Advances in pulmonary hypertension diagnosis and risk stratification.

editorial reviewedPulmonary hypertension (PH) is a common clinical condition linked to chronic cardiopulmonary illnesses. It must be distinguished from pulmonary arterial hypertension (PAH), a rare disease characterized by a specific involvement of the pulmonary arterial bed. An early diagnosis and accurate classification by a multidisciplinary team are necessary for a multimodal and individualized therapy approach. This article aims to provide a summary of the most recent ESC/ERS recommendations published in 2022.L’hypertension pulmonaire (HTP) est une entité clinique fréquemment retrouvée chez les patients atteints d’affections cardio-pulmonaires chroniques. Elle est à différentier de l’hypertension artérielle pulmonaire (HTAP) qui est, quant à elle, une maladie rare caractérisée par une atteinte spécifique du lit artériel pulmonaire. Une identification précoce et une classification correcte, en équipe pluridisciplinaire, sont primordiales pour une prise en charge thérapeutique multimodale et personnalisée. Cet article a pour but de résumer, de façon pratique, les dernières recommandations des sociétés européennes de cardiologie (ESC) et de pneumologie (ERS) publiées en 2022

Response variability to multiple stressors in gudgeons (Gobio occitaniae)

Dans le milieu naturel, les poissons sont exposés à une multitude de facteurs de stress biotiques et abiotiques, mais leurs interactions sont encore mal connues. La hausse des températures et la contamination par les éléments trace métalliques (ETMs) sont des sources importantes de stress pour les poissons. Les parasites ont également des effets sur la physiologie de leur hôte, mais sont rarement considérés en tant que facteurs de stress. Ces trois facteurs de stress agissent via des voies physiologiques communes (immunité, stress oxydant, métabolisme) et sont donc susceptibles d'interagir de manière complexe (e.g. antagonisme, synergisme). De plus, il existe souvent une grande variabilité des réponses entre échelles biologiques, des molécules aux populations. Notamment, l'historique d'exposition des populations de poisson dans leur milieu naturel pourrait conditionner leur capacité de réponse au stress. La prise en compte de ces deux niveaux de variabilité (i.e. interactions entre stress et entre échelles d'organisation) représente donc un verrou scientifique majeur pour mieux comprendre les effets des stress multiples sur les populations de poissons d'eau douce. Cette thèse vise donc à évaluer les effets combinés de facteurs de stress abiotique (i.e. température, ETMs) et biotique (i.e. challenge immunitaire provoqué par le parasitisme) sur les réponses des poissons d'eau douce via une approche multi-échelles. Afin de remplir ces objectifs, le Goujon (Gobio occitaniae) a été utilisé comme espèce modèle dans le cadre de trois approches méthodologiques : (i) une approche transversale de terrain visant à comparer l'état de santé de population de poissons le long des gradients de stress ; puis, (ii) des expérimentations en conditions contrôlées afin de distinguer les effets des différents facteurs de stress simples dans différentes populations sauvages ; enfin (iii) une expérience de translocation réciproque (i.e. encagement sur le terrain) entre sites contaminés et peu contaminés afin de tester l'adaptation locale des populations. Les résultats montrent que les stress simples ont des effets importants aux échelles biologiques fines et induisent la mise en place de stratégies métaboliques de compensation : les poissons investissent dans les défenses immunitaires et antioxydantes, avec une réduction des réserves énergétiques. De plus, les ajustements comportementaux (i.e. activité de nage, recherche de nourriture) sont particulièrement importants sous stress simples, et permettent d'ajuster l'acquisition d'énergie ce qui limite les effets sur la survie et la croissance. Au contraire, les stress multiples ont peu d'effets aux échelles moléculaires et cellulaires, mais provoquent des réponses complexes à l'échelle individuelle, ce qui se traduit par des effets antagonistes sur le comportement et des effets négatifs sur la survie et la croissance. Ces résultats suggèrent que sous stress multiples, les capacités de réponse des poissons pourraient être dépassées, menant ainsi à une stratégie de conservation, avec des effets délétères sur la fitness. Cependant, les réponses observées étaient fortement variables selon la population considérée. [...]Aquatic ecosystems are increasingly exposed to multiple stressors. Among them, temperature increase and contamination by trace metal elements are major stressors for freshwater fish populations. In addition, parasites and their associated immune challenges can cause a wide range of responses in fish populations, but they are still rarely considered as biotic stressors. These three stressors trigger similar physiological pathways (i.e. immunity, oxidative stress and metabolism). Hence, they are likely to interact strongly but their combined effects (i.e. antagonism and synergism) are still poorly documented, thereby hindering our ability to predict the responses of wild populations to multiple stressors under global changes. In addition, responses to stressors could vary according to the level of organisation considered (i.e molecules, cells, individuals, populations). In particular, different populations could have different sensitivity to stressors depending on their past exposure in the wild. Thus it is essential to incorporate these levels of variability to better understand and predict the effects of multiple stressors in wild fish populations. This PhD project aimed at assessing the effects of a multiple abiotic (i.e. temperature, trace metal contamination) and biotic (i.e. immune challenge) stressors across biological levels of organisation, using the gudgeon fish (Gobio occitaniae) as a model species. First, I used a cross-sectional field study in 16 wild populations to compare fish health along stress gradients. Then, I used experimental approaches under controlled conditions to disentangle the role of each single and multiple stressors across levels of organisation in different fish populations. Finally, I used reciprocal translocation experiments between polluted vs. unpolluted rivers to test for local adaptation in response to multiple stressors. Taken together, results show that single stressors affect mostly the molecular and cellular levels, in accordance with a compensatory strategy. Indeed, costly physiological defences (immunity, anti-oxidant responses) were set up and behavioural adjustments (i.e. changes in activity and foraging) enable fish to increase energy acquisition and respond adequately to single stressors, with limited deleterious effects on survival and growth. On the contrary, multiple stressors affected mostly the individual level, in accordance with a conservation metabolic strategy. Indeed, multiple stressors lead to complex antagonistic effects between stressors (i.e. antagonistic inhibition of behavioural responses), potentially due to the high energy demand incurred, resulting in deleterious effects on survival or growth. This suggests that physiological and behavioural responses might be exceeded under multiple stressors with deleterious consequences on fitness, thereby raising concerns about the effects of multiple global changes on wild populations. [...

Variabilité de réponse aux stress multiples chez le goujon (Gobio occitaniae)

Aquatic ecosystems are increasingly exposed to multiple stressors. Among them, temperature increase and contamination by trace metal elements are major stressors for freshwater fish populations. In addition, parasites and their associated immune challenges can cause a wide range of responses in fish populations, but they are still rarely considered as biotic stressors. These three stressors trigger similar physiological pathways (i.e. immunity, oxidative stress and metabolism). Hence, they are likely to interact strongly but their combined effects (i.e. antagonism and synergism) are still poorly documented, thereby hindering our ability to predict the responses of wild populations to multiple stressors under global changes. In addition, responses to stressors could vary according to the level of organisation considered (i.e molecules, cells, individuals, populations). In particular, different populations could have different sensitivity to stressors depending on their past exposure in the wild. Thus it is essential to incorporate these levels of variability to better understand and predict the effects of multiple stressors in wild fish populations. This PhD project aimed at assessing the effects of a multiple abiotic (i.e. temperature, trace metal contamination) and biotic (i.e. immune challenge) stressors across biological levels of organisation, using the gudgeon fish (Gobio occitaniae) as a model species. First, I used a cross-sectional field study in 16 wild populations to compare fish health along stress gradients. Then, I used experimental approaches under controlled conditions to disentangle the role of each single and multiple stressors across levels of organisation in different fish populations. Finally, I used reciprocal translocation experiments between polluted vs. unpolluted rivers to test for local adaptation in response to multiple stressors. Taken together, results show that single stressors affect mostly the molecular and cellular levels, in accordance with a compensatory strategy. Indeed, costly physiological defences (immunity, anti-oxidant responses) were set up and behavioural adjustments (i.e. changes in activity and foraging) enable fish to increase energy acquisition and respond adequately to single stressors, with limited deleterious effects on survival and growth. On the contrary, multiple stressors affected mostly the individual level, in accordance with a conservation metabolic strategy. Indeed, multiple stressors lead to complex antagonistic effects between stressors (i.e. antagonistic inhibition of behavioural responses), potentially due to the high energy demand incurred, resulting in deleterious effects on survival or growth. This suggests that physiological and behavioural responses might be exceeded under multiple stressors with deleterious consequences on fitness, thereby raising concerns about the effects of multiple global changes on wild populations. [...]Dans le milieu naturel, les poissons sont exposés à une multitude de facteurs de stress biotiques et abiotiques, mais leurs interactions sont encore mal connues. La hausse des températures et la contamination par les éléments trace métalliques (ETMs) sont des sources importantes de stress pour les poissons. Les parasites ont également des effets sur la physiologie de leur hôte, mais sont rarement considérés en tant que facteurs de stress. Ces trois facteurs de stress agissent via des voies physiologiques communes (immunité, stress oxydant, métabolisme) et sont donc susceptibles d'interagir de manière complexe (e.g. antagonisme, synergisme). De plus, il existe souvent une grande variabilité des réponses entre échelles biologiques, des molécules aux populations. Notamment, l'historique d'exposition des populations de poisson dans leur milieu naturel pourrait conditionner leur capacité de réponse au stress. La prise en compte de ces deux niveaux de variabilité (i.e. interactions entre stress et entre échelles d'organisation) représente donc un verrou scientifique majeur pour mieux comprendre les effets des stress multiples sur les populations de poissons d'eau douce. Cette thèse vise donc à évaluer les effets combinés de facteurs de stress abiotique (i.e. température, ETMs) et biotique (i.e. challenge immunitaire provoqué par le parasitisme) sur les réponses des poissons d'eau douce via une approche multi-échelles. Afin de remplir ces objectifs, le Goujon (Gobio occitaniae) a été utilisé comme espèce modèle dans le cadre de trois approches méthodologiques : (i) une approche transversale de terrain visant à comparer l'état de santé de population de poissons le long des gradients de stress ; puis, (ii) des expérimentations en conditions contrôlées afin de distinguer les effets des différents facteurs de stress simples dans différentes populations sauvages ; enfin (iii) une expérience de translocation réciproque (i.e. encagement sur le terrain) entre sites contaminés et peu contaminés afin de tester l'adaptation locale des populations. Les résultats montrent que les stress simples ont des effets importants aux échelles biologiques fines et induisent la mise en place de stratégies métaboliques de compensation : les poissons investissent dans les défenses immunitaires et antioxydantes, avec une réduction des réserves énergétiques. De plus, les ajustements comportementaux (i.e. activité de nage, recherche de nourriture) sont particulièrement importants sous stress simples, et permettent d'ajuster l'acquisition d'énergie ce qui limite les effets sur la survie et la croissance. Au contraire, les stress multiples ont peu d'effets aux échelles moléculaires et cellulaires, mais provoquent des réponses complexes à l'échelle individuelle, ce qui se traduit par des effets antagonistes sur le comportement et des effets négatifs sur la survie et la croissance. Ces résultats suggèrent que sous stress multiples, les capacités de réponse des poissons pourraient être dépassées, menant ainsi à une stratégie de conservation, avec des effets délétères sur la fitness. Cependant, les réponses observées étaient fortement variables selon la population considérée. [...

Compilation of Inductive Definitions to PCE form in Separation Logic

The predicate definitions in Separation Logic (SL) play an important role: they capture a large spectrum of unbounded heap shapes due to their inductiveness. This expressiveness power comes with a limitation: the entailment problem is undecidable if predicates have general inductive definitions (ID). Iosif et al. proposed syntactic and semantic conditions, called PCE, on the ID of predicates to ensure the decidability of the entailment problem. We provide a (possibly nonterminating) algorithm to transform arbitrary ID into equivalent PCE definitions when possible.This algorithm is coded in OCaml using the Cyclist framework. The benchmarks are included

Encaged Chironomus riparius larvae in assessment of trace metal bioavailability and transfer in a landfill leachate collection pond

International audienceHousehold wastes may constitute a vector of environmental contamination when buried, in particular through degradation and production of leachates containing significant trace metal (TM) concentrations that may constitute a serious risk to biota. The objectives of this study were to assess the bioavailability and transfer potential of various TMs present in water and sediments in a reservoir receiving landfill leachates. An active biomonitoring approach was adopted consisting of exposing naive laboratory organisms in cages deployed in the field. Aquatic insects such as Chironomus riparius larvae are good candidates since they represent key organisms in the trophic functioning of aquatic ecosystems. The results show that water, suspended particles, and sediments were significantly contaminated by various TMs (As, Cd, Cu, Ni, Pb, and Zn). Their contribution to the transfer of TMs depends, however, on the specific element considered, e.g., Cd in sediments or Pb in both suspended particles and sediments. The internal fate of TMs was investigated according to their fractionation between an insoluble and a cytosolic fraction. This approach revealed different detoxification strategies capable of preventing the induction of deleterious effects at the individual scale. However, the accumulation of several TMs in C. riparius larvae tissues may also represent a significant load potentially transferable to higher trophic level

Encaged Chironomus riparius larvae in assessment of trace metal bioavailability and transfer in a landfill leachate collection pond

International audienceHousehold wastes may constitute a vector of environmental contamination when buried, in particular through degradation and production of leachates containing significant trace metal (TM) concentrations that may constitute a serious risk to biota. The objectives of this study were to assess the bioavailability and transfer potential of various TMs present in water and sediments in a reservoir receiving landfill leachates. An active biomonitoring approach was adopted consisting of exposing naive laboratory organisms in cages deployed in the field. Aquatic insects such as Chironomus riparius larvae are good candidates since they represent key organisms in the trophic functioning of aquatic ecosystems. The results show that water, suspended particles, and sediments were significantly contaminated by various TMs (As, Cd, Cu, Ni, Pb, and Zn). Their contribution to the transfer of TMs depends, however, on the specific element considered, e.g., Cd in sediments or Pb in both suspended particles and sediments. The internal fate of TMs was investigated according to their fractionation between an insoluble and a cytosolic fraction. This approach revealed different detoxification strategies capable of preventing the induction of deleterious effects at the individual scale. However, the accumulation of several TMs in C. riparius larvae tissues may also represent a significant load potentially transferable to higher trophic level

Chapitre VII. Les larves de Chironomidae dans les approches écotoxicologiques d’évaluation de la qualité des milieux aquatiques

1. Introduction L’industrialisation, l’urbanisation, l’agriculture intensive et leurs cortèges de produits chimiques (éléments traces métalliques, hydrocarbures, pesticides, médicaments, etc.) ont accru la contamination des eaux continentales de surface et souterraines de manière chronique ou aiguë. Aujourd’hui, plus de 67 millions de substances chimiques sont connues dont environ 100 000 sont considérées d’utilisation courante. Véhiculées par les pluies, les eaux de lessivage des sols, rejet..

High Impact: The Role of Promiscuous Binding Sites in Polypharmacology

International audienceThe literature focuses on drug promiscuity, which is a drug's ability to bind to several targets, because it plays an essential role in polypharmacology. However, little work has been completed regarding binding site promiscuity, even though its properties are now recognized among the key factors that impact drug promiscuity. Here, we quantified and characterized the promiscuity of druggable binding sites from protein-ligand complexes in the high quality Mother Of All Databases while using statistical methods. Most of the sites (80%) exhibited promiscuity, irrespective of the protein class. Nearly half were highly promiscuous and able to interact with various types of ligands. The corresponding pockets were rather large and hydrophobic, with high sulfur atom and aliphatic residue frequencies, but few side chain atoms. Consequently, their interacting ligands can be large, rigid, and weakly hydrophilic. The selective sites that interacted with one ligand type presented less favorable pocket properties for establishing ligand contacts. Thus, their ligands were highly adaptable, small, and hydrophilic. In the dataset, the promiscuity of the site rather than the drug mainly explains the multiple interactions between the drug and target, as most ligand types are dedicated to one site. This underlines the essential contribution of binding site promiscuity to drug promiscuity between different protein classes

Nano-litter from cigarette butts: Environmental implications and urgent consideration

International audienceCigarette butts (CGB) are equivalent to plastic litter in terms of number of pieces released directly into the environment. Due to their small size and social use, CGB are commonly found in natural systems, and several questions have been raised concerning the contaminants that are released with CGB, including metals, organic species, and nanoparticles. The aim of the present study is to investigate the release of nanoscale particles from CGB by leaching with rainwater. After seven days of passive stirring of both smoked and unsmoked CGB in synthetic rainwater, the solutions were treated and analyzed by specific nano-analytical methods. Our results demonstrate the release of 4.12 ± 0.24% (w/CGB) organic carbon in the range of 10 nm up to 400 nm and with a z-average diameter of 202.4 ± 74.1 nm. The fractal dimension (Df) of the nanoscale particles ranges from 1.14 to 1.52 and suggests a soot (carbon)-based composition. The analysis of some metallic species (As, Pb, Cd, Cu, Ni, Cr, Co, Al, Mn, Zn, and Fe) shows that these species are essentially attached to the nanoscale particles per gram of carbon released. By considering the diffusion of the nanomaterials into different environmental compartments, our results suggest a new emerging and global contamination of the environment by cigarette butts, comparable to plastic litter, which urgently needs to be considered