The phosphorylation state of heptapeptide repeats within the C-terminal domain (CTD) of the largest subunit of RNA Polymerase II (PolII) controls the transcription cycle and is maintained by the competing action of kinases and phosphatases. Rtr1 was recently proposed to be the enzyme responsible for the transition of PolII into the elongation and termination phases of transcription by removing the phosphate marker on Serine 5, but this attribution was questioned by the apparent lack of enzymatic activity. Here we demonstrate that Rtr1 is a phosphatase of new structure that is auto-inhibited by its own C-terminus. The enzymatic activity of the protein in vitro is functionally important in vivo as well: a single amino acid mutation that reduces activity leads to the same phenotype in vivo as deletion of the protein-coding gene from yeast. Surprisingly, Rtr1 dephosphorylates not only Serine 5 on the CTD, but also the newly described anti-termination Tyrosine 1 marker, supporting the hypothesis that Rtr1 and its homologs promote the transition from transcription to termination.
SUMMARY Despite the known causality of copy number variations (CNVs) to human neurodevelopmental disorders, the mechanisms behind each genes’ contribution to the constellation of neural phenotypes remains elusive. Here, we investigated the 7q11.23 CNV, whose hemideletion causes Williams syndrome (WS), and uncovered mitochondrial dysfunction participates in WS pathogenesis. Dysfunction is facilitated in part by the 7q11.23 protein DNAJC30, which interacts with mitochondrial ATP synthase machinery. Removal of Dnajc30 in mice resulted in hypofunctional mitochondria, diminished morphological features of neocortical pyramidal neurons, and altered behaviors reminiscent of WS. The mitochondrial features are consistent with the decreased integrity of oxidative phosphorylation supercomplexes and ATP synthase dimers we observed in WS. Thus, we reveal DNAJC30 as a novel auxiliary component of ATP synthase machinery, and link mitochondrial maladies as underlying certain defects in brain development and function associated with WS.
Synaptic plasticity is identified as innate to hypothalamic feeding circuits in their adaptation to the changing metabolic milieu in control of feeding and obesity. However, less is known about the regulatory principles of the dynamic changes of AgRP perikarya, a crucial region of the neuron gating excitation, and hence, feeding. Here we show that AgRP neurons activated either by food deprivation, ghrelin or chemogenetics decreased their own inhibitory tone while triggering mitochondrial adaptations in neighboring astrocytes. We found that it was the inhibitory neurotransmitter, GABA, released by AgRP neurons that evoked this astrocytic response, which in turn, resulted in increased glial ensheetment of AgRP perikaryal by glial processes and increased excitability of AgRP neurons. We also identified astrocyte-derived prostaglandin E2, which directly activated, via EP2 receptors, AgRP neurons. Taken together, these observations unmasked a feedforward, self-exciting loop in AgRP neuronal control mediated by astrocytes, a mechanism directly relevant for hunger, feeding and overfeeding.
Purpose: To demonstrate robust myelin water fraction (MWF) mapping using an artificial neural network (ANN) with multi-echo gradient-echo (GRE) signal. Methods: Multi-echo gradient-echo signals simulated with a three-pool exponential model were used to generate the training data set for the ANN, which was designed to yield the MWF. We investigated the performance of our proposed ANN for various conditions using both numerical simulations and in vivo data. Simulations were conducted with various SNRs to investigate the performance of the ANN. In vivo data with high spatial resolutions were applied in the analyses, and results were compared with MWFs derived by the nonlinear least-squares algorithm using a complex three-pool exponential model. Results: The network results for the simulations show high accuracies against noise compared with nonlinear least-squares MWFs: RMS-error value of 5.46 for the nonlinear least-squares MWF and 3.56 for the ANN MWF at an SNR of 150 (relative gain = 34.80%). These effects were also found in the in vivo data, with reduced SDs in the region-of-interest analyses. These effects of the ANN demonstrate the feasibility of acquiring high-resolution myelin water images. Conclusion: The simulation results and in vivo data suggest that the ANN facilitates more robust MWF mapping in multi-echo gradient-echo sequences compared with the conventional nonlinear least-squares method. K E Y W O R D S artificial neural network, multi-echo gradient echo, myelin water imaging, T * 2 distribution [Correction added after online publication 18 August, 2020. The authors have corrected the spelling of author name Won-Jin Moon.] | 381 JUNG et al. 1 | INTRODUCTION Myelin water fraction (MWF) as a method for measuring quantitative myelin signals has demonstrated potential to diagnose various demyelinating diseases such as multiple sclerosis, schizophrenia, and stroke. 1,2 Conventional myelin water imaging (MWI) uses multi-echo spin-echo acquisition and nonnegative least-squares estimation, 3,4 whereas more recently multi-echo gradient echo (mGRE) has been suggested. 5-9 These methods provide benefits such as faster acquisition time and lower specific absorption rates. Several studies have proposed methods to acquire high-quality MWI data using mGRE. Such studies suggest applying the nonlinear least-squares (NLLS) algorithm to the acquired signal using a defined model, such as the three-pool exponential model. 8,10 These methods are based on the assumption that the white-matter (WM) water can be reliably modeled by three-pool exponential components with individual frequency shifts. 5,6,8 These methods can be further improved by physiological noise compensation 11 and B 0 field inhomogeneity correction. 10,12,13 Despite these developments, there are still challenges in improving the accuracy and robustness of the MWF. The NLLS (used for estimating MWFs) has been reported to be inaccurate and unstable, especially at low-to-moderate SNRs. 14-16 This requires high SNR data acquisition for MWFs, limiting the scan...
Higher dietary intakes of saturated fatty acid increase the risk of developing Alzheimer’s disease and dementia, and even in people without diabetes higher glucose levels may be a risk factor for dementia. The mechanisms causing neuronal dysfunction and dementia by consuming high-fat diet degrading the integrity of the blood-brain barrier (BBB) has been suggested but are not yet fully understood, and metabolic state of the brain by this type of insult is still veiled. The objective of this study was to investigate the effect of high-fat diet on the brain metabolism by a multimodal imaging method using the hyperpolarizedcarbon 13 (13C)-pyruvate magnetic resonance (MR) spectroscopy and dynamic contrast-enhanced MR imaging in conjunction with the biochemical assay and the behavior test in a mouse model fed high-fat diet (HFD). In mice were fed 60% HFD for 6 months, hyperpolarized [1-13C] pyruvate MR spectroscopy showed decreased perfusion (p < 0.01) and increased conversion from pyruvate to lactate (p < 0.001) in the brain. The hippocampus and striatum showed the highest conversion ratio. The functional integrity of the blood-brain barrier tested by dynamic contrast-enhanced MR imaging showed no difference to the control. Lactate was increased in the cortex (p < 0.01) and striatum (p < 0.05), while PDH activity was decreased in the cortex (p < 0.01) and striatum (p < 0.001) and the phosphorylated PDH was increased in the striatum (p < 0.05). Mice fed HFD showed less efficiency in learning memory compared with control (p < 0.05). To determine whether hyperpolarized 13C-pyruvate magnetic resonance (MR) spectroscopy could detect a much earier event in the brain. Mice fed HFD for 3 months did not show a detectable cognitive decline in water maze based learning memory. Hyperpolarized [1-13C] pyruvate MR spectroscopy showed increased lactate conversion (P < .001), but no difference in cerebral perfusion. These results suggest that the increased hyperpolarized [1-13C] lactate signal in the brain of HFD-fed mice represent that altered metabolic alteration toward to glycolysis and hypoperfusion by the long-term metabolic stress by HFD further promote to glycolysis. The hyperpolarized [1-13C] pyruvate MR spectroscopy can be used to monitor the brain metabolism and will provide information helpful to understand the disease process.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0415-2) contains supplementary material, which is available to authorized users.
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