Ribosome biogenesis factors-from names to functions.

The assembly of ribosomal subunits is a highly orchestrated process that involves a huge cohort of accessory factors. Most eukaryotic ribosome biogenesis factors were first identified by genetic screens and proteomic approaches of pre-ribosomal particles in Saccharomyces cerevisiae. Later, research on human ribosome synthesis not only demonstrated that the requirement for many of these factors is conserved in evolution, but also revealed the involvement of additional players, reflecting a more complex assembly pathway in mammalian cells. Yet, it remained a challenge for the field to assign a function to many of the identified factors and to reveal their molecular mode of action. Over the past decade, structural, biochemical, and cellular studies have largely filled this gap in knowledge and led to a detailed understanding of the molecular role that many of the players have during the stepwise process of ribosome maturation. Such detailed knowledge of the function of ribosome biogenesis factors will be key to further understand and better treat diseases linked to disturbed ribosome assembly, including ribosomopathies, as well as different types of cancer.

[Implantable cardioverter-defibrillator deactivation at the end of life: ethical, clinical and communication issues]. / La disattivazione del defibrillatore impiantabile alla fine della vita: etica, clinica, comunicazione.

The number of cardioverter-defibrillator implants is increasing worldwide, with the main indication being primary prevention of sudden cardiac death. During the follow-up, patients may die from progression of their underlying heart disease or from nonarrhythmic causes, such as malignancies, dementia and lung disease, without receiving appropriate shocks until the last few days or weeks of their life. These events occur roughly in 30% of patients, mainly in the last 24 hours before death. In this case, inappropriate and even appropriate shock deliveries can no longer prolong life and may simply lead to pain and reduced quality of life. Therefore, it appears important to discuss early with the patients and their relatives about deactivation of the implantable cardioverter-defibrillator (ICD) at the end of life.The goal of this review is to provide an overview of the ethical, clinical and communication issues of ICD deactivation, with a special focus on patients' wishes. It is outlined that patients are not adequately informed about risks and benefits of ICD and the option of ICD deactivation; the doctors are not used to discuss with the patients the topics of end-of-life decisions. Complete information must be part of current informed consent before ICD implantation and should be updated during the follow-up, with special attention to patients with heart failure in relation to their prognosis and advance directives, as suggested by international guidelines.

Potent dual inhibitors of Plasmodium falciparum M1 and M17 aminopeptidases through optimization of S1 pocket interactions.

Malaria remains a global health problem, and though international efforts for treatment and eradication have made some headway, the emergence of drug-resistant parasites threatens this progress. Antimalarial therapeutics acting via novel mechanisms are urgently required. Plasmodium falciparum M1 and M17 are neutral aminopeptidases which are essential for parasite growth and development. Previous work in our group has identified inhibitors capable of dual inhibition of PfA-M1 and PfA-M17, and revealed further regions within the protease S1 pockets that could be exploited in the development of ligands with improved inhibitory activity. Herein, we report the structure-based design and synthesis of novel hydroxamic acid analogues that are capable of potent inhibition of both PfA-M1 and PfA-M17. Furthermore, the developed compounds potently inhibit Pf growth in culture, including the multi-drug resistant strain Dd2. The ongoing development of dual PfA-M1/PfA-M17 inhibitors continues to be an attractive strategy for the design of novel antimalarial therapeutics.

Identification and Validation of a Potent Dual Inhibitor of the P. falciparum M1 and M17 Aminopeptidases Using Virtual Screening.

The Plasmodium falciparum PfA-M1 and PfA-M17 metalloaminopeptidases are validated drug targets for the discovery of antimalarial agents. In order to identify dual inhibitors of both proteins, we developed a hierarchical virtual screening approach, followed by in vitro evaluation of the highest scoring hits. Starting from the ZINC database of purchasable compounds, sequential 3D-pharmacophore and molecular docking steps were applied to filter the virtual 'hits'. At the end of virtual screening, 12 compounds were chosen and tested against the in vitro aminopeptidase activity of both PfA-M1 and PfA-M17. Two molecules showed significant inhibitory activity (low micromolar/nanomolar range) against both proteins. Finally, the crystal structure of the most potent compound in complex with both PfA-M1 and PfA-M17 was solved, revealing the binding mode and validating our computational approach.

Two-pronged attack: dual inhibition of Plasmodium falciparum M1 and M17 metalloaminopeptidases by a novel series of hydroxamic acid-based inhibitors.

Plasmodium parasites, the causative agents of malaria, have developed resistance to most of our current antimalarial therapies, including artemisinin combination therapies which are widely described as our last line of defense. Antimalarial agents with a novel mode of action are urgently required. Two Plasmodium falciparum aminopeptidases, PfA-M1 and PfA-M17, play crucial roles in the erythrocytic stage of infection and have been validated as potential antimalarial targets. Using compound-bound crystal structures of both enzymes, we have used a structure-guided approach to develop a novel series of inhibitors capable of potent inhibition of both PfA-M1 and PfA-M17 activity and parasite growth in culture. Herein we describe the design, synthesis, and evaluation of a series of hydroxamic acid-based inhibitors and demonstrate the compounds to be exciting new leads for the development of novel antimalarial therapeutics.

Synthesis and structure-activity relationships of phosphonic arginine mimetics as inhibitors of the M1 and M17 aminopeptidases from Plasmodium falciparum.

The malaria parasite Plasmodium falciparum employs two metallo-aminopeptidases, PfA-M1 and PfA-M17, which are essential for parasite survival. Compounds that inhibit the activity of either enzyme represent leads for the development of new antimalarial drugs. Here we report the synthesis and structure-activity relationships of a small library of phosphonic acid arginine mimetics that probe the S1 pocket of both enzymes and map the necessary interactions that would be important for a dual inhibitor.

Transient trifascicular block complicating myocardial contusion after blunt chest trauma: a case report.

Cardiac contusion may be frequently found in patients with blunt chest trauma, and it presents clinically as a spectrum of injuries of varying severity, including transient disorders of impulse formation and propagation. A rare observation of transient trifascicular block in a previously fit 32-year-old man involved in a car accident is reported. The importance of ECG monitoring and biochemical assessment of markers to unmask myocardial contusion is discussed.