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The use of sulfur (S) in polluted soils can reduce metal(loid) toxicity and enhance phytoremediation effectiveness. Here we studied the response of barley plants to As in soil amended with sulfate or elemental sulfur throughout the growing cycle. A greenhouse experiment was carried out using 4-L pots filled with clay-loam soil spiked with 60 mg kg−1 As (Na2HAsO4·7H2O). Two chemical forms of sulfur (elemental sulfur (S0) or sulfate (CaSO4·2H2O)) were applied at a dose of 1 and 3 Mg ha−1, respectively, and two previously seeded barley plants were transplanted in each pot, using eight pots per treatment. At the end of the growing cycle, the biomass, nutrients, and metal(loid) content, as well as several physiological and biochemical parameters of the plants were analyzed. Moreover, the effect of the treatments on soil characteristics was also evaluated, including soil pore water. The treatment with sulfur promoted the growth of barley plants through their vegetative cycle, enhancing photosynthesis, although biomass did not significantly increase. Both sources of S promoted the accumulation of As in the root, thereby limiting its translocation to the aerial part of the plant, sulfate being more effective (an increase of 300%) than elemental S (an increase of 82%). The addition of S decreased soil pH. Furthermore, both treatments, but particularly sulfate, increased soluble sulfate and stimulated soil biological properties. In conclusion, the application of sulfate to As-polluted soil can enhance As phytostabilization by barley plants while simultaneously improving the biological properties of the soil.

The global rise in population highlights the need for a greater production of quality food. In this regard, intensification of the agricultural sector and an increased use of fertilizers are key. Phosphorus (P), together with nitrogen (N) and potassium (K), is one of the essential elements for plant growth. Modern agriculture is dependent on P derived from phosphate rock, which is a non-renewable resource whose high-quality reserves are becoming increasingly scarce and expensive. In this context, alternative sources of P and the development of new recovery technologies are required. Such technologies are increasingly focused on struvite (MgNH4PO4·6H2O) (STR) from urban or livestock wastewater, whose accessibility is guaranteed. In this study, the medium–long term efficiency of STR from urban wastewater as a fertilizer was evaluated in three successive lettuce crops using a 25 kg pot trial. To this end, STR application was compared with the use of other conventional P fertilizers (NPK, monoammonium phosphate (MAP), and single superphosphate (SSP)) at a dose of 100 kg P ha−1. Crop biomass yield, P uptake, and the nutritional quality of the plants were determined. Moreover, the effect of STR on soil quality was examined using several soil biological indicators. In general, the STR treatment yielded similar biomass results to those obtained with NPK in the three successive lettuce crops. MAP and SSP treatments produced higher biomass in the first crop, but these values diminished in the next two. In relation to the effect on soil, STR treatment maintained the concentration of available P during the three growing cycles and enhanced microbial activity and functional diversity. On the basis of our findings, STR emerges as a sustainable P-fertilization strategy for lettuce production.

Hutchinson–Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by progerin, a mutant lamin A variant. HGPS patients display accelerated aging and die prematurely, typically from atherosclerosis complications. Recently, we demonstrated that progerin‐driven vascular smooth muscle cell (VSMC) loss accelerates atherosclerosis leading to premature death in apolipoprotein E‐deficient mice. However, the molecular mechanism underlying this process remains unknown. Using a transcriptomic approach, we identify here endoplasmic reticulum stress (ER) and the unfolded protein responses as drivers of VSMC death in two mouse models of HGPS exhibiting ubiquitous and VSMC‐specific progerin expression. This stress pathway was also activated in HGPS patient‐derived cells. Targeting ER stress response with a chemical chaperone delayed medial VSMC loss and inhibited atherosclerosis in both progeria models, and extended lifespan in the VSMC‐specific model. Our results identify a mechanism underlying cardiovascular disease in HGPS that could be targeted in patients. Moreover, these findings may help to understand other vascular diseases associated with VSMC death, and provide insight into aging‐dependent vascular damage related to accumulation of unprocessed toxic forms of lamin A. Synopsis In mouse models of Hutchinson–Gilford progeria syndrome (HGPS) featuring ubiquitous or vascular smooth muscle cell (VSMC)‐specific progerin expression, RNA sequencing of medial aortas identified a new pathway involved in the etiopathology of the disease. Activation of endoplasmic reticulum (ER) stress and of the unfolded protein response (UPR) was observed prior signs of vascular disease in VSMC‐rich aortic media from mouse models of HGPS. ER stress and the UPR were activated in cultured cells derived from HGPS patients and in some organs of the ubiquitous HGPS mouse model. VSMC loss was ameliorated and atherosclerosis was prevented in the HGPS mouse models upon tauroursodeoxycholic acid (TUDCA) treatment. VSMC‐specific progeroid mice survival was prolonged by TUDCA, demonstrating its potential as a treatment for vascular disease in HGPS. Graphical Abstract In mouse models of Hutchinson–Gilford progeria syndrome (HGPS) featuring ubiquitous or vascular smooth muscle cell (VSMC)‐specific progerin expression, RNA sequencing of medial aortas identified a new pathway involved in the etiopathology of the disease.

Macrophages (Mφs) produce factors that participate in cardiac repair and remodeling after myocardial infarction (MI); however, how these factors crosstalk with other cell types mediating repair is not fully understood. Here we demonstrated that cardiac Mφs increased the expression of Mmp14 (MT1-MMP) 7 days post-MI. We selectively inactivated the Mmp14 gene in Mφs using a genetic strategy ( Mmp14 f/f : Lyz2 -Cre). This conditional KO (MAC-Mmp14 KO) resulted in attenuated post-MI cardiac dysfunction, reduced fibrosis, and preserved cardiac capillary network. Mechanistically, we showed that MT1-MMP activates latent TGFβ1 in Mφs, leading to paracrine SMAD2-mediated signaling in endothelial cells (ECs) and endothelial-to-mesenchymal transition (EndMT). Post-MI MAC-Mmp14 KO hearts contained fewer cells undergoing EndMT than their wild-type counterparts, and Mmp14 -deficient Mφs showed a reduced ability to induce EndMT in co-cultures with ECs. Our results indicate the contribution of EndMT to cardiac fibrosis and adverse remodeling post-MI and identify Mφ MT1-MMP as a key regulator of this process.

Dormant or slow-cycling tumor cells can form a residual chemoresistant reservoir responsible for relapse in patients, years after curative surgery and adjuvant therapy. We have adapted the pulse-chase expression of H2BeGFP for labeling and isolating slow-cycling cancer cells (SCCCs). SCCCs showed cancer initiation potential and enhanced chemoresistance. Cells at this slow-cycling status presented a distinctive nongenetic and cell-autonomous gene expression profile shared across different tumor types. We identified TET2 epigenetic enzyme as a key factor controlling SCCC numbers, survival, and tumor recurrence. 5-Hydroxymethylcytosine (5hmC), generated by TET2 enzymatic activity, labeled the SCCC genome in carcinomas and was a predictive biomarker of relapse and survival in cancer patients. We have shown the enhanced chemoresistance of SCCCs and revealed 5hmC as a biomarker for their clinical identification and TET2 as a potential drug target for SCCC elimination that could extend patients' survival.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare disease caused by the expression of progerin, an aberrant protein produced by a point mutation in the LMNA gene. HGPS patients show accelerated aging and die prematurely mainly from complications of atherosclerosis such as myocardial infarction, heart failure, or stroke. However, the mechanisms underlying HGPS vascular pathology remain ill-defined. We used single-cell RNA sequencing to characterize the aorta in progerin-expressing Lmna G609G/G609G mice and wild-type controls, with a special focus on endothelial cells (ECs). HGPS ECs showed gene expression changes associated with extracellular matrix alterations, increased leukocyte extravasation, and activation of the yes-associated protein 1/transcriptional activator with PDZ-binding domain (YAP/TAZ) mechanosensing pathway, all validated by different techniques. Atomic force microscopy experiments demonstrated stiffer subendothelial extracellular matrix in progeroid aortae, and ultrasound assessment of live HGPS mice revealed disturbed aortic blood flow, both key inducers of the YAP/TAZ pathway in ECs. YAP/TAZ inhibition with verteporfin reduced leukocyte accumulation in the aortic intimal layer and decreased atherosclerosis burden in progeroid mice. Our findings identify endothelial YAP/TAZ signaling as a key mechanism of HGPS vascular disease and open a new avenue for the development of YAP/TAZ-targeting drugs to ameliorate progerin-induced atherosclerosis.

Pathological angiogenesis contributes to cancer progression and chronic inflammatory diseases. In inflammatory bowel disease, the microvasculature expands by intussusceptive angiogenesis (IA), a poorly characterized mechanism involving increased blood flow and splitting of pre‐existing capillaries. In this report, mice lacking the protease MT1‐MMP in endothelial cells (MT1 iΔ EC ) presented limited IA in the capillary plexus of the colon mucosa assessed by 3D imaging during 1% DSS‐induced colitis. This resulted in better tissue perfusion, preserved intestinal morphology, and milder disease activity index. Combined in vivo intravital microscopy and lentiviral rescue experiments with in vitro cell culture demonstrated that MT1‐MMP activity in endothelial cells is required for vasodilation and IA, as well as for nitric oxide production via binding of the C‐terminal fragment of MT1‐MMP substrate thrombospondin‐1 (TSP1) to CD47/αvβ3 integrin. Moreover, TSP1 levels were significantly higher in serum from IBD patients and in vivo administration of an anti‐MT1‐MMP inhibitory antibody or a nonamer peptide spanning the αvβ3 integrin binding site in TSP1 reduced IA during mouse colitis. Our results identify MT1‐MMP as a new actor in inflammatory IA and a promising therapeutic target for inflammatory bowel disease. Synopsis Inflammatory bowel disease comprising ulcerative colitis and Crohn's disease does not have a universal efficient therapy. This study identifies the molecular axis MT1‐MMP/thrombospondin‐1/αvβ3 integrin/nitric oxide as a target to reduce inflammatory intussusceptive angiogenesis and improve colitis. Early expansion of the capillaries in the intestinal mucosa during colitis was caused by intussusceptive/splitting angiogenesis (IA). Deletion of the protease MT1‐MMP from endothelial cells reduced IA and colitis severity. Thrombospondin‐1 (TSP1) processing by MT1‐MMP promoted nitric oxide production, vasodilation and IA. High levels of TSP1 were found in sera from patients suffering low active IBD. Targeting MT1‐MMP/TSP1/αvβ3 integrin/nitric oxide pathway by monoclonal antibodies or minipump‐delivered peptides decreased IA and ameliorates colitis. Graphical Abstract Inflammatory bowel disease comprising ulcerative colitis and Crohn's disease does not have a universal efficient therapy. This study identifies the molecular axis MT1‐MMP/thrombospondin‐1/αvβ3 integrin/nitric oxide as a target to reduce inflammatory intussusceptive angiogenesis and improve colitis.

The retinoid X receptor α (RXRα) plays a central role in the regulation of many intracellular receptor signaling pathways and can mediate ligand-dependent transcription by forming homodimers or heterodimers with other nuclear receptors. Although several members of the nuclear hormone receptor superfamily have emerged as important regulators of macrophage gene expression, the existence in vivo of an RXR signaling pathway in macrophages has not been established. Here, we provide evidence that RXRα regulates the transcription of the chemokines Cd6 and Cd9 in macrophages independently of heterodimeric partners. Mice lacking RXRα in myeloid cells exhibit reduced levels of CCL6 and CCL9, impaired recruitment of leukocytes to sites of inflammation, and lower susceptibility to sepsis. These studies demonstrate that macrophage RXRα plays key roles in the regulation of innate immunity and represents a potential target for immunotherapy of sepsis.

PurposeThe effect of organic matter on the As bioavailability in soils and thus on phytoremediation processes is still controversial. The objective of the present study was to evaluate the combined effect of compost and microorganisms from rhizosphere on the tolerance of barley and wheat plants to soil polluted with different concentrations of As for the application on phytoremediation strategies.Materials and methodsA greenhouse experiment was performed using soil artificially contaminated with As at two doses. A compost obtained from sewage sludge composted with pruning waste was used (40 t/ha) as amendment. Plants were grown until the end of their growing cycle. Arsenic uptake and plant physiological and biochemical parameters as well as As availability and physicochemical properties in soil samples were analyzed. The impact of compost addition on the structure and diversity of the microbial communities of the rhizosphere was also evaluated using PCR-DGGE.Results and discussionCompost application induced a different behavior in both species. Compared to wheat and irrespective of As doses, in compost amended soils, barley plants showed an enhanced As translocation to the aerial part. The different bacterial communities structure found for each species, according to the PCR-DGGE cluster analysis, suggested that specific rhizobacteria of barley may have increased As bioavailability, and would therefore enhance its translocation to aerial parts.ConclusionsBoth species could be used for phytoremediation proposes of As-polluted soils, and specifically, barley would be an interesting option for phytoextraction due to its higher biomass and high As translocation when compost is applied to As-polluted soil.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder for which no cure exists. The disease is characterized by premature aging and inevitable death in adolescence due to cardiovascular complications. Most HGPS patients carry a heterozygous de novo LMNA c.1824C > T mutation, which provokes the expression of a dominant-negative mutant protein called progerin. Therapies proven effective in HGPS-like mouse models have yielded only modest benefit in HGPS clinical trials. To overcome the gap between HGPS mouse models and patients, we have generated by CRISPR-Cas9 gene editing the first large animal model for HGPS, a knockin heterozygous LMNA c.1824C > T Yucatan minipig. Like HGPS patients, HGPS minipigs endogenously co-express progerin and normal lamin A/C, and exhibit severe growth retardation, lipodystrophy, skin and bone alterations, cardiovascular disease, and die around puberty. Remarkably, the HGPS minipigs recapitulate critical cardiovascular alterations seen in patients, such as left ventricular diastolic dysfunction, altered cardiac electrical activity, and loss of vascular smooth muscle cells. Our analysis also revealed reduced myocardial perfusion due to microvascular damage and myocardial interstitial fibrosis, previously undescribed readouts potentially useful for monitoring disease progression in patients. The HGPS minipigs provide an appropriate preclinical model in which to test human-size interventional devices and optimize candidate therapies before advancing to clinical trials, thus accelerating the development of effective applications for HGPS patients.