The acetylation status of lysine residues on histone proteins has long been attributed to a balance struck between the catalytic activity of histone acetyl transferases and histone deacetylases (HDAC). HDACs were identified as the sole removers of acetyl post-translational modifications (PTM) of histone lysine residues. Studies into the biological role of HDACs have also elucidated their role as removers of acetyl PTMs from lysine residues of nonhistone proteins. These findings, coupled with high-resolution mass spectrometry studies that revealed the presence of acyl-group PTMs on lysine residues of nonhistone proteins, brought forth the possibility of HDACs acting as removers of both acyl- and acetyl-based PTMs. We posited that HDACs fulfill this dual role and sought to investigate their specificity. Utilizing a fluorescence-based assay and biologically relevant acyl-substrates, the selectivities of zinc-dependent HDACs toward these acyl-based PTMs were identified. These findings were further validated using cellular models and molecular biology techniques. As a proof of principal, an HDAC3 selective inhibitor was designed using HDAC3’s substrate preference. This resulting inhibitor demonstrates nanomolar activity and >30 fold selectivity toward HDAC3 compared to the other class I HDACs. This inhibitor is capable of increasing p65 acetylation, attenuating NF-κB activation, and thereby preventing downstream nitric oxide signaling. Additionally, this selective HDAC3 inhibition allows for control of HMGB-1 secretion from activated macrophages without altering the acetylation status of histones or tubulin.

Wellbore pressure management is a critical part of the drilling process. In normal drilling practices, static and dynamic fluid pressures are used to contain formation pressures and to assure wellbore stability. Excessive fluid pressure while circulating can create problems including reduced operating margins between fracture and pore pressures and, in the extreme, lost circulation. To address these problems, an Equivalent Circulation Density (ECD) Reduction Tool (RT) has been developed. The ECD RT is designed to counter the frictional pressure effects that exist while circulating. The tool is expected to have a broad range of drilling applications including; the narrow pore/fracture pressure margin deepwater environment, wellbores prone to instability, pressure depleted reservoirs, and extended reach wells. The tool has the potential to:Improve wellbore stabilityExtend hole intervals and reduce casing requirementsImprove well controlReduce lost circulationReduce differential stickingImprove hole cleaning in ERD wells through the use of higher flow rates This paper describes a new downhole tool for ECD reduction, which is run as an integral part of the drill string. A prototype tool has been built to operate inside 10–3/4" to 13–3/8" casing. This tool has undergone laboratory testing and full-scale technology trials are in progress. The design features of this prototype are discussed along with the laboratory test results obtained to date. Introduction This paper describes the development of a novel system for reducing the Equivalent Circulating Density (ECD) of drilling mud. The drive for reducing ECD has become apparent as the industry is faced with increasingly difficult drilling challenges. The initial focus and development for ECD reduction has been directed towards applications in deepwater. Here the issue is overcoming the significant hydrostatic pressure in the riser when it is full of weighted mud (Reference 1). However the concept affords potential benefits in a wide range of drilling applications. The work reported in this study covers the design and testing of a prototype ECD RT that in principle can be applied to a wide range of drilling opportunities (including both onshore and offshore). Benefits of ECD Reduction As the industry has strived to recover hydrocarbons in increasingly challenging areas, it has become apparent that one of the major restrictions is maintaining downhole pressures within the narrow window between pore pressure and fracture gradient. In practice, the window may become even narrower if the minimum required downhole pressure is governed by wellbore stability issues rather than just pore pressure (Reference 2). Since the size of this operating widow dictates the maximum ECD that the well can tolerate, there is clearly a big prize in reducing the magnitude of ECD. The hydrostatic head of the mud column and the frictional pressure loss in the annulus govern ECD. Therefore there are many factors that influence ECD. Conventional well designs often exploit the controlling parameters to ensure ECD's can be minimized. Such optimization methods include: reducing frictional losses through the use of low fluid rheologies; use of casing strings with wider annular clearances; the application of expandable tubulars to preserve hole size; use of drilling liners rather than full casing strings and controlled penetration rates to avoid overloading the annulus with cuttings. In addition, there are more radical methods that can be employed to reduce downhole pressures and hence ECD's. The industry has pioneered underbalanced drilling as a successful method to exploit low pressure and depleted reservoirs. Benefits in penetration rate have also been realized by appropriate application of underbalanced drilling.

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TX 75083-3836 U.S.A., fax 01-972-952-9435. AbstractWellbore pressure management is a critical part of normal drilling practices, where static and dynamic fluid pressures are used to contain formation pressures and to assure wellbore stability. Excessive fluid pressure while circulating can create problems including reduced operating margins between fracture and pore pressures and, in the extreme, lost circulation.To address these problems, an Equivalent Circulation Density (ECD) Reduction Tool (RT) has been developed.The ECD RT is designed to counter the frictional pressure effects that exist while circulating. The tool is expected to have a broad range of drilling applications including the narrow pore/fracture pressure margin deepwater environment, wellbores prone to instability, pressure depleted reservoirs and extended reach wells.The tool has the potential to:• Improve wellbore stability.• Extend hole intervals and reduce casing requirements.• Improve rate of penetration (ROP).• Reduce lost circulation.• Reduce differential sticking.• Improve hole cleaning in extended-reach drilling (ERD) wells through the use of higher flow rates.This paper describes a new downhole tool for ECD reduction, which is run as an integral part of the drill string. A prototype tool has been built, to operate inside 10-3/4" to 13-3/8" casing strings, which has undergone testing in a flow loop and in two experimental wells. The design features of this prototype and the test results obtained so far are discussed in this paper.