Dual inhibitors of virulence factors LecA and LasB.

Dual inhibitors of two key virulence factors of , the lectin LecA and the protease LasB, open up an opportunity in the current antimicrobial-resistance crisis. A molecular hybridization approach enabled the discovery of potent, selective, and non-toxic thiol-based inhibitors, which simultaneously inhibit these two major extracellular virulence factors and therefore synergistically interfere with virulence. We further demonstrated that the dimerization of these monovalent dual inhibitors under physiological conditions affords divalent inhibitors of LecA with a 200-fold increase in binding affinity.

Extracorporeal cardiopulmonary resuscitation for hypothermic refractory cardiac arrests in urban areas with temperate climates.

Background: Accidental hypothermia designates an unintentional drop in body temperature below 35 °C. There is a major risk of ventricular fibrillation below 28 °C and cardiac arrest is almost inevitable below 24 °C. In such cases, conventional cardiopulmonary resuscitation is often inefficient.

Discrimination between Alpha-Synuclein Protein Variants with a Single Nanometer-Scale Pore.

Alpha-synuclein is one of several key factors in the regulation of nerve activity. It is striking that single- or multiple-point mutations in the 140-amino-acid-long protein can change its structure, which leads to the protein's aggregation and fibril formation (which is associated with several neurodegenerative diseases, , Parkinson's disease). We recently demonstrated that a single nanometer-scale pore can identify proteins based on its ability to discriminate between protease-generated polypeptide fragments.

Hydrogeochemical and isotopic assessment for characterizing groundwater quality in the Mitidja plain (northern Algeria).

Coastal aquifer overexploitation represents a concerning trigger for water salinization around the world and especially in arid and semi-arid regions along with urban growth and urbanization, as well as land use human-induced changes. This study aims to assess the groundwater quality in the Mitidja alluvial aquifer (northern Algeria) along with its suitability for domestic and agricultural utilizations. A hydrogeochemical approach, based on the interpretation of groundwater physiochemical parameters (EC, pH, dry residue, Ca, Mg, Na, K, Cl, SO, HCO, and NO) collected during the wet and dry periods for the years 2005 and 2017 along with an isotopic characterization, including stable isotopes to identify the recharge sources for the samples collected in October 2017, has been proposed.

Sleep Disorders and Quality of Life in Patients With Cancer: Prospective Observational Study of the Rafael Institute.

Background: Sleep disorders are a common occurrence in the general population. Yet today, it is clearly agreed that sleep disorders represent both a cancer risk factor and a biological consequence of the of the activation of the immuno-inflammatory system induced by cancer itself.

Objective: The aim of this study was to assess the impact of sleep disorders on quality of life and identify the type of disorder and its causes in order to offer an adapted and personalized care plan.

Spontaneous regression of an orbital Langerhans cell histiocytosis after biopsy: A case report. Spontaneous regression of an orbital Langerhans cell histiocytosis.

Langerhans histiocytosis or Langerhans cell histiocytosis (LCH) is a rare benign pathology representing less than 1% of orbital tumors. It can cause either localized or generalized lesions, leading to the destruction of hard and soft tissues. Eosinophilic granuloma is the most benign form and the predominant clinical presentation of LCH.

Inborn Errors of Immunity in Algerian Children and Adults: A Single-Center Experience Over a Period of 13 Years (2008-2021).

Background: Inborn errors of immunity (IEI) predispose patients to various infectious and non-infectious complications. Thanks to the development and expanding use of flow cytometry and increased awareness, the diagnostic rate of IEI has markedly increased in Algeria the last decade.

Aim: This study aimed to describe a large cohort of Algerian patients with probable IEI and to determine their clinical characteristics and outcomes.

On possible trypsin-induced biases in peptides analysis with aerolysin nanopore.

Nanopore-based single-molecule analysis technique is a promising approach in the field of proteomics. In this Technical Brief, the interaction between the biological nanopore of Aerolysin (AeL) and peptides is investigated, focusing on potential biases depending on the AeL activation protocol. Our results reveal that residual trypsin, which may be unintentionally introduced in analyte solution when using a classical AeL activation protocol, can induce a significant formation of shorter peptides by enzymatic degradation of longer ones, which may lead to unwanted effects and/or misinterpretations.

-Aryl Mercaptopropionamides as Broad-Spectrum Inhibitors of Metallo-β-Lactamases.

Drug-resistant pathogens pose a global challenge to public health as they cause diseases that are extremely difficult to cure. Metallo-β-lactamases (MBLs) are a diverse set of zinc-containing enzymes that catalyze the hydrolysis of β-lactam drugs, including carbapenems, which are considered as the last resort to fight severe infections. To restore the activity of current β-lactam antibiotics and to offer an orthogonal strategy to the discovery of new antibiotics, we have identified a series of polar -aryl mercaptopropionamide derivatives as potent inhibitors of several class B1 MBLs.

-Aryl mercaptoacetamides as potential multi-target inhibitors of metallo-β-lactamases (MBLs) and the virulence factor LasB from .

Increasing antimicrobial resistance is evolving to be one of the major threats to public health. To reduce the selection pressure and thus to avoid a fast development of resistance, novel approaches aim to target bacterial virulence instead of growth. Another strategy is to restore the activity of antibiotics already in clinical use.

Substrate-Inspired Fragment Merging and Growing Affords Efficacious LasB Inhibitors.

Extracellular virulence factors have emerged as attractive targets in the current antimicrobial resistance crisis. The Gram-negative pathogen Pseudomonas aeruginosa secretes the virulence factor elastase B (LasB), which plays an important role in the infection process. Here, we report a sub-micromolar, non-peptidic, fragment-like inhibitor of LasB discovered by careful visual inspection of structural data.

A New PqsR Inverse Agonist Potentiates Tobramycin Efficacy to Eradicate Pseudomonas aeruginosa Biofilms.

Pseudomonas aeruginosa (PA) infections can be notoriously difficult to treat and are often accompanied by the development of antimicrobial resistance (AMR). Quorum sensing inhibitors (QSI) acting on PqsR (MvfR) - a crucial transcriptional regulator serving major functions in PA virulence - can enhance antibiotic efficacy and eventually prevent the AMR. An integrated drug discovery campaign including design, medicinal chemistry-driven hit-to-lead optimization and in-depth biological profiling of a new QSI generation is reported.

DIAG a Diagnostic Web Application Based on Lung CT Scan Images and Deep Learning.

Coronavirus disease is a pandemic that has infected millions of people around the world. Lung CT-scans are effective diagnostic tools, but radiologists can quickly become overwhelmed by the flow of infected patients. Therefore, automated image interpretation needs to be achieved.

Impact of local treatment on survival from hematological malignancies causing spinal cord compression.

Background: Various hematological malignancies, including multiple myeloma, plasmacytoma, aggressive lymphoma, and indolent lymphoma, rarely result in spinal cord compression.

Methods: Here, we retrospectively analyzed 32 patients with multiple myeloma (50%), plasmacytoma (13%), aggressive lymphoma (28%), and indolent lymphoma (9%), resulting in spinal cord compression (2004 and 2016). Patients averaged 57 years of age and presented with the indolent onset of spinal cord compression (91% of cases) resulting mostly in motor deficits (69%).

High affinity rigidified AT receptor ligands with indane scaffolds.

Rigidification of the isobutyl side chain of drug-like AT receptor agonists and antagonists that are structurally related to the first reported selective AT receptor agonist 1 (C21) delivered bioactive indane derivatives. Four enantiomer pairs were synthesized and the enantiomers were isolated in an optical purity >99%. The enantiomers , , , , , , and bind to the AT receptor with moderate ( = 54-223 nM) to high affinity ( = 2.

Multitarget Therapeutic Strategies for Alzheimer's Disease: Review on Emerging Target Combinations.

Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions.

-Aryl-3-mercaptosuccinimides as Antivirulence Agents Targeting Elastase and Collagenases.

In light of the global antimicrobial-resistance crisis, there is an urgent need for novel bacterial targets and antibiotics with novel modes of action. It has been shown that elastase (LasB) and () collagenase (ColH) play a significant role in the infection process and thereby represent promising antivirulence targets. Here, we report novel -aryl-3-mercaptosuccinimide inhibitors that target both LasB and ColH, displaying potent activities and high selectivity for the bacterial over human metalloproteases.

Semisynthesis and biological evaluation of amidochelocardin derivatives as broad-spectrum antibiotics.

To address the global challenge of emerging antimicrobial resistance, the hitherto most successful strategy to new antibiotics has been the optimization of validated natural products; most of these efforts rely on semisynthesis. Herein, we report the semisynthetic modification of amidochelocardin, an atypical tetracycline obtained via genetic engineering of the chelocardin producer strain. We report modifications at C4, C7, C10 and C11 by the application of methylation, acylation, electrophilic substitution, and oxidative C-C coupling reactions.

A Novel Anti-amnesic Agent, Specially Designed to Express Both Acetylcholinesterase (AChE) Inhibitory, Serotonergic Subtype 4 Receptor (5-HTR) Agonist and Serotonergic Subtype 6 Receptor (5-HTR) Inverse Agonist Activities, With a Potential Interest Against Alzheimer's Disease.

This work describes the conception, synthesis, and biological evaluation of novel Multi-Target Directed Ligands (MTDL) able to both activate 5-HT receptors, block 5-HT receptors and inhibit acetylcholinesterase activity (AChE), in order to exert a synergistic anti-amnesic effect, potentially useful in the treatment of Alzheimer's disease (AD). Indeed, both activation of 5-HT and blockage of 5-HT receptors led to an enhanced acetylcholine release, suggesting it could lead to efficiently restoring the cholinergic neurotransmission deficit observed in AD. Furthermore, 5-HT receptor agonists are able to promote the non-amyloidogenic cleavage of the amyloid precursor protein (APP) and to favor the production of the neurotrophic protein sAPPα.

Aurone derivatives as promising antibacterial agents against resistant Gram-positive pathogens.

A set of variously substituted aurones was synthesized and evaluated against Methicillin-Resistant S. aureus (MRSA) and P. aeruginosa.

Tackling Pseudomonas aeruginosa Virulence by a Hydroxamic Acid-Based LasB Inhibitor.

In search of novel antibiotics to combat the challenging spread of resistant pathogens, bacterial proteases represent promising targets for pathoblocker development. A common motif for protease inhibitors is the hydroxamic acid function, yet this group has often been related to unspecific inhibition of various metalloproteases. In this work, the inhibition of LasB, a harmful zinc metalloprotease secreted by Pseudomonas aeruginosa, through a hydroxamate derivative is described.

Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa.

The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target.