Paradoxical enhancement of fear extinction memory and synaptic plasticity by inhibition of the histone acetyltransferase p300

It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory.

Loss of neuronatin expression is associated with promoter hypermethylation in pituitary adenoma

The imprinted gene, neuronatin (NNAT), is one of the most abundant transcripts in the pituitary and is thought to be involved in the development and maturation of this gland. In a recent whole-genome approach, exploiting a pituitary tumour cell line, we identified hypermethylation associated loss of NNAT. In this report, we determined the expression pattern of NNAT in individual cell types of the normal gland and within each of the different pituitary adenoma subtypes. In addition, we determined associations between expression and CpG island methylation and used colony forming efficiency assays (CFE) to gain further insight into the tumour-suppressor function of this gene. Immunohistochemical (IHC) co-localization studies of normal pituitaries showed that each of the hormone secreting cells (GH, PRL, ACTH, FSH and TSH) expressed NNAT. However, 33 out of 47 adenomas comprising, 11 somatotrophinomas, 10 prolactinomas, 12 corticotrophinomas and 14 non-functioning tumours, irrespective of subtype failed to express either NNAT transcript or protein as determined by quantitative real-time RT-PCR and IHC respectively. In normal pituitaries and adenomas that expressed NNAT the promoter-associated CpG island showed characteristics of an imprinted gene where approximately 50% of molecules were densely methylated. However, in the majority of adenomas that showed loss or significantly reduced expression of NNAT, relative to normal pituitaries, the gene-associated CpG island showed significantly increased methylation. Induced expression of NNAT in transfected AtT-20 cells significantly reduced CFE. Collectively, these findings point to an important role for NNAT in the pituitary and perhaps tumour development in this gland.

Pituitary tumours : all silent on the epigenetics front

Investigation of the epigenome of sporadic pituitary tumours is providing a more detailed understanding of aberrations that characterise this tumour type. Early studies, in this and other tumour types adopted candidate-gene approaches to characterise CpG island methylation as a mechanism responsible for or associated with gene silencing. However, more recently, investigators have adopted approaches that do not require a priori knowledge of the gene and transcript, as example differential display techniques, and also genome-wide, array-based approaches, to 'uncover' or 'unmask' silenced genes. Furthermore, through use of chromatin immunoprecipitation as a selective enrichment technique; we are now beginning to identify modifications that target the underlying histones themselves and that have roles in gene-silencing events. Collectively, these studies provided convincing evidence that change to the tumour epigenome are not simply epiphenomena but have functional consequences in the context of pituitary tumour evolution. Our ability to perform these types of studies has been and is increasingly reliant upon technological advances in the genomics and epigenomics arena. In this context, other more recent advances and developing technologies, and, in particular, next generation or flow cell re-sequencing techniques offer exciting opportunities for our future studies of this tumour type.

Genome-wide analysis in a murine Dnmt1 knockdown model identifies epigenetically silenced genes in primary human pituitary tumors

DNA methylation at promoter CpG islands (CGI) is an epigenetic modification associated with inappropriate gene silencing in multiple tumor types. In the absence of a human pituitary tumor cell line, small interfering RNA-mediated knockdown of the maintenance methyltransferase DNA methyltransferase (cytosine 5)-1 (Dnmt1) was used in the murine pituitary adenoma cell line AtT-20. Sustained knockdown induced reexpression of the fully methylated and normally imprinted gene neuronatin (Nnat) in a time-dependent manner. Combined bisulfite restriction analysis (COBRA) revealed that reexpression of Nnat was associated with partial CGI demethylation, which was also observed at the H19 differentially methylated region. Subsequent genome-wide microarray analysis identified 91 genes that were significantly differentially expressed in Dnmt1 knockdown cells (10% false discovery rate). The analysis showed that genes associated with the induction of apoptosis, signal transduction, and developmental processes were significantly overrepresented in this list (P < 0.05). Following validation by reverse transcription-PCR and detection of inappropriate CGI methylation by COBRA, four genes (ICAM1, NNAT, RUNX1, and S100A10) were analyzed in primary human pituitary tumors, each displaying significantly reduced mRNA levels relative to normal pituitary (P < 0.05). For two of these genes, NNAT and S100A10, decreased expression was associated with increased promoter CGI methylation. Induced expression of Nnat in stable transfected AtT-20 cells inhibited cell proliferation. To our knowledge, this is the first report of array-based "epigenetic unmasking" in combination with Dnmt1 knockdown and reveals the potential of this strategy toward identifying genes silenced by epigenetic mechanisms across species boundaries.

Specific rolling circle amplification of low-copy human polyomaviruses BKV, HPyV6, HPyV7, TSPyV, and STLPyV

Eleven new human polyomaviruses have been recently discovered, yet for most of these viruses, little is known of their biology and clinical impact. Rolling circle amplification (RCA) is an ideal method for the amplification of the circular polyomavirus genome due to its high fidelity amplification of circular DNA. In this study, a modified RCA method was developed to selectively amplify a range of polyomavirus genomes. Initial evaluation showed a multiplexed temperature-graded reaction profile gave the best yield and sensitivity in amplifying BK polyomavirus in a background of human DNA, with up to 1 × 10(8)-fold increases in viral genomes from as little as 10 genome copies per reaction. Furthermore, the method proved to be more sensitive and provided a 200-fold greater yield than that of random hexamers based standard RCA. Application of the method to other novel human polyomaviruses showed successful amplification of TSPyV, HPyV6, HPyV7, and STLPyV from low-viral load positive clinical samples, with viral genome enrichment ranging from 1 × 10(8) up to 1 × 10(10). This directed RCA method can be applied to selectively amplify other low-copy polyomaviral genomes from a background of competing non-specific DNA, and is a useful tool in further research into the rapidly expanding Polyomaviridae family.

Effect of the Queensland Shark Control Program on non target species : whale, dugong, turtle and dolphin : a review

The Queensland Shark Control Program (QSCP) aims to protect swimmers at ten beach areas on the east coast of Queensland between Cairns (17°S) and the Gold coast (28°S). Since its inception in 1962 it has deployed shark nets and baited drumlines in a `mixed gear strategy' that adapts the type of gear to the characteristics of a site (e .g . extreme tidal range, high energy wave action, or proximity of turtle breeding areas) . The policy has provided swimmer protection, and the incidental capture of non-target species has been lower than that resulting from deployment of nets alone (Dudley 1997; Gribble et al. 1998b). The QSCP is the only major public-safety shark-control program to routinely use mixed gear. Both the New South Wales (Holt 1998) and KwaZulu-Natal (Dudley 1998) programs use nets exclusively, although the KwaZulu-Natal program has recently tested drumlines on an experimental basis (Dudley 1998; Dudley, personal communication).

Uriah P. Levy collection undated, 1787-1948, 1959, 1961, 1985, 2005.

Contains the notebook and correspondence of Abram Kanof relating to the naval career and activities of Uriah P. Levy; the correspondence, memoranda, newspaper clippings, and a manuscript paper of Isaac Markens pertaining to the alleged claim that Levy was instrumental in abolishing flogging in the Navy; personal documents including a letter to Captain E.A.F. Lavalette concerning the behavior of officers under Levy's command as commodore of the Mediterranean fleet (1859), a photostatic copy of his will and the inventory of his estate (1862), and published material by and about Uriah Phillips Levy including a bound typewritten copy of "Record of Naval Court of Inquiry, 1857;" An essay on flogging in the Navy, 1849; Memorial of Uriah P. Levy, ... 1855; an original copy of a Manual of rules for men-of-war by Captain U.P. Levy, 1862; and Monticello and its preservation, since Jefferson's death, 1862-1902, by George Alfred Townsend. Also contains the halitza of Virginia Lopez Levy, widow of Uriah P. Levy, 1866, signed by J.J. Lyons; copies of letters of Michael Levy to Henry Deering and Dudley Woolridge, 1787-1788, and a published copy of The defense of Captain Jonas P. Levy. Gift, in part, of the Elsie O. and Philip D. Sang Foundation, 1979 and of Herman Herst, Jr., 1987.

Detection of recently discovered human polyomaviruses in a longitudinal kidney transplant cohort

A large number of human polyomaviruses have been discovered in the last 7 years. However, little is known about the clinical impact on vulnerable immunosuppressed patient populations. Blood, urine, and respiratory swabs collected from a prospective, longitudinal adult kidney transplant cohort (n = 167) generally pre-operatively, at day 4, months 1, 3, and 6 posttransplant, and at BK viremic episodes within the first year were screened for 12 human polyomaviruses using real-time polymerase chain reaction. Newly discovered polyomaviruses were most commonly detected in the respiratory tract, with persistent shedding seen for up to 6 months posttransplant. Merkel cell polyomavirus was the most common detection, but was not associated with clinical symptoms or subsequent development of skin cancer or other skin abnormalities. In contrast, KI polyomavirus was associated with respiratory disease in a subset of patients. Human polyomavirus 9, Malawi polyomavirus, and human polyomavirus 12 were not detected in any patient samples.

Marine Flora and Fauna of the Eastern United States: Copepoda, Cyclopoida: Archinotodelphyidae, Notodelphyidae, and Ascidicolidae

This manual includes an introduction to the general biology, a selected bibliography, and an illustrated key to 11 genera and 17 species of copepods of the Crustacea, Subclass Copepoda, Order Cyclopoida, Families Archinotodelphyidae, Notodelphyidae and Ascidicolidae, associated with ascidians from the Atlantic Coast of the United States. Species distributed from the Gulf of Maine to Long Island Sound are emphasized. An annotated systematic list, with statements of the world distribution and new records of association with hosts, and a systematic index are also provided. (PDF file contains 44 pages.)

Larval Fish Recruitment and Research in the Americas: Proceedings of the Thirteenth Annual Larval Fish Conference Merida, Mexico, 21-26 May 1989

The 13th Annual Larval Fish Conference and Annual Meeting of the American Fisheries Society Early Life History Section cohosted by Mote Marine Laboratory, United States, and the Instituto Nacional de la Pesca, Mexico, were held 21-26 May 1989, in Merida, Yucatan, Mexico. The purpose of holding the meeting in Mexico was to encourage the participation of our Latin American and Caribbean colleagues and to provide a forum for the exchange of ideas and information among researchers working in the Americas. More than 150 participants represented 24 U.S. states, the District of Columbia, and 13 foreign countries including Mexico, Canada, Puerto Rico, Costa Rico, Panama, Cuba, Columbia, Chile, Peru, Brazil, Argentina, South Africa, and West Germany. The Conference began with registration and a social in the courtyard patio of the Merida Holiday Inn. Fresh red grouper, the most important commercial finfish species of the State of Yucatan, was prepared and served by the hotel staff, courtesy of CPI, Itzamex, and the Terramar Trading Company. (PDF file contains 146 pages.)

Atlantic menhaden, Brevoortia tyrannus, Purse Seine Fishery, 1972-84, with a brief discussion of age and size composition of the Landings

This report summarizes (I) annual purse seine landings of Atlantic menhaden, Brevoortia tyrannus, for 1972-84, (2) estimated numbers of fish caught by fishing area. (3) estimates of nominal fishing effort and catch-per-unit-effort, (4) mean fish length and weight, and (5) major changes in the fishery. During the 1970s stock size and recruitment increased and the age composition broadened. reversing trends witnessed during the fishery's decline in the 1960s. Landings steadily improved and by 1980 the total coast wide landings exceeded 400,000 metric tons. Nevertheless, the character of the fishery changed considerably. Eleven reduction plants processed fish at seven ports in 1972, but in 1984 only eight plants operated at live ports. Beginning in the mid-1960s the center of fishing aclivity shifted from the Middle Atlantic area to the Chesapeake Bay area, which has continued to dominate the fishery in landings and effort through the 1970s and 1980s. During this period the average size and age of fish in the catches declined. (PDF file contains 30 pages.)