digital assistant for Flemish citizens

Public service fragmentation across more than 800 digital channels of government administrations in the region of Flanders (Belgium), causes administrative burden and frustrations, as citizens expect a coherent service. Given the autonomy of the various entities, the fragmentation of information and budget constraints, it is not feasible to rewire the entire e-gov ecosystem to a single portal. Therefore, the Flemish Government is building a smart digital assistant, which supports citizens on the governmental portals, by integrating status information of various transactions. This paper outlines our ongoing research on a method for raising semantic interoperability between different information systems and actors. In this approach, semantic agreements are maintained and implemented end-to-end using the design principles of Linked Data. The lessons learned can speed-up the process in other countries that face the complexity of integrating e-government portals

Non-symmetric approach to single-screw expander and compressor modeling

Single-screw type volumetric machines are employed both as compressors in refrigeration systems and, more recently, as expanders in organic Rankine cycle (ORC) applications. The single-screw machine is characterized by having a central grooved rotor and two mating toothed starwheels that isolate the working chambers. One of the main features of such machine is related to the simultaneous occurrence of the compression or expansion processes on both sides of the main rotor which results in a more balanced loading on the main shaft bearings with respect to twin-screw machines. However, the meshing between starwheels and main rotor is a critical aspect as it heavily affects the volumetric performance of the machine. To allow flow interactions between the two sides of the rotor, a non-symmetric modelling approach has been established to obtain a more comprehensive model of the single-screw machine. The resulting mechanistic model includes in-chamber governing equations, leakage flow models, heat transfer mechanisms, viscous and mechanical losses. Forces and moments balances are used to estimate the loads on the main shaft bearings as well as on the starwheel bearings. An 11 kWe single-screw expander (SSE) adapted from an air compressor operating with R245fa as working fluid is used to validate the model. A total of 60 steady-steady points at four different rotational speeds have been collected to characterize the performance of the machine. The maximum electrical power output and overall isentropic efficiency measured were 7.31 kW and 51.91%, respectively

Genetic background may contribute to the latitude-dependent prevalence of dermatomyositis and anti-TIF1-γ autoantibodies in adult patients with myositis

Background: The prevalence of dermatomyositis (DM) versus DM and polymyositis (PM) combined has been shown to be negatively associated with latitude. This observation has been attributed to increasing exposure to ultraviolet (UV) light towards the equator. In this study, we investigated whether differing genetic background in populations could contribute to this distribution of DM. Methods: Case data derived from the MYOGEN (Myositis Genetics Consortium) Immunochip study (n = 1769) were used to model the association of DM prevalence and DM-specific autoantibodies with latitude. Control data (n = 9911) were used to model the relationship of human leucocyte antigen (HLA) associated with DM autoantibodies and DM or PM single-nucleotide polymorphisms (suggestive significance in the Immunochip project, P < 2.25 x 10(-5)) in healthy control subjects with latitude. All variables were analysed against latitude using ordered logistic regression, adjusted for sex. Results: The prevalence of DM, as a proportion of DM and PM combined, and the presence of anti-transcription intermediary factor 1 (anti-TIF1-gamma) autoantibodies were both significantly negatively associated with latitude (OR 0.96, 95% CI 0.95-0.98, P < 0.001; and OR 0.95, 95% CI 0.92-0.99, P = 0.004, respectively). HLA alleles significantly associated with anti-Mi-2 and anti-TIF1-gamma autoantibodies also were strongly negatively associated with latitude (OR 0.97, 95% CI 0.96-0.98, P < 0.001 and OR 0.98, 95% CI 0.97-0.99, P < 0.001, respectively). The frequency of five PM- or DM-associated SNPs showed a significant association with latitude (P < 0.05), and the direction of four of these associations was consistent with the latitude associations of the clinical phenotypes. Conclusions: These results lend some support to the hypothesis that genetic background, in addition to UV exposure, may contribute to the distribution of DM