The energy sensor AMPK regulates Hedgehog signaling in human cells through a unique Gli1 metabolic checkpoint

Hedgehog signaling controls proliferation of cerebellar granule cell precursors (GCPs) and its aberrant activation is a leading cause of Medulloblastoma, the most frequent pediatric brain tumor. We show here that the energy sensor AMPK inhibits Hh signaling by phosphorylating a single residue of human Gli1 that is not conserved in other species.Studies with selective agonists and genetic deletion have revealed that AMPK activation inhibits canonical Hh signaling in human, but not in mouse cells. Indeed we show that AMPK phosphorylates Gli1 at the unique residue Ser408, which is conserved only in primates but not in other species. Once phosphorylated, Gli1 is targeted for proteasomal degradation. Notably, we show that selective AMPK activation inhibits Gli1-driven proliferation and that this effect is linked to Ser408 phosphorylation, which represents a key metabolic checkpoint for Hh signaling.Collectively, this data unveil a novel mechanism of inhibition of Gli1 function, which is exclusive for human cells and may be exploited for the treatment of Medulloblastoma or other Gli1 driven tumors

Overcrowding analysis in emergency department through indexes: a single center study

Overcrowding in the Emergency Department (ED) is one of the major issues that must be addressed in order to improve the services provided in emergency circumstances and to optimize their quality. As a result, in order to help the patients and professionals engaged, hospital organizations must implement remedial and preventative measures. Overcrowding has a number of consequences, including inadequate treatment and longer hospital stays; as a result, mortality and the average duration of stay in critical care units both rise. In the literature, a number of indicators have been used to measure ED congestion. EDWIN, NEDOCS and READI scales are considered the most efficient ones, each of which is based on different parameters regarding the patient management in the ED

Efficiency measures of emergency departments: an Italian systematic literature review

Life expectancy globally increased in the last decades: the number of people aged 65 or older is consequently projected to grow, and healthcare demand will increase as well. In the recent years, the number of patients visiting the hospital emergency departments (EDs) rocked in almost all countries of the world. These departments are crucial in all healthcare systems and play a critical role in providing an efficient assistance to all patients. A systematic literature review covering PubMed, Scopus and the Cochrane Library was performed from 2009 to 2019. Of the 718 references found in the literature research, more than 25 studies were included in the current review. Different predictors were associated with the quality of EDs care, which may help to define and implement preventive strategies in the near future. There is no harmonisation in efficiency measurements reflecting the performance in the ED setting. The identification of consistent measures of efficiency is crucial to build an evidence base for future initiatives. The aim of this study is to review the literature on the problems encountered in the efficiency of EDs around the world in order to identify an organisational model or guidelines that can be implemented in EDs to fill inefficiencies and ensure access optimal treatment both in terms of resources and timing. This review will support policy makers to improve the quality of health facilities, and, consequently of the entire healthcare systems

In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors.

Aberrant Hedgehog (Hh)/glioma-associated oncogene (GLI) signaling has been implicated in cancer progression. Here, we analyzed GLI1, Sonic Hedgehog (Shh) and NF-κB expression in 51 breast cancer (ductal carcinoma) tissues using immunohistochemistry. We found a positive correlation between nuclear GLI1 expression and tumor grade in ductal carcinoma cases. Cytoplasmic Shh staining significantly correlated with a lower tumor grade. Next, the in vitro effects of two Hh signaling pathway inhibitors on breast cancer cell lines were evaluated using the Smoothened (SMO) antagonist GDC-0449 and the direct GLI1 inhibitor GANT-61. GDC-0449 and GANT-61 exhibited the following effects: a) inhibited breast cancer cell survival; b) induced apoptosis; c) inhibited Hh pathway activity by decreasing the mRNA expression levels of GLI1 and Ptch and inhibiting the nuclear translocation of GLI1; d) increased/decreased EGFR and ErbB2 protein expression, reduced p21- Ras and ERK1/ERK2 MAPK activities and inhibited AKT activation; and e) decreased the nuclear translocation of NF-κB. However, GANT-61 exerted these effects more effectively than GDC-0449. The in vivo antitumor activities of GDC-0449 and GANT- 61 were analyzed in BALB/c mice that were subcutaneously inoculated with mouse breast cancer (TUBO) cells. GDC-0449 and GANT-61 suppressed tumor growth of TUBO cells in BALB/c mice to different extents. These findings suggest that targeting the Hh pathway using antagonists that act downstream of SMO is a more efficient strategy than using antagonists that act upstream of SMO for interrupting Hh signaling in breast cancer

Recurrent transient global amnesia as presenting symptoms of CADASIL

Despite transient global amnesia is considered unusual in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and causal relation is still unclear, this report suggests to consider CADASIL in those patients with recurrent transient global amnesia, especially when MRI shows multifocal hyperintensities affecting the cerebral white matter or when it is followed by cognitive decline

β-arrestin1-mediated acetylation of Gli1 regulates Hedgehog/Gli signaling and modulates self-renewal of SHH medulloblastoma cancer stem cells

Background Aberrant Sonic Hedgehog/Gli (Hh/Gli) signaling pathway is a critical regulator of Sonic hedgehog medulloblastoma (SHH-MB). Cancer stem cells (CSCs), thought to be largely responsible for tumor initiation, maintenance, dissemination and relapse, have been identified in SHH-MB. Since we previously demonstrated that Hh/Gli signaling controls CSCs features in SHH-MB and that in these tumors miR-326 is down regulated, here we investigated whether there is a functional link between Hh/Gli signaling and miR-326. Methods We evaluated β-arrestin1 (Arrb1) and its intragenic miR-326 levels in CSCs derived from SHH-MB. Subsequently, we modulated the expression of Arrb1 and miR-326 in CSCs in order to gain insight into their biological role. We also analyzed the mechanism by which Arrb1 and miR-326 control Hh/Gli signaling and self-renewal, using luciferase and protein immunoprecipitation assays. Results Low levels of Arrb1 and miR-326 represent a feature of CSCs derived from SHH-MB. We observed that re-expression of Arrb1 and miR-326 inhibits Hh/Gli signaling pathway at multiple levels, which cause impaired proliferation and self-renewal, accompanied by down regulation of Nanog levels. In detail, miR-326 negatively regulates two components of the Hh/Gli pathway the receptor Smoothened (Smo) and the transcription factor Gli2, whereas Arrb1 suppresses the transcriptional activity of Gli1, by potentiating its p300-mediated acetylation. Conclusions Our results identify a new molecular mechanism involving miR-326 and Arrb1 as regulators of SHH-MB CSCs. Specifically, low levels of Arrb1 and miR-326 trigger and maintain Hh/Gli signaling and self-renewal

Effect of iron and nanolites on Raman spectra of volcanic glasses:A reassessment of existing strategies to estimate the water content

Global peatlands are a valuable but vulnerable resource. They represent a significant carbon and energy reservoir and play major roles in water and biogeochemical cycles. Peat soils are highly complex porous media with distinct characteristic physical and hydraulic properties. Pore sizes in undecomposed peat can exceed 5 mm, but significant shrinkage occurs during dewatering, compression and decomposition, reducing pore-sizes. The structure of peat soil consists of pores that are open and connected, dead-ended or isolated. The resulting dual-porosity nature of peat soils affects water flow and solute migration, which influence reactive transport processes and biogeochemical functions. Advective movement of aqueous and colloidal species is restricted to the hydrologically active (or mobile) fraction of the total porosity, i.e. the open and connected pores. Peat may attenuate solute migration through molecular diffusion into the closed and dead-end pores, and for reactive species, also through sorption and degradation reactions. Slow, diffusion-limited solute exchanges between the mobile and immobile regions may give rise to pore-scale chemical gradients and heterogeneous distributions of microbial habitats and activity in peat soils. While new information on the diversity and functionalities of peat microbial communities is rapidly accumulating, the significance of the geochemical and geomicrobial study on peat stands to benefit from a basic understanding of the physical structure of peat soils. In this paper, we review the current knowledge of key physical and hydraulic properties related to the structure of globally available peat soils and briefly discuss their implications for water storage, flow and the migration of solutes. This paper is intended to narrow the gap between the ecohydrological and biogeochemical research communities working on peat soils

Valorisation of typical products through characterising and promoting actions: morpho-biometric traits, sensory analysis and flavonol content in Cipolla di Giarratana

The performances of 9 accessions of Cipolla di Giarratana landrace were evaluated at 5 different sites located 2 in the area where this landrace is traditionally grown (South-Eastern Sicily, 550 m asl), 2 in the neighbor areas with similar average altitude, and one on the South East coast of Sicily (sea level). Biometric and morphological traits, flavonol content and sensory profile were all considered in the valorisation of a typical product of a marginal area of Sicily. Data on the actual yield and crop management at farm scale were also obtained involving more than half of the growers actually cultivating Cipolla di Giarratana , and measuring yield, plant density, and bulb weight directly on the farms. The Cipolla di Giarratana landrace is characterised by a large and heavy bulb (535 g), strongly flattened at the poles, with the maximum diameter at the central section, and white in colour. Significant differences in bulb weight and diameter were found among accessions and locations, but there were no interactions between them and one accession reported the highest bulb weight value in all of the locations studied. With regards to bulb weight, farm scale data confirm the results we obtained at the experimental locations. Fifty percent of registered yield at farm scale ranged between 86 and 152 t ha –1 with a median of 119 t ha –1 , and measured plant density revealed that 50% of the farmers planted 20-27 plants per square meter. Analysis of the UV-vis and mass spectra showed the presence of 10 different flavonols with Quercetin as the most represented flavonol. The sensory profile of Cipolla di Giarratana onion showed that this landrace is characterised by a high intensity of sweet, typical fresh flavour and texture perception

Nature-based solutions for hydro-meteorological hazards: revised concepts, classification schemes and databases

Hydro-meteorological hazards (HMHs) have had a strong impact on human societies and ecosystems. Their impact is projected to be exacerbated by future climate scenarios. HMHs cataloguing is an effective tool to evaluate their associated risks and plan appropriate remediation strategies. However, factors linked to HMHs origin and triggers remain uncertain, which poses a challenge for their cataloguing. Focusing on key HMHs (floods, storm surge, landslides, droughts, and heatwaves), the goal of this review paper is to analyse and present a classification scheme, key features, and elements for designing nature-based solutions (NBS) and mitigating the adverse impacts of HMHs in Europe. For this purpose, we systematically examined the literature on NBS classification and assessed the gaps that hinder the widespread uptake of NBS. Furthermore, we critically evaluated the existing literature to give a better understanding of the HMHs drivers and their interrelationship (causing multi-hazards). Further conceptualisation of classification scheme and categories of NBS shows that relatively few studies have been carried out on utilising the broader concepts of NBS in tackling HMHs and that the classification and effectiveness of each NBS are dependent on the location, architecture, typology, green species, environmental conditions as well as interrelated non-linear systems. NBS are often more cost-effective than hard engineering approaches used within the existing systems, especially when taking into consideration their potential co-benefits. We also evaluated the sources of available data for HMHs and NBS, highlighted gaps in data, and presented strategies to overcome the current shortcomings for the development of the NBS for HMHs. We highlighted specific gaps and barriers that need to be filled since the uptake and upscaling studies of NBS in HMHs reduction is rare. The fundamental concepts and the key technical features of past studies reviewed here could help practitioners to design and implement NBS in a real-world situation