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Metabolic production of acetyl coenzyme A (acetyl-CoA) is linked to histone acetylation and gene regulation, but the precise mechanisms of this process are largely unknown. Here we show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) directly regulates histone acetylation in neurons and spatial memory in mammals. In a neuronal cell culture model, ACSS2 increases in the nuclei of differentiating neurons and localizes to upregulated neuronal genes near sites of elevated histone acetylation. A decrease in ACSS2 lowers nuclear acetyl-CoA levels, histone acetylation, and responsive expression of the cohort of neuronal genes. In adult mice, attenuation of hippocampal ACSS2 expression impairs long-term spatial memory, a cognitive process that relies on histone acetylation. A decrease in ACSS2 in the hippocampus also leads to defective upregulation of memory-related neuronal genes that are pre-bound by ACSS2. These results reveal a connection between cellular metabolism, gene regulation, and neural plasticity and establish a link between acetyl-CoA generation 'on-site' at chromatin for histone acetylation and the transcription of key neuronal genes.

Drug addiction is a behavioral disorder characterized by dysregulated learning about drugs and associated cues that result in compulsive drug seeking and relapse. Learning about drug rewards and predictive cues is a complex process controlled by a computational network of neural connections interacting with transcriptional and molecular mechanisms within each cell to precisely guide behavior. The interplay between rapid, temporally specific neuronal activation, and longer-term changes in transcription is of critical importance in the expression of appropriate, or in the case of drug addiction, inappropriate behaviors. Thus, these factors and their interactions must be considered together, especially in the context of treatment. Understanding the complex interplay between epigenetic gene regulation and circuit connectivity will allow us to formulate novel therapies to normalize maladaptive reward behaviors, with a goal of modulating addictive behaviors, while leaving natural reward-associated behavior unaffected., (© 2017 Elsevier B.V. All rights reserved.)

Metabolic state and chromatin structure are tightly linked, enabling adaptation of gene expression to changing environment and metabolism. The bioenergetic pathways and enzymes that provide metabolic cofactors for histone modification have recently emerged as central regulators of chromatin. Current research therefore focuses on the dynamic interface of cellular metabolism and chromatin structure. Here, we provide an adaptable approach to examine broadly in changing physiological states, how chromatin structure is dynamically modulated by metabolic activity. We employ two complementary methods: high-throughput sequencing to establish the location of epigenetic changes, and stable isotope tracing using mass spectrometry to evaluate chromatin modification dynamics. Our two-pronged approach is of particular advantage when interrogating how metabolic and oncogenic mutations influence the dynamic relationship between metabolism, nutritional environment, and chromatin regulation., (© 2016 Elsevier Inc. All rights reserved.)

Cell growth is attuned to nutrient availability to sustain homeostatic biosynthetic processes. In unfavorable environments, cells enter a nonproliferative state termed quiescence but rapidly return to the cell cycle once conditions support energetic needs. Changing cellular metabolite pools are proposed to directly alter the epigenome via histone acetylation. Here we studied the relationship between histone modification dynamics and the dramatic transcriptional changes that occur during nutrient-induced cell cycle reentry from quiescence in the yeast Saccharomyces cerevisiae. SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry showed that histone methylation-in contrast to histone acetylation-is surprisingly static during quiescence exit. Chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) revealed genome-wide shifts in histone acetylation at growth and stress genes as cells exit quiescence and transcription dramatically changes. Strikingly, however, the patterns of histone methylation remain intact. We conclude that the functions of histone methylation and acetylation are remarkably distinct during quiescence exit: acetylation rapidly responds to metabolic state, while methylation is independent. Thus, the initial burst of growth gene reactivation emerging from quiescence involves dramatic increases of histone acetylation but not of histone methylation., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Background and Purpose: There is controversy as to the best mode of treating MCA aneurysms. We report the results of a large endovascular series of patients treated at our center., Materials and Methods: This study was a retrospective analysis of a prospectively acquired data base. All patients with saccular MCA aneurysms treated between November 1996 and June 2012 were included. World Federation of Neurosurgical Societies grade, aneurysm site, size, and aneurysm neck size were recorded, along with clinical outcome assessed with the Glasgow Outcome Scale and radiographic occlusion assessed with the Raymond classification at 6 months and 2.5 years., Results: A total of 295 patients with 300 MCA aneurysms were treated including 244 ruptured aneurysms (80.7%). The technical failure rate was 4.3% (13 patients). Complete occlusion or neck remnant was achieved in 264 (91.4%). Complications included rupture in 15 patients (5%), thromboembolism in 17 patients (5.7%), and early rebleeding in 3 patients (1%). Overall permanent procedural-related morbidity and mortality were seen in 12 patients (7.8%). Of the ruptured aneurysms, 189 (79.4%) had a favorable clinical outcome (Glasgow Outcome Scale score, 4-5). A total of 33 patients (13.6%) died. On initial angiographic follow-up, aneurysm remnant was seen in 18 aneurysms (8.1%). A total of 13 patients (4.3%) were re-treated., Conclusions: Our experience demonstrates that endovascular treatment of MCA aneurysms has an acceptable safety profile with low rates of technical failure and re-treatment. Therefore, coiling is acceptable as the primary treatment of MCA aneurysms.

Object: The purpose of this study was to evaluate the usefulness of preoperative magnetic resonance spectroscopy (MRS) in neurosurgical patients with diagnostically challenging intracranial lesions., Methods: Included in this study are twenty-three consecutive patients presenting to the neurosurgery service with diagnostically challenging intracranial lesions and who were investigated by conventional MR imaging and proton ((1)H) MRS, followed by surgery with subsequent histopathological diagnosis. An experienced neuroradiologist (RJ) blinded to the final histopathology evaluated the imaging studies retrospectively. Provisional diagnoses based on preoperative clinical and conventional MR data versus preoperative MRS data were compared with definitive histopathological diagnoses., Results: Compared with preoperative clinical and conventional MR data, (1)H MRS improved the accuracy of MR imaging from 60.9% to 83%. We found (1)H MRS reliably distinguished between abscess and high-grade tumour, and between high-grade glioma and low-grade glioma, but was not able to reliably distinguish between recurrent glioma and radiation necrosis. In 12/23 cases (52%) the (1)H MRS findings positively altered our clinical management. Two representative cases are presented., Conclusions: Our study supports a beneficial role for (1)H MRS in certain diagnostic intracranial dilemmas presenting to neurosurgeons. The information gleaned from preoperative (1)H MRS can be a useful adjunct to clinical and conventional MR imaging data in guiding the management of patients with intracranial pathologies, particularly high-grade tumour versus abscess, and high-grade versus low-grade glioma. Further larger prospective studies are needed to clearly define the utility of (1)H MRS in diagnostically challenging intracranial lesions in neurosurgery.

Tumour cytokinetics estimated in vivo as potential doubling times (T(pot) values) have been found to range in a variety of human cancers from 2 days to several weeks and are often related to clinical outcome. We have previously developed a method to estimate culture cycle times of short-term cultures of surgical material for several tumour types and found, surprisingly, that their range was similar to that reported for T(pot) values. As T(pot) is recognised as important prognostic variable in cancer, we wished to determine whether culture cycle times had clinical significance. Brain tumour material obtained at surgery from 70 patients with glioblastoma, medulloblastoma, astrocytoma, oligodendroglioma and metastatic melanoma was cultured for 7 days on 96-well plates, coated with agarose to prevent proliferation of fibroblasts. Culture cycle times were estimated from relative (3)H-thymidine incorporation in the presence and absence of cell division. Patients were divided into two groups on the basis of culture cycle times of < or =10 days and >10 days and patient survival was compared. For patients with brain cancers of all types, median survival for the < or =10-day and >10-day groups were 5.1 and 12.5 months, respectively (P=0.0009). For 42 patients with glioblastoma, the corresponding values were 6.5 and 9.0 months, respectively (P=0.03). Lower grade gliomas had longer median culture cycle times (16 days) than those of medulloblastomas (9.9 days), glioblastomas (9.8 days) or melanomas (6.7 days). We conclude that culture cycle times determined using short-term cultures of surgical material from brain tumours correlate with patient survival. Tumour cells thus appear to preserve important cytokinetic characteristics when transferred to culture.

Background: It is now generally accepted that chronic pancreatic injury and fibrosis may result from repeated episodes of acute pancreatic necroinflammation (the necrosis-fibrosis sequence). Recent studies suggest that pancreatic stellate cells (PSCs), when activated, may play an important role in the development of pancreatic fibrosis. Factors that may influence PSC activation during pancreatic necroinflammation include cytokines known to be important in the pathogenesis of acute pancreatitis, such as tumour necrosis factor alpha (TNF-alpha), and the interleukins 1, 6, and 10 (IL-1, IL-6, and IL-10)., Aim: To determine the effects of these cytokines on PSC activation, as assessed by cell proliferation, alpha smooth muscle actin (alpha-SMA) expression, and collagen synthesis., Methods: Cultured rat PSCs were incubated with cytokines for 24 hours. Cell proliferation was assessed by measuring (3)H thymidine incorporation into cellular DNA, alpha-SMA expression by western blotting, and collagen synthesis by incorporation of (14)C proline into collagenase sensitive protein. mRNA levels for procollagen alpha(1)(1) in PSCs were determined by northern and dot blotting methods., Results: Expression of alpha-SMA by PSCs was increased on exposure to each of the cytokines used in the study. Stellate cell proliferation was stimulated by TNF-alpha but inhibited by IL-6, while IL-1 and IL-10 had no effect on PSC proliferation. Collagen synthesis by PSCs was stimulated by TNF-alpha and IL-10, inhibited in response to IL-6, and unaltered by IL-1. Changes in collagen protein synthesis in response to TNF-alpha, IL-10, and IL-6 were not regulated at the mRNA level in the cells., Conclusion: This study has demonstrated that PSCs have the capacity to respond to cytokines known to be upregulated during acute pancreatitis. Persistent activation of PSCs by cytokines during acute pancreatitis may be a factor involved in the progression from acute pancreatitis to chronic pancreatic injury and fibrosis.