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Relief learning is the association of environmental cues with the cessation of aversive events. While there is increasing knowledge about the neural circuitry mediating relief learning, the respective molecular pathways are not known. Therefore, the aim of the present study was to examine different putative molecular pathways underlying relief learning. To this purpose, male rats were subjected either to relief conditioning or to a pseudo conditioning procedure. Forty-five minutes or 6 h after conditioning, samples of five different brain regions, namely the prefrontal cortex, nucleus accumbens (NAC), dorsal striatum, dorsal hippocampus, and amygdala, were collected. Using quantitative Western blots, the expression level of CREB, pCREB, ERK1/2, pERK1/2, CaMKIIα, MAP2K, PKA, pPKA, Akt, pAkt, DARPP-32, pDARPP-32, 14-3-3, and neuroligin2 were studied. Our analyses revealed that relief conditioned rats had higher CREB phosphorylation in NAC 6 h after conditioning than pseudo conditioned rats. The data further revealed that this CREB phosphorylation was mainly induced by dopamine D1 receptor-mediated activation of PKA, however, other kinases, downstream of the NMDA receptor, may also contribute. Taken together, the present study suggests that CREB phosphorylation, induced by a combination of different molecular pathways downstream of dopamine D1 and NMDA receptors, is essential for the acquisition and consolidation of relief learning.In migraine pain, cannabis has a promising analgesic action, which, however, is associated with side psychotropic effects. To overcome these adverse effects of exogenous cannabinoids, we propose migraine pain relief via activation of the endogenous cannabinoid system (ECS) by inhibiting enzymes degrading endocannabinoids. To provide a functional platform for such purpose in the peripheral and central parts of the rat nociceptive system relevant to migraine, we measured by activity-based protein profiling (ABPP) the activity of the main endocannabinoid-hydrolases, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). We found that in trigeminal ganglia, the MAGL activity was nine-fold higher than that of FAAH. MAGL activity exceeded FAAH activity also in DRG, spinal cord and brainstem. However, activities of MAGL and FAAH were comparably high in the cerebellum and cerebral cortex implicated in migraine aura. MAGL and FAAH activities were identified and blocked by the selective and potent inhibitors JJKK-048/KML29 and JZP327A, respectively. The high MAGL activity in trigeminal ganglia implicated in the generation of nociceptive signals suggests this part of ECS as a priority target for blocking peripheral mechanisms of migraine pain. In the CNS, both MAGL and FAAH represent potential targets for attenuation of migraine-related enhanced cortical excitability and pain transmission.The design and application of Soft Sensors (SSs) in the process industry is a growing research field, which needs to mediate problems of model accuracy with data availability and computational complexity. Black-box machine learning (ML) methods are often used as an efficient tool to implement SSs. Many efforts are, however, required to properly select input variables, model class, model order and the needed hyperparameters. The aim of this work was to investigate the possibility to transfer the knowledge acquired in the design of a SS for a given process to a similar one. This has been approached as a transfer learning problem from a source to a target domain. The implementation of a transfer learning procedure allows to considerably reduce the computational time dedicated to the SS design procedure, leaving out many of the required phases. Two transfer learning methods have been proposed, evaluating their suitability to design SSs based on nonlinear dynamical models. Recurrent neural structures have been used to implement the SSs. In detail, recurrent neural networks and long short-term memory architectures have been compared in regard to their transferability. An industrial case of study has been considered, to evaluate the performance of the proposed procedures and the best compromise between SS performance and computational effort in transferring the model. The problem of labeled data scarcity in the target domain has been also discussed. The obtained results demonstrate the suitability of the proposed transfer learning methods in the design of nonlinear dynamical models for industrial systems.In basketball, the end of the ball possession has been described as one of the most important determinants of successful offensive play by a team. The present study aimed to (i) investigate outcomes according to the play types of ends of the ball possession; (ii) find the most efficient ball possessions during the game; (iii) predict most efficient ends of the ball possession by time in an elite basketball competition. The sample was composed of 38,640 situations of ends of the ball possession from 240 games of the 2017-2018 regular season of the men’s Euroleague that were quantitatively analyzed. According to the results, the predictive model can be used in modern basketball. The most efficient ends of the ball possession are the 2-point field goals on the fast break (78.2%), cuts (64.8%), pick and roll (P&R) screener (61.5%), and transition and offensive rebound (57.4%) situations. This information allows a better collective understanding of basketball, and it could be a great tool to use for coaches to prove which tactical solutions are to be considered when improving offense and defense strategies. It also contributes to the design of precise practice tasks of the coach that improve the game.(1) Background Decreased sound tolerance is a significant problem in tinnitus sufferers. The aim of the study was to evaluate the relationship between tinnitus and decreased sound tolerance (hyperacusis and misophonia). (2) Methods The study sample consisted of 74 patients with tinnitus and decreased sound tolerance. The procedure comprised patient interviews, pure tone audiometry, impedance audiometry, measurement of uncomfortable loudness levels, and administration of the Hyperacusis Questionnaire, Tinnitus Handicap Inventory, and Visual Analogue Scales. (3) Results The majority (69%) of the patients reported that noise aggravated their tinnitus. The correlation between tinnitus and hyperacusis was found to be statistically significant and positive r = 0.44; p 0.05). (4) Conclusions For tinnitus patients the more significant problem was hyperacusis rather than misophonia. The diagnosis and treatment of decreased sound tolerance should take into account not only audiological, but also psychological problems of the patients.Recent study points to the value of a non-linear heart rate variability (HRV) biomarker using detrended fluctuation analysis (DFA a1) for aerobic threshold determination (HRVT). Significance of recording artefact, correction methods and device bias on DFA a1 during exercise and HRVT is unclear. Gas exchange and HRV data were obtained from 17 participants during an incremental treadmill run using both ECG and Polar H7 as recording devices. First, artefacts were randomly placed in the ECG time series to equal 1, 3 and 6% missed beats with correction by Kubios software’s automatic and medium threshold method. Based on linear regression, Bland Altman analysis and Wilcoxon paired testing, there was bias present with increasing artefact quantity. Regardless of artefact correction method, 1 to 3% missed beat artefact introduced small but discernible bias in raw DFA a1 measurements. At 6% artefact using medium correction, proportional bias was found (maximum 19%). Despite this bias, the mean HRVT determination was within 1 bpm across all artefact levels and correction modalities. Second, the HRVT ascertained from synchronous ECG vs. Polar H7 recordings did show an average bias of minus 4 bpm. Polar H7 results suggest that device related bias is possible but in the reverse direction as artefact related bias.Mammalian oocytes must degrade maternal transcripts through a process called translational mRNA decay, in which maternal mRNA undergoes translational activation, followed by deadenylation and mRNA decay. Once a transcript is translationally activated, it becomes deadenylated by the CCR4-NOT complex. Knockout of CCR4-NOT Transcription Complex Subunit 6 Like (Cnot6l), a deadenylase within the CCR4-NOT complex, results in mRNA decay defects during metaphase I (MI) entry. Knockout of B-cell translocation gene-4 (Btg4), an adaptor protein of the CCR4-NOT complex, results in mRNA decay defects following fertilization. Therefore, mechanisms controlling mRNA turnover have significant impacts on oocyte competence and early embryonic development. Post-transcriptional inosine RNA modifications can impact mRNA stability, possibly through a translation mechanism. Here, we assessed inosine RNA modifications in oocytes, eggs, and embryos from Cnot6l-/- and Btg4-/- mice, which display stabilization of mRNA and over-translation of the stabilized transcripts. If inosine modifications have a role in modulating RNA stability, we hypothesize that in these mutant backgrounds, we would observe changes or a disruption in inosine mRNA modifications. To test this, we used a computational approach to identify inosine RNA modifications in total and polysomal RNA-seq data during meiotic maturation (GV, MI, and MII stages). We observed pronounced depletion of inosine mRNA modifications in samples from Cnot6l-/-, but not in Btg4-/- mice. Additionally, analysis of ribosome-associated RNA revealed clearance of inosine modified mRNA. These observations suggest a novel mechanism of mRNA clearance during oocyte maturation, in which inosine-containing transcripts decay in an independent, but parallel mechanism to CCR4-NOT deadenylation.Regulation of calcineurin, a Ca2+/calmodulin-regulated phosphatase, is important for the nervous system, and its abnormal activity is associated with various pathologies, including neurodegenerative disorders. In yeast cells lacking the VPS13 gene (vps13Δ), a model of VPS13-linked neurological diseases, we recently demonstrated that calcineurin is activated, and its downregulation reduces the negative effects associated with vps13Δ mutation. Selisistat Here, we show that overexpression of the RCN2 gene, which encodes a negative regulator of calcineurin, is beneficial for vps13Δ cells. We studied the molecular mechanism underlying this effect through site-directed mutagenesis of RCN2. The interaction of the resulting Rcn2 variants with a MAPK kinase, Slt2, and subunits of calcineurin was tested. We show that Rcn2 binds preferentially to Cmp2, one of two alternative catalytic subunits of calcineurin, and partially inhibits calcineurin. Rcn2 ability to bind to and reduce the activity of calcineurin was important for the suppression. The binding of Rcn2 to Cmp2 requires two motifs in Rcn2 the previously characterized C-terminal motif and a new N-terminal motif that was discovered in this study. Altogether, our findings can help to better understand calcineurin regulation and to develop new therapeutic strategies against neurodegenerative diseases based on modulation of the activity of selected calcineurin isoforms.