Stress granules induced by oxidative stress in cultured fibroblast from TDP-43 mutant ALS patients

Stress granules (SGs) are transient cytoplasmic aggregates that rapidly form when cells are exposed to stress and consist of large messenger ribonucleoprotein (mRNPs) complexes. The SGs seem to function as storage depots for translation silenced complex and are implicated in stress-induced inhibition of global protein synthesis. Protein aggregation, has been observed in several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). The protein TDP-43 (TAR DNA-Binding Protein-43), encoded by one of the ALS-causative gene (TARDBP), is a major constituent of pathological inclusions in this disease and it is seems to be implicated in the regulation of SGs. Therefore we investigated the different characteristics of SGs in human cultured fibroblasts from ALS patients carrying TARDBPA382T mutation (group 1) versus healthy subjects (group 2). The cells were exposed to stressful conditions using sodium arsenite (SA) at different concentrations (0.5 mM, 1 mM) and exposure times (30 min, 1h). Preliminary results showed, after 30 minutes, small and sporadic cytoplasmic inclusions immunostained for TIA-1(T-cell internal antigen-1), an early marker for SGs, in both groups of cells. After 1h, the TIA-1 immunostained granules were bright, copious and scattered into the cytosol. Interestingly, we observed a significantly higher number of cells exhibiting SGs in fibroblasts from healthy controls (66%) compared to ALS patients (34%). In parallel, we identified the RNA binding protein HuR-1 (Human antigen R) in a fraction of Tia-1 positive SGs, as well as TDP- 43 localized into the nucleus of all the cells. These data raise the possibility that TDP-43 may modulate the stress granule formation, contributing to the cellular response to acute stress. Moreover the TDP-43 may regulate gene expression as well as cellular recovery and survival, and consequently its mutation may contribute to the neurodegeneration

A new point-of-care test for the rapid antimicrobial susceptibility assessment of uropathogens.

Bacterial resistance to antimicrobials is considered a major issue worldwide. This condition may account for treatment failure of urinary tract infections, which are among the most common infections both in community and healthcare settings. Therapy against uropathogens is generally administered empirically, possibly leading to unsuccessful therapy, recurrence and development of antibiotic resistance. The reduction in analytical time to obtain antimicrobial susceptibility test (AST) results could play a key role in reducing the cost of healthcare, providing information about antibiotic efficacy and thus preventing from either exploiting new and expensive antibiotics unnecessarily or using obsolete and ineffective ones. A more rational choice among treatment options would hence lead to more effective treatment and faster resolution. In this paper we evaluated the performance of a new Point Of Care Test (POCT) for the rapid prediction of antimicrobial susceptibility in urine samples performed without the need of a laboratory or specialized technicians. 349 patients were enrolled in two open-label, monocentric, non-interventional clinical trials in partnership with an Emergency Medicine ward and the Day Hospital of two large healthcare facilities in Rome. Antibiogram was carried out on 97 patients. Results from analysis of urine samples with the POCT were compared with those from routine AST performed on culture-positive samples, displaying high accuracy (>90%) for all tested antimicrobial drugs and yielding reliable results in less than 12 hours from urine collection thus reducing analytical and management costs

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use.

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders1. They are heritable2,3 and etiologically related4,5 behaviors that have been resistant to gene discovery efforts6-11. In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

New national and regional Annex I Habitat records: from #83 to #101

New Italian data on the distribution of 17 Annex I Habitats are reported in this contribution. Specifically, 11 new occurrences in Natura 2000 sites are presented and 30 new cells are added in the EEA 10 km × 10 km reference grid. The new data refer to the Italian administrative regions of Apulia, Campania, Calabria, Lazio, Sardinia, Sicily and Tuscany

Preservation of modern and MIS 5.5 erosional landforms and biological structures as sea level markers : a matter of luck?

The Mediterranean Basin is characterized by a significant variability in tectonic behaviour, ranging from subsidence to uplifting. However, those coastal areas considered to be tectonically stable show coastal landforms at elevations consistent with eustatic and isostatic sea level change models. In particular, geomorphological indicators—such as tidal notches or shore platforms—are often used to define the tectonic stability of the Mediterranean coasts. We present the results of swim surveys in nine rocky coastal sectors in the central Mediterranean Sea using the Geoswim approach. The entire route was covered in 22 days for a total distance of 158.5 km. All surveyed sites are considered to have been tectonically stable since the last interglacial (Marine Isotope Stage 5.5 [MIS 5.5]), because related sea level markers fit well with sea level rise models. The analysis of visual observations and punctual measurements highlighted that, with respect to the total length of surveyed coast, the occurrence of tidal notches, shore platforms, and other indicators accounts for 85% of the modern coastline, and only 1% of the MIS 5.5 equivalent. Therefore, only 1% of the surveyed coast showed the presence of fossil markers of paleo sea levels above the datum. This significant difference is mainly attributable to erosion processes that did not allow the preservation of the geomorphic evidence of past sea level stands. In the end, our research method showed that the feasibility of applying such markers to define long-term tectonic behaviour is much higher in areas where pre-modern indicators have not been erased, such as at sites with hard bedrock previously covered by post-MIS 5.5 continental deposits, e.g., Sardinia, the Egadi Islands, Ansedonia, Gaeta, and Circeo. In general, the chances of finding such preserved indicators are very low.peer-reviewe

Chronic Immune Activation in Systemic Lupus Erythematosus and the Autoimmune PTPN22 Trp620 Risk Allele Drive the Expansion of FOXP3+ Regulatory T Cells and PD-1 Expression.

In systemic lupus erythematosus (SLE), perturbed immunoregulation underpins a pathogenic imbalance between regulatory and effector CD4+ T-cell activity. However, to date, the characterization of the CD4+ regulatory T cell (Treg) compartment in SLE has yielded conflicting results. Here we show that patients have an increased frequency of CD4+FOXP3+ cells in circulation owing to a specific expansion of thymically-derived FOXP3+HELIOS+ Tregs with a demethylated FOXP3 Treg-specific demethylated region. We found that the Treg expansion was strongly associated with markers of recent immune activation, including PD-1, plasma concentrations of IL-2 and the type I interferon biomarker soluble SIGLEC-1. Since the expression of the negative T-cell signaling molecule PTPN22 is increased and a marker of poor prognosis in SLE, we tested the influence of its missense risk allele Trp620 (rs2476601C>T) on Treg frequency. Trp620 was reproducibly associated with increased frequencies of thymically-derived Tregs in blood, and increased PD-1 expression on both Tregs and effector T cells (Teffs). Our results support the hypothesis that FOXP3+ Tregs are increased in SLE patients as a consequence of a compensatory mechanism in an attempt to regulate pathogenic autoreactive Teff activity. We suggest that restoration of IL-2-mediated homeostatic regulation of FOXP3+ Tregs by IL-2 administration could prevent disease flares rather than treating at the height of a disease flare. Moreover, stimulation of PD-1 with specific agonists, perhaps in combination with low-dose IL-2, could be an effective therapeutic strategy in autoimmune disease and in other immune disorders

Genetic loci linked to Type 1 Diabetes and Multiple Sclerosis families in Sardinia

<p>Abstract</p> <p>Background</p> <p>The Mediterranean island of Sardinia has a strikingly high incidence of the autoimmune disorders Type 1 Diabetes (T1D) and Multiple Sclerosis (MS). Furthermore, the two diseases tend to be co-inherited in the same individuals and in the same families. These observations suggest that some unknown autoimmunity variant with relevant effect size could be fairly common in this founder population and could be detected using linkage analysis.</p> <p>Methods</p> <p>To search for T1D and MS loci as well as any that predispose to both diseases, we performed a whole genome linkage scan, sequentially genotyping 593 microsatellite marker loci in 954 individuals distributed in 175 Sardinian families. In total, 413 patients were studied; 285 with T1D, 116 with MS and 12 with both disorders. Model-free linkage analysis was performed on the genotyped samples using the Kong and Cox logarithm of odds (LOD) score statistic.</p> <p>Results</p> <p>In T1D, aside from the HLA locus, we found four regions showing a lod-score ≥1; 1p31.1, 6q26, 10q21.2 and 22q11.22. In MS we found three regions showing a lod-score ≥1; 1q42.2, 18p11.21 and 20p12.3. In the combined T1D-MS scan for shared autoimmunity loci, four regions showed a LOD >1, including 6q26, 10q21.2, 20p12.3 and 22q11.22. When we typed more markers in these intervals we obtained suggestive evidence of linkage in the T1D scan at 10q21.2 (LOD = 2.1), in the MS scan at 1q42.2 (LOD = 2.5) and at 18p11.22 (LOD = 2.6). When all T1D and MS families were analysed jointly we obtained suggestive evidence in two regions: at 10q21.1 (LOD score = 2.3) and at 20p12.3 (LOD score = 2.5).</p> <p>Conclusion</p> <p>This suggestive evidence of linkage with T1D, MS and both diseases indicates critical chromosome intervals to be followed up in downstream association studies.</p

Association studies of up to 1.2 million individuals yield new insights into the genetic etiology of tobacco and alcohol use

Tobacco and alcohol use are leading causes of mortality that influence risk for many complex diseases and disorders 1 . They are heritable 2,3 and etiologically related 4,5 behaviors that have been resistant to gene discovery efforts 6–11 . In sample sizes up to 1.2 million individuals, we discovered 566 genetic variants in 406 loci associated with multiple stages of tobacco use (initiation, cessation, and heaviness) as well as alcohol use, with 150 loci evidencing pleiotropic association. Smoking phenotypes were positively genetically correlated with many health conditions, whereas alcohol use was negatively correlated with these conditions, such that increased genetic risk for alcohol use is associated with lower disease risk. We report evidence for the involvement of many systems in tobacco and alcohol use, including genes involved in nicotinic, dopaminergic, and glutamatergic neurotransmission. The results provide a solid starting point to evaluate the effects of these loci in model organisms and more precise substance use measures

Genetic diversity fuels gene discovery for tobacco and alcohol use

Tobacco and alcohol use are heritable behaviours associated with 15% and 5.3% of worldwide deaths, respectively, due largely to broad increased risk for disease and injury(1-4). These substances are used across the globe, yet genome-wide association studies have focused largely on individuals of European ancestries(5). Here we leveraged global genetic diversity across 3.4 million individuals from four major clines of global ancestry (approximately 21% non-European) to power the discovery and fine-mapping of genomic loci associated with tobacco and alcohol use, to inform function of these loci via ancestry-aware transcriptome-wide association studies, and to evaluate the genetic architecture and predictive power of polygenic risk within and across populations. We found that increases in sample size and genetic diversity improved locus identification and fine-mapping resolution, and that a large majority of the 3,823 associated variants (from 2,143 loci) showed consistent effect sizes across ancestry dimensions. However, polygenic risk scores developed in one ancestry performed poorly in others, highlighting the continued need to increase sample sizes of diverse ancestries to realize any potential benefit of polygenic prediction.Peer reviewe