Ozanimod, recently approved for treating relapsing MS, produced a disproportionate, active, MAO B-catalyzed metabolite (CC112273) that showed remarkable interspecies differences and led to challenges in safety testing. This study explored the kinetics of CC112273 formation from its precursor RP101075. Incubations with human liver mitochondrial fractions revealed KMapp, Vmax and Clint for CC112273 formation to be 4.8 mM, 50.3 pmol/min/mg protein and 12 ml/min/mg, respectively, while KM with human recombinant MAO B was 1.1 mM. Studies with liver mitochondrial fractions from preclinical species led to KMapp, Vmax and Clint estimates of 3.0, 35 and 33 mM, 80.6, 114, 37.3 pmol/min/mg and 27.2, 3.25 and 1.14 ml/min/mg in monkey, rat and mouse, respectively, and revealed marked differences between rodents and primates, primarily attributable to differences in the KM Comparison of Clint estimates revealed monkey to be ~two-fold more efficient and the mouse and rat to be 11 and 4-fold less efficient than humans in CC1at marked species difference and notable stereospecificity was observed in MAO B catalyzed biotransformation when the indaneamine enantiomers were used as a substrates.Ferroptosis is a form of oxidative cell death which is increasingly recognized as a key mechanism in neurodegeneration but also in regulated cell death causing disease in other tissues. In neurons, major hallmarks of ferroptosis involve the accumulation of lipid reactive oxygen species (ROS) and impairment of mitochondrial morphology and function. Compounds that interfere with ferroptosis could provide novel treatment options for neurodegenerative disorders and other diseases involving ferroptosis. In the present study, we developed new compounds by refining structural elements of the BID inhibitor BI-6c9, that was previously demonstrated to block ferroptosis signaling at the level of mitochondria. Here, we inserted an antioxidative diphenylamine (DPA) structure to the BI-6c9 structure. These DPA compounds were then tested in models of erastin and RSL-3 induced ferroptosis in neuronal HT22 cells. The DPA compounds showed an increased protective potency against ferroptotic cell death compared to the scaffold m by preventing the development of different ROS species and by protecting mitochondria from ferroptotic impairments.Opioid use disorder (OUD) is a major socioeconomic burden. An ideal OUD pharmacotherapy will mitigate the suffering associated with opioid-withdrawal, inhibit the effects of high efficacy opioids and minimize opioid-cravings, while being safe and accessible to a diverse patient population. Although current OUD pharmacotherapies inhibit the euphoric effects of opioids of abuse, the extent to which they safely alleviate withdrawal and opioid-cravings, corresponds with their intrinsic µ opioid receptor (MOR) efficacy. The medium efficacy MOR agonist buprenorphine in addition to inhibiting the euphoric effects of opioids of abuse, alleviates withdrawal and opioid-cravings, but its intrinsic MOR-efficacy is sufficient such that its utility is limited by abuse and safety liabilities. In contrast, although the MOR antagonist naltrexone minimizes euphoria and has no abuse liability, it exacerbates suffering associated with withdrawal and opioid-cravings. These observations indicate that a therapeutic with intrinsic MOR activity between the partial agonist (buprenorphine) and the antagonist (naltrexone) would strike a balance between the benefits and liabilities of these two therapeutics. To address this need, we derived RM1490, a MOR-agonist based on a non-morphinan scaffold, which exhibits approximately half the intrinsic MOR efficacy of buprenorphine. In a series of preclinical assays, we compared RM1490 to buprenorphine and naltrexone at doses that achieve therapeutic levels of occupancy of CNS MORs. RM1490 exhibited a behavioral profile consistent with reduced reward, dependence and precipitated withdrawal liabilities. RM1490 was also more effective than buprenorphine at reversing the respiratory depressant effects of fentanyl, and did not suppress respiration when combined with diazepam. Significance Statement In preclinical our studies, RM1490 has a physiological and behavioral profile suitable for OUD maintenance therapy.Tumor cells can evade immune surveillance and immune killing during the emergence of endocrine therapy resistance in prostate cancer, but the mechanisms underlying this phenomenon are still unclear. Flightless I homolog (FLII) is a coregulator for transcription factors in several malignancies. Here, we have demonstrated that endocrine therapy resistance can induce an immunosuppressive prostate tumor microenvironment and immune evasion through FLII downregulation, which leads to activation of the YBX1/PD-L1 signaling pathway. FLII expression negatively correlated with expression of PD-L1 in tumors. Mechanism studies demonstrated that FLII physically interacted with YBX1 to inhibit nuclear localization of YBX1 and thereby suppress transcription of PDL1 in enzalutamide-resistant tumors. Restoration of FLII expression reversed enzalutamide resistance through activation of T-cell responses in the tumor microenvironment through inhibition of the YBX1/PD-L1 pathway. We also found that reversal of endocrine therapy resistance and immune evasion was mediated by proliferation of effector CD8+ T cells and inhibition of tumor infiltration by regulatory T cells and myeloid-derived suppressor cells. Taken together, our results demonstrate a functional and biological interaction between endocrine therapy resistance and immune evasion mediated through the FLII/YBX1/PD-L1 cascade. Combination therapy with FLII expression and endocrine therapy may benefit patients with prostate cancer by preventing tumor immune evasion.Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (HTT) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, Htt Q175/+, and from wild-type controls. We used 14- to 15-month-old male mice, a time point at which multiple behavioral, neuroanatomical, and neurophysiological changes are present but at which there is no known cell death. check details Thousands of differentially expressed genes (DEGs) were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell type-specific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes.