Comprehensive genomic screens identify a role for PLZF-RAR alpha as a positive regulator of cell proliferation via direct regulation of c-MYC

The t(11; 17)(q23;q21) translocation is associated with a retinoic acid (RA)-insensitive form of acute promyelocytic leukemia (APL), involving the production of reciprocal fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor alpha (PLZF-RAR alpha) and RAR alpha-PLZF. Using a combination of chromatin immuno-precipitation promotor arrays (ChIP-chip) and gene expression profiling, we identify novel, direct target genes of PLZF-RAR alpha that tend to be repressed in APL compared with other myeloid leukemias, supporting the role of PLZF-RAR alpha as an aberrant repressor in APL. In primary murine hematopoietic progenitors, PLZF-RAR alpha promotes cell growth, and represses Dusp6 and Cdkn2d, while inducing c-Myc expression, consistent with its role in leukemogenesis. PLZF-RAR alpha binds to a region of the c-MYC promoter overlapping a functional PLZF site and antagonizes PLZF-mediated repression, suggesting that PLZF-RAR alpha may act as a dominant-negative version of PLZF by affecting the regulation of shared targets. RA induced the differentiation of PLZF-RAR alpha-transformed murine hematopoietic cells and reduced the frequency of clonogenic progenitors, concomitant with c-Myc down-regulation. Surviving RA-treated cells retained the ability to be replated and this was associated with sustained c-Myc expression and repression of Dusp6, suggesting a role for these genes in maintaining a self-renewal pathway triggered by PLZF-RAR alpha. (Blood. 2009; 114: 5499-5511)

Carbachol triggers RyR-dependent Ca(2+) release via activation of IP(3) receptors in isolated rat gastric myocytes.

Possible interactions between different intracellular Ca(2+) release channels were studied in isolated rat gastric myocytes using agonist-evoked Ca(2+) signals. Spontaneous, local Ca(2+) transients were observed in fluo-4-loaded cells with linescan confocal imaging. These were blocked by ryanodine (100 microM) but not by the inositol 1,4,5-trisphosphate receptor (IP(3)R) blocker, 2-aminoethoxydiphenyl borate (100 microM), identifying them as Ca(2+) sparks. Caffeine (10 mM) and carbachol (10 microM) initiated Ca(2+) release at sites which co-localized with each other and with any Ca(2+) spark sites. In fura-2-loaded cells extracellular 2-aminoethoxydiphenyl borate and intracellular heparin (5 mg ml(-1)) both inhibited the global cytoplasmic [Ca(2+)] transient evoked by carbachol, confirming that it was IP(3)R-dependent. 2-Aminoethoxydiphenyl borate and heparin also increased the response to caffeine. This probably reflected an increased Ca(2+) store content since 2-aminoethoxydiphenyl borate more than doubled the amplitude of transients evoked by ionomycin. Ryanodine completely abolished carbachol and caffeine responses but only reduced ionomycin transients by 30 %, suggesting that blockade of carbachol transients by ryanodine was not simply due to store depletion. Double labelling of IP(3)Rs and RyRs demonstrated extensive overlap in their distribution. These results suggest that carbachol stimulates Ca(2+) release through co-operation between IP(3)Rs and RyRs, and implicate IP(3)Rs in the regulation of Ca(2+) store content.

Role of IP(3) in modulation of spontaneous activity in pacemaker cells of rabbit urethra.

Isolated interstitial ("pacemaker") cells from rabbit urethra were examined using the perforated-patch technique. Under voltage clamp at -60 mV, these cells fired large spontaneous transient inward currents (STICs), averaging -860 pA and >1 s in duration, which could account for urethral pacemaker activity. Spontaneous transient outward currents (STOCs) were also observed and fell into two categories, "fast" (1 s in duration). The latter were coupled to STICs, suggesting that they shared the same mechanism, while the former occurred independently at faster rates. All of these currents were abolished by cyclopiazonic acid, caffeine, or ryanodine, suggesting that they were activated by Ca(2+) release. When D-myo-inositol 1,4,5-trisphosphate (IP(3))-sensitive stores were blocked with 2-aminoethoxydiphenyl borate, the STICs and slow STOCs were abolished, but the fast STOCs remained. In contrast, the fast STOCs were more nifedipine sensitive than the STICs or the slow STOCs. These results suggest that while fast STOCs are mediated by a mechanism similar to STOCs in smooth muscle, STICs and slow STOCs are driven by IP(3). These results support the hypothesis that pacemaker activity in the urethra is driven by the IP(3)-sensitive store. PMID: 11287348 [PubMed - indexed for MEDLINE]

Reuseable Silicon IP Cores for Discrete Wavelet Transform Applications

Architectures and methods for the rapid design of silicon cores for implementing discrete wavelet transforms over a wide range of specifications are described. These architectures are efficient, modular, scalable, and cover orthonormal and biorthogonal wavelet transform families. They offer efficient hardware utilization by exploiting a number of core wavelet filter properties and allow the creation of silicon designs that are highly parameterized, including in terms of wavelet type and wordlengths. Control circuitry is embedded within these systems allowing them to be cascaded for any desired level of decomposition without any interface glue logic. The time to produce chip designs for a specific wavelet application is typically less than a day and these are comparable in area and performance to handcrafted designs. They are also portable across a wide range of silicon foundries and suitable for field programmable gate array and programmable logic data implementation. The approach described has also been extended to wavelet packet transforms.

Platform-Independent IP Transmission over Wireless Networks: The WINE Approach

First demonstration of a working dynamically configurable architecture for wireless IP networks. The programmable architecture was as result of a European collaboration between Industry and University and was applied to a range of IP wireless networks. The work laid the foundations for subsequent research initiatives (including the UK) into programmable wireless networks as well as influencing future wireless standards (e.g. ITU-T).EU project WINE (Wireless Internet NEtworking), -1999-10028.

WFI Optimised PWGPS for Wireless IP Networks

The paper describes the design and analysis of a packet scheduler intended to operate over wireless channels with spatially selective error bursts. A particularly innovative aspect in the design is the optimization of the scheduler algorithm to minimize the worst-case fairness index (WFI) for real-time IP traffic.

Packet classification by multi-level cutting of the classification space: An algorithmic-architectural solution for IP packet classification in next generation networks

Traditionally, the Internet provides only a “best-effort” service, treating all packets going to the same destination equally. However, providing differentiated services for different users based on their quality requirements is increasingly becoming a demanding issue. For this, routers need to have the capability to distinguish and isolate traffic belonging to different flows. This ability to determine the flow each packet belongs to is called packet classification. Technology vendors are reluctant to support algorithmic solutions for classification due to their non-deterministic performance. Although CAMs are favoured by technology vendors due to their deterministic high lookup rates, they suffer from the problems of high power dissipation and high silicon cost. This paper provides a new algorithmic-architectural solution for packet classification that mixes CAMs with algorithms based on multi-level cutting the classification space into smaller spaces. The provided solution utilizes the geometrical distribution of rules in the classification space. It provides the deterministic performance of CAMs, support for dynamic updates, and added flexibility for system designers.

Low-frequency electrical response to microbial induced sulfide precipitation

We investigated the sensitivity of low-frequency electrical measurements to microbe-induced metal sulfide precipitation. Three identical sand-packed monitoring columns were used; a geochemical column, an electrical column and a control column. In the first experiment, continuous upward flow of nutrients and metals in solution was established in each column. Cells of Desulfovibrio vulgaris (D. vulgaris) were injected into the center of the geochemical and electrical columns. Geochemical sampling and post-experiment destructive analysis showed that microbial induced sulfate reduction led to metal precipitation on bacteria cells, forming motile biominerals. Precipitation initially occurred in the injection zone, followed by chemotactic migration of D. vulgaris and ultimate accumulation around the nutrient source at the column base. Results from this experiment conducted with metals show (1) polarization anomalies, up to 14 mrad, develop at the bacteria injection and final accumulation areas, (2) the onset of polarization increase occurs concurrently with the onset of lactate consumption, (3) polarization profiles are similar to calculated profiles of the rate of lactate consumption, and (4) temporal changes in polarization and conduction correlate with a geometrical rearrangement of metal-coated bacterial cells. In a second experiment, the same biogeochemical conditions were established except that no metals were added to the flow solution. Polarization anomalies were absent when the experiment was replicated without metals in solution. We therefore attribute the polarization increase observed in the first experiment to a metal-fluid interfacial mechanism that develops as metal sulfides precipitate onto microbial cells and form biominerals. Temporal changes in polarization and conductivity reflect changes in (1) the amount of metal-fluid interfacial area, and (2) the amount of electronic conduction resulting from microbial growth, chemotactic movement and final coagulation. This polarization is correlated with the rate of microbial activity inferred from the lactate concentration gradient, probably via a common total metal surface area effect.

Design of silicon IP cores for biorthogonal wavelet transforms

A methodology for rapid silicon design of biorthogonal wavelet transform systems has been developed. This is based on generic, scalable architectures for the forward and inverse wavelet filters. These architectures offer efficient hardware utilisation by combining the linear phase property of biorthogonal filters with decimation and interpolation. The resulting designs have been parameterised in terms of types of wavelet and wordlengths for data and coefficients. Control circuitry is embedded within these cores that allows them to be cascaded for any desired level of decomposition without any interface logic. The time to produce silicon designs for a biorthogonal wavelet system is only the time required to run synthesis and layout tools with no further design effort required. The resulting silicon cores produced are comparable in area and performance to hand-crafted designs. These designs are also portable across a range of foundries and are suitable for FPGA and PLD implementations.

SLA-driven flexible bandwidth reservation negotiation schemes for QoS aware IP networks

We present a generic Service Level Agreement (SLA)-driven service provisioning architecture, which enables dynamic and flexible bandwidth reservation schemes on a per-user or a per-application basis. Various session level SLA negotiation schemes involving bandwidth allocation, service start time and service duration parameters are introduced and analysed. The results show that these negotiation schemes can be utilised for the benefits of both end user and network provide such as getting the highest individual SLA optimisation in terms of Quality of Service (QoS) and price. A prototype based on an industrial agent platform has also been built to demonstrate the negotiation scenario and this is presented and discussed.

An agent-based control mechanism for WFQ in IP networks

This paper presents a new packet scheduling scheme called agent-based WFQ to control and maintain QoS parameters in virtual private networks (VPNs) within the confines of adaptive networks. Future networks are expected to be open heterogeneous environments consisting of more than one network operator. In this adaptive environment, agents act on behalf of users or third-party operators to obtain the best service for their clients and maintain those services through the modification of the scheduling scheme in routers and switches spanning the VPN. In agent-based WFQ, an agent on the router monitors the accumulated queuing delay for each service. In order to control and to keep the end-to-end delay within the bounds, the weights for services are adjusted dynamically by agents on the routers spanning the VPN. If there is an increase or decrease in queuing delay of a service, an agent on a downstream router informs the upstream routers to adjust the weights of their queues. This keeps the end-to-end delay of services within the specified bounds and offers better QoS compared to VPNs using static WFQ. This paper also describes the algorithm for agent-based WFQ, and presents simulation results. (C) 2003 Elsevier Science Ltd. All rights reserved.