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Bile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs) did not affect the expression of BA-related peroxisomal enzymes. In contrast, hepatocyte nuclear factor 4α (HNF4α) inhibition down-regulated acyl-CoA oxidase 2 (ACOX2). ACOX2 was repressed by fibroblast growth factor 19 (FGF19), which was prevented by extracellular signal-regulated kinase (ERK) pathway inhibition. These changes were paralleled by altered BA synthesis (HPLC-MS/MS). Cytokines able to down-regulate cholesterol-7α-hydroxylase (CYP7A1) had little effect on peroxisomal enzymes involved in BA synthesis except for ACOX2 and bile acid-CoA:amino acid N-acyltransferase (BAAT), which were down-regulated, mainly by oncostatin M (OSM). This effect was prevented by Janus kinase (JAK) inhibition, which restored BA side chain shortening and conjugation. The binding of OSM to the extracellular matrix accounted for a persistent effect after culture medium replacement. In silico analysis of four databases (n = 201) and a validation cohort (n = 90) revealed an inverse relationship between liver inflammation and ACOX2/BAAT expression which was associated with changes in HNF4α levels. In conclusion, BA side chain shortening and conjugation are inhibited by inflammatory effectors. However, other mechanisms involved in BA homeostasis counterbalance any significant impact on the serum BA profile. [ABSTRACT FROM AUTHOR]

Environmental requirements for seed germination can operate as an important ffilter in determining the regeneration niche and ultimately the habitat preference of many plant species. We hypothesize that morphological and morphophysiological seed dormancy may play a major role in habitat selection, because underdeveloped embryos responsible for those dormancy types usually require strict species-specific environmental conditions to grow and to overcome dormancy, imposing marked constraints to recruitment and thus to species distribution. We analyzed the influence of temperature and light on embryo growth and seed germination, as well as germination phenology in three Lonicera (Caprifoliaceae) species. Lonicera xylosteum L. seeds had morphological dormancy. Those of Lonicera etrusca Santi had unusual within-species dormancy variability, with a fraction being able to show both morphological and morphophysiological dormancy. Seeds of Lonicera arborea had deep complex morphophysiological dormancy. The close correspondence between the environmental conditions that each Lonicera species requires to break seed dormancy and their altitudinal range suggests that morphological and morphophysiological dormancies act as important ffilters in determining the regeneration niches of species, probably because such dormancy mechanisms impose markedly specific environmental requirements during the earlier stages of recruitment. Key words: altitudinal gradient, dormancy break, morphological seed dormancy, morphophysiological seed dormancy, regeneration niche, seed-germination phenology. Les besoins environnementaux pour la germination des graines peut constituer un filtre important dans la determination des niches de regeneration et ultimement de l'habitat prefere de plusieurs especes de plantes. Les auteurs ont formule l'hypothese que la dormance morphologique et morphophysiologique des graines peut jouer un role majeur dans la selection de l'habitat, puisque les embryons incompletement developpes responsables pour ces types de dormance, imposent des contraintes prononcees au recrutement et consequemment a la distribution des especes. Les auteurs ont analyse l'influence de la temperature et de la lumiere sur la croissance de l'embryon et la germination des graines, ainsi que la phenologie de la germination chez trois especes Lonicera (Caprifoliaceae). Les graines du Lonicera xylosteum L. ont une dormance morphologique. Celles du Lonicera etrusca Santi possedent une variabilite intraspecifique inhabituelle de la dormance, une fraction etant capable de montrer a la fois une dormance morphologique et morphophysiologique. Les graines du Lonicera arborea montrent une dormance morphophysiologique complexe. L'etroite correspondance entre les conditions environnementales dont chaque espece a besoin pour briser la dormance de ses graines et leurs aires altitudinales suggerent que les dormances morphologiques et morphophysiologiques agissent comme filtre important pour determiner les niches de regeneration des especes, probablement du a ce que les mecanismes de dormance imposent des besoins environnementaux nettement speciiques au cours des premiers stades du recrutement. [Traduit par la Redaction] Mots-cles : gradient altitudinal, bris de dormance, dormance morphologique des graines, dormance morphophysiologique des graines, niches de regeneration, phenologie de la germination des graines., Introduction Dormancy provides seeds with a mechanism that enables them to skip periods favorable to germination but unfavorable to seedling establishment (Baskin and Baskin 1998; Fenner and Thompson 2005; Vandelook [...]

[Display omitted] • Puffinus shearwaters have been under intense taxonomic debate for decades. • Current taxonomies do not provide an accurate delineation of these shearwater species. • We propose a more accurate taxonomy combining results across several genomic analyses. • We highlight the need for management of ESUs below the species level. Speciation is a continuous and complex process shaped by the interaction of numerous evolutionary forces. Despite the continuous nature of the speciation process, the implementation of conservation policies relies on the delimitation of species and evolutionary significant units (ESUs). Puffinus shearwaters are globally distributed and threatened pelagic seabirds. Due to remarkable morphological status the group has been under intense taxonomic debate for the past three decades. Here, we use double digest Restriction-Site Associated DNA sequencing (ddRAD-Seq) to genotype species and subspecies of North Atlantic and Mediterranean Puffinus shearwaters across their entire geographical range. We assess the phylogenetic relationships and population structure among and within the group, evaluate species boundaries, and characterise the genomic landscape of divergence. We find that current taxonomies are not supported by genomic data and propose a more accurate taxonomy by integrating genomic information with other sources of evidence. Our results show that several taxon pairs are at different stages of a speciation continuum. Our study emphasises the potential of genomic data to resolve taxonomic uncertainties, which can help to focus management actions on relevant taxa, even if they do not necessarily coincide with the taxonomic rank of species. [ABSTRACT FROM AUTHOR]

Simple Summary: Chronic liver injury and inflammation leads to excessive deposition of extracellular matrix, known as liver fibrosis, and the distortion of the hepatic parenchyma. Liver fibrosis may progress to cirrhosis, a condition in which hepatic function is impaired and most cases of liver tumors occur. Currently, there are no effective therapies to inhibit and reverse the progression of liver fibrosis, and therefore, chronic liver disease remains a global health problem. In this study we have tested the efficacy of a new class of molecules that simultaneously target two molecular pathways known to be involved in the pathogenesis of hepatic fibrosis. In a clinically relevant mouse model of liver injury and inflammation we show that the combined inhibition of histones deacetylases and the cyclic guanosine monophosphate (cGMP) phosphodiesterase phosphodiesterase 5 (PDE5) results in potent anti-inflammatory and anti-fibrotic effects. Our findings open new avenues for the treatment of liver fibrosis and therefore, the prevention of hepatic carcinogenesis. Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy. [ABSTRACT FROM AUTHOR]

The influence of high temperatures on germination of four Cistus andfive Halimium taxa is analysed. Seeds were heated to a range of temperatures (from 50 deg. C to 150 deg. C) and a range of exposure times(from 1 to 60 min), simulating those heat conditions registered on the soil surface during wildfires. After the thermal pretreatments, seeds were sown in plastic Petri dishes and monitored for germination over 60 days. For all the species, germination was increased significantly over the control set (untreated seeds) by at least one of the thermal pretreatments. Temperatures of 120 and 150 deg. C were the mostefficient temperatures promoting seed germination, although germination was interrupted at 150 deg. C if exposure times were equal to or longer than 5 minutes for the majority of species. The preheating at 50 deg. C was effective only for C. populifolius, but only at long exposure times (60 min). H. atriplicifolium had the highest heat requirements for stimulating germination, requiring at least 120 deg. C for5 min. H. halimifolium subsp. halimifolium seeds showed the highest heat resistance: the final germination level reached at 150 deg. C for 7.5 minutes ranged between 52.5 and 55.5%. The germination rates after preheating were much lower than in mechanically scarified seeds, and closely resembled those of the untreated seeds. In general, species sharing the same habitat showed different heat requirements in promoting germination. For C. crispus and H. halimifolium subsp. halimifolium, the experiment was carried out on seeds collected from two different localities. For both species the germination patterns were similar between populations, although some high temperature pretreatments showed different germination percentages. [ABSTRACT FROM AUTHOR]

Objective: Acute intermittent porphyria (AIP) is a rare metabolic disorder caused by haploinsufficiency of hepatic porphobilinogen deaminase (PBGD), the third enzyme of the heme biosynthesis. Individuals with AIP experience neurovisceral attacks closely associated with hepatic overproduction of potentially neurotoxic heme precursors., Design: We replicated AIP in non-human primates (NHPs) through selective knockdown of the hepatic PBGD gene and evaluated the safety and therapeutic efficacy of human PBGD (hPBGD) mRNA rescue., Results: Intrahepatic administration of a recombinant adeno-associated viral vector containing short hairpin RNA against endogenous PBGD mRNA resulted in sustained PBGD activity inhibition in liver tissue for up to 7 months postinjection. The administration of porphyrinogenic drugs to NHPs induced hepatic heme synthesis, elevated urinary porphyrin precursors and reproduced acute attack symptoms in patients with AIP, including pain, motor disturbances and increased brain GABAergic activity. The model also recapitulated functional anomalies associated with AIP, such as reduced brain perfusion and cerebral glucose uptake, disturbances in hepatic TCA cycle, one-carbon metabolism, drug biotransformation, lipidomic profile and abnormal mitochondrial respiratory chain activity. Additionally, repeated systemic administrations of hPBGD mRNA in this AIP NHP model restored hepatic PBGD levels and activity, providing successful protection against acute attacks, metabolic changes in the liver and CNS disturbances. This approach demonstrated better efficacy than the current standards of care for AIP., Conclusion: This novel model significantly expands our understanding of AIP at the molecular, biochemical and clinical levels and confirms the safety and translatability of multiple systemic administration of hPBGD mRNA as a potential aetiological AIP treatment., Competing Interests: Competing interests: LJ and PGVM are employees of Moderna Inc. focusing on the development of therapeutic approaches for rare diseases. MAA is Editor of Gut Journal. The rest of the authors have no conflict of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)