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Background: Vascular calcification (VC) is a cardiovascular complication associated with a high mortality rate among patients with diseases such as atherosclerosis and chronic kidney disease. During VC, vascular smooth muscle cells (VSMCs) undergo an osteogenic switch and secrete a heterogeneous population of extracellular vesicles (EVs). Recent studies have shown involvement of EVs in the inflammation and oxidative stress observed in VC. We aimed to decipher the role and mechanism of action of macrophage-derived EVs in the propagation of inflammation and oxidative stress on VSMCs during VC. Methods: The macrophage murine cell line RAW 264.7 treated with lipopolysaccharide (LPS-EK) was used as a cellular model for inflammatory and oxidative stress. EVs secreted by these macrophages were collected by ultracentrifugation and characterized by transmission electron microscopy, cryo-electron microscopy, nanoparticle tracking analysis, and the analysis of acetylcholinesterase activity, as well as that of CD9 and CD81 protein expression by western blotting. These EVs were added to a murine VSMC cell line (MOVAS-1) under calcifying conditions (4 mM Pi—7 or 14 days) and calcification assessed by the o-cresolphthalein calcium assay. EV protein content was analyzed in a proteomic study and EV cytokine content assessed using an MSD multiplex immunoassay. Results: LPS-EK significantly decreased macrophage EV biogenesis. A 24-h treatment of VSMCs with these EVs induced both inflammatory and oxidative responses. LPS-EK-treated macrophage-derived EVs were enriched for pro-inflammatory cytokines and CAD, PAI-1, and Saa3 proteins, three molecules involved in inflammation, oxidative stress, and VC. Under calcifying conditions, these EVs significantly increase the calcification of VSMCs by increasing osteogenic markers and decreasing contractile marker expression. Conclusion: Our results show that EVs derived from LPS-EK–treated-macrophages are able to induce pro-inflammatory and pro-oxidative responses in surrounding cells, such as VSMCs, thus aggravating the VC process.

Background: Infectious gastroenteritis is a risk factor for the development of post-infectious Irritable Bowel Syndrome (PI-IBS). Recent clinical studies reported a higher prevalence of the intestinal parasite Blastocystis in IBS patients. Using a rat model, we investigated the possible association between Blastocystis infection, colonic hypersensitivity (CHS), behavioral disturbances and gut microbiota changes.Methods: Rats were orally infected with Blastocystis subtype 4 (ST4) cysts, isolated from human stool samples. Colonic sensitivity was assessed by colorectal distension and animal behavior with an automatic behavior recognition system (PhenoTyper), the Elevated Plus Maze test and the Forced Swimming tests. Feces were collected at different time points after infection to study microbiota composition by 16 S rRNA amplicon sequencing and for short-chain fatty acid (SFCA) analysis.Results: Blastocystis-infected animals had non-inflammatory CHS with increased serine protease activity. Infection was also associated with anxiety- and depressive-like behaviors. Analysis of fecal microbiota composition showed an increase in bacterial richness associated with altered microbiota composition. These changes included an increase in the relative abundance of Oscillospira and a decrease in Clostridium, which seem to be associated with lower levels of SCFAs in the feces from infected rats.Conclusions: Our findings suggest that experimental infection of rats with Blastocystis mimics IBS symptoms with the establishment of CHS related to microbiota and metabolic shifts.

Zinc (Zn) is an essential cofactor for numerous bacterial proteins and altering Zn availability is an important component of host innate immunity. During infection, adaptation to both Zn deprivation and excess is critical for pathogenic bacteria development. To understand the adaptive responses to Zn availability of Streptococcus agalactiae , a pathogen causing invasive infections of neonates, global transcriptional profiling was conducted. Results highlight that in response to Zn limitation, genes belonging to the AdcR regulon, the master regulator of Zn homeostasis in streptococci, were overexpressed. Through a combination of in silico analysis and experimental validation, new AdcR-regulated targets were identified. Among them, we identified a duplicated ribosomal protein, RpsNb, and an ABC transporter, and examined the role of these genes in bacterial growth under Zn-restricted conditions. Our results indicated that, during Zn restriction, both the RpsNb protein and a potential secondary Zn transporter are important for S. agalactiae adaptation to Zn deficiency. IMPORTANCE Streptococcus agalactiae is a bacterial human pathobiont causing invasive diseases in neonates. Upon infection, S. agalactiae is presented with Zn limitation and excess but the genetic systems that allow bacterial adaptation to these conditions remain largely undefined. A comprehensive analysis of S. agalactiae global transcriptional response to Zn availability shows that this pathogen manages Zn limitation mainly through upregulation of the AdcR regulon. We demonstrate that several AdcR-regulated genes are important for bacterial growth during Zn deficiency, including human biological fluids. Taken together, these findings reveal new mechanisms of S. agalactiae adaptation under conditions of metal deprivation.

Obesity is a risk factor for many diseases, such as type 2 diabetes and cardiovascular diseases. In line with the need for precision medicine, the search for biomarkers reporting the progression of obesity- and diet-associated disorders is urgent. We used NMR to determine the metabolomics profile of key organs (lung, liver, heart, skeletal muscle, kidney, and brain) and serum from male C57Bl/6J mice (5 weeks old) fed for 6, 10, and 14 weeks on a high-fat and high-sucrose diet (HFHSD) vs. a standard diet (STD). We determined metabolite concentrations in the organs at each time point, which allowed us to discriminate age- and diet-related effects as well as the interactions between both, highlighting the need to evaluate the influence of age as a confounding factor on metabolic signatures. Notably, the analysis revealed the influence of time on metabolite concentrations in the STD condition, probably reflecting the juvenile-to-adult transition. Variations impacted the liver and lung metabolites, revealing the strong influence of the HFHS diet on normal metabolism maturation during youth.

Over the past few years, radiopharmaceutical therapy has emerged as a groundbreaking therapeutic modality, taking advantage of the unique properties of radionuclides to deliver molecularly targeted therapy with high precision and transforming the landscape of precision oncology and personalized medicine. Its development reflects decades of advances in nuclear medicine, chemistry, and cancer biology. However, until recently, definitive clinical evidence was lacking to establish it into treatment plans, with few large randomized controlled clinical studies. The last two decades witnessed a paradigm shift, with three successful phase 3 studies which shed light on radiopharmaceutical therapy. This paper offers a brief overview of currently active phase 3 studies to highlight the dynamism and promise of this clinical domain, as well as the large variety of cancers being treated.

Bee populations are facing numerous stressors globally, including environmental pollution by trace metals and metalloids. Understanding whether bees can detect and avoid these pollutants in their food is pivotal, as avoidance abilities may mitigate their exposure to xenobiotics. While these pollutants are known to induce sublethal effects in bees, such as disrupting physiological mechanisms, their potential impacts on locomotive abilities, fat metabolism, and reproductive physiology remain poorly understood. In this study, utilising workers of the buff-tailed bumble bee and two prevalent trace metals, namely cadmium and copper, we aimed to address these knowledge gaps for field-realistic concentrations. Our findings reveal that workers did not reject field-realistic concentrations of cadmium and copper in sucrose solutions. Moreover, they did not reject lethal concentrations of cadmium, although they rejected lethal concentrations of copper. Additionally, we observed no significant effects of field-realistic concentrations of these metals on the walking and flying activities of workers, nor on their fat metabolism and reproductive physiology. Overall, our results suggest that bumble bees may not avoid cadmium and copper at environmental concentrations, but ingestion of these metals in natural settings may not adversely affect locomotive abilities, fat metabolism, or reproductive physiology. However, given the conservative nature of our study, we still recommend future research to employ higher concentrations over longer durations to mimic conditions in heavily polluted areas (i.e., mine surrounding). Furthermore, investigations should ascertain whether field-realistic concentrations of metals exert no impact on bee larvae.

Although originally primarily a system for functional biology, Arabidopsis thaliana has, owing to its broad geographical distribution and adaptation to diverse environments, developed into a powerful model in population genomics. Here we present chromosome-level genome assemblies of 69 accessions from a global species range. We found that genomic colinearity is very conserved, even among geographically and genetically distant accessions. Along chromosome arms, megabase-scale rearrangements are rare and typically present only in a single accession. This indicates that the karyotype is quasi-fixed and that rearrangements in chromosome arms are counter-selected. Centromeric regions display higher structural dynamics, and divergences in core centromeres account for most of the genome size variations. Pan-genome analyses uncovered 32,986 distinct gene families, 60% being present in all accessions and 40% appearing to be dispensable, including 18% private to a single accession, indicating unexplored genic diversity. These 69 new Arabidopsis thaliana genome assemblies will empower future genetic research.

Parascaris sp. is the only ascarid parasitic nematode in equids and one of the most threatening infectious organisms in horses. Only a limited number of compounds are available for treatment of horse helminthiasis, and Parascaris sp. worms have developed resistance to the three major anthelmintic families. In order to overcome the appearance of resistance, there is an urgent need for new therapeutic strategies. The active ingredients of herbal essential oils are potentially effective antiparasitic drugs. Carvacrol is one of the principal chemicals of essential oil from Origanum, Thymus, Coridothymus, Thymbra, Satureja and Lippia herbs. However, the antiparasitic mode of action of carvacrol is poorly understood. Here, the objective of the work was to characterize the activity of carvacrol on Parascaris sp. nicotinic acetylcholine receptor (nAChR) function both in vivo with the use of worm neuromuscular flap preparations and in vitro with two-electrode voltage-clamp electrophysiology on nAChRs expressed in Xenopus oocytes. We developed a neuromuscular contraction assay for Parascaris body flaps and obtained acetylcholine concentration-dependent contraction responses. Strikingly, we observed that 300 µM carvacrol fully and irreversibly abolished Parascaris sp. muscle contractions elicited by acetylcholine. Similarly, carvacrol antagonized acetylcholine-induced currents from both the nicotine-sensitive AChR and the morantel-sensitive AChR subtypes. Thus, we show for the first time that body muscle flap preparation is a tractable approach to investigating the pharmacology of Parascaris sp. neuromuscular system. Our results suggest an intriguing mode of action for carvacrol, being a potent antagonist of muscle nAChRs of Parascaris sp. worms, which may account for its antiparasitic potency.

Pesticide resistance poses a critical threat to agriculture, human health and biodiversity. Mixtures of fungicides are recommended and widely used in resistance management strategies. However, the components of the efficiency of such mixtures remain unclear. We performed an experimental evolutionary study on the fungal pathogen Z. tritici to determine how mixtures managed resistance. We compared the effect of the continuous use of single active ingredients to that of mixtures, at the minimal dose providing full control of the disease, which we refer to as the “efficient” dose. We found that the performance of efficient-dose mixtures against an initially susceptible population depended strongly on the components of the mixture. Such mixtures were either as durable as the best mixture component used alone, or worse than all components used alone. Moreover, efficient dose mixture regimes probably select for generalist resistance profiles as a result of the combination of selection pressures exerted by the various components and their lower doses. Our results indicate that mixtures should not be considered a universal strategy. Experimental evaluations of specificities for the pathogens targeted, their interactions with fungicides and the interactions between fungicides are crucial for the design of sustainable resistance management strategies.

The Bacillus cereus sensu lato group consists of several closely related species, including B. anthracis, B. cereus sensu stricto, and B. thuringiensis. Spores of these pathogenic bacteria are commonly found in the soil but evidence suggests that they are unable to grow in such a natural environment in the absence of nutrient input. Amoebas have been reported to be an amplifier for several species of pathogenic bacteria and their potential involvement to explain the large amount of B. thuringiensis and B. cereus spores in soil has been frequently proposed. Here, we studied the fate of Bacillus and amoebas when cultured together. We show that the virulence factors produced by B. thuringiensis and B. cereus do not affect the amoeba Acanthamoeba castellanii, which, on the contrary, can phagocytose and effectively digest vegetative Bacillus cells to grow and prevent the formation of cysts. Bacterial spores can germinate in the amoeba environment and the vegetative cells can then form chains or aggregates that appear to be less efficiently phagocyted by the amoeba. The use of transcriptional fusions between fluorescent reporter genes and stationary phase- and sporulation-specific promoters showed that the sporulation process occurs more efficiently in the presence of amoebas than in their absence. Moreover, our results showed the amoeba environment to promote spore germination and allow the bacteria to complete their developmental cycle. Overall, this study suggests that the amoeba-Bacillus interaction creates a virtuous circle in which each protagonist helps the other to develop.