Integral Solvent-Induced Protein Precipitation for Target-Engagement Studies in .

The limited understanding of the mechanism of action (MoA) of several antimalarials and the rise of drug resistance toward existing malaria therapies emphasizes the need for new strategies to uncover the molecular target of compounds in . Integral solvent-induced protein precipitation (iSPP) is a quantitative mass spectrometry-based (LC-MS/MS) proteomics technique. The iSPP leverages the change in solvent-induced denaturation of the drug-bound protein relative to its unbound state, allowing identification of the direct drug-protein target without the need to modify the drug.

Studying Target-Engagement of Anti-Infectives by Solvent-Induced Protein Precipitation and Quantitative Mass Spectrometry.

Antimicrobial resistance (AMR) poses a serious threat to global health. The rapid emergence of resistance contrasts with the slow pace of antimicrobial development, emphasizing the urgent need for innovative drug discovery approaches. This study addresses a critical bottleneck in early drug development by introducing integral solvent-induced protein precipitation (iSPP) to rapidly assess the target-engagement of lead compounds in extracts of pathogenic microorganisms under close-to-physiological conditions.

Targeting the IspE Enzyme.

The enzyme IspE in is considered an attractive drug target, as it is essential for parasite survival and is absent in the human proteome. Yet it still has not been addressed by a small-molecule inhibitor. In this study, we conducted a high-throughput screening campaign against the IspE enzyme.

Targeting IspD in the Methyl-d-erythritol Phosphate Pathway: Urea-Based Compounds with Nanomolar Potency on Target and Low-Micromolar Whole-Cell Activity.

The methyl-d-erythritol phosphate (MEP) pathway has emerged as an interesting target in the fight against antimicrobial resistance. The pathway is essential in many human pathogens, including (), but is absent in human cells. In the present study, we report on the discovery of a new chemical class targeting IspD, the third enzyme in the pathway.

Maternal sensitivity in early childhood and body mass index in adolescence: A population-based study on the role of self-regulation as a mediator.

Maternal sensitivity has been implicated in various aspects of child health and development, including overweight. However, long-term effects, the role of paternal sensitivity and the explanatory pathways are unclear. This study examined whether maternal sensitivity in early childhood is prospectively associated with adolescent body mass index and whether children's self-regulation mediates this relation.

Targeting the IspD Enzyme in the MEP Pathway: Identification of a Novel Fragment Class.

The enzymes of the 2-C-methylerythritol-d-erythritol 4-phosphate (MEP) pathway (MEP pathway or non-mevalonate pathway) are responsible for the synthesis of universal precursors of the large and structurally diverse family of isoprenoids. This pathway is absent in humans, but present in many pathogenic organisms and plants, making it an attractive source of drug targets. Here, we present a high-throughput screening approach that led to the discovery of a novel fragment hit active against the third enzyme of the MEP pathway, PfIspD.

Using Exploratory Structural Equation Modeling (ESEM) to Examine the Internal Structure of Posttraumatic Stress Disorder Symptoms.

Several studies have reported the factor structure of posttraumatic stress disorder (PTSD) using confirmatory factor analysis (CFA). The results show models with different number of factors, high correlations between factors, and symptoms that belong to different factors in different models without affecting the fit index. These elements could suppose the existence of considerable item cross-loading, the overlap of different factors or even the presence of a general factor that explains the items common source of variance.

High plasma adenosine levels in overweight/obese pregnant women.

We aim to investigate whether overweight/obese pregnant women have elevated plasma levels of adenosine associated with increased consumption of high-calorie food. Sixty women were included. They were divided into lean (n = 23 and n = 12) or overweight/obese (n = 7 and n = 18) non-pregnant and pregnant women, respectively.

Comparative effect of human and Trypanosoma cruzi calreticulin in wound healing.

In orthopaedics, the use of factors that enhance granulation tissue formation and prevent or delay new bone regeneration is sometimes desirable. Calreticulin (CRT), a unique endoplasmic reticulum luminal Ca(2+) -binding chaperone widely distributed in eukaryotic cells, is involved in many cellular functions. Among them, CRT has an important influence in cutaneous wound healing and diverse processes associated with cutaneous repair, inhibition of angiogenesis, promotion of cell adhesion and antitumour effect.