Sex-specific tonic 2-arachidonoylglycerol signaling at inhibitory inputs onto dopamine neurons of Lister Hooded rats

Addiction as a psychiatric disorder involves interaction of inherited predispositions and environmental factors. Similarly to humans, laboratory animals self-administer addictive drugs, whose appetitive properties result from activation and suppression of brain reward and aversive pathways, respectively. The ventral tegmental area (VTA) where dopamine (DA) cells are located is a key component of brain reward circuitry, whereas the rostromedial tegmental nucleus (RMTg) critically regulates aversive behaviors. Reduced responses to either aversive intrinsic components of addictive drugs or to negative consequences of compulsive drug taking might contribute to vulnerability to addiction. In this regard, female Lister Hooded (LH) rats are more vulnerable than male counterparts to cannabinoid self-administration. We, therefore, took advantage of sex differences displayed by LH rats, and studied VTA DA neuronal properties to unveil functional differences. Electrophysiological properties of DA cells were examined performing either single cell extracellular recordings in anesthetized rats or whole-cell patch-clamp recordings in slices. In vivo, DA cell spontaneous activity was similar, though sex differences were observed in RMTg-induced inhibition of DA neurons. In vitro, DA cells showed similar intrinsic and synaptic properties. However, females displayed larger depolarization-induced suppression of inhibition (DSI) than male LH rats. DSI, an endocannabinoid-mediated form of short term plasticity, was mediated by 2-arachidonoylglycerol (2-AG) activating type 1-cannabinoid (CB1) receptors. We found that sex-dependent differences in DSI magnitude were not ascribed to CB1 number and/or function, but rather to a tonic 2-AG signaling. We suggest that sex specific tonic 2-AG signaling might contribute to regulate responses to aversive intrinsic properties to cannabinoids, thus resulting in faster acquisition/initiation of cannabinoid taking and, eventually, in progression to addiction

Preoperative assessment of cardiovascular risk in patients undergoing noncardiac surgery: The Orion study

In patients undergoing noncardiac surgery risk indices can estimate patients' perioperative risk of major cardiovascular complications. The indexes currently in use were derived from observational studies that are now outdated with respect to the current clinical context. We undertook a prospective, observational, cohort study to derive, validate, and compare a new risk index with established risk indices. We evaluated 7335 patients (mean age 63±13 years) who underwent noncardiac surgery. Based on prospective data analysis of 4600 patients (derivation cohort) we developed an Updated Cardiac Risk Score (UCRS), and validated the risk score on 2735 patients (validation cohort). Four variables (i.e. the UCRS) were significantly associated with the risk of a major perioperative cardiovascular events: high-risk surgery, preoperative estimate glomerular filtration rate <30 ml/min/1.73 m2, age ≥75 years, and history of heart failure. Based on the UCRS we created risk classes 1,2,3 and 4 and their corresponding 30-day risk of a major cardiovascular complication was 0.8% (95% confidence interval [CI] 0.5-1.7), 2.5 (95% CI 1.6-5.6), 8.7 (95% CI 5.2-18.9) and 27.2 (95% CI 11.8-50.3), respectively. No significant differences were found between the derivation and validation cohorts. Receiver operating characteristic (ROC) curves demonstrate a high predictive performance of the new index, with greater power to discriminate between the various classes of risk than the indexes currently used. The high predictive performance and simplicity of the UCRS make it suitable for wide-scale use in preoperative cardiac risk assessment of patients undergoing noncardiac surgery

Tectonic setting of the kenya rift in the nakuru area, based on geophysical prospecting

In this paper, we present results of tectonic and geophysical investigations in the Kenya Rift valley, in the Nakuru area. We compiled a detailed geological map of the area based on published earlier works, well data and satellite imagery. The map was then integrated with original fieldwork and cross sections were constructed. In key areas, we then performed geophysical survey using Electrical Resistivity Tomography (ERT), Hybrid Source AudioMagnetoTelluric (HSAMT), and single station passive seismic measurements (HVSR). In the study area, a volcano-sedimentary succession of the Neogene-Quaternary age characterized by basalts, trachytes, pyroclastic rocks, and tephra with intercalated lacustrine and fluvial deposits crops out. Faulting linked with rift development is evident and occurs throughout the area crosscutting all rock units. We show a rotation of the extension in this portion of the Kenya rift with the NE-SW extension direction of a Neogene-Middle Pleistocene age, followed by the E-Wextension direction of anUpper Pleistocene-Present age. Geophysical investigations allowed to outline main lithostratigraphic units and tectonic features at depth and were also useful to infer main cataclasites and fractured rock bodies, the primary paths for water flow in rocks. These investigations are integrated in a larger EU H2020 Programme aimed to produce a geological and hydrogeological model of the area to develop a sustainable water management system

The use of distance learning and e-learning in students with learning disabilities: A review on the effects and some hint of analysis on the use during covid-19 outbreak

Even if the use of distance learning and E-learning has a long tradition all over the world and both have been used to keep in contact with students and to provide lessons, support and learning materials, there is an open debate on the balance between advantages and disadvantages in the use of distance learning. This debate is even more central in their use to support students with Learning Disabilities (LDs), an overarching group of neurodevelopmental disorders that affect more than 5% of students. The current COVID-19 outbreak caused school closures and the massive use of E-learning all over the world and it put higher attention on the debate of the effects of E-learning. This paper aims to review papers that investigated the positive and negative effects of the use of Distance Learning and E-learning in students with LDs. We conducted a literature review on the relationship between Distance Learning, E-learning and Learning Disabilities, via Scopus, Eric and Google Scholar electronic database, according to Prisma Guidelines. The findings are summarized using a narrative, but systematic, approach. According to the data resulting from the papers, we also discuss issues to be analyzed in future research and in the use of E-learning during the current pandemic of COVID-19

Cholesterol-metabolism, plant sterols, and long-term cognitive decline in older people - Effects of sex and APOEe4.

Neurodegenerative, vascular, and dementia diseases are linked to dysregulations in cholesterol metabolism. Dietary plant sterols, or phytosterols, may interfere to neurodegeneration and cognitive decline, and have cholesterol-lowering, anti-inflammatory, and antioxidant qualities. Here, we investigated the potential associations between circulating cholesterol precursors and metabolites, triglycerides, and phytosterols with cognitive decline in older people by performing multivariate analysis on 246 participants engaged in a population-based prospective study. In our analysis we considered the potential effect of sex and APOEe4. We reveal particular dysregulations of diet-derived phytosterols and endogenous cholesterol synthesis and metabolism, and their variations over time linked to cognitive decline in the general population. These results are significant to the development of interventions to avoid cognitive decline in older adults and suggest that levels of circulating sterols should be taken into account when evaluating risk

High levels of CRBN isoform lacking IMiDs binding domain predicts for a worse response to IMiDs-based upfront therapy in newly diagnosed myeloma patients

In recent years, the immunoderivative (IMiD) agents have been extensively used for the treatment of multiple myeloma (MM). IMiDs and their newer derivatives CRBN E3 ligase modulator bind the E3 ligase substrate recognition adapter protein cereblon (CRBN), which has been recognized as one of the IMiDs’ direct target proteins, and it is essential for the therapeutic effect of these agents. High expression of CRBN was associated with improved clinical response in patients with MM treated with IMiDs, further confirming that the expression of IMiDs’ direct target protein CRBN is required for the anti-MM activity. CRBN’s central role as a target of IMiDs suggests potential utility as a predictive biomarker of response or resistance to IMiDs therapy. Additionally, the presence of alternatively spliced variants of CRBN in MM cells, especially those lacking the drug-binding domain for IMiDs, raise questions concerning their potential biological function, making difficult the transcript measurement, which leads to inaccurate overestimation of full-length CRBN transcripts. In sight of this, in the present study, we evaluated the CRBN expression, both full-length and spliced isoforms, by using real-time assay data from 87 patients and RNA sequencing data from 50 patients (n = 137 newly diagnosed MM patients), aiming at defining CRBN’s role as a predictive biomarker for response to IMiDs-based induction therapy. We found that the expression level of the spliced isoform tends to be higher in not-responding patients, confirming that the presence of a more CRBN spliced transcript predicts for lack of IMiDs response

Multi-dimensional scaling techniques unveiled gain1q&loss13q co-occurrence in Multiple Myeloma patients with specific genomic, transcriptional and adverse clinical features

The complexity of Multiple Myeloma (MM) is driven by several genomic aberrations, interacting with disease-related and/or -unrelated factors and conditioning patients’ clinical outcome. Patient’s prognosis is hardly predictable, as commonly employed MM risk models do not precisely partition high- from low-risk patients, preventing the reliable recognition of early relapsing/refractory patients. By a dimensionality reduction approach, here we dissect the genomic landscape of a large cohort of newly diagnosed MM patients, modelling all the possible interactions between any MM chromosomal alterations. We highlight the presence of a distinguished cluster of patients in the low-dimensionality space, with unfavorable clinical behavior, whose biology was driven by the co-occurrence of chromosomes 1q CN gain and 13 CN loss. Presence or absence of these alterations define MM patients overexpressing either CCND2 or CCND1, fostering the implementation of biology-based patients’ classification models to describe the different MM clinical behaviors

A population-specific reference panel empowers genetic studies of Anabaptist populations

Genotype imputation is a powerful strategy for achieving the large sample sizes required for identification of variants underlying complex phenotypes, but imputation of rare variants remains problematic. Genetically isolated populations offer one solution, however population-specific reference panels are needed to assure optimal imputation accuracy and allele frequency estimation. Here we report the Anabaptist Genome Reference Panel (AGRP), the first whole-genome catalogue of variants and phased haplotypes in people of Amish and Mennonite ancestry. Based on high-depth whole-genome sequence (WGS) from 265 individuals, the AGRP contains >12 M high-confidence single nucleotide variants and short indels, of which ~12.5% are novel. These Anabaptist-specific variants were more deleterious than variants with comparable frequencies observed in the 1000 Genomes panel. About 43,000 variants showed enriched allele frequencies in AGRP, consistent with drift. When combined with the 1000 Genomes Project reference panel, the AGRP substantially improved imputation, especially for rarer variants. The AGRP is freely available to researchers through an imputation server