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Despite clear technical superiority of genome sequencing (GS) over other diagnostic methods such as exome sequencing (ES), few studies are available regarding the advantages of its clinical application. We analyzed 1007 consecutive index cases for whom GS was performed in a diagnostic setting over a 2-year period. We reported pathogenic and likely pathogenic (P/LP) variants that explain the patients’ phenotype in 212 of the 1007 cases (21.1%). In 245 additional cases (24.3%), a variant of unknown significance (VUS) related to the phenotype was reported. selleck chemical We especially investigated patients which had had ES with no genetic diagnosis (n = 358). For this group, GS diagnostic yield was 14.5% (52 patients with P/LP out of 358). GS should be especially indicated for ES-negative cases since up to 29.6% of them could benefit from GS testing (14.5% with P/LP, n = 52 and 15.1% with VUS, n = 54). Genetic diagnoses in most of the ES-negative/GS-positive cases were determined by technical superiority of GS, i.e., access to noncoding regions and more uniform coverage. Importantly, we reported 79 noncoding variants, of which, 41 variants were classified as P/LP. Interpretation of noncoding variants remains challenging, and in many cases, complementary methods based on direct enzyme assessment, biomarker testing and RNA analysis are needed for variant classification and diagnosis. We present the largest cohort of patients with GS performed in a clinical setting to date. The results of this study should direct the decision for GS as standard second-line, or even first-line stand-alone test.Mitochondrial dysfunction is considered to be one of the important pathogenesis in Parkinson’s disease (PD). We previously showed that pyrroloquinoline quinone (PQQ) could protect SH-SY5Y cells and dopaminergic neurons from cytotoxicity and prevent mitochondrial dysfunction in rotenone-induced PD models. In the present study we investigated the mechanisms underlying the protective effects of PQQ in a mouse PD model, which was established by intraperitoneal injection of rotenone (3 mg·kg-1·d-1, ip) for 3 weeks. Meanwhile the mice were treated with PQQ (0.8, 4, 20 mg·kg-1·d-1, ip) right after rotenone injection for 3 weeks. We showed that PQQ treatment dose-dependently alleviated the locomotor deficits and nigral dopaminergic neuron loss in PD mice. Furthermore, PQQ treatment significantly diminished the reduction of mitochondria number and their pathological change in the midbrain. PQQ dose-dependently blocked rotenone-caused reduction in the expression of PGC-1α and TFAM, two key activators of mitochondrial gene transcription, in the midbrain. In rotenone-injured human neuroblastoma SH-SY5Y cells, PTMScan Direct analysis revealed that treatment with PQQ (100 μM) differentially regulated protein phosphorylation; the differentially expressed phosphorylated proteins included the signaling pathways related with adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) pathway. We conducted Western blot analysis and confirmed that AMPK was activated by PQQ both in PD mice and in rotenone-injured SH-SY5Y cells. Pretreatment with AMPK inhibitor dorsomorphin (4 μM) significantly attenuated the protective effect and mitochondrial biogenesis by PQQ treatment in rotenone-injured SH-SY5Y cells. Taken together, PQQ promotes mitochondrial biogenesis in rotenone-injured mice and SH-SY5Y cells via activation of AMPK signaling pathway.Forsythin extracted from Forsythiae Fructus is widely used to treat fever caused by the common cold or influenza in China, Japan and Korea. The present study aimed to analyze the pharmacokinetics, metabolism and excretion routes of forsythin in humans and determine the major enzymes and transporters involved in these processes. After a single oral administration, forsythin underwent extensive metabolism via hydrolysis and further sulfation. In total, 3 of the 13 metabolites were confirmed by comparison to reference substances, i.e., aglycone M1, M1 sulfate (M2), and M1 glucuronide (M7). Hydrolysis was the initial and main metabolic pathway of the parent compound, followed by extensive sulfation to form M2 and a reduced level of glucuronidation to form M7. In addition, the plasma exposure of M2 and M7 were 86- and 4.2-fold higher than that of forsythin. Within 48 h, ~75.1% of the administered dose was found in urine, with M2 accounting for 71.6%. Further phenotyping experiments revealed that sulfotransferase 1A1 and UDP-glucuronosyltransferase 1A8 were the most active hepatic enzymes involved in the formation of M2 and M7, respectively. The in vitro kinetic study provided direct evidence that M1 showed a preference for sulfation. Sulfated conjugate M2 was identified as a specific substrate of organic anion transporter 3, which could facilitate the renal excretion of M2. Altogether, our study demonstrated that sulfation dominated the metabolism and pharmacokinetics of forsythin, while the sulfate conjugate was excreted mainly in the urine.Despite a growing literature supporting the salutary effects of mindfulness meditation on emotion regulation, the underlying mechanisms linking neural and subjective changes occurring during the actual practice of meditation with emotion regulatory effects observed after meditation remains virtually unexplored. The current study sought to address this gap in knowledge by testing the hypothesis that adoption of internally-directed focused attention, indexed by increased alpha and theta spectral power, during brief open monitoring (OM) mindfulness meditation predicts reduced emotional reactivity, as measured by the late positive potential (LPP). Results revealed that the OM meditation did not produce demonstrable differences in alpha and theta power but did increase self-reported sleepiness relative to controls. Follow-up analyses showed that sleepiness uniquely moderated the effect of meditation on the LPP, such that less sleepiness during meditation, but not the control audio, corresponded to smaller LPPs to negative images. Change in theta, but not alpha power, between meditation and rest was positively correlated with the LPP even after controlling for sleepiness. Although the primary hypothesis was unsupported, the findings demonstrate that phenomenological and neural changes occurring during OM meditation may modulate its subsequent “off-the-cushion” effects on emotional reactivity.