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

Impact of chromophores on colour appearance in a computational skin model

Early diagnosis of skin cancer offers the patient more favorable treatment options. Color fidelity of skin images is a major concern for dermatologists as adoption of digital dermatoscopes is increasing rapidly. Accurate color depiction of the lesion and surrounding skin are vital in diagnostic evaluation of a lesion. We previously introduced VCT-Derma, a pipeline for dermatological Virtual Clinical Trials (VCTs) including detailed and flexible models of human skin and lesions, which represent the patient in the entire dermatoscopy-based diagnostic process. However, those initial models of skin and lesions did not properly account for tissue colors. Our new skin model accounts for tissue color appearance by incorporating chromophores (e.g., melanin, blood) into the tissue model, and simulating the optical properties of the various skin layers. The physical properties of the skin and lesion were selected from clinically plausible values. The model and simulated dermatoscope images were created in open modelling software, assuming a linear camera model. We have assumed ambient white lighting, with a 6mm distance to the camera. Our model of color appearance was characterised by comparing the brightness of the lesion to its depth. The brightness of the lesion is compared through the variability of the mean gray values of a cropped region around the lesion. We compare two skin models, one without extensive chromophore content and one with. Our preliminary evaluation of increasing chromophore content shows promise based on the results presented here. Further refinement and validation of the model is ongoing

Potential of Organic Rankine Cycles (ORC) for waste heat recovery on an Electric Arc Furnace (EAF)

The organic Rankine cycle (ORC) is a mature technology to convert low temperature waste heat to electricity. While several energy intensive industries could benefit from the integration of an ORC, their adoption rate is rather low. One important reason is that the prospective end-users find it difficult to recognize and realise the possible energy savings. In more recent years, the electric arc furnaces (EAF) are considered as a major candidate for waste heat recovery. Therefore, in this work, the integration of an ORC coupled to a 100 MWe EAF is investigated. The effect of working with averaged heat profiles, a steam buffer and optimized ORC architectures is investigated. The results show that it is crucial to take into account the heat profile variations for the typical batch process of an EAF. An optimized subcritical ORC (SCORC) can generate an electricity output of 752 kWe with a steam buffer working at 25 bar. However, the use of a steam buffer also impacts the heat transfer to the ORC. A reduction up to 61.5% in net power output is possible due to the additional isothermal plateau of the steam

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

Recessive osteogenesis imperfecta caused by LEPRE1 mutations: clinical documentation and identification of the splice form responsible for prolyl 3-hydroxylation

Abstract: Background: Recessive forms of osteogenesis imperfecta (OI) may be caused by mutations in LEPRE1, encoding prolyl 3-hydroxylase-1 (P3H1) or in CRTAP, encoding cartilage associated protein. These proteins constitute together with cyclophilin B (CyPB) the prolyl 3-hydroxylation complex that hydroxylates the Pro986 residue in both the type I and type II collagen alpha 1-chains. Methods: We screened LEPRE1, CRTAP and PPIB (encoding CyPB) in a European/Middle Eastern cohort of 20 lethal/severe OI patients without a type I collagen mutation. Results: Four novel homozygous and compound heterozygous mutations were identified in LEPRE1 in four probands. Two probands survived the neonatal period, including one patient who is the eldest reported patient (17(7/12) years) so far with P3H1 deficiency. At birth, clinical and radiologic features were hardly distinguishable from those in patients with autosomal dominant (AD) severe/lethal OI. Follow-up data reveal that the longer lived patients develop a severe osteochondrodysplasia that overlaps with, but has some distinctive features from, AD OI. A new splice site mutation was identified in two of the four probands, affecting only one of three LEPRE1 mRNA splice forms, detected in this study. The affected splice form encodes a 736 amino acid (AA) protein with a "KDEL'' endoplasmic reticulum retention signal. While western blotting and immunocytochemical analysis of fibroblast cultures revealed absence of this P3H1 protein, mass spectrometry and SDS-urea-PAGE data showed severe reduction of alpha 1(I) Pro986 3-hydroxylation and overmodification of type I (pro) collagen chains in skin fibroblasts of the patients. Conclusion: These findings suggest that the 3-hydroxylation function of P3H1 is restricted to the 736AA splice form

Belgian Poison Centre impact on healthcare expenses of unintentional poisonings : a cost-benefit analysis

Objectives: This study evaluates the impact of the Belgian Poison Centre (BPC) on national healthcare expenses for calls from the public for unintentional poisonings. Methods: The probability of either calling the BPC, consulting a general practitioner (GP) or consulting an emergency department (ED) was examined in a telephone survey (February-March 2016). Callers were asked what they would have done in case of unavailability of the BPC. The proportion and cost for ED-ambulatory care, ED 24-h observation or hospitalisation were calculated from individual invoices. A cost-benefit analysis was performed. Results: Unintentional cases (n = 485) from 1045 calls to the BPC were included. After having called the BPC, 92.1% did not seek further medical help, 4.2% consulted a GP and 3.7% went to an ED. In the absence of the BPC, 13.8% would not have sought any further help, 49.3% would have consulted a GP and 36.9% would have gone to the hospital. The cost-benefit ratio of the availability of the BPC as versus its absence was estimated at 5.70. Conclusions: Financial savings can be made if people first call the BPC for unintentional poisonings

Characteristics and costs in adults with acute poisoning admitted to the emergency department of a university hospital in Belgium

Objective The aims of this study were to assess the characteristics of all acute poisoning admissions among adult emergency department (ED) patients, to identify factors associated with admission and to calculate direct medical cost. Methods Data of 2017 (1st January to 31st December) were collected and analyzed retrospectively using patients' medical records and hospital invoices. Factors associated with type of hospitalization were identified using appropriate statistics. Results A total of 1,214 hospital admissions were included, accounting for 3.6% of all ED admissions. Men (62.2%) and the age group 21-40 years (43.0%) accounted for the largest proportion. Substances most commonly involved were ethanol (52.9%), benzodiazepines (9.7%), cocaine (4.9%), cannabis (4.6%), antidepressants (4.6%) and psychostimulants (4.6%). A total of 4,561 treatment acts were recorded, most commonly monitoring of vital signs (63.6%) and medication and/or intravenous drip administration (62.9%). Patients were discharged home after having received care in the emergency department (ED-amb) in 54.5% of admissions, were admitted to the emergency-department-24-hours-observation unit (ED-24h) or were hospitalized (Hosp) in 24.6% and 20.9% of admissions, respectively. Factors found to be associated with hospitalization type were age, hour of admission, victim location, degree of severity, use of antidotes, involvement of antidepressants, antipsychotics, psychostimulants, benzodiazepines and ethanol. Total cost was (sic)1,512,346 with an average of (sic)1,287 per admission. Conclusion Poisonings entail a considerable percentage of patients admitted to an ED and financial burden. In particular, ethanol poisonings account for the largest proportion of all ED admissions. Comparison of our figures with other data is hampered by the heterogeneity in inclusion criteria. Availability of a uniform template would facilitate comparison and allow better monitoring policies for prevention and cost reduction

Performance analysis of internally reformed MCFC/IT-SOFC combined cycle

Paper presented at the 6th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, South Africa, 30 June - 2 July, 2008.High temperature fuel cells such as the solid oxide fuel cell (SOFC) and molten carbonate fuel cell (MCFC) are considered extremely suitable for electrical power plant application. The intermediate temperature (IT) SOFC and MCFC performances are calculated using numerical models which are built in Aspen customer modeler for the internally reformed (IR) fuel cells. These models are integrated in Aspen PlusTM. In this article, a new combined cycle is proposed: this combined cycle consisting of two-staged of MCFC and IT-SOFC. The MCFC&IT-SOFC combined cycle and single-staged cycle with MCFC only are simulated in order to evaluate and compare their performances. The simulations results indicate that the net efficiency of MCFC&IT-SOFC combined cycle is 64.6 % under standard operation conditions. On the other hand, the net efficiency of single-staged MCC cycle is 51.6%. In other words, the cycle with two-staged MCFC and IT-SOFC gives much better net efficiency than the cycle with single-staged MCFC.vk201