Development and Appraisal of the Pyridazinedione Scaffold to Form Next-Generation Bioconjugates

Over the last two decades, the functionalisation of proteins through bioconjugation reactions (often in a therapeutic setting) has been of great interest in the field of chemical biology and within the pharmaceutical industry. Novel strategies for the modification of cysteine residues are of major relevance to the field of protein bioconjugation due to the pharmacokinetically superior nature of the homogenous products that can be formed through site-selective methodologies. Researchers have strived to enable stable, covalent modification of cysteine residues, which has been the driver behind forming leading biologics (e.g. in the formation of antibody-drug conjugates (ADCs)). In recent years, the cysteine reactive pyridazinedione (PD) scaffold has been developed to facilitate the efficient formation of stable, homogenous and multi-functional bioconjugates. However, whilst the PD scaffold is a highly promising reagent for bioconjugation (especially when modifying antibodies and antibody derived proteins), this is still considered an early technology; the full potential of this scaffold as a next generation bioconjugation reagent has yet to be unlocked. This work aimed to provide greater accessibility and deepen current knowledge surrounding the PD functionalisation technology. This was achieved through the optimisation of synthetic routes to form PDs as well as providing an assessment of the extent of PD modification on native antibody function. Furthermore, novel applications that stemmed from novel fundamental PD-based chemistry were developed to provide a platform for site-selective tri-functionalisation of proteins, as well as dynamic reversible cysteine modification

The use of bromopyridazinedione derivatives in chemical biology

Tools that facilitate the chemical modification of peptides and proteins are gaining an increasing amount of interest across many avenues of chemical biology as they enable a plethora of therapeutic, imaging and diagnostic applications. Cysteine residues and disulfide bonds have been highlighted as appealing targets for modification due to the highly homogenous nature of the products that can be formed through their site-selective modification. Amongst the reagents available for the site-selective modification of cysteine(s)/disulfide(s), pyridazinediones (PDs) have played a particularly important and enabling role. In this review, we outline the unique chemical features that make PDs especially well-suited to cysteine/disulfide modification on a wide variety of proteins and peptides, as well as provide context as to the problems solved (and applications enabled) by this technology

Thonides debarques par les pecheurs artisans dans la zone d’abidjan (Cote d’Ivoire) source potentielle d’une amelioration de la securite alimentaire

Dans le cadre des activités de suivi de la pêche artisanale maritime, une étude sur la production des thonidés débarqués a été réalisée. Elle avait pour but d’obtenir les informations indispensables à une estimation de la capture nationale de thonidés, à l’égard de la problématique de la sécuritéalimentaire. La méthodologie utilisée a consisté à collecter les données chaque jour par des techniciens des structures de recherches de 2014 à 2017, sur les sites de débarquements d’abobodoumé, de zimbabwé et du port. Les résultats obtenus indiquent une similarité dans les productions de 2014 à 2016 avec une augmentation en importante en 2017 due à l’intérêt que suscite la pêche des thonidés chez les pêcheurs. Compte tenu des prises importantes de ces espèces de poisson, une organisation rigoureuse des activités pourrait militer davantage en faveur des moyens et stratégies à mettre en oeuvre pour assurer le renforcement de la sécurité alimentaire dans ce sous-secteur de la pêche.Mots clés : Thonidés, Pêcheurs artisans, Production, Sécurité alimentaire, Côte d’Ivoire

Quantitative Methods for Optimizing Patient Outcomes in Liver Transplantation

Liver transplantation continues to be the gold standard for treating patients with end-stage liver diseases. However, despite the huge success of liver transplantation in improving patient outcomes, long term graft survival continues to be a major problem. The current clinical practice in the management of liver transplant patients is centered around immunosuppressive multidrug regimens. Current research has been focusing on phenotypic personalized medicine as a novel approach in the optimization of immunosuppression, a regressional math modeling focusing on individual patient dose and response using specific markers like transaminases. A prospective area of study includes the development of a mechanistic computational math modeling for optimizing immunosuppression to improve patient outcomes and increase long-term graft survival by exploring the intricate immune/drug interactions to help us further our understanding and management of medical problems like transplants, autoimmunity, and cancer therapy. Thus, by increasing long-term graft survival, the need for redo transplants will decrease, which will free up organs and potentially help with the organ shortage problem promoting equity and equal opportunity for transplants, as well as decreasing the medical costs associated with additional testing and hospital admissions. Although long-term graft survival remains challenging, computational and quantitative methods have led to significant improvements. In this article, we review recent advances and remaining opportunities. We focus on the following topics: donor organ availability and allocation with a focus on equity, monitoring of patient and graft health, and optimization of immunosuppression dosing.Comment: 2 figures, including a graphical abstrac

Modelling the critical care pathway for cardiothoracic surgery

The west of Scotland heart and lung center based at the Golden Jubilee National Hospital houses all adult cardiothoracic surgery for the region. Increased demand for scheduled patients and fluctuations in emergency referrals resulted in increasing waiting times and patient cancellations. The main issue was limited resources, which was aggravated by the stochastic nature of the length of stay (LOS) and arrival of patients. Discrete event simulation (DES) was used to assess if an enhanced schedule was sufficient, or more radical changes, such as capacity or other resource reallocations should be considered in order to solve the problem. Patients were divided into six types depending on their condition and LOS at the different stages of the process. The simulation model portrayed each patient type’s pathway with sufficient detail. Patient LOS figures were analyzed and distributions were formed from historical data, which were then used in the simulation. The model proved successful as it showed figures that were close to actual observations. Acquiring results and knowing exactly when and what caused a cancellation was another strong point of the model. The results demonstrated that the bottleneck in the system was related to the use of High Dependency Unit (HDU) beds, which were the recovery beds used by most patients. Enhancing the schedule by leveling out the daily arrival of patients to HDUs reduced patient cancellations by 20%. However, coupling this technique with minor capacity reallocations resulted in more than 60% drop in cancellations