P2Y(1) antagonists: Combining receptor-based modeling and QSAR for a quantitative prediction of the biological activity based on consensus scoring

P2Y(1) is an ADP-activated G protein-coupled receptor (GPCR). Its antagonists impede platelet aggregation in vivo and are potential antithrombotic agents. Combining ligand and structure-based modeling we generated a consensus model (LIST-CM) correlating antagonist structures with their potencies. We docked 45 antagonists into our rhodopsin-based human P2Y(1) homology model and calculated docking scores and free binding energies with the Linear Interaction Energy (LIE) method in continuum-solvent. The resulting alignment was also used to build QSAR based on CoMFA, CoMSIA, and molecular descriptors. To benefit from the strength of each technique and compensate for their limitations, we generated our LIST-CM with a PLS regression based on the predictions of each methodology. A test set featuring untested substituents was synthesized and assayed in inhibition of 2-MeSADP-stimulated PLC activity and in radioligand binding. LIST-CM outperformed internal and external predictivity of any individual model to predict accurately the potency of 75% of the test set.

Late Quaternary glaciations in Far NE Russia; combining moraines, topography and chronology to assess regional and global glaciation synchrony

During various periods of Late Quaternary glaciation, small ice-sheets, -caps, -fields and valley glaciers, occupied the mountains and uplands of Far NE Russia (including the Verkhoyansk, Suntar-Khayata, and Chersky Mountains; the KolymaeAnyuy and Koryak Highlands; and much of the Kamchatka and Chukchi
Peninsulas). Here, the margins of former glaciers across this region are constrained through the comprehensive mapping of moraines from remote sensing data (Landsat 7 ETM+ satellite images; ASTER Global Digital Elevation Model (GDEM2); and Viewfinder Panorama DEM data). A total of 8414 moraines
are mapped, and this record is integrated with a series of published age-estimates (n = 25), considered to chronologically-constrain former ice-margin positions. Geomorphological and chronological data are compiled in a Geographic Information System (GIS) to produce ‘best estimate’ reconstructions of ice extent during the global Last Glacial Maximum (gLGM) and, to a lesser degree, during earlier phases of glaciation. The data reveal that much of Far NE Russia (~1,092,427 km2) preserves a glaciated landscape (i.e. is bounded by moraines), but there is no evidence of former ice masses having extended more than 270 km beyond mountain centres (suggesting that, during the Late Quaternary, the region has not been occupied by extensive ice sheets). During the gLGM, specifically, glaciers occupied ~253,000 km2, and rarely extended more than 50 km in length. During earlier (pre-gLGM) periods, glaciers were more extensive, though the timing of former glaciation, and the maximum Quaternary extent, appears to have been asynchronous across the region, and out-of-phase with ice-extent maxima elsewhere in the Northern Hemisphere. This glacial history is partly explained through consideration of climatic-forcing
(particularly moisture-availability, solar insolation and albedo), though topographic-controls upon the former extent and dynamics of glaciers are also considered, as are topographic-controls upon moraine deposition and preservation. Ultimately, our ability to understand the glacial and climatic history of this region is restricted when the geomorphological-record alone is considered, particularly as directly-dated glacial deposits are few, and topographic and climatic controls upon the moraine record are difficult to
distinguish.

A 76-84 GHz SiGe power amplifier array employing low-loss four-way differential combining transformer

This paper presents holistic design of a novel four-way differential power-combining transformer for use in millimeter-wave power-amplifier (PA). The combiner with an inner radius of 25 µm exhibits a record low insertion loss of 1.25 dB at 83.5 GHz. It is designed to simultaneously act as a balanced-to-unbalanced converter, removing the need for additional BALUNs typically required in differential circuits. A complete circuit comprised of a power splitter, two-stage differential cascode PA array, a power combiner as well as input and output matching elements was designed and realized in SiGe technology with f/f 170/250 GHz. Measured small-signal gain of at least 16.8 dB was obtained from 76.4 to 85.3 GHz with a peak 19.5 dB at 83 GHz. The prototype delivered 12.5 dBm output referred 1 dB compression point and 14 dBm saturated output power when operated from a 3.2 V dc supply voltage at 78 GHz.

Amplitude-modulation characteristics of power-combining Class-E amplifier with finite choke

Power back-off performances of a new variant power-combining Class-E amplifier under different amplitude-modulation schemes such as continuous wave (CW), envelope elimination and restoration (EER), envelope tracking (ET) and outphasing are for the first time investigated in this study. Finite DC-feed inductances rather than massive RF chokes as used in the classic single-ended Class-E power amplifier (PA) resulted from the approximate yet effective frequency-domain circuit analysis provide the wherewithal to increase modulation bandwidth up to 80% higher than the classic single-ended Class-E PA. This increased modulation bandwidth is required for the linearity improvement in the EER/ET transmitters. The modified output load network of the power-combining Class-E amplifier adopting three-harmonic terminations technique relaxes the design specifications for the additional filtering block typically required at the output stage of the transmitter chain. Qualitative agreements between simulation and measurement results for all four schemes were achieved where the ET technique was proven superior to the other schemes. When the PA is used within the ET scheme, an increase of average drain efficiency of as high as 40% with respect to the CW excitation was obtained for a multi-carrier input signal with 12 dB peak-to-average power ratio. © 2011 The Institution of Engineering and Technology.

2.4 GHz high-efficiency power-combining Class-E amplifier with transmission-line harmonic traps

Experimental assessments of the modified power-combining Class-E amplifier are described. The technique used to combine the output of individual power amplifiers (PAs) into an unbalanced load without the need for bulky transformers permits the use of small RF chokes useful for the deployment in the EER transmitter. The modified output load network of the PA results in excellent 50 dBc and 46 dBc second and third-harmonic suppressions, dispensing the need for additional lossy filtering block. Operating from a 3.2 V dc supply voltage, the PA exhibits 64% drain efficiency at 24 dBm output power. Over a wide bandwidth of 350 MHz, drain efficiency of better than 60% at output power higher than 22 dBm were achieved. © 2010 IEICE Institute of Electronics Informati.

Power back-off behaviour of high-efficiency power-combining Class-E amplifier

Power back-off performances of the modified power-combining Class-E amplifier under different amplitudemodulation schemes such as envelope elimination and restoration (EER) and envelope tracking (ET) are experimentally assessed in this paper. The modified output load network adopting three-harmonic terminations technique eliminates the need for additional lossy filtering section in the transmitter chain. Small dc-feed inductances rather than massive RF chokes as in the classic Class-E amplifier are used so as to increase the modulation bandwidth and therefore improve the linearity of the EER transmitter. High efficiency over a wide dynamic range using amplitude modulation through drain-voltage control (EER) was achieved and this agrees well with the Class-E theoretical prediction. When the PA was used within the ET scheme, an increase of average drain efficiency of as high as 40% with respect to the CW excitation was obtained for a multi-carrier input signal with 12dB peak-to-average power ratio. © 2011 Institut fur Mikrowellen.

Combining missing-feature theory, speech enhancement, and speaker-dependent/-independent modeling for speech separation

This paper considers the separation and recognition of overlapped speech sentences assuming single-channel observation. A system based on a combination of several different techniques is proposed. The system uses a missing-feature approach for improving crosstalk/noise robustness, a Wiener filter for speech enhancement, hidden Markov models for speech reconstruction, and speaker-dependent/-independent modeling for speaker and speech recognition. We develop the system on the Speech Separation Challenge database, involving a task of separating and recognizing two mixing sentences without assuming advanced knowledge about the identity of the speakers nor about the signal-to-noise ratio. The paper is an extended version of a previous conference paper submitted for the challenge.

A 75-81 GHz, 14.3 dBm Peak Output Power, 21 dB Peak Gain, SiGe Power-Combining Amplifier Operating from a Single 3.3 V Supply

A compact differential 4-way power combiner with 2.3 dB loss and high common-mode rejection characteristic for use in mm-wave PAs is presented. A complete circuit comprised of a power splitter, two-stage cascode PA array, and a power combiner was implemented in SiGe technology. Measured small-signal gain of at least 17 dB was obtained from 74.5 GHz to 80.5 GHz with a peak 21 dB at 79 GHz. The prototype delivered 13.2 dBm P1dB and 14.3 dBm Psat when operated from a single 3.3 V supply at 75 GHz.

Combining diverse knowledge: The role of specialist and generalist learning

Purpose
– The aim of this paper is to contribute to understanding the nature of specialist and generalist human capital by exploring the ways in which knowledge workers view their experience of working in specialist and generalist roles in pharmaceutical firms in Ireland and the UK.

Design/methodology/approach
– The findings are based on interviews with 55 knowledge workers employed in a range of scientific, technical and managerial positions in four Irish and two UK firms located in the pharmaceutical sector. Interviews were also conducted with nine human resource/training and development managers within these six firms.

Findings
– The findings suggest that the categorisation of human capital as either specialist or generalist is too rigid and does not take account of the fact that individuals may themselves choose to shape their careers by investing in a range of education, training and development opportunities that will enable them to move between specialist and generalist roles.

Originality/value
– The paper unpacks the concepts of specialist and generalist human capital from an employee perspective and challenges the sharp distinction that is made between specialist and generalist human capital.