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Parkinson's disease (PD) risk is increased by stress and certain gene mutations, including the most prevalent PD-linked mutation LRRK2-G2019S. Both PD and stress increase risk for psychiatric symptoms, yet it is unclear how PD-risk genes alter neural circuitry in response to stress that may promote psychopathology. Here we show significant differences between adult G2019S knockin and wildtype (wt) mice in stress-induced behaviors, with an unexpected uncoupling of depression-like and hedonic-like responses in G2019S mice. Moreover, mutant spiny projection neurons in nucleus accumbens (NAc) lack an adaptive, stress-induced change in excitability displayed by wt neurons, and instead show stress-induced changes in synaptic properties that wt neurons lack. Some synaptic alterations in NAc are already evident early in postnatal life. Thus, G2019S alters the magnitude and direction of behavioral responses to stress that may reflect unique modifications of adaptive plasticity in cells and circuits implicated in psychopathology in humans.Decisions are made based on the subjective value that the brain assigns to options. However, subjective value is a mathematical construct that cannot be measured directly, but rather inferred from choices. Recent results have demonstrated that reaction time, amplitude, and velocity of movements are modulated by reward, raising the possibility that there is a link between how the brain evaluates an option, and how it controls movements toward that option. Here, we asked people to choose among risky options represented by abstract stimuli, some associated with gain (points in a game), and others with loss. From their choices we estimated the subjective value that they assigned to each stimulus. In probe trials, a single stimulus appeared at center, instructing subjects to make a saccade to a peripheral target. We found that the reaction time, peak velocity, and amplitude of the peripherally directed saccade varied roughly linearly with the subjective value that the participant had assigned to the central stimulus reaction time was shorter, velocity was higher, and amplitude was larger for stimuli that the participant valued more. Naturally, participants differed in how much they valued a given stimulus. Remarkably, those who valued a stimulus more, as evidenced by their choices in decision trials, tended to move with shorter reaction time and greater velocity in response to that stimulus in probe trials. Overall, the reaction time of the saccade in response to a stimulus partly predicted the subjective value that the brain assigned to that stimulus.Background Lermoyez syndrome (LS) is a rare auditory disorder, the details of LS remain unclear.Objectives To investigate the grades of endolymphatic hydrops (ELH) and clinical characteristics of clinically diagnosed LS.Material and methods Nine patients with clinically diagnosed LS were included. three-dimensional-real-infra red imaging characteristics were analyzed. ELH grades and detailed clinical characteristics were evaluated.Results The group consisted of two women and seven men with an age at presentation of 48.4 ± 10.9 (28-61) years, an onset age of 40.9 ± 12.0 (23-58) years, and a disease duration of 7.6 ± 7.5 years. Of the nine patients, ELH was observed in 100% of the patients on the clinically affected side. In addition, 22.2% of vestibular ELH and 77.8% of cochlear ELH were classified as mild or moderate in grade.Conclusions and significance The patients with LS had Meniere's triad, fluctuation of hearing that occurred in a reverse relationship to that of the vertiginous attack, and vestibular and cochlear ELH, which may suggest that LS is a variant of MD. However, the sex difference and milder cochlear ELH in LS compared with those in typical MD may indicate an underlying intrinsic difference in the mechanism of LS.Objectives Tinnitus is a condition that commonly affects individuals' daily activities. Samotolisib We aimed to evaluate the anxiety sensitivity, levels of anxiety and depression, and personality traits of patients with chronic subjective tinnitus.Methods The study included 42 patients, who visited the Otorhinolaryngology Clinic, complained of having tinnitus for at least 1 year and did not have any previous peripheral vestibular diseases or psychiatric treatment history. Forty-five healthy individuals volunteered to be in the control group. We administered the Tinnitus-Severity-Index (TSI), Anxiety-Sensitivity-Index-3 (ASI-3), Beck-Anxiety Inventory (BAI), Beck-Depression-Inventory (BDI) and Eysenck-Personality- Questionnaire (EPQ) to the study participants.Results The BDI score was significantly higher in the patient group. The ASI-3, EPQ, and BAI scores of the patients did not differ statistically. A positive correlation was found between the EPQ neuroticism subscale scores and the ASI-3, BDI, and BAI scores of the patient cases. There was also a positive correlation between the TSI scores and the BAI, ASI-3, and neuroticism scores of the tinnitus group.Conclusion To the best of our knowledge, few studies have evaluated anxiety sensitivity, anxiety and depression levels, and personality traits and no studies evaluating patients and controls together. In cases where tinnitus and psychiatric diseases are comorbid, both conditions should be treated to achieve the best outcomes for the patients' quality of life.KEY POINTSAlthough patients with tinnitus were selected among cases without any psychiatric treatment history, we found that depressive symptoms in this group were high.The participants' anxiety sensitivity, anxiety, and neuroticism scores increased as the severity of their tinnitus increased.The anxiety sensitivity, anxiety, and depressive scores increased along with the increase in the neuroticism scores of the patients with chronic subjective tinnitus.Leukemic stem cells (LSCs) are a major cause of treatment failure and recurrence of acute myeloid leukemia (AML). Targeting LSC is essential to developing a potential cure for patients with relapsed/refractory AML. Here we investigated the effect of aryl hydrocarbon receptor (AhR) signaling on AML stem/progenitor proportion and examined the combined effect of AhR agonist and tyrosine kinase inhibitor. The AhR agonist, 6-formylindolo[3,2-b]carbazole (FICZ), significantly decreased the LSC proportion and clonogenicity and increased differentiation markers in AML primary cells. Synergistic/additive effects of FICZ and gilteritinib, FMS-like tyrosine kinase 3 (FLT3) inhibitor, were confirmed in AML cells with FLT3-ITD. We present evidence that combination of both agents inhibits FLT3 downstream molecules and degrades clonogenicity. Collectively, our results suggest that FICZ not only compels LSC differentiation, but also enhances the efficacy of gilteritinib when combined. Clinical application of this combined approach may pave a new therapeutic strategy for patients with FLT3 mutated AML.
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