Publications by authors named "James M Stafford"

20 Publications

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A Novel Switch Identified to Extinguish Drug-Associated Behaviors.

Authors:
James M Stafford

Biol Psychiatry 2020 06;87(11):e33-e34

Department of Neurological Sciences, University of Vermont, Burlington, Vermont. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2020.03.019DOI Listing
June 2020

Genetic inactivation of mTORC1 or mTORC2 in neurons reveals distinct functions in glutamatergic synaptic transmission.

Elife 2020 03 3;9. Epub 2020 Mar 3.

University of Vermont, Department of Neurological Sciences, Burlington, United States.

Although mTOR signaling is known as a broad regulator of cell growth and proliferation, in neurons it regulates synaptic transmission, which is thought to be a major mechanism through which altered mTOR signaling leads to neurological disease. Although previous studies have delineated postsynaptic roles for mTOR, whether it regulates presynaptic function is largely unknown. Moreover, the mTOR kinase operates in two complexes, mTORC1 and mTORC2, suggesting that mTOR's role in synaptic transmission may be complex-specific. To better understand their roles in synaptic transmission, we genetically inactivated mTORC1 or mTORC2 in cultured mouse glutamatergic hippocampal neurons. Inactivation of either complex reduced neuron growth and evoked EPSCs (eEPSCs), however, the effects of mTORC1 on eEPSCs were postsynaptic and the effects of mTORC2 were presynaptic. Despite postsynaptic inhibition of evoked release, mTORC1 inactivation enhanced spontaneous vesicle fusion and replenishment, suggesting that mTORC1 and mTORC2 differentially modulate postsynaptic responsiveness and presynaptic release to optimize glutamatergic synaptic transmission.
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http://dx.doi.org/10.7554/eLife.51440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080408PMC
March 2020

Automethylation of PRC2 promotes H3K27 methylation and is impaired in H3K27M pediatric glioma.

Genes Dev 2019 10 5;33(19-20):1428-1440. Epub 2019 Sep 5.

Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.

The histone methyltransferase activity of PRC2 is central to the formation of H3K27me3-decorated facultative heterochromatin and gene silencing. In addition, PRC2 has been shown to automethylate its core subunits, EZH1/EZH2 and SUZ12. Here, we identify the lysine residues at which EZH1/EZH2 are automethylated with EZH2-K510 and EZH2-K514 being the major such sites in vivo. Automethylated EZH2/PRC2 exhibits a higher level of histone methyltransferase activity and is required for attaining proper cellular levels of H3K27me3. While occurring independently of PRC2 recruitment to chromatin, automethylation promotes PRC2 accessibility to the histone H3 tail. Intriguingly, EZH2 automethylation is significantly reduced in diffuse intrinsic pontine glioma (DIPG) cells that carry a lysine-to-methionine substitution in histone H3 (H3K27M), but not in cells that carry either EZH2 or EED mutants that abrogate PRC2 allosteric activation, indicating that H3K27M impairs the intrinsic activity of PRC2. Our study demonstrates a PRC2 self-regulatory mechanism through its EZH1/2-mediated automethylation activity.
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http://dx.doi.org/10.1101/gad.328773.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771381PMC
October 2019

Role of Radiation Therapy in the Management of Diffuse Intrinsic Pontine Glioma: A Systematic Review.

Adv Radiat Oncol 2019 Jul-Sep;4(3):520-531. Epub 2019 Mar 30.

Department of Radiation Oncology, Icahn School of Medicine at Mount Sinai, New York, New York.

Purpose: Diffuse intrinsic pontine glioma (DIPG) is the most aggressive primary pediatric brain tumor, with <10% of children surviving 2 years. Radiation therapy (RT) remains the mainstay of treatment, but there is a great clinical need for improvements and advancements in treatment strategies. The aim of this systematic review was to identify all available studies in which RT was used to treat patients with DIPG.

Methods And Materials: A literature search for studies published up to March 10, 2018 was conducted using the PubMed database. We identified 384 articles using search items "diffuse intrinsic pontine glioma" and 221 articles using search items "diffuse brainstem glioma radiotherapy." Included studies were prospective and retrospective series that reported outcomes of DIPG treatment with RT.

Results: We identified 49 studies (1286 patients) using upfront conventionally fractionated RT, 5 studies (92 patients) using hypofractionated RT, and 8 studies (348 patients) using hyperfractionated RT. The mean median overall survival (OS) was 12.0 months, 10.2 months, and 7.9 months in patients who received conventional, hyperfractionated, and hypofractionated RT regimens, respectively. Patients undergoing radiosensitizing therapy had a mean median OS of 11.5 months, and patients who did not receive concomitant systemic therapy had an OS of 9.4 months. In patients who received salvage RT, the mean median OS from initial diagnosis was 16.3 months.

Conclusions: As one of the largest systematic reviews examining RT for DIPG, this report may serve as a useful tool to help clinicians choose the most appropriate treatment approach, while also providing a platform for future investigations into the utility of RT and systemic therapy.
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http://dx.doi.org/10.1016/j.adro.2019.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639749PMC
March 2019

PRC2 is high maintenance.

Genes Dev 2019 08 23;33(15-16):903-935. Epub 2019 May 23.

Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA.

As the process that silences gene expression ensues during development, the stage is set for the activity of Polycomb-repressive complex 2 (PRC2) to maintain these repressed gene profiles. PRC2 catalyzes a specific histone posttranslational modification (hPTM) that fosters chromatin compaction. PRC2 also facilitates the inheritance of this hPTM through its self-contained "write and read" activities, key to preserving cellular identity during cell division. As these changes in gene expression occur without changes in DNA sequence and are inherited, the process is epigenetic in scope. Mutants of mammalian PRC2 or of its histone substrate contribute to the cancer process and other diseases, and research into these aberrant pathways is yielding viable candidates for therapeutic targeting. The effectiveness of PRC2 hinges on its being recruited to the proper chromatin sites; however, resolving the determinants to this process in the mammalian case was not straightforward and thus piqued the interest of many in the field. Here, we chronicle the latest advances toward exposing mammalian PRC2 and its high maintenance.
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http://dx.doi.org/10.1101/gad.325050.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6672058PMC
August 2019

Multiple modes of PRC2 inhibition elicit global chromatin alterations in H3K27M pediatric glioma.

Sci Adv 2018 10 31;4(10):eaau5935. Epub 2018 Oct 31.

Department of Biochemistry and Molecular Pharmacology, NYUSoM, New York, NY, USA.

A methionine substitution at lysine-27 on histone H3 variants (H3K27M) characterizes ~80% of diffuse intrinsic pontine gliomas (DIPG) and inhibits polycomb repressive complex 2 (PRC2) in a dominant-negative fashion. Yet, the mechanisms for this inhibition and abnormal epigenomic landscape have not been resolved. Using quantitative proteomics, we discovered that robust PRC2 inhibition requires levels of H3K27M greatly exceeding those of PRC2, seen in DIPG. While PRC2 inhibition requires interaction with H3K27M, we found that this interaction on chromatin is transient, with PRC2 largely being released from H3K27M. Unexpectedly, inhibition persisted even after PRC2 dissociated from H3K27M-containing chromatin, suggesting a lasting impact on PRC2. Furthermore, allosterically activated PRC2 is particularly sensitive to H3K27M, leading to the failure to spread H3K27me from PRC2 recruitment sites and consequently abrogating PRC2's ability to establish H3K27me2-3 repressive chromatin domains. In turn, levels of polycomb antagonists such as H3K36me2 are elevated, suggesting a more global, downstream effect on the epigenome. Together, these findings reveal the conditions required for H3K27M-mediated PRC2 inhibition and reconcile seemingly paradoxical effects of H3K27M on PRC2 recruitment and activity.
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http://dx.doi.org/10.1126/sciadv.aau5935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209383PMC
October 2018

Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma.

Nat Commun 2018 07 20;9(1):2868. Epub 2018 Jul 20.

Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.

Pineoblastoma is a rare and highly aggressive brain cancer of childhood, histologically belonging to the spectrum of primitive neuroectodermal tumors. Patients with germline mutations in DICER1, a ribonuclease involved in microRNA processing, have increased risk of pineoblastoma, but genetic drivers of sporadic pineoblastoma remain unknown. Here, we analyzed pediatric and adult pineoblastoma samples (n = 23) using a combination of genome-wide DNA methylation profiling and whole-exome sequencing or whole-genome sequencing. Pediatric and adult pineoblastomas showed distinct methylation profiles, the latter clustering with lower-grade pineal tumors and normal pineal gland. Recurrent variants were found in genes involved in PKA- and NF-κB signaling, as well as in chromatin remodeling genes. We identified recurrent homozygous deletions of DROSHA, acting upstream of DICER1 in microRNA processing, and a novel microduplication involving chromosomal region 1q21 containing PDE4DIP (myomegalin), comprising the ancient DUF1220 protein domain. Expresion of PDE4DIP and DUF1220 proteins was present exclusively in pineoblastoma with PDE4DIP gain.
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http://dx.doi.org/10.1038/s41467-018-05029-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054684PMC
July 2018

Low-Grade Astrocytoma Mutations in IDH1, P53, and ATRX Cooperate to Block Differentiation of Human Neural Stem Cells via Repression of SOX2.

Cell Rep 2017 Oct;21(5):1267-1280

Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA; Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA; Brain Tumor Center, NYU School of Medicine, New York, NY 10016, USA; Neuroscience Institute, NYU School of Medicine, New York, NY 10016, USA. Electronic address:

Low-grade astrocytomas (LGAs) carry neomorphic mutations in isocitrate dehydrogenase (IDH) concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer. This occurred because of reduced binding of the chromatin organizer CTCF to its DNA motifs and disrupted chromatin looping. Our human model of IDH mutant LGA formation implicates impaired NSC differentiation because of repression of SOX2 as an early driver of gliomagenesis.
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http://dx.doi.org/10.1016/j.celrep.2017.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687844PMC
October 2017

Pediatric high-grade glioma: biologically and clinically in need of new thinking.

Neuro Oncol 2017 02;19(2):153-161

Departments of Pediatrics, Neurology, and Neurological Surgery, University of California San Francisco, San Francisco, California, USA.

High-grade gliomas in children are different from those that arise in adults. Recent collaborative molecular analyses of these rare cancers have revealed previously unappreciated connections among chromatin regulation, developmental signaling, and tumorigenesis. As we begin to unravel the unique developmental origins and distinct biological drivers of this heterogeneous group of tumors, clinical trials need to keep pace. It is important to avoid therapeutic strategies developed purely using data obtained from studies on adult glioblastoma. This approach has resulted in repetitive trials and ineffective treatments being applied to these children, with limited improvement in clinical outcome. The authors of this perspective, comprising biology and clinical expertise in the disease, recently convened to discuss the most effective ways to translate the emerging molecular insights into patient benefit. This article reviews our current understanding of pediatric high-grade glioma and suggests approaches for innovative clinical management.
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http://dx.doi.org/10.1093/neuonc/now101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464243PMC
February 2017

An AUTS2-Polycomb complex activates gene expression in the CNS.

Nature 2014 Dec;516(7531):349-54

Howard Hughes Medical Institute, New York University Langone School of Medicine, Department of Biochemistry and Molecular Pharmacology, New York, New York 10016, USA.

Naturally occurring variations of Polycomb repressive complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, autism susceptibility candidate 2 (AUTS2). Although AUTS2 is often disrupted in patients with neuronal disorders, the mechanism underlying the pathogenesis is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.
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http://dx.doi.org/10.1038/nature13921DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323097PMC
December 2014

Large-scale topology and the default mode network in the mouse connectome.

Proc Natl Acad Sci U S A 2014 Dec 15;111(52):18745-50. Epub 2014 Dec 15.

Departments of Behavioral Neuroscience and Psychiatry and Advanced Imaging Research Center, and

Noninvasive functional imaging holds great promise for serving as a translational bridge between human and animal models of various neurological and psychiatric disorders. However, despite a depth of knowledge of the cellular and molecular underpinnings of atypical processes in mouse models, little is known about the large-scale functional architecture measured by functional brain imaging, limiting translation to human conditions. Here, we provide a robust processing pipeline to generate high-resolution, whole-brain resting-state functional connectivity MRI (rs-fcMRI) images in the mouse. Using a mesoscale structural connectome (i.e., an anterograde tracer mapping of axonal projections across the mouse CNS), we show that rs-fcMRI in the mouse has strong structural underpinnings, validating our procedures. We next directly show that large-scale network properties previously identified in primates are present in rodents, although they differ in several ways. Last, we examine the existence of the so-called default mode network (DMN)--a distributed functional brain system identified in primates as being highly important for social cognition and overall brain function and atypically functionally connected across a multitude of disorders. We show the presence of a potential DMN in the mouse brain both structurally and functionally. Together, these studies confirm the presence of basic network properties and functional networks of high translational importance in structural and functional systems in the mouse brain. This work clears the way for an important bridge measurement between human and rodent models, enabling us to make stronger conclusions about how regionally specific cellular and molecular manipulations in mice relate back to humans.
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http://dx.doi.org/10.1073/pnas.1404346111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284535PMC
December 2014

Epigenetic inheritance: histone bookmarks across generations.

Trends Cell Biol 2014 Nov 18;24(11):664-74. Epub 2014 Sep 18.

Howard Hughes Medical Institute, Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY, USA. Electronic address:

Multiple circuitries ensure that cells respond correctly to the environmental cues within defined cellular programs. There is increasing evidence suggesting that cellular memory for these adaptive processes can be passed on through cell divisions and generations. However, the mechanisms by which this epigenetic information is transferred remain elusive, largely because it requires that such memory survive through gross chromatin remodeling events during DNA replication, mitosis, meiosis, and developmental reprogramming. Elucidating the processes by which epigenetic information survives and is transmitted is a central challenge in biology. In this review, we consider recent advances in understanding mechanisms of epigenetic inheritance with a focus on histone segregation at the replication fork, and how an epigenetic memory may get passed through the paternal lineage.
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http://dx.doi.org/10.1016/j.tcb.2014.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4254315PMC
November 2014

Exposure to a fearful context during periods of memory plasticity impairs extinction via hyperactivation of frontal-amygdalar circuits.

Learn Mem 2013 Feb 19;20(3):156-63. Epub 2013 Feb 19.

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239-3098, USA.

An issue of increasing theoretical and translational importance is to understand the conditions under which learned fear can be suppressed, or even eliminated. Basic research has pointed to extinction, in which an organism is exposed to a fearful stimulus (such as a context) in the absence of an expected aversive outcome (such as a shock). This extinction process results in the suppression of fear responses, but is generally thought to leave the original fearful memory intact. Here, we investigate the effects of extinction during periods of memory lability on behavioral responses and on expression of the immediate-early gene c-Fos within fear conditioning and extinction circuits. Our results show that long-term extinction is impaired when it occurs during time periods during which the memory should be most vulnerable to disruption (soon after conditioning or retrieval). These behavioral effects are correlated with hyperactivation of medial prefrontal cortex and amygdala subregions associated with fear expression rather than fear extinction. These findings demonstrate that behavioral experiences during periods of heightened fear prevent extinction and prolong the conditioned fear response.
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http://dx.doi.org/10.1101/lm.029801.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3578276PMC
February 2013

Increasing histone acetylation in the hippocampus-infralimbic network enhances fear extinction.

Biol Psychiatry 2012 Jul 29;72(1):25-33. Epub 2012 Jan 29.

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, 97239-3098, USA.

Background: A key finding from recent studies of epigenetic mechanisms of memory is that increasing histone acetylation after a learning experience enhances memory consolidation. This has been demonstrated in several preparations, but little is known about whether excitatory and inhibitory memories are equally sensitive to drugs that promote histone acetylation and how transcriptional changes in the hippocampal-medial prefrontal cortex network contribute to these drug effects.

Methods: We compare the long-term behavioral consequences of systemic, intrahippocampal and intra-medial prefrontal cortex administration of the histone deacetylase inhibitor sodium butyrate (NaB) after contextual fear conditioning and extinction 1 and/or 14 days later in male c57BL/6J mice (n = 302). Levels of histone acetylation and expression of the product of the immediate-early gene c-Fos were assessed by immunohistochemistry following infusion of NaB into the hippocampus (n = 26).

Results: Across a variety of conditions, the effects of NaB on extinction were larger and more persistent compared to the effects on initial memory formation. NaB administered following weak extinction induced behavioral extinction, infralimbic histone acetylation and c-Fos expression consistent with strong extinction. No similar effect was seen in the prelimbic cortex. The involvement of the infralimbic cortex was confirmed as infusions of NaB into the infralimbic, but not prelimbic cortex, induced extinction enhancements.

Conclusions: These studies show that the memory modulating ability of drugs that enhance acetylation is sensitive to a variety of behavioral and molecular conditions. We further identify transcriptional changes in the hippocampal-infralimbic circuit associated with extinction enhancements induced by the histone deacetylase inhibitor NaB.
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http://dx.doi.org/10.1016/j.biopsych.2011.12.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3352991PMC
July 2012

Is an epigenetic switch the key to persistent extinction?

Neurobiol Learn Mem 2011 Jul 23;96(1):35-40. Epub 2011 Apr 23.

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, United States.

Many studies of learning have demonstrated that conditioned behavior can be eliminated when previously established relations between stimuli are severed. This extinction process has been extremely important for the development of learning theories and, more recently, for delineating the neurobiological mechanisms that underlie memory. A key finding from behavioral studies of extinction is that extinction eliminates behavior without eliminating the original memory; extinguished behavior often returns with time or with a return to the context in which the original learning occurred. This persistence of the original memory after extinction creates a challenge for clinical applications that use extinction as part of a treatment intervention. Consequently, a goal of recent neurobiological research on extinction is to identify potential pharmacological targets that may result in persistent extinction. Drugs that promote epigenetic changes are particularly promising because they can result in a long-term molecular signal that, combined with the appropriate behavioral treatment, can cause persistent changes in behavior induced by extinction. We will review evidence demonstrating extinction enhancements by drugs that target epigenetic mechanisms and will describe some of the challenges that epigenetic approaches face in promoting persistent suppression of memories.
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http://dx.doi.org/10.1016/j.nlm.2011.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3111857PMC
July 2011

When the medial prefrontal cortex fails: implications for extinction and posttraumatic stress disorder treatment.

J Neurosci 2010 May;30(21):7124-6

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239-3098, USA.

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http://dx.doi.org/10.1523/JNEUROSCI.1413-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2891040PMC
May 2010

Direct comparisons of the size and persistence of anisomycin-induced consolidation and reconsolidation deficits.

Learn Mem 2009 Aug 24;16(8):494-503. Epub 2009 Jul 24.

Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon 97239-3098, USA.

An issue of increasing theoretical interest in the study of learning is to compare the processes that follow an initial learning experience (such as learning an association between a context and a shock; memory consolidation processes) with those that follow retrieval of that learning experience (such as exposure to the context in the absence of shock; memory reconsolidation and extinction processes). Much of what is known about these processes comes from separate experiments examining one process or the other; there have been few attempts to compare these processes directly in a single experiment. A challenge in between-experiment comparisons of consolidation and reconsolidation deficits is that they frequently involve comparisons between groups that are not matched on factors that may influence the size and persistence of these deficits (e.g., prior learning experience, memory expression prior to deficit). The following experiments examined the size and persistence of these deficits after matching both the amount of experience with a context and the levels of performance in that context prior to delivery of the protein synthesis inhibitor anisomycin. We found that systemic or intrahippocampal administration of anisomycin caused a deficit in groups receiving context conditioning (consolidation groups) or reactivation (reconsolidation groups) immediately prior to the injections. With systemic injections, the deficit was larger and more persistent in consolidation groups; with intrahippocampal injections, the initial deficit was statistically identical, yet was more persistent in the consolidation group. These experiments showed that when experiences and performance are matched prior to anisomycin injections, consolidation deficits are generally larger and more persistent compared to reconsolidation deficits.
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http://dx.doi.org/10.1101/lm.1452209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726013PMC
August 2009

What does it take to demonstrate memory erasure? Theoretical comment on Norrholm et al. (2008).

Behav Neurosci 2008 Oct;122(5):1186-90

Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239-3098, USA.

An issue of increasing interest in Pavlovian conditioning is to identify ways to facilitate the development and persistence of extinction. Both behavioral and molecular lines of evidence demonstrate that learning during extinction can be enhanced. Similar evidence has been offered to support the idea that extinction causes the original association to be unlearned, or erased. Differentiating between extinction and erasure accounts is extremely difficult and requires many assumptions about the fundamental nature of how memory storage maps into memory expression. In this issue of Behavioral Neuroscience, Norrholm et al. (see record 2008-13280-002) describe a study of extinction with humans that has the potential to serve as a translational bridge between rodent work and clinical applications. They find less recovery of a conditioned fear response when extinction occurs 10 min compared with 72 hr after conditioning; however, the recovery of subjects' expectancies of the fearful stimulus is independent of when extinction occurred. These findings and others discussed in this article demonstrate some of the challenges in making inferences about memory erasure during extinction.
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http://dx.doi.org/10.1037/a0012993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2559954PMC
October 2008

Accessibility of the distal heme face, rather than Fe-His bond strength, determines the heme-nitrosyl coordination number of cytochromes c': evidence from spectroscopic studies.

Biochemistry 2005 Jun;44(24):8664-72

Department of Chemistry & Biochemistry, Eastern Oregon University, La Grande, Oregon 97850-2899, USA.

The heme coordination chemistry and spectroscopic properties of Rhodobacter capsulatus cytochrome c' (RCCP) have been compared to data from Alcaligenes xylosoxidans (AXCP), with the aim of understanding the basis for their different reactivities with nitric oxide (NO). Whereas ferrous AXCP reacts with NO to form a predominantly five-coordinate heme-nitrosyl complex via a six-coordinate intermediate, RCCP forms an equilibrium mixture of six-coordinate and five-coordinate heme-nitrosyl species in approximately equal proportions. Ferrous RCCP and AXCP both exhibit high Fe-His stretching frequencies (227 and 231 cm(-)(1), respectively), suggesting that factors other than the Fe-His bond strength account for their differences in heme-nitrosyl coordination number. Resonance Raman spectra of ferrous-nitrosyl RCCP confirm the presence of both five-coordinate and six-coordinate heme-NO complexes. The six-coordinate heme-nitrosyl of RCCP exhibits a fairly typical Fe-NO stretching frequency (569 cm(-)(1)), in contrast to the relatively high value (579 cm(-)(1)) of the AXCP six-coordinate heme-nitrosyl intermediate. It is proposed that NO experiences greater steric hindrance in binding to the distal face of AXCP, as compared to RCCP, leading to a more distorted Fe-N-O geometry and an elevated Fe-NO stretching frequency. Evidence that RCCP has a more accessible distal coordination site than in AXCP stems from the fact that ferric RCCP readily forms a heme complex with exogenous imidazole, whereas AXCP does not. A model is proposed in which distal heme-face accessibility, rather than the proximal Fe-His bond strength, determines the heme-nitrosyl coordination number in cytochromes c'.
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http://dx.doi.org/10.1021/bi050428gDOI Listing
June 2005

Hemophilic pseudotumor: radiologic-pathologic correlation.

Radiographics 2003 Jul-Aug;23(4):852-6

Department of Radiology, University of Tennessee Medical Center, Knoxville 37920, USA.

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http://dx.doi.org/10.1148/rg.234025154DOI Listing
August 2003