Forebulge migration in the foreland basin system of the central-southern Apennine fold-thrust belt (Italy): New high-resolution Sr-isotope dating constraints

The Apennines are a retreating collisional belt where the foreland basin system, across large domains, is floored by a subaerial forebulge unconformity developed due to forebulge uplift and erosion. This unconformity is overlain by a diachronous sequence of three lithostratigraphic units made of (a) shallow-water carbonates, (b) hemipelagic marls and shales and (c) siliciclastic turbidites. Typically, the latter two have been interpreted regionally as the onset of syn-orogenic deposition in the foredeep depozone, whereas little attention has been given to the underlying unit. Accordingly, the rate of migration of the central-southern Apennine fold-thrust belt-foreland basin system has been constrained, so far, exclusively considering the age of the hemipelagites and turbidites, which largely post-date the onset of foredeep depozone. In this work, we provide new high-resolution ages obtained by strontium isotope stratigraphy applied to calcitic bivalve shells sampled at the base of the first syn-orogenic deposits overlying the Eocene-Cretaceous pre-orogenic substratum. Integration of our results with published data indicates progressive rejuvenation of the strata sealing the forebulge unconformity towards the outer portions of the fold-thrust belt. In particular, the age of the forebulge unconformity linearly scales with the pre-orogenic position of the analysed sites, pointing to an overall constant migration velocity of the forebulge wave in the last 25 Myr

Iloprost in Acute Post-kidney Transplant Atheroembolism: A Case Report of Two Successful Treatments

Cholesterol embolization (CE) is a rare and alarming post-transplant complication, responsible for primary non-function (PNF) or delayed graft function (DGF). Its incidence is expected to rise due to increasingly old donors and recipients and the extended criteria for donation. Therapy with statins and steroids has not been shown to be effective, while agonism of prostaglandin I2 has been reported to be useful in systemic CE. We report two cases of acute post-transplant CE in which intravenous iloprost (0.05 mg/kg/day) was added to standard statin and steroid therapy. In the first instance, CE was due to embolization from the kidney artery resulting in embolization of the small vessels; after a long DGF and 15 days of iloprost therapy, renal function recovered. The second instance is a case of embolization from the iliac artery of the recipient, where CE manifested as a partial renal infarction. After 5 days of iloprost administration, creatinine levels improved. Iloprost acts on vasodilation and on different inflammatory pathways, improving the anti-inflammatory profile. Post-transplant CE is difficult to diagnose and, if not treated, can lead to loss of function. Iloprost added to standard therapy could be beneficial in accelerating renal function recovery immediately after transplant

Foreign bodies in the ears causing complications and requiring hospitalization in children 0-14 age: results from the ESFBI study

The occurrence of foreign bodies (FBs) in otorhinolaryngological practice is a common and serious problem among patients in paediatric age. The aim of this work is to characterize the risk of complications and prolonged hospitalization due to foreign bodies in ears in terms of the characteristics of the injured patients (age, gender), typology and features of the foreign bodies, the circumstances of the accident and the hospitalization's details

Impact of a probiotic diet on well-being of healthy senior: THE PROBIOSENIOR PROJECT

Aims: The aim of this work was to assess the effects of a probiotic diet on well-being of healthy seniors living in boarding and private homes in Marche Region, Italy. In particular, we focused on the modulation of high-sensitivity C-reactive protein (HsCRP), intestinal microbiota and short-chain fatty acids (SCFAs). Methods and Results: Ninety-seven healthy seniors took part in a double-blind, placebo-controlled feeding study (59 fed probiotics, 38 fed placebo) for 6 months. Each volunteer ingested daily one food product or a dietary supplement enriched with Synbio® blend (Synbiotec Srl, Camerino, Italy) or the placebo (control group). Blood and faecal samples were collected before and at the end of the intervention period to perform biochemical and microbiological analyses. The serum HsCRP difference value after 6 months of treatment was significantly higher in the probiotic group than placebo (p < 0.05). After the intervention, a significant increase in faecal lactobacilli and a bifidobacteria increase in more participants were observed in the probiotic group. The 16S NGS analysis on the probiotic group showed a decreasing trend of Proteobacteria at the end of the treatment and conversely, an increasing trend of Actinobacteria and Verrucomicrobia phyla, to which the increase of Akkermansiaceae and Bifidobacteriaceae contributes at the family level. Finally, total short-chain fatty acids (SCFAs) and butyric acid were significantly higher in the probiotic group at the end of the treatment respect to the beginning. Conclusions: Overall, this study emphasizes the beneficial anti-inflammageing effect of a prolonged diet based on functional foods enriched with Synbio® through the modulation of the intestinal microbiota and the consequent increase in the SCFA production. Significance and Impact of the Study: Synbio® integration in elderly daily diet may be a preventive strategy to support healthy ageing

Rapamycin and the transcription factor C/EBPβ as a switch in osteoclast differentiation: implications for lytic bone diseases

Lytic bone diseases and in particular osteoporosis are common age-related diseases characterized by enhanced bone fragility due to loss of bone density. Increasingly, osteoporosis poses a major global health-care problem due to the growth of the elderly population. Recently, it was found that the gene regulatory transcription factor CCAAT/enhancer binding protein beta (C/EBPβ) is involved in bone metabolism. C/EBPβ occurs as different protein isoforms of variable amino terminal length, and regulation of the C/EBPβ isoform ratio balance was found to represent an important factor in osteoclast differentiation and bone homeostasis. Interestingly, adjustment of the C/EBPβ isoform ratio by the process of translational control is downstream of the mammalian target of rapamycin kinase (mTOR), a sensor of the nutritional status and a target of immunosuppressive and anticancer drugs. The findings imply that modulating the process of translational control of C/EBPβ isoform expression could represent a novel therapeutic approach in osteolytic bone diseases, including cancer and infection-induced bone loss

PRAS40 and PRR5-Like Protein Are New mTOR Interactors that Regulate Apoptosis

TOR (Target of Rapamycin) is a highly conserved protein kinase and a central controller of cell growth. TOR is found in two functionally and structurally distinct multiprotein complexes termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2). In the present study, we developed a two-dimensional liquid chromatography tandem mass spectrometry (2D LC-MS/MS) based proteomic strategy to identify new mammalian TOR (mTOR) binding proteins. We report the identification of Proline-rich Akt substrate (PRAS40) and the hypothetical protein Q6MZQ0/FLJ14213/CAE45978 as new mTOR binding proteins. PRAS40 binds mTORC1 via Raptor, and is an mTOR phosphorylation substrate. PRAS40 inhibits mTORC1 autophosphorylation and mTORC1 kinase activity toward eIF-4E binding protein (4E-BP) and PRAS40 itself. HeLa cells in which PRAS40 was knocked down were protected against induction of apoptosis by TNFα and cycloheximide. Rapamycin failed to mimic the pro-apoptotic effect of PRAS40, suggesting that PRAS40 mediates apoptosis independently of its inhibitory effect on mTORC1. Q6MZQ0 is structurally similar to proline rich protein 5 (PRR5) and was therefore named PRR5-Like (PRR5L). PRR5L binds specifically to mTORC2, via Rictor and/or SIN1. Unlike other mTORC2 members, PRR5L is not required for mTORC2 integrity or kinase activity, but dissociates from mTORC2 upon knock down of tuberous sclerosis complex 1 (TSC1) and TSC2. Hyperactivation of mTOR by TSC1/2 knock down enhanced apoptosis whereas PRR5L knock down reduced apoptosis. PRR5L knock down reduced apoptosis also in mTORC2 deficient cells. The above suggests that mTORC2-dissociated PRR5L may promote apoptosis when mTOR is hyperactive. Thus, PRAS40 and PRR5L are novel mTOR-associated proteins that control the balance between cell growth and cell death

Regulation of mTORC1 Signaling by pH

BACKGROUND: Acidification of the cytoplasm and the extracellular environment is associated with many physiological and pathological conditions, such as intense exercise, hypoxia and tumourigenesis. Acidification affects important cellular functions including protein synthesis, growth, and proliferation. Many of these vital functions are controlled by mTORC1, a master regulator protein kinase that is activated by various growth-stimulating signals and inactivated by starvation conditions. Whether mTORC1 can also respond to changes in extracellular or cytoplasmic pH and play a role in limiting anabolic processes in acidic conditions is not known. METHODOLOGY/FINDINGS: We examined the effects of acidifying the extracellular medium from pH 7.4 to 6.4 on human breast carcinoma MCF-7 cells and immortalized mouse embryo fibroblasts. Decreasing the extracellular pH caused intracellular acidification and rapid, graded and reversible inhibition of mTORC1, assessed by measuring the phosphorylation of the mTORC1 substrate S6K. Fibroblasts deleted of the tuberous sclerosis complex TSC2 gene, a major negative regulator of mTORC1, were unable to inhibit mTORC1 in acidic extracellular conditions, showing that the TSC1-TSC2 complex is required for this response. Examination of the major upstream pathways converging on the TSC1-TSC2 complex showed that Akt signaling was unaffected by pH but that the Raf/MEK/ERK pathway was inhibited. Inhibition of MEK with drugs caused only modest mTORC1 inhibition, implying that other unidentified pathways also play major roles. CONCLUSIONS: This study reveals a novel role for the TSC1/TSC2 complex and mTORC1 in sensing variations in ambient pH. As a common feature of low tissue perfusion, low glucose availability and high energy expenditure, acidic pH may serve as a signal for mTORC1 to downregulate energy-consuming anabolic processes such as protein synthesis as an adaptive response to metabolically stressful conditions

Local Translation in Primary Afferent Fibers Regulates Nociception

Recent studies have demonstrated the importance of local protein synthesis for neuronal plasticity. In particular, local mRNA translation through the mammalian target of rapamycin (mTOR) has been shown to play a key role in regulating dendrite excitability and modulating long-term synaptic plasticity associated with learning and memory. There is also increased evidence to suggest that intact adult mammalian axons have a functional requirement for local protein synthesis in vivo. Here we show that the translational machinery is present in some myelinated sensory fibers and that active mTOR-dependent pathways participate in maintaining the sensitivity of a subpopulation of fast-conducting nociceptors in vivo. Phosphorylated mTOR together with other downstream components of the translational machinery were localized to a subset of myelinated sensory fibers in rat cutaneous tissue. We then showed with electromyographic studies that the mTOR inhibitor rapamycin reduced the sensitivity of a population of myelinated nociceptors known to be important for the increased mechanical sensitivity that follows injury. Behavioural studies confirmed that local treatment with rapamycin significantly attenuated persistent pain that follows tissue injury, but not acute pain. Specifically, we found that rapamycin blunted the heightened response to mechanical stimulation that develops around a site of injury and reduced the long-term mechanical hypersensitivity that follows partial peripheral nerve damage - a widely used model of chronic pain. Our results show that the sensitivity of a subset of sensory fibers is maintained by ongoing mTOR-mediated local protein synthesis and uncover a novel target for the control of long-term pain states

mTOR: from growth signal integration to cancer, diabetes and ageing

In all eukaryotes, the target of rapamycin (TOR) signalling pathway couples energy and nutrient abundance to the execution of cell growth and division, owing to the ability of TOR protein kinase to simultaneously sense energy, nutrients and stress and, in metazoans, growth factors. Mammalian TOR complex 1 (mTORC1) and mTORC2 exert their actions by regulating other important kinases, such as S6 kinase (S6K) and Akt. In the past few years, a significant advance in our understanding of the regulation and functions of mTOR has revealed the crucial involvement of this signalling pathway in the onset and progression of diabetes, cancer and ageing.National Institutes of Health (U.S.)Howard Hughes Medical InstituteWhitehead Institute for Biomedical ResearchJane Coffin Childs Memorial Fund for Medical Research (Postdoctoral Fellowship)Human Frontier Science Program (Strasbourg, France