3Hydroxyisobutyrate dehydrogenase HIBADH deficiencyA story dysfunction involving valine metabolic rate

The emergence of the drugs targeting epigenetic alterations has brought an optimistic outlook for cancer patients and probably put an end into the devastating effects of the disease. Given to the prominent involvement of histone deacetylase (HDAC) enzymes in the formation of neoplastic nature of acute promyelocytic leukemia (APL), this study was aimed to evaluate the suppressive effect of pan-HDAC inhibitor panobinostat on both NB4 and primary APL patients cells, either in the context of mono- or co-culture with mesenchymal stem cells (MSC). Panobinostat effectively reduced the survival of APL cells; however, as compared to NB4, the viability of primary cells was inhibited at higher concentrations. Our results also showed that although HDAC inhibition could merely block the survival signals transduced from MSC, the presence of PI3K inhibitor could robustly reinforce panobinostat cytotoxicity; suggesting that MSC-induced activation of PI3K may attenuate, at least partly, the efficacy of HDAC inhibition in APL cells. In addition, cellular and molecular investigations on NB4 revealed that not only panobinostat induced p21-mediated G1 arrest and ROS-mediated apoptosis, but also exerted a superior cytotoxicity when combined with c-Myc and autophagy inhibitors. Last but not least, we found that panobinostat combined with arsenic trioxide (ATO) prompted a synergistic effect and provided an improved therapeutic value in NB4; proposing that the abrogation of HDAC using panobinostat might be a befitting approach in APL, either as a single agent or in a combined-modal strategy. Zearalenone, produced by various Fusarium species, is a non-steroidal estrogenic mycotoxin that contaminates cereals, resulting in adverse effects on human health. We investigated the effects of zearalenone and its metabolite alpha zearalenol on epigenetic modifications and its relationship with metabolic pathways in human hepatocellular carcinoma cells following 24 h of exposure. Zearalenone and alpha zearalenol at the concentrations of 1, 10 and 50 μM significantly increased global levels of DNA methylation and global histone modifications (H3K27me3, H3K9me3, H3K9ac). Expression levels of the chromatin modifying enzymes EHMT2, ESCO1, HAT1, KAT2B, PRMT6 and SETD8 were upregulated by 50 μM of zearalenone exposure using PCR arrays, consistent with the results of global histone modifications. Zearalenone and alpha zearalenol also changed expression levels of the AhR, LXRα, PPARα, PPARɣ, L-fabp, LDLR, Glut2, Akt1 and HK2 genes, which are related to nuclear receptors and metabolic pathways. PPARɣ, a key regulator of lipid metabolism, was selected from among these genes for further analysis. The PPARɣ promoter reduced methylation significantly following zearalenone exposure. Taken together, the epigenetic mechanisms of DNA methylation and histone modifications may be key mechanisms in zearalenone toxicity. Furthermore, effects of zearalenone in metabolic pathways could be mediated by epigenetic modifications. BACKGROUND Previous histopathology and MRI studies have addressed the differences between focal white matter lesions (FWML) and diffusely abnormal white matter (DAWM) in multiple sclerosis (MS). These two categories of white matter T2-weighted (T2w) hyperintensity show different degrees of demyelination, axonal loss and immune cell density on histopathology, potentially offering distinct correlations with symptoms. OBJECTIVES 1) To automate the separation of FWML and DAWM using T2w MRI intensity thresholds and to investigate their differences in magnetization transfer ratios (MTR), which are sensitive to myelin content; 2) to correlate MTR values in FWML and DAWM with normalized signal intensity values on fluid attenuated inversion recovery (FLAIR), T2w, and T1-weighted (T1w) contrasts, as well as with the ratio of T2w/T1w normalized values, in order to determine whether these normalized intensities can be used when MTR is not available. METHODS We used three MRI datasets datasets 1 and 2 had 20 MS participanlized T1w (r ​= ​0.77 to 0.94) intensities. CONCLUSIONS The separation of FWML and DAWM on MRI scans of MS patients using automated intensity thresholds on T2w images is feasible. MTR values are significantly lower in FWML than DAWM, and DAWM values are significantly lower than NAWM, reflecting potentially greater demyelination within focal lesions. T1w normalized intensity values exhibit a significant correlation with MTR values in both tissues of interest and could be used as a proxy to assess demyelination when MTR or other myelin-sensitive images are not available. Increasing the reproducibility of neuroimaging measurement addresses a central impediment to the advancement of human neuroscience and its clinical applications. Recent efforts demonstrating variance in functional brain organization within and between individuals shows a need for improving reproducibility of functional parcellations without long scan times. We apply bootstrap aggregation, or bagging, to the problem of improving reproducibility in functional parcellation. We use two large datasets to demonstrate that compared to a standard clustering framework, bagging improves the reproducibility and test-retest reliability of both cortical and subcortical functional parcellations across a range of sites, scanners, samples, scan lengths, clustering algorithms, and clustering parameters (e.g., number of clusters, spatial constraints). With as little as 6 min of scan time, bagging creates more reproducible group and individual level parcellations than standard approaches with twice as much data. This suggests that regardless of the specific parcellation strategy employed, bagging may be a key method for improving functional parcellation and bringing functional neuroimaging-based measurement closer to clinical impact. TL12-186 PROTAC inhibitor While learning from an instructor by watching a 'how-to' video has become common practice, we know surprisingly little about the relation between brain activities in instructor and observers. In this fMRI study we investigated the temporal synchronization between instructor and observers using intersubject correlation in the naturalistic setting of learning to fold origami. Brain activity of blindfolded instructor during action production was compared to the observers while they viewed the instructor's video-taped actions. We demonstrate for the first time that the BOLD activity in the instructor's and observer's brain are synchronized while observing and learning a manual complex task with the goal of reproducing it. We can rule out that this synchrony originates from visual feedback. Observers exhibiting higher synchrony with the instructor in the ventral premotor cortex, while viewing the video for the first time, were more successful in reproducing the origami afterwards. Furthermore, changes in instructor-observer synchrony across observational learning sessions reside occurs in cerebellar areas, as well as differences in instructor-observer synchrony between learning and the counting folds, our non-learning control.