In Vitro and In Vivo Interactions of TOR Inhibitor AZD8055 and Azoles against Pathogenic Fungi

Limited options of antifungals and the emergence of drug resistance in fungal pathogens has been a multifaceted clinical challenge. Combination therapy represents a valuable alternative to antifungal monotherapy.

Differencing strategies for SLR observations at the Wettzell observatory

The precise estimation of geodetic parameters using single- and double-differenced SLR observations is investigated. While the differencing of observables is a standard approach for the GNSS processing, double differences of simultaneous SLR observations are practically impossible to obtain due to the SLR basic principle of observing one satellite at a time. Despite this, the availability of co-located SLR telescopes and the use of the alternative concept of quasi-simultaneity allow the forming of SLR differences under certain assumptions, thus enabling the use of these processing strategies. These differences are in principle almost free of both, satellite- and station-specific error sources, and are shown to be a valuable tool to obtain relative coordinates and range biases, and to validate local ties. Tested with the two co-located SLR telescopes at the Geodetic Observatory Wettzell (Germany) using SLR observations to GLONASS and LAGEOS, the developed differencing approach shows that it is possible to obtain single- and double-difference residuals at the millimetre level, and that it is possible to estimate parameters, such as range biases at the stations and the local baseline vector with a precision at the millimetre level and an accuracy comparable to traditional terrestrial survey methods. The presented SLR differences constitute a valuable alternative for the monitoring of the local baselines and the estimation of geodetic parameters.

Microwave Heating Promotes the S-Alkylation of Aziridine Catalyzed by Molecular Sieves: A Post-Synthetic Approach to Lanthionine-Containing Peptides

Aziridine derivatives involved in nucleophilic ring-opening reactions have attracted great interest, since they allow the preparation of biologically active molecules. A chemoselective and mild procedure to convert a peptide cysteine residue into lanthionine via S-alkylation on aziridine substrates is presented in this paper. The procedure relies on a post-synthetic protocol promoted by molecular sieves to prepare lanthionine-containing peptides and is assisted by microwave irradiation. In addition, it represents a valuable alternative to the stepwise approach, in which the lanthionine precursor is incorporated into peptides as a building block.

Production of 6-l-[18F]Fluoro-m-tyrosine in an Automated Synthesis Module for 11C-Labeling

6-l-[18F]Fluoro-m-tyrosine (6-l-[18F]FMT) represents a valuable alternative to 6-l-[18F]FDOPA which is conventionally used for the diagnosis and staging of Parkinson’s disease. However, clinical applications of 6-l-[18F]FMT have been limited by the paucity of practical production methods for its automated production. Herein we describe the practical preparation of 6-l-[18F]FMT using alcohol-enhanced Cu-mediated radiofluorination of Bpin-substituted chiral Ni(II) complex in the presence of non-basic Bu4ONTf using a volatile iPrOH/MeCN mixture as reaction solvent. A simple and fast radiolabeling procedure afforded the tracer in 20.0 ± 3.0% activity yield within 70 min. The developed method was directly implemented onto a modified TracerLab FX C Pro platform originally designed for 11C-labeling. This method enables an uncomplicated switch between 11C- and 18F-labeling. The simplicity of the developed procedure enables its easy adaptation to other commercially available remote-controlled synthesis units and paves the way for a widespread application of 6-l-[18F]FMT in the clinic.

1299 Observational Study of The Use of Spinal Anaesthesia As an Alternative to General Anaesthetic For Ureteroscopy During The COVID-19 Pandemic

Introduction General anaesthetic has traditionally been felt to be more appropriate than spinal anaesthesia for patients undergoing ureteroscopy as it is difficult to achieve a suitably high block. During the COVID-19 pandemic, our centre moved elective operating to an alternative day-case surgical environment where the anaesthetic team performed predominantly spinal anaesthesia and were therefore very experienced with this modality. In view of concerns of COVID-19 transmission by aerosolisation during the intubation and extubation phases of general anaesthetic, spinal anaesthesia as an alternative first line modality was trialled with the option of converting to general anaesthesia if surgery could not be achieved safely and comfortably for the patient. Method During a three-month period, unless contraindicated, spinal anaesthesia was used as the first line anaesthetic for ureteroscopy cases. A retrospective study of outcomes was then undertaken. Results 44 patients were treated with a conversion rate to general anaesthetic of 9% (n = 4). There was a complication rate of 20% (n = 9); 4 partial procedures, 4 readmissions with symptomatic residual fragments or sepsis and 1 patient required post-operative overnight stay due to anaesthetic. Spinal anaesthetic time averaged 25minutes. Conclusions The global COVID-19 pandemic has led to change in practice and we have demonstrated that spinal anaesthesia is a valuable alternative to general anaesthetic in the majority of ureteroscopy cases. When undertaken by an experienced anaesthetic team, using this method does not significantly add to procedure time.

Flipped learning: an alternative pedagogical approach in the untact age

Flipped learning, abbreviated as “FL” is a new pedagogical approach that reverses the order of a typical lecture. It was developed to compensate for the shortcomings of a typical teaching method. Students learn by watching video clips before class and continue to learn through peer discussion in the classroom. The educational benefits of FL like student’s positive attitude were revealed in the previous studies. FL can be a valuable alternative to the existing classes in the untact age of coronavirus disease 2019.

A Review of Hybrid Electric Architectures in Construction, Handling and Agriculture Machines

Recent regulations on pollutant emissions have pushed working machines manufacturers towards research and development efforts to meet the strict limits imposed. For a long time, the use of gas aftertreatment systems have been the most widely accepted solution to reduce the amount of pollutants produced per unit of work done. However, lower emissions limits lead to larger systems and consequently higher difficulties in vehicle integration. Thus, alternative solutions have been studied in the last years to solve the emissions problem using wisely the on-board space. Hybrid electric technologies represent a valuable alternative in this direction. In this work, a review of the current state of the art in the adoption of hybrid and electric technologies on working vehicles is proposed. Due to the high amount of application fields and concepts for special applications, the analysis focused on the three major fields which however includes most of the working machines: Construction, Handling and Agriculture. This work highlights how the requirements of each specific field, strongly affects the design of an optimal hybrid electric architectures.

Exploring Personal and Contextual Variables of the Global Entrepreneurship Monitor through the Rasch Mathematical Model

This article studies the variables of entrepreneurship at the regional (countries) level proposed by the Global Entrepreneurship Monitor (GEM) in its periodic global reports. This response to the suggestions and concerns of various authors is related to the need to analyze the theoretical foundation of the variables used by GEM. The validity and reliability of GEM data for the scientific study of entrepreneurship are also analyzed. Finally, the potential of GEM data to manage entrepreneurship variables at the country level is studied. Data from the GEM global report and the fifty countries for which data are available on all variables are used in the study. The methodology used is the Rasch mathematical model, a valuable alternative to the Classical Theory of the Test. The results confirm the theoretical validity of GEM data, its validity and reliability for the development of scientific studies, and its potential for managing entrepreneurship variables at the country level. Both the methodology used and the conclusions obtained constitute novel contributions to this field.

Targeting Systems to the Brain Obtained by Merging Prodrugs, Nanoparticles, and Nasal Administration

About 40 years ago the lipidization of hydrophilic drugs was proposed to induce their brain targeting by transforming them into lipophilic prodrugs. Unfortunately, lipidization often transforms a hydrophilic neuroactive agent into an active efflux transporter (AET) substrate, with consequent rejection from the brain after permeation across the blood brain barrier (BBB). Currently, the prodrug approach has greatly evolved in comparison to lipidization. This review describes the evolution of the prodrug approach for brain targeting considering the design of prodrugs as active influx substrates or molecules able to inhibit or elude AETs. Moreover, the prodrug approach appears strategic in optimization of the encapsulation of neuroactive drugs in nanoparticulate systems that can be designed to induce their receptor-mediated transport (RMT) across the BBB by appropriate decorations on their surface. Nasal administration is described as a valuable alternative to obtain the brain targeting of drugs, evidencing that the prodrug approach can allow the optimization of micro or nanoparticulate nasal formulations of neuroactive agents in order to obtain this goal. Furthermore, nasal administration is also proposed for prodrugs characterized by peripheral instability but potentially able to induce their targeting inside cells of the brain.