Epigenetics meets GPCR: inhibition of histone H3 methyltransferase (G9a) and histamine H3 receptor for Prader-Willi Syndrome.

The role of epigenetic regulation is in large parts connected to cancer, but additionally, its therapeutic claim in neurological disorders has emerged. Inhibition of histone H3 lysine N-methyltransferase, especially G9a, has been recently shown to restore candidate genes from silenced parental chromosomes in the imprinting disorder Prader-Willi syndrome (PWS). In addition to this epigenetic approach, pitolisant as G-protein coupled histamine H3 receptor (H3R) antagonist has demonstrated promising therapeutic effects for Prader-Willi syndrome. To combine these pioneering principles of drug action, we aimed to identify compounds that combine both activities, guided by the pharmacophore blueprint for both targets. However, pitolisant as selective H3R inverse agonist with FDA and EMA-approval did not show the required inhibition at G9a. Pharmacological characterization of the prominent G9a inhibitor A-366, that is as well an inhibitor of the epigenetic reader protein Spindlin1, revealed its high affinity at H3R while showing subtype selectivity among subsets of the histaminergic and dopaminergic receptor families. This work moves prominent G9a ligands forward as pharmacological tools to prove for a potentially combined, symptomatic and causal, therapy in PWS by bridging the gap between drug development for G-protein coupled receptors and G9a as an epigenetic effector in a multi-targeting approach.

Lung injury risk assessment during blast exposure.

Blast pulmonary trauma are common consequences of modern war and terrorism action. To better protect soldiers from that threat, the injury risk level when protected and unprotected must be assessed. Knowing from the literature that a possible amplification of the blast threat would be provided by some thoracic protective systems, the objective is to propose an original approach to correlate a measurable parameter on a manikin with a pulmonary risk level. Using a manikin whose response is correlated with the proposed tolerance limits should help in the evaluation of thoracic protective system regarding injury outcomes. A database including lung injury data from large mammals have been created, allowing the definition of iso-impulse tolerance limits from no lung injury to severe ones (∼60% of ecchymosis). As the use of this metric is not sufficient to evaluate the performance of protective systems on a manikin, the iso-impulse tolerance limits were associated with the thoracic response of post-mortem swine under blast loading. It was found that the lung injury threshold in terms of incident impulse is 58.3 kPa·ms, corresponding to a chest wall peak of acceleration/velocity/displacement of 7350 m/s2, 3.7 m/s and 6.4 mm respectively. Lung injuries are considered as severe (30-60% of ecchymosis) when the incident impulse exceed 232.8 kPa·ms, leading to a chest wall peak of acceleration/velocity/displacement of 79.7 km/s2, 14.7 m/s and 30.1 mm respectively. The defined lung tolerance limits are valid for a 50 kg swine (unprotected) exposed side-on to the blast threat and against a wall.

Chest response assessment of post-mortem swine under blast loadings.

To better protect soldiers from blast threat, that principally affect air-filled organs such a lung, it is necessary to develop an adapted injury criterion and, prior to this, to evaluate the response of a biological model against that threat. The objective of this study is to provide some robust data to quantify the chest response of post-mortem swine under blast loadings. 7 post-mortem swine (54.5 ±â€¯2.6 kg), placed side-on to the threat and against the ground, were exposed to 5 shock-waves of increasing intensities. Their thorax were instrumented with a piezo-resistive pressure sensor, an accelerometer directly exposed to the shock-wave and a target was mounted on the latter in order to track the chest wall displacement. For incident impulses ranging from 47 kPa ms±2% to 173 kPa ms ±6%, the measured maximum of linear chest wall acceleration (Γmax) goes from 5800 m/s2 ±16% to 41,000 m/s2 ±â€¯8%, with a duration of 0.8 ms. Chest wall displacements ranging from 5 mm ±â€¯20% to 20 mm ±â€¯15%, with a duration of 9 ms, are reached. These reproducible data were used to find simple relations (linear, 2nd and 3rd order polynomials) between the kinematic parameters (plus the viscous criterion) and the incident and reflected impulses. Correlating the new reproducible data with the prediction from the Bowen curves showed a lung injury threshold in terms of Γmax similar to that of Cooper (10,000 m/s2). However, the limits defined for the viscous criterion in the automobile field and for non-lethal weapons seems not adapted for the blast threat.

A critical literature review on primary blast thorax injury and their outcomes.

Since World War II, researchers have been interested in exploring the injury mechanisms involved in primary blast on the thorax by using animal model surrogates. These studies were mostly concerned with the finding of the lung injury threshold, the relationship between the physical components of the air blast wave, and the biological response. Studies have also been conducted to investigate the effect of repeated blast exposures on the injury outcome threshold. This has led to several injury criteria, such as the Bowen curves based on pressure history's characteristics or the Axelsson Chest Wall Velocity Predictor that used measurement from the mammals' chest wall. This article aims at doing a critical literature review of this specific topic.

Experimental mechanical characterization of abdominal organs: liver, kidney & spleen.

Abdominal organs are the most vulnerable body parts during vehicle trauma, leading to high mortality rate due to acute injuries of liver, kidney, spleen and other abdominal organs. Accurate mechanical properties and FE models of these organs are required for simulating the traumas, so that better designing of the accident environment can be done and the organs can be protected from severe damage. Also from biomedical aspect, accurate mechanical properties of organs are required for better designing of surgical tools and virtual surgery environments. In this study porcine liver, kidney and spleen tissues are studied in vitro and hyper-elastic material laws are provided for each. 12 porcine kidneys are used to perform 40 elongation tests on renal capsule and 60 compression tests on renal cortex, 5 porcine livers are used to perform 45 static compression tests on liver parenchyma and 5 porcine spleens are used to carry out 20 compression tests. All the tests are carried out at a static speed of 0.05 mm/s. A comparative analysis of all the results is done with the literature and though the results are of same order of magnitude, a slight dissonance is observed for the renal capsule. It is also observed that the spleen is the least stiff organ in the abdomen whereas the kidney is the stiffest. The results of this study would be essential to develop the FE models of liver, kidney and spleen which can be further used for impact biomechanical and biomedical applications.