Resistance to abomasal nematodes and individual genetic variability in reindeer

Resistance to parasites is believed to have a widespread influence on demographic and adaptive processes. In systems where parasites impose a fitness cost on their host, heterozygotes may be selected because they are more resistant to parasites than homozygotes. Our objective was to assess the relationships between genomewide individual heterozygosity and abomasal nematode burdens in female Svalbard reindeer (Rangifer tarandus platyrhynchus) after the effects of host age, locality, season, and year had been accounted for. Samples were obtained from 306 female reindeer that were culled and genotyped at nine microsatellite loci. Reindeer in our study populations are mainly parasitized by the gastrointestinal nematodes Ostertagia gruehneri and Marshallagia marshalli. The infection intensity of each parasite differed between subpopulations, and among host age classes, seasons and years. We found no significant relationships between abomasal worm burdens, or lumen and mucosa larvae, of either O. gruehneri or M. marshalli and individual heterozygosity (or mean d(2)) alone or in interactions with host age, locality, and year. Although we analysed one of the largest data set available to date on gastrointestinal nematodes of a wild ruminant, we used a typical data set of nine genetic neutral markers that may have had low power to detect heterozygosity-fitness correlations. We conclude that the proportion of the variance in parasite resistance explained by individual heterozygosity for neutral genetic markers is low in Svalbard reindeer and in vertebrates in general, and we suggest that the candidate-gene approach might be more fruitful for further research on gene-fitness correlations.     

Regions of Drosophila Notch that contribute to ligand binding and the modulatory influence of Fringe

Two glycosyltransferases that transfer sugars to epidermal growth factor (EGF) domains, OFUT1 and Fringe, regulate Notch signaling. To characterize the impact of glycosylation at the 23 consensus O-fucose sites in Drosophila Notch, we conducted deletion mapping and site-specific mutagenesis and then assayed the binding of soluble forms of Notch to cell-surface ligands. Our results support the conclusion that EGF11 and EGF12 are essential for ligand binding, but indicate that other EGF domains also make substantial contributions to ligand binding. Characterization of Notch deletion constructs and O-fucose site mutants further revealed that no single site or region can account for the influence of Fringe on Notch-ligand binding. Additionally, we observed an influence of Fringe on a Notch fragment including only 4 of its 36 EGF domains (EGF10-13). Together, our observations imply that glycosylation influences Notch-ligand interactions through a distributive mechanism that involves local interactions with multiple EGF domains and led us to suggest a structural model for how Notch interacts with its ligands.     

Dachs: an unconventional myosin that functions downstream of Fat to regulate growth, affinity and gene expression in Drosophila

The dachs gene was first identified almost a century ago based on its requirements for appendage growth, but has been relatively little studied. Here, we describe the phenotypes of strong dachs mutations, report the cloning of the dachs gene, characterize the localization of Dachs protein, and investigate the relationship between Dachs and the Fat pathway. Mutation of dachs reduces, but does not abolish, the growth of legs and wings. dachs encodes an unconventional myosin that preferentially localizes to the membrane of imaginal disc cells. dachs mutations suppress the effects of fat mutations on gene expression, cell affinity and growth in imaginal discs. Dachs protein localization is influenced by Fat, Four-jointed and Dachsous, consistent with its genetic placement downstream of fat. However, dachs mutations have only mild tissue polarity phenotypes, and only partially suppress the tissue polarity defects of fat mutants. Our results implicate Dachs as a crucial downstream component of a Fat signaling pathway that influences growth, affinity and gene expression during development.     

Spatial variance of nutrient limitation of periphyton in montane, headwater streams (McLeod River, Alberta, Canada)

There have been few studies that have examined the spatial variance of nutrient limitation over the scale of an entire set of headwater streams. We used nutrient diffusing substrata experiments (control, nitrogen addition, phosphorus addition, and nitrogen+phosphorus addition) to examine how nutrient limitation varied throughout the five creeks that comprise the McLeod River headwaters (Alberta, Canada). We assessed the variance of chlorophyll a accrual at spatial scales within reach, within creek, among creeks and across linear distance within the entire watershed to assess the consistency and scale of nutrient limitation. We analyzed the importance of the spatial scale using several methods. We assessed the coefficient of variation at different scales, the spatial covariance of nitrogen and phosphorus deficiency indices using a spline correlogram, and the variance through traditional analyses of variance methods. Chlorophyll a accrual responded significantly to nutrients in all creeks, though the response varied in magnitude and in the limiting nutrient among reaches and among creeks. Variance in chlorophyll a accrual was due primarily to the factor of creek (R ²=0.40) and secondarily to reach (R ²=0.07). The CV was 31.4% among creeks, 18.4% among reaches, and 17.9% within reaches. The N deficiency index showed a positive correlation at sites located <4 km apart and a negative correlation at sites greater than 6.5 km apart. The P deficiency index showed no discernible spatial correlation. Our results suggest that nutrient limitation varies on small scales and is often driven by local processes.     

A flexible multi-dimensional QoS performance measure framework for distributed heterogeneous systems

When users’ tasks in a distributed heterogeneous computing environment (e.g., cluster of heterogeneous computers) are allocated resources, the total demand placed on some system resources by the tasks, for a given interval of time, may exceed the availability of those resources. In such a case, some tasks may receive degraded service or be dropped from the system. One part of a measure to quantify the success of a resource management system (RMS) in such a distributed environment is the collective value of the tasks completed during an interval of time, as perceived by the user, application, or policy maker. The Flexible Integrated System Capability (FISC) measure presented here is a measure for quantifying this collective value. The FISC measure is a flexible multi-dimensional measure such that any task attribute can be inserted and may include priorities, versions of a task or data, deadlines, situational mode, security, application- and domain-specific QoS, and task dependencies. For an environment where it is important to investigate how well data communication requests are satisfied, the data communication request satisfied can be the basis of the FISC measure instead of tasks completed. The motivation behind the FISC measure is to determine the performance of resource management schemes if tasks have multiple attributes that needs to be satisfied. The goal of this measure is to compare the results of different resource management heuristics that are trying to achieve the same performance objective but with different approaches. This research was supported by the DARPA/ITO Quorum Program, by the DARPA/ISO BADD Program and the Office of Naval Research under ONR grant number N00014-97-1-0804, by the DARPA/ITO AICE program under contract numbers DABT63-99-C-0010 and DABT63-99-C-0012, and by the Colorado State University George T. Abell Endowment. Intel and Microsoft donated some of the equipment used in this research. Jong-Kook Kim is pursuing a Ph.D. degree from the School of Electrical and Computer Engineering at Purdue University (expected in August 2004). Jong-Kook received his M.S. degree in electrical and computer engineering from Purdue University in May 2000. He received his B.S. degree in electronic engineering from Korea University, Seoul, Korea in 1998. He has presented his work at several international conferences and has been a reviewer for numerous conferences and journals. His research interests include heterogeneous distributed computing, computer architecture, performance measure, resource management, evolutionary heuristics, and power-aware computing. He is a student member of the IEEE, IEEE Computer Society, and ACM. Debra Hensgen is a member of the Research and Evaluation Team at OpenTV in Mountain View, California. OpenTV produces middleware for set-top boxes in support of interactive television. She received her Ph.D. in the area of Distributed Operating Systems from the University of Kentucky. Prior to moving to private industry, as an Associate Professor in the systems area, she worked with students and colleagues to design and develop tools and systems for resource management, network re-routing algorithms and systems that preserve quality of service guarantees, and visualization tools for performance debugging of parallel and distributed systems. She has published numerous papers concerning her contributions to the Concurra toolkit for automatically generating safe, efficient concurrent code, the Graze parallel processing performance debugger, the SAAM path information base, and the SmartNet and MSHN Resource Management Systems. Taylor Kidd is currently a Software Architect for Vidiom Systems in Portland Oregon. His current work involves the writing of multi-company industrial specifications and the architecting of software systems for the digital cable television industry. He has been involved in the establishment of international specifications for digital interactive television in both Europe and in the US. Prior to his current position, Dr. Kidd has been a researcher for the US Navy as well as an Associate Professor at the Naval Postgraduate School. Dr Kidd received his Ph.D. in Electrical Engineering in 1991 from the University of California, San Diego. H. J. Siegel was appointed the George T. Abell Endowed Chair Distinguished Professor of Electrical and Computer Engineering at Colorado State University (CSU) in August 2001, where he is also a Professor of Computer Science. In December 2002, he became the first Director of the CSU Information Science and Technology Center (ISTeC). ISTeC is a university-wide organization for promoting, facilitating, and enhancing CSU’s research, education, and outreach activities pertaining to the design and innovative application of computer, communication, and information systems. From 1976 to 2001, he was a professor at Purdue University. He received two BS degrees from MIT, and the MA, MSE, and PhD degrees from Princeton University. His research interests include parallel and distributed computing, heterogeneous computing, robust computing systems, parallel algorithms, parallel machine interconnection networks, and reconfigurable parallel computer systems. He has co-authored over 300 published papers on parallel and distributed computing and communication, is an IEEE Fellow, is an ACM Fellow, was a Coeditor-in-Chief of the Journal of Parallel and Distributed Computing, and was on the Editorial Boards of both the IEEE Transactions on Parallel and Distributed Systems and the IEEE Transactions on Computers. He was Program Chair/Co-Chair of three major international conferences, General Chair/Co-Chair of four international conferences, and Chair/Co-Chair of five workshops. He has been an international keynote speaker and tutorial lecturer, and has consulted for industry and government. David St. John is Chief Information Officer for WeatherFlow, Inc., a weather services company specializing in coastal weather observations and forecasts. He received a master’s degree in Engineering from the University of California, Irvine. He spent several years as the head of staff on the Management System for Heterogeneous Networks project in the Computer Science Department of the Naval Postgraduate School. His current relationship with cluster computing is as a user of the Regional Atmospheric Modeling System (RAMS), a numerical weather model developed at Colorado State University. WeatherFlow runs RAMS operationally on a Linux-based cluster. Cynthia Irvine is a Professor of Computer Science at the Naval Postgraduate School in Monterey, California. She received her Ph.D. from Case Western Reserve University and her B.A. in Physics from Rice University. She joined the faculty of the Naval Postgraduate School in 1994. Previously she worked in industry on the development of high assurance secure systems. In 2001, Dr. Irvine received the Naval Information Assurance Award. Dr. Irvine is the Director of the Center for Information Systems Security Studies and Research at the Naval Postgraduate School. She has served on special panels for NSF, DARPA, and OSD. In the area of computer security education Dr. Irvine has most recently served as the general chair of the Third World Conference on Information Security Education and the Fifth Workshop on Education in Computer Security. She co-chaired the NSF workshop on Cyber-security Workforce Needs Assessment and Educational Innovation and was a participant in the Computing Research Association/NSF sponsored Grand Challenges in Information Assurance meeting. She is a member of the editorial board of the Journal of Information Warfare and has served as a reviewer and/or program committee member of a variety of security related conferences. She has written over 100 papers and articles and has supervised the work of over 80 students. Professor Irvine is a member of the ACM, the AAS, a life member of the ASP, and a Senior Member of the IEEE. Timothy E. Levin is a Research Associate Professor at the Naval Postgraduate School. He has spent over 18 years working in the design, development, evaluation, and verification of secure computer systems, including operating systems, databases and networks. His current research interests include high assurance system design and analysis, development of models and methods for the dynamic selection of QoS security attributes, and the application of formal methods to the development of secure computer systems. Viktor K. Prasanna received his BS in Electronics Engineering from the Bangalore University and his MS from the School of Automation, Indian Institute of Science. He obtained his Ph.D. in Computer Science from the Pennsylvania State University in 1983. Currently, he is a Professor in the Department of Electrical Engineering as well as in the Department of Computer Science at the University of Southern California, Los Angeles. He is also an associate member of the Center for Applied Mathematical Sciences (CAMS) at USC. He served as the Division Director for the Computer Engineering Division during 1994–98. His research interests include parallel and distributed systems, embedded systems, configurable architectures and high performance computing. Dr. Prasanna has published extensively and consulted for industries in the above areas. He has served on the organizing committees of several international meetings in VLSI computations, parallel computation, and high performance computing. He is the Steering Co-chair of the International Parallel and Distributed Processing Symposium [merged IEEE International Parallel Processing Symposium (IPPS) and the Symposium on Parallel and Distributed Processing (SPDP)] and is the Steering Chair of the International Conference on High Performance Computing(HiPC). He serves on the editorial boards of the Journal of Parallel and Distributed Computing and the Proceedings of the IEEE. He is the Editor-in-Chief of the IEEE Transactions on Computers. He was the founding Chair of the IEEE Computer Society Technical Committee on Parallel Processing. He is a Fellow of the IEEE. Richard F. Freund is the originator of GridIQ’s network scheduling concepts that arose from mathematical and computing approaches he developed for the Department of Defense in the early 1980’s. Dr. Freund has over twenty-five years experience in computational mathematics, algorithm design, high performance computing, distributed computing, network planning, and heterogeneous scheduling. Since 1989, Dr. Freund has published over 45 journal articles in these fields. He has also been an editor of special editions of IEEE Computer and the Journal of Parallel and Distributed Computing. In addition, he is a founder of the Heterogeneous Computing Workshop, held annually in conjunction with the International Parallel Processing Symposium. Dr. Freund is the recipient of many awards, which includes the prestigious Department of Defense Meritorious Civilian Service Award in 1984 and the Lauritsen-Bennet Award from the Space and Naval Warfare Systems Command in San Diego, California.     

Nitroreductase-based therapy of prostate cancer, enhanced by raising expression of heat shock protein 70, acts through increased anti-tumour immunity

Gene-directed enzyme-prodrug therapy (GDEPT) using nitroreductase (NTR), with efficient adenoviral delivery, and CB1954 (CB), is an effective means of directly killing tumours. However, an immune-mediated bystander effect remains an important product of GDEPT since it is often critical to the elimination of untransduced tumour cells both locally and at distal metastatic sites through generation of tumour-specific immunity without the need for tumour antigen identification or the generation of a personalised vaccine. The mode of induced tumour cell death is thought to contribute to the immunisation process, together with the induction and release of stress proteins. Here, RM-9 murine prostate tumour cells were efficiently killed by adenovirally delivered NTR/CB treatment both in vitro and in vivo, and bystander effects were observed. Cells appeared to die by pathways that suggest necrosis more than that of classical apoptosis. NTR/CB-induced expression of a range of stress proteins was determined by proteomic analysis, revealing chiefly heat shock protein (HSP)25 and HSP70 upregulation, whilst immune responses in vivo were weak. In an attempt to enhance the anti-tumour effect, an adenoviral vector was constructed that co-expressed NTR and HSP70, the latter being a known immune stimulator and chaperone of antigen. This combination elicited significantly enhanced protection over NTR alone for both the treated tumour and a subsequent re-challenge. Protection was CD4⁺ and CD8⁺ T cell-dependent and was associated with tumour-specific CTL, IFNγ and IL-5 responses. The use of such a cytotoxic and immunomodulatory gene combination in cancer therapy warrants further pursuit.     

Recent histories of six productive lakes in the Irish Ecoregion based on multiproxy palaeolimnological evidence

Palaeolimnological data from six mesotrophic, eutrophic and hypertrophic lakes in the Irish Ecoregion, in the form of microfossil (cladocera, diatoms and pollen) and sediment chemistry data from radiometrically dated sediment cores, were used to reconstruct past variations in lake water quality and catchment conditions. Basal sediments from sediment cores from the six sites ranged in age from the late 18th century to the early 20th century. A weighted averaging partial least squares regression model was developed to reconstruct past epilimnetic total phosphorus concentrations. The results indicate that all but one of the study sites currently are in a far more productive state compared with the beginning of the sediment core record and that those same five lakes have experienced accelerated enrichment post c. 1980. Two of the sites demonstrated long-term enrichment, in one case beginning in the late 19th century, while both eutrophication and oligotrophication have occurred at three sites. The results highlight the difficulties in applying a general temporal end-point for reference conditions and demonstrate that productive lakes in the Irish Ecoregion have complex, locally specific and often long histories of enrichment. These may not be responsive to reduced external loadings of phosphorus and, as a result, restoration could prove particularly challenging. The results also provide evidence of the ways in which palaeolimnological techniques can assist implementation of the EU Water Framework Directive. Electronic supplementary material Electronic supplementary material is available for this article at and accessible for authorised users.     

Nuclear inositide signalling -- expansion, structures and clarification

The extent and content of this review issue highlights how our understanding of lipid signalling in the nucleus has grown, both in what we actually know, and the breadth of signalling pathways that we now have to consider. Here, a few key issues with regard to nuclear inositide signalling are briefly addressed.     

Living with primary ciliary dyskinesia: a prospective qualitative study of knowledge sharing, symptom concealment, embarrassment, mistrust, and stigma

Background

Primary ciliary dyskinesia (PCD) is a chronic respiratory disease for which there is little psycho-social research and no qualitative studies of individuals living with the condition. A questionnaire-based survey in 2003 found evidence of stigmatisation in some individuals with PCD. Although the questionnaire had face and construct validity, stigmatisation was not cross-validated against interviews. The present study had the twin aims of carrying out a qualitative study of the adult patients living with PCD, and using a structured design to validate the questionnaire measure of stigma.

Methods

Interviews were carried out with six pairs of individuals with PCD, matched for sex, situs, and age, one with a high stigma score in 2003 and the other with a low stigma score. Depth-qualitative interviews were conducted by one author to explore themes surrounding the psycho-social impact of PCD using a grounded theory analysis. The interviewer was blind to the stigma scores of participants, and after the qualitative analysis was completed, the interviewer made an assessment of which member of each pair seemed the more stigmatised, after which the code was broken.

Results

Interviews revealed a number of themes, including other people's knowledge of PCD, the sharing of knowledge about PCD, the concealment of symptoms of PCD, embarrassment at symptoms, changes of behaviour in response to PCD, mistrust of medical care, in particular in relation to problems in diagnosis, a mistrust of general practitioners who were seen as poorly informed, and the importance of expert care at tertiary referral centres. Although stigmatisation as such was rarely mentioned directly by respondents, when the interviewer's judgement on level of stigmatisation was correlated with stigma scores from 2003, it was found that the more stigmatised member had been correctly identified in all six pairs (p = .016).

Conclusion

Our results suggest that some people with PCD feel isolated through mistrust in medicine, and lack of knowledge surrounding PCD. Many responses to PCD can be explained in terms of stigmatisation, and in particular felt stigma. The correlation between questionnaire used several years previously, and the interviewer's judgements of stigmatisation suggest that the stigma questionnaire had both predictive validity and long-term stability. As in other chronic conditions, stigmatisation occurs only in some individuals with PCD, and the present study explores the basis of stigmatisation, and validate the questionnaire as a measure of difference in stigma.