Antimicrobial and antibiofilm activities of new synthesized Silver Ultra-NanoClusters (SUNCs) against Helicobacter pylori

Helicobacter pylori colonizes approximately 50% of the world\u2019s population and it is the cause of chronic gastritis, peptic ulcer disease and gastric cancer. The increase of antibiotic resistance is one of the biggest challenges of our century due to its constant increase. In order to identify an alternative or adjuvant strategy to the standard antibiotic therapy, the in vitro activity of newly synthesized Silver Ultra-NanoClusters (SUNCs), characterized by an average size inferior to 5 nm, against clinical strains of Helicobacter pylori, with different antibiotic susceptibilities, was evaluated in this study. MICs and MBCs were determined by the broth microdilution method, whereas the effect of drug combinations by the checkerboard assay. The Minimum Biofilm Eradication Concentration (MBEC) was measured using AlamarBlue (AB) assay and Colony Forming Unit (CFU) counts. The cytotoxicity was evaluated by performing the MTT assay on AGS cell line. The inhibitory activity was expressed in terms of bacteriostatic and bactericidal potential, with MIC50, MIC90, and MBC50 of 0.33 mg/L against planktonic Helicobacter pylori strains. Using the fractional inhibitory concentration index, SUNCs showed synergism with metronidazole in one clinical strain, and very close to synergistic effect on the reference strain; the combination with clarythromicin evidenced an effect very close to synergism on both strains considered. The biofilm eradication was obtained after treatment with 2X, 3X and 4X MIC value. Moreover, SUNCs showed low toxicity on human cells and was effective in eradicating a mature biofilm produced by H. pylori. The data presented in this study demonstrate that SUNCs could represent a novel strategy for the treatment of H. pylori infections either alone or in combination with metronidazole

Meta-analysis of genetic variants associated with human exceptional longevity

Despite evidence from family studies that there is a strong genetic influence upon exceptional longevity, relatively few genetic variants have been associated with this trait. One reason could be that many genes individually have such weak effects that they cannot meet standard thresholds of genome wide significance, but as a group in specific combinations of genetic variations, they can have a strong influence. Previously we reported that such genetic signatures of 281 genetic markers associated with about 130 genes can do a relatively good job of differentiating centenarians from non-centenarians particularly if the centenarians are 106 years and older. This would support our hypothesis that the genetic influence upon exceptional longevity increases with older and older (and rarer) ages. We investigated this list of markers using similar genetic data from 5 studies of centenarians from the USA, Europe and Japan. The results from the meta-analysis show that many of these variants are associated with survival to these extreme ages in other studies. Since many centenarians compress morbidity and disability towards the end of their lives, these results could point to biological pathways and therefore new therapeutics to increase years of healthy lives in the general population

A Multivariate Analysis of Depression Prevalence in Psoriasis Patients: A Cohort Study

The literature reported higher depression rates in psoriasis patients compared to the general population. Our study aimed to verify whether variability in depression prevalence was due to using different diagnostic tools. We also aimed to determine whether dysfunctional coping strategies might increase the depression burden. We assessed psoriasis severity by the Psoriasis Area Severity Index (PASI) and PSOdisk. We analyzed mental alterations of 120 outpatients by Hamilton Depression and Anxiety Rating Scales (HAM-D and HAM-A), Symptom Checklist-90-Revised (SCL-90-R), plus coping strategies and quality of life by Coping Orientation to Problems Experienced (COPE) Inventory and 36-Item Short Form Health Survey (SF-36). We divided our cohort into five subgroups from minimal to severe psoriasis using the PSOdisk total score. Depression prevalence varied according to the assessment criteria for specificity, frequency, and severity. Different mood disorders other than major depression emerged when we used DSM-IV-TR criteria. Correlation analysis of the criteria we used to diagnose depression or depressed mood indicated that a dysfunctional coping strategy was highly and positively correlated only in patients of the severe subgroup. Differently, a negative correlation emerged between the SF-36 Mental Summary Component (MSC) and behavioral disengagement, thus suggesting that psychopathological distress might induce patients with a marked/severe psoriasis to adopt dysfunctional coping strategies. Dermatologists are fundamental in detecting comorbid depression, referring psoriasis patients to mental health specialists to achieve adequate treatments, and preventing suicide risk

A Genome-Wide Screening and SNPs-to-Genes Approach to Identify Novel Genetic Risk Factors Associated with Frontotemporal Dementia

Frontotemporal dementia (FTD) is the second most prevalent form of early onset dementia after Alzheimer’s disease (AD). We performed a case-control association study in an Italian FTD cohort (n = 530) followed by the novel SNPs-to-genes approach and functional annotation analysis. We identified two novel potential loci for FTD. Suggestive SNPs reached p-values ~10-7 and OR > 2.5 (2p16.3) and 1.5 (17q25.3). Suggestive alleles at 17q25.3 identified a disease-associated haplotype causing decreased expression of -cis genes such as RFNG and AATK involved in neuronal genesis and differentiation, and axon outgrowth, respectively. We replicated this locus through the SNPs-to-genes approach. Our functional annotation analysis indicated significant enrichment for functions of the brain (neuronal genesis, differentiation and maturation), the synapse (neurotransmission and synapse plasticity), and elements of the immune system, the latter supporting our recent international FTD-GWAS. This is the largest genome-wide study in Italian FTD to date. Although our results are not conclusive, we set the basis for future replication studies and identification of susceptible molecular mechanisms involved in FTD pathogenesis

A Complete Meteo/Hydro/Hydraulic Chain Application to Support Early Warning and Monitoring Systems: The Apollo Medicane Use Case

Because of the ongoing changing climate, extreme rainfall events’ frequency at the global scale is expected to increase, thus resulting in high social and economic impacts. A Meteo/Hydro/Hydraulic forecasting chain combining heterogeneous observational data sources is a crucial component for an Early Warning System and is a fundamental asset for Civil Protection Authorities to correctly predict these events, their effects, and put in place anticipatory actions. During the last week of October 2021 an intense Mediterranean hurricane (Apollo) affected many Mediterranean countries (Tunisia, Algeria, Malta, and Italy) with a death toll of seven people. The CIMA Meteo/Hydro/Hydraulic forecasting chain, including the WRF model, the hydrological model Continuum, the automatic system for water detection (AUTOWADE), and the hydraulic model TELEMAC-2D, was operated in real-time to predict the Apollo weather evolution as well as its hydrological and hydraulic impacts, in support of the early warning activities of the Italian Civil Protection Department. The WRF model assimilating radar data and in situ weather stations showed very good predictive capability for rainfall timing and location over eastern Sicily, thus supporting accurate river flow peak forecasting with the hydrological model Continuum. Based on WRF predictions, the daily automatic system for water detection (AUTOWADE) run using Sentinel 1 data was anticipated with respect to the scheduled timing to quickly produce a flood monitoring map. Ad hoc tasking of the COSMO-SkyMed satellite constellation was also performed to overcome the S1 data latency in eastern Sicily. The resulting automated operational mapping of floods and inland waters was integrated with the subsequent execution of the hydraulic model TELEMAC-2D to have a complete representation of the flooded area with water depth and water velocity

Targeting Hypoxia in Cancer Cells by Restoring Homeodomain Interacting Protein-Kinase 2 and p53 Activity and Suppressing HIF-1α

BACKGROUND:The tumor suppressor homeodomain-interacting protein kinase-2 (HIPK2) by phosphorylating serine 46 (Ser46) is a crucial regulator of p53 apoptotic function. HIPK2 is also a transcriptional co-repressor of hypoxia-inducible factor-1alpha (HIF-1alpha) restraining tumor angiogenesis and chemoresistance. HIPK2 can be deregulated in tumors by several mechanisms including hypoxia. Here, we sought to target hypoxia by restoring HIPK2 function and suppressing HIF-1alpha, in order to provide evidence for the involvement of both HIPK2 and p53 in counteracting hypoxia-induced chemoresistance. METHODOLOGY/PRINCIPAL FINDINGS:Upon exposure of colon and lung cancer cells to hypoxia, by either low oxygen or cobalt, HIPK2 function was impaired allowing for increased HIF-1alpha expression and inhibiting the p53-apoptotic response to drug. Cobalt suppressed HIPK2 recruitment onto HIF-1alpha promoter. Hypoxia induced expression of the p53 target MDM2 that downregulates HIPK2, thus MDM2 inhibition by siRNA restored the HIPK2/p53Ser46 response to drug. Zinc supplementation to hypoxia-treated cells increased HIPK2 protein stability and nuclear accumulation, leading to restoration of HIPK2 binding to HIF-1alpha promoter, repression of MDR1, Bcl2, and VEGF genes, and activation of the p53 apoptotic response to drug. Combination of zinc and ADR strongly suppressed tumor growth in vivo by inhibiting HIF-1 pathway and upregulating p53 apoptotic target genes. CONCLUSIONS/SIGNIFICANCE:We show here for the first time that hypoxia-induced HIPK2 deregulation was counteracted by zinc that restored HIPK2 suppression of HIF-1 pathway and reactivated p53 apoptotic response to drug, underscoring the potential use of zinc supplementation in combination with chemotherapy to address hypoxia and improve tumor treatment

IT-SNOW: a snow reanalysis for Italy blending modeling, in situ data, and satellite observations (2010-2021)

We present IT-SNOW, a serially complete and multi-year snow reanalysis for Italy (similar to 301 x 10(3) km(2)) - a transitional continental-to-Mediterranean region where snow plays an important but still poorly constrained societal and ecological role. IT-SNOW provides similar to 500 m daily maps of snow water equivalent (SWE), snow depth, bulk snow density, and liquid water content for the initial period 1 September 2010-31 August 2021, with future updates envisaged on a regular basis. As the output of an operational chain employed in real-world civil protection applications (S3M Italy), IT-SNOW ingests input data from thousands of automatic weather stations, snow-covered-area maps from Sentinel-2, MODIS (Moderate Resolution Imaging Spectroradiometer), and H SAF products, as well as maps of snow depth from the spatialization of over 350 on-the-ground snow depth sensors. Validation using Sentinel-1-based maps of snow depth and a variety of independent, in situ snow data from three focus regions (Aosta Valley, Lombardy, and Molise) show little to no mean bias compared to the former, and root mean square errors are of the typical order of 30-60 cm and 90-300 mm for in situ, measured snow depth and snow water equivalent, respectively. Estimates of peak SWE by IT-SNOW are also well correlated with annual streamflow at the closure section of 102 basins across Italy (0.87), with ratios between peak water volume in snow and annual streamflow that are in line with expectations for this mixed rain-snow region (22 % on average and 12 % median). Examples of use allowed us to estimate 13.70 +/- 4.9 Gm3 of water volume stored in snow across the Italian landscape at peak accumulation, which on average occurs on 4 March +/- 10 d. Nearly 52 % of the mean seasonal SWE is accumulated across the Po river basin, followed by the Adige river (23 %), and central Apennines (5 %). IT-SNOW is freely available at https://doi.org/10.5281/zenodo.7034956 (Avanzi et al., 2022b) and can contribute to better constraining the role of snow for seasonal to annual water resources - a crucial endeavor in a warming and drier climate