Type I interferons (IFNs) are highly expressed in the gut mucosa of celiac disease (CD) gut mucosa and stimulates immune response prompted by gluten ingestion, but the processes that maintain the ...production of these inflammatory molecules are not well understood. Adenosine deaminase acting on RNA 1 (ADAR1), an RNA-editing enzyme, plays a crucial role in inhibiting self or viral RNAs from activating auto-immune mediated responses, most notably within the type-I IFN production pathway. The aim of this study was to assess whether ADAR1 could contribute to the induction and/or progression of gut inflammation in patients with celiac disease.
ADAR1 expression was assessed by Real time PCR and Western blotting in duodenal biopsy taken from inactive and active celiac disease (CD) patients and normal controls (CTR). To analyze the role of ADAR1 in inflamed CD mucosa, lamina propria mononuclear cells (LPMC) were isolated from inactive CD and ADAR1 was silenced in with a specific antisense oligonucleotide (AS) and then incubated with a synthetic analogue of viral dsRNA (poly I:C). IFN-inducing pathways (IRF3, IRF7) in these cells were evaluated with Western blotting and inflammatory cytokines were evaluated with flow cytometry. Lastly, the role of ADAR1 was investigated in a mouse model of poly I:C-driven small intestine atrophy.
Reduced ADAR1 expression was seen in duodenal biopsies compared to inactive CD and normal controls.
organ cultures of duodenal mucosal biopsies, taken from inactive CD patients, stimulated with a peptic-tryptic digest of gliadin displayed a decreased expression of ADAR1. ADAR1 silencing in LPMC stimulated with a synthetic analogue of viral dsRNA strongly boosted the activation of IRF3 and IRF7 and the production of type-I IFN, TNF-α and IFN-γ. Administration of ADAR1 antisense but not sense oligonucleotide to mice with poly I:C-induced intestinal atrophy, significantly increased gut damage and inflammatory cytokines production.
These data show that ADAR1 is an important regulator of intestinal immune homeostasis and demonstrate that defective ADAR1 expression could provide to amplifying pathogenic responses in CD intestinal mucosa.
A number of data indicate that the sources of different kinds of PDAC may be discovered at the transcription/transduction stage. RNA metabolism is manipulated at various steps by different ...RNA-binding proteins (RBPs), and the deregulation or irregular activity of RBPs is known to contribute to tumor promotion and progression. The insulin-like growth factor 2 mRNA-binding protein family (IMPs), and IMP1 in particular, has been linked with a poor prognosis in PDAC patients; however, little is known about its contribution in PDAC carcinogenesis. In this study, we investigated the function of IMP1 in PDAC. To evaluate IMP1 expression and correlation with PDAC prognosis, we utilized several public databases. Using a specific siRNA IMP1, we analyzed cell death and cell cycle progression in PDAC cell lines and 3D spheroids. The role of IMP1 was also evaluated in vivo in a Panc-1-derived tumor xenograft murine model. Public data suggest that PDAC patients with higher expression of IMP1 showed poor overall and progression-free survival. IMP1 silencing leads to reduced cell growth in PDAC cells and three-dimensional spheroids. Abrogation of IMP1 in PDAC cells showed lower levels of CDC25A, increased phosphorylation of the cyclin-dependent kinase (CDK)2, and accumulation of PDAC cells in the G1 phase. Immunoprecipitation experiments revealed that IMP1 binds CDC25A mRNA, thus controlling cell-cycle progression. Ultimately, we proved that suppression of IMP1 blocked in vivo growth of Panc-1 transferred into immunodeficient mice. Our results indicate that IMP1 drives the PDCA cell cycle and represents a novel strategy for overcoming PDCA cell proliferation.
Objective:
Pulmonary embolism (PE) is a potentially life-threatening disorder. Beyond its usefulness in the prognostic stratification of heart failure, sST2 can represent a biomarker with high ...utility in several acute conditions. Our study was aimed to investigate whether sST2 can be used as a clinical marker of severity and prognostic outcome in acute PE.
Design and method:
We enrolled 72 patients with documented PE and 38 healthy subjects; we measured the plasma concentrations of sST2 to evaluate the prognostic and severity performance of different levels of sST2 according to its association with the pulmonary embolism severity index (PESI) score and several parameters of respiratory function.
Results:
PE patients had significantly higher levels of sST2 compared with healthy subjects (87.74 ± 17.1 vs. 17.1 ± 0.4 ng/mL, p < 0.001); we found higher PESI scores and serum lactate values in the group of patients with sST2 > 35 ng/mL compared with patients with sST2 < 35 ng/mL (138.7 ± 14.9 vs. 103.7 ± 15.1 and 2.43 ± 0.69 vs. 1.025 ± 0.05 mmol/L, respectively; p < 0.05). Patients with sST2 > 35 ng/mL showed higher radiological severity of PE compared with patients with sST2 < 35 ng/mL. Moreover, sST2 was the strongest parameter with a discriminative capacity for the development of acute respiratory failure and a PESI score >106 with respect to C reactive protein (CRP), creatinine, d-dimer, and serum lactate.
Conclusions:
We clearly demonstrated that sST2 significantly increased in PE and that its elevation was associated with disease severity. Therefore, sST2 may be used as a clinical marker in the evaluation of PE severity. However, further studies with larger patient populations are required to confirm these findings.
Olfactory dysfunction is a well-known phenomenon in neurological diseases with anosmia and hyposmia serving as clinical or preclinical indicators of Alzheimer's disease, Parkinson's disease, and ...other neurodegenerative disorders. Since glaucoma is a neurodegenerative disease of the visual system, it may also entail alterations in olfactory function, warranting investigation into potential sensory interconnections.
A review of the current literature of the last 15 years (from 1 April 2008 to 1 April 2023) was conducted by two different authors searching for topics related to olfaction and glaucoma.
three papers met the selection criteria. According to these findings, patients with POAG appear to have worse olfaction than healthy subjects. Furthermore, certain predisposing conditions to glaucoma, such as pseudoexfoliation syndrome and primary vascular dysregulation, could possibly induce olfactory changes that can be measured with the Sniffin Stick test.
the scientific literature on this topic is very limited, and the pathogenesis of olfactory changes in glaucoma is not clear. However, if the results of these studies are confirmed by further research, olfactory testing may be a non-invasive tool to assist clinicians in the early diagnosis of glaucoma.
Summary
The grain of 17 coloured barley F8 recombinant inbred lines from three backcross programs using three barley parental lines were studied. The main objectives were to characterise the ...anthocyanin profiles and antioxidant activities of these different lines of coloured barley grain when grown in southern Italy. HPLC and spectrophotometric analyses were performed. The overall profile of anthocyanins across the grain of these genotypes comprised 51.8% malvidin 3‐glucoside, 12.7% delphinidin 3‐glucoside, 5.0% cyanidin, ~2.5% both petunidin and peonidin 3‐glucoside, and ~1.4% both delphinidin 3‐rutinoside anthocyanidin 3‐glucoside, with the remaining 23% as unidentified anthocyanins. Principal component analysis showed that the antioxidant activities of the barley grain were significantly correlated with the levels of phenolic compounds. Furthermore, the grain of some of these coloured barley RILs had the highest radical scavenging activities, which indicated their potential use in preparation of both food and nutraceuticals, for protective effects on human health, and in breeding programs.
Experimental approach for the characterization of anthocyanin profile of Italian coloured barley.
The long sedimentary sequence of Notarchirico has yielded evidence of one of the earliest Acheulean manifestations in Europe and of recurrent hominin occupation, spanning from the end of the ...interglacial MIS 17 to the glacial MIS 16 (~695–610 ka). Here, we report the new discovery of a lion, Panthera spelaea, from the site, based on a metatarsal from layer A. This part of the sequence dates to ~660–612 ka (MIS 16, 40Ar/39Ar age). Therefore, Notarchirico's lion represents the earliest confirmed occurrence of the species in southwestern Europe, although older findings are known from adjacent areas. Lions and several other large mammal species dispersed into Europe during the Early–Middle Pleistocene Transition, which also witnessed the spread of the Acheulean. Ecological and behavioural adaptability was probably key, for hominins and other species, to cope with the intense and recurrent environmental fluctuations that occurred during this period.
Biological invasions are a widespread problem worldwide, as invasive non-indigenous species (NIS) may affect native populations through direct (e. g., predation) or indirect (e.g., competition) ...trophic interactions, leading to changes in the food web structure. The trophic relationships of the invasive eastern mosquitofish
Gambusia holbrooki
and the native big-scale sand smelt
Atherina boyeri
coexisting in three Mediterranean coastal ponds characterized by different trophic statuses (from oligotrophic to hypereutrophic) were assessed in spring through isotopic niche analysis and Bayesian mixing models. The two fish relied on the distinctive trophic pathways in the different ponds, with the evidence of minimal interspecific niche overlap indicating site-specific niche divergence mechanisms. In more detail, under hypereutrophic and mesotrophic conditions, the two species occupied different trophic positions but relying on a single trophic pathway, whereas, under oligotrophic conditions, both occupied a similar trophic position but belonging to distinct trophic pathways. Furthermore, the invaders showed the widest niche breadth while the native species showed a niche compression and displacement in the ponds at a higher trophic status compared to the oligotrophic pond. We argue that this may be the result of an asymmetric competition arising between the two species because of the higher competitive ability of
G. holbrooki
and may have been further shaped by the trophic status of the ponds, through a conjoint effect of prey availability and habitat complexity. While the high trophic plasticity and adaptability of both species to different environmental features and resource availability may have favored their coexistence through site-specific mechanisms of niche segregation, we provide also empirical evidence of the importance of environmental control in invaded food webs, calling for greater attention to this aspect in future studies.
Bardet‐Biedl syndrome (BBS) is a ciliopathy characterized by retinal degeneration, obesity, renal abnormalities, postaxial polydactyly, and developmental defects. Genes mutated in BBS encode for ...components and regulators of the BBSome, an octameric complex that controls the trafficking of cargos and receptors within the primary cilium. Although both structure and function of the BBSome have been extensively studied, the impact of ubiquitin signaling on BBSome is largely unknown. We identify the E3 ubiquitin ligase PJA2 as a novel resident of the ciliary compartment and regulator of the BBSome. Upon GPCR‐cAMP stimulation, PJA2 ubiquitylates BBSome subunits. We demonstrate that ubiquitylation of BBS1 at lysine 143 increases the stability of the BBSome and promotes its binding to BBS3, an Arf‐like GTPase protein controlling the targeting of the BBSome to the ciliary membrane. Downregulation of PJA2 or expression of a ubiquitylation‐defective BBS1 mutant (BBS1K143R) affects the trafficking of G‐protein‐coupled receptors (GPCRs) and Shh‐dependent gene transcription. Expression of BBS1K143R in vivo impairs cilium formation, embryonic development, and photoreceptors' morphogenesis, thus recapitulating the BBS phenotype in the medaka fish model.
Synopsis
PJA2 is a novel resident of the ciliary compartment. Upon GPCR‐cAMP stimulation, PJA2 ubiquitylates BBSome subunits and controls the assembly and disassembly of BBSome at cilia. Defects in ubiquitylation may induce Bardet‐Biedl syndrome in medaka fish.
E3 ubiquitin ligase PJA2 is a component of the ciliary compartment and interacts with subunits of the BBSome.
GPCR‐cAMP stimulation induces PJA2‐mediated ubiquitylation of BBS1 and BBS2 and BBSome complex assembly.
Downregulation of PJA2 or expression of a ubiquitylation‐defective BBS1 mutant (BBS1K143R) impairs the trafficking of G‐protein‐coupled receptors (GPCRs) and cilium formation.
Expression of BBS1K143R affects cilium formation, embryo development, and photoreceptor morphogenesis in the medaka fish model.
PJA2 is a novel resident of the ciliary compartment. Upon GPCR‐cAMP stimulation, PJA2 ubiquitylates BBSome subunits and controls the assembly and disassembly of BBSome at cilia. Defects in ubiquitylation may induce Bardet‐Biedl syndrome in medaka fish.
Context:
Interplay between adipose tissue and adrenal glands has been recently suggested, without well-founded actions of locally adipose tissue surrounding the adrenal glands.
Objective:
We ...hypothesized that the local expression of leptin and adiponectin can be associated with pathological changes of the adrenal glands.
Patients and Main Outcome Measures:
We evaluated RT-PCR of leptin and adiponectin mRNA expression from the adipose tissue surrounding adrenal glands in 30 patients, collecting adipose tissue surrounding the adrenal neoplasms, peri-renal and subcutaneous depots.
Results:
Leptin mRNA levels from adrenal neoplasia and peri-renal fat were significantly higher in aldosterone-producing adenoma than in nonfunctioning adenomas (P < 0.001 and P < 0.02, respectively). In patients with Cushing's syndrome leptin mRNA levels were significantly higher in adrenal fat than in peri-renal (P < 0.05) and subcutaneous adipose tissue (P < 0.001). Adiponectin mRNA expression from adrenal neoplasia was significantly lower than that from peri-renal and subcutaneous fat depots (P < 0.05). Leptin and adiponectin plasma levels significantly correlated with their mRNA expression from the fat depot surrounding the adrenal neoplasia.
Conclusions:
Our findings suggest an active role of the fat depot surrounding the adrenal neoplasia, with local secretion of leptin and adiponectin.
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