bluuebunny/crossref_metadata_2025 huggingface dataset:
A Methodology for Constructing Collective Causal Maps*
Authors: Scavarda Annibal José , Bouzdine‐Chameeva Tatiana , Goldstein Susan Meyer , Hays Julie M. , Hill Arthur V.
Published: July 2006

This article develops a new approach for constructing causal maps called the Collective Causal Mapping Methodology (CCMM). This methodology collects information asynchronously from a group of dispersed and diverse subject‐matter experts via Web technologies. Through three rounds of data collection, analysis, mapping, and interpretation, CCMM constructs a parsimonious collective causal map. The article illustrates the CCMM by constructing a causal map as a teaching tool for the field of operations management. Causal maps are an essential tool for managers who seek to improve complex systems in the areas of quality, strategy, and information systems. These causal maps are known by many names, including Ishikawa (fishbone) diagrams, cause‐and‐effect diagrams, impact wheels, issue trees, strategy maps, and risk‐assessment mapping tools. Causal maps can be used by managers to focus attention on the root causes of a problem, find critical control points, guide risk management and risk mitigation efforts, formulate and communicate strategy, and teach the fundamental causal relationships in a complex system. Only two basic methods for creating causal maps are available to managers today—brainstorming and interviews. However, these methods are limited, particularly when the subject‐matter experts cannot easily meet in the same place at the same time. Managers working with complex systems across large, geographically dispersed organizations can employ the CCMM presented here to efficiently and effectively construct causal maps to facilitate improving their systems.
From basic to clinical research: a journey with the retina, the retinal pigment epithelium, the cornea, age‐related macular degeneration and hereditary degenerations, as seen in the rear view mirror
Authors: Nilsson Sven Erik G.
Published: July 2006

Purpose:  This Acta Ophthalmologica Award and Gold Medal Honorary Lecture (the Lundsgaard Gold Medal Honorary Lecture) reviews some of the work I have carried out with my mentors and many of my wonderful collaborators and research students over more than 40 years, also including related work by other groups. It concentrates on the basic electrophysiology and ultrastructure of the retina and the retinal pigment epithelium (RPE), as well as covering basic and clinical aspects of the cornea, contact lenses, age‐related macular degeneration (AMD) and hereditary diseases.

Methods:  The review describes research performed using light and electron microscopy, basic and clinical electrophysiology, genetics and biochemistry in animal experiments and in research on patients. It also outlines clinically used techniques, such as laser and photodynamic treatment and scanning laser ophthalmoscopy.

Results:  The paper reports on the following subjects: the mechanisms behind some of the electrical potentials originating in the retina and the RPE and the use of these potentials in hereditary diseases; corneal receptors for lectins and presumably for bacteria; the turnover of the photoreceptor outer segment and the formation of lipofuscin, including the relation of these processes to AMD; certain treatments for AMD, and hereditary degenerations in animal models, such as the RPE65 gene mutation in Briard dogs, which makes them a model of Leber's congenital amaurosis. The dogs are now treated successfully with gene therapy in the USA, and a clinical trial is in preparation.

Conclusions:  During the last 40 years we have had the good fortune to experience a dramatic growth in knowledge and understanding within ophthalmic science of basic mechanisms. Huge progress has been made in diagnostics and clinical ophthalmological treatments, much to the benefit of our patients. Even a small contribution made by my group to these developments has been well worth the effort, particularly as scientific work is not just deeply satisfying: it is also fun!
Serum TK levels in CLL identify Binet stage A patients within biologically defined prognostic subgroups most likely to undergo disease progression
Authors: Matthews Christine , Catherwood Mark A. , Morris T. C. M. , Kettle Paul J. , Drake Mary B. , Gilmore William S. , Alexander H. Denis
Published: July 2006

Abstract:  Objective: Serum thymidine kinase (TK) levels have been shown to be correlated with survival in many malignancies, including chronic lymphocytic leukaemia (CLL). This study was designed to investigate associations between TK levels and other prognostic markers, in newly and previously diagnosed Binet stage A patients. Furthermore, the use of serum TK measurement to identify subcategories of disease within those defined by IgVH mutational status, gene usage and chromosomal aberrations was investigated. Methods: Ninety‐one CLL patients were enrolled. Serum TK levels were measured using a radioenzyme assay. IgVH mutational status and VH gene usage were determined using BIOMED‐2 primers and protocol. Recurring chromosomal abnormalities were detected by interphase fluorescent in situ hybridisation (FISH). Flow cytometry and reverse transcriptase polymerase chain reaction (RT‐PCR) determined CD38 and Zap‐70 expression, respectively. Results: Significantly higher serum TK levels were found in IgVH unmutated, compared with IgVH mutated, patients (P < 0.001). Elevated TK levels were also found in patients with CD38 and Zap‐70 positivity (P = 0.004, P < 0.001, respectively), short lymphocyte doubling time (LDT) (P = 0.044) and poor or intermediate prognosis chromosomal aberrations (P < 0.001). Conclusion: A TK level of >8.5 U/L best identified patients with progressive disease. Elevated TK levels could identify patients categorised, at diagnosis, into good prognosis subgroups by the various biological markers (mutated IgVH, good prognosis chromosomal aberrations, Zap‐70− and CD38−) who subsequently showed disease progression. Additionally, patients with VH3‐21 gene usage showed high TK levels, irrespective of mutational status, and serum TK measurement retained predictive power as disease progressed in all subcategories studied.
Favorable outcome of primary cutaneous marginal zone lymphoma treated with intralesional rituximab
Authors: Kyrtsonis Maria‐Christina , Siakantaris Marina P. , Kalpadakis Christina , Dimopoulou Maria N. , Vassilakopoulos Theodoros P. , Kontopidou Flora N. , Antoniou Christina , Korkolopoulou Penelope , Panayiotidis Panayiotis , Pangalis Gerassimos A.
Published: July 2006

Abstract:  Primary cutaneous marginal zone lymphoma (PCMZL) is an indolent disease. Treatment options include excision, local irradiation, interferon‐α or chemotherapy. We present two patients with PCMZL and multiple skin lesions successfully treated with intralesional administration of the anti‐CD20 monoclonal antibody rituximab. The first presented with four red skin lesions and the second with two. Biopsy of the largest lesion revealed marginal zone B‐cell lymphoma in both patients. There was no evidence of systemic involvement in either patient. Both patients were treated with intralesional rituximab for 18 consecutive weeks. Skin lesions gradually regressed. Apart from mild local pain during the injection, no other adverse effects were observed. In conclusion, rituximab can be safely administered intralesionally in patients with PCMZL and can produce disease remission.
Histomorphometrical study in cavernous lymphangioma of the tongue
Authors: Yaita T , Onodera K , Xu H , Ooya K
Published: July 2006

Objective:  To study the histomorphometrical characteristics of lymphatic vessels in cavernous lymphangiomas of the tongue.

Material and methods:  Immunohistochemical stainings were prepared in the 20 specimens with three antibodies [D2‐40, CD31 and proliferating cell nuclear antigen (PCNA)]. Three‐dimensional (3D) reconstruction and histometrical analysis of the lymphatic vessels was also examined.

Results:  Distinctly positive staining for D2‐40 was found in dilated lymphatic vessels located in the lamina propria beneath the thinned covering epithelium. Small blood vessels stained positively for CD31 were present in the lamina propria. PCNA‐positive lymphatic endothelial cells were scattered in both control and lymphangioma. The 3D architecture of lymphatic vessels was characterized by a complex network with irregular branches in the lamina propria. Histometrical analysis showed that the number of lymphatic endothelial cells per lymphatic vessel perimeter in cavernous lymphangioma was significantly higher than that in control. There were no significant differences in the lymphatic density and the ratio of PCNA‐positive lymphatic endothelial cell nuclei to the total number of lymphatic endothelial cell nuclei between control and lymphangioma.

Conclusions:  These results indicate the absence of excessive endothelial cell proliferation in dilated lymphatic vessels in cavernous lymphangioma. Cavernous lymphangioma may be attributed to the enlargement of lymphatic vessels without the tumorous proliferation of lymphatic endothelial cells.
Viscosity and wettability of animal mucin solutions and human saliva
Authors: Park M‐S , Chung J‐W , Kim Y‐K , Chung S‐C , Kho H‐S
Published: July 2006

Objective:  The purpose of this study was to compare viscosity and wettability between animal mucin solutions and human saliva.

Materials and Methods:  Human whole and glandular saliva, porcine gastric mucin, bovine submaxillary mucin, and a mucin‐based saliva substitute were used. Viscosity was measured with a cone‐and‐plate digital viscometer, while wettability on acrylic resin and Co–Cr alloy was determined by the contact angle.

Results:  The viscosity of animal mucin solutions was proportional to mucin concentration, with the animal mucin solution of concentration 5.0 mg ml−1 displaying similar viscosity to stimulated whole saliva. A decrease in contact angle was found with increasing animal mucin concentration. For the saliva samples tested, viscosity increased in the following order: stimulated parotid saliva, stimulated whole saliva, unstimulated whole saliva, stimulated submandibular–sublingual saliva. Contact angles of human saliva on the tested solid phases were inversely correlated with viscosity. Contact angles of human saliva on acrylic resin were much lower than those of animal mucin solutions and of those on Co–Cr alloy (P < 0.01).

Conclusions:  The effectiveness of animal mucin solutions in terms of their rheological properties was objectively confirmed, indicating a vital role for mucin in proper oral function as well as the development of effective salivary substitutes.
What are “Things” Saying in Renaissance Studies?
Authors: Yates Julian
Published: July 2006

This essay takes up the recent turn to “things” in Renaissance literary studies and attempts to adjudicate the kinds of advances this turn might offer beyond the New Historicist project of the 1980s and 1990s. Offering thumbnail sketches of key contributions by variously Marxist or materialist critics and also by the eclectic group of approaches that name themselves “historical phenomenology,” it argues that the new volubility of “things” in our discipline augurs a return to the urgent theoretical questions of the early 1980s on the interrelation between form and history. In order to keep this field of possibilities open to further experimentation, the essay concludes by introducing readers to two theorists whose work shapes the current conversation, anthropologist William Pietz and sociologist of science Bruno Latour, and suggests some ways in which their work might further be used by literary critics and historians.
Development of an exercise program for fall prevention for elderly persons in a long‐term care facility
Authors: KATO Mayumi , IZUMI Kiyoko , HIRAMATSU Tomoko , SHOGENJI Miho
Published: July 2006

Aim:  The purpose of this study was to develop an exercise program for elderly individuals in a long‐term care facility. Developed through the synthesis of evidence‐based nursing with the use of available research related to falls and exercise, the program was designed to increase balance, mobility, and muscle strength in the lower extremities in order to prevent falls and improve the self‐efficacy of the patients.

Methods:  We developed an exercise program consisting of a warm‐up, static stretching, muscle strengthening in the lower extremities, toe exercises, proprioceptive neuromuscular facilitation, and cool‐down. The study design was a prospective clinical trial. The intervention period was 3 months, with the outcomes measured before and after intervention and 3 months after cessation of the intervention. The 30 participants were elderly residents of a long‐term care facility, 16 of whom were in the intervention group and 14 of whom were in the control group. The outcome values were mobility, muscle strength in the lower extremities, postural sway, fall efficacy, and the number of fallers and falls. The Friedman test was used to analyze the effectiveness of the outcomes.

Results:  The intervention group showed increased balance, maintained mobility, and showed a decreased number of fallers and falls, although the muscle strength and fall efficacy did not increase. No training‐related medical problems occurred.

Conclusion:  The exercise program was shown to be acceptable to use for the prevention of falls among elderly individuals in a long‐term care facility.
Current characteristics of cassava mosaic disease in postepidemic areas increase the range of possible management options
Authors: Mallowa S.O. , Isutsa D.K. , Kamau A.W. , Obonyo R. , Legg J.P.
Published: July 2006

As a case study to document the current characteristics of cassava mosaic virus disease (CMD) in postepidemic areas, surveys were carried out, in 2003 and 2004, in Siaya District of western Kenya. This was an area affected by a severe CMD pandemic in the late 1990s. Data recorded on cassava varieties were CMD incidence, severity index and number of adult whiteflies. Farmers (174) were interviewed on their understanding of the disease and their knowledge and practice of management interventions. Cassava cultivation was being re‐established, but local landraces predominated. Resistant varieties were present 13% in 2003, and 4% in 2004, of the surveyed fields. Adhiambolera was the most common variety, occurring in 35% and 40% of fields in 2003 and 2004, respectively, and had an average CMD incidence of 82% in 2003 and 73% in 2004. By contrast, the CMD‐resistant variety Migyera had a low mean incidence (28% in 2003). The overall incidence for both years was 71%, consisting of 61% as a result of infection through planting diseased cuttings and 10% as a result of whitefly infection. In 2003, the total incidence was 72% and the average severity 2.7 (severity index), while in 2004 the incidence was 78% and the severity 2.6. There were significant severity variations in each division of the Siaya District during the 2 years except for Karemo and Ukwala. The abundance of whiteflies on the top five leaves of plants was low in 2003 but high in 2004, with means of 1 and 16, respectively, over the same seven divisions in both years, although this variation was thought to be because of seasonal factors. East African cassava mosaic virus‐Uganda was the predominant geminivirus present in every division. Phytosanitation by farmers was minimal, as evidenced by 29% of farmers using a selection of CMD‐free stems for planting and 15% using hand‐roguing for CMD management. Occurrence of more than 25% CMD‐free plants in 2004, moderate CMD severity and limited spread provide a conducive environment for the use of phytosanitation as a CMD control measure that can be immediately used by farmers growing their own cassava varieties.
Impact of the Little Fire Ant, Wasmannia auropunctata, on Native Forest Ants in Gabon1
Authors: Walker Kendra L.
Published: July 2006

The Neotropical little fire ant, Wasmannia auropunctata, is notorious for its negative impacts on the native biota of tropical islands, such as the Galapagos and New Caledonia, where it has been introduced. Here, I evaluate the impact of exotic W. auropunctata populations on continental Africa. I surveyed ants at nine sites in Lopé National Park in Gabon, Central Africa, and found a highly significant correlation between ant diversity and length of infestation by W. auropunctata. I found many more native ant species present in areas not infested with W. auropunctata (39.0 ± 4.6) compared with areas infested by W. auropunctata for approximately 5–10 yr (7.0 ± 6.2 and 1.7 ± 1.2, respectively). In infested areas, W. auropunctata made up the bulk of specimens collected in every plot. This study demonstrates that the threat posed by W. auropunctata to biodiversity is as serious in continental ecosystems as it is in the more fragile island ecosystems of previous studies. Introductions near waterways are particularly devastating: in Lopé, the infested territory is most extensive along waterways and occurs in a pattern that strongly suggests moving water facilitates colonization.
A brief review of the status, distribution and biology of wild Asian elephantsElephas maximus
Authors: SUKUMAR R.
Published: July 2006

The Asian elephantElephas maximusis distributed discontinuously across the Asian continent. The total wild population is 38 500‐52 500, with a further c. 16 000 in captivity, the majority of which are in range countries. India has 60% of the global population of wild Asian elephants. The species has a multi‐tiered social system with ♀♀ living in matriarchal groups of five to 20 individuals that interact with other family units in the area. Adult ♂♂ live alone or in small, temporary groups with weak social bonds. Asian elephants are megaherbivores that spend 12‐18 hours per day feeding, and they eat browse and plants depending on availability and season. Home‐range size is dependant on the availability of food, water and shelter in the region. Loss and fragmentation of habitat, human‐elephant conflicts and poaching are the greatest threats to the species. Asian elephants are managed using traditional and modern methods but progress still needs to be made to improve welfare, training and breeding for these animals.
The feeding of rhinoceros in captivity
Authors: CLAUSS M. , HATT J.‐M.
Published: July 2006

Rhinoceros are large herbivores that are adapted for gaining energy from the fermentation of fibrous plant material. In this paper we address issues of oversupplementation of energy (leading to obesity) and minerals (particularly iron in Black rhinocerosDiceros bicornis), outline a diet design that relies on forage as the staple component with a reduction in use of pelleted compound feeds and give suggestions for supplement provision. Acquisition of adequate roughage is probably the most important step in the feeding management of large herbivores and should be regarded and organized accordingly. Ration calculation must be an integral part of diet design to avoid the imbalances that are currently observed, especially in relation to mineral provision. The use of grain or grain products in pelleted compound feeds is largely discouraged.
The EAZA Rhino Campaign
Authors: DEAN C. , BOS C. A.
Published: July 2006

Each year the European Association of Zoos and Aquaria (EAZA) co‐ordinates a year‐long fund‐raising and awareness campaign, focusing on a particular taxa or conservation issue. Rhinoceros species have been chosen as the subject of the current campaign, which runs from September 2005 until October 2006. A fundraising target of Euros 350 000 has been set and 100% of the funds raised will be donated to in situ rhinoceros‐conservation projects. Save the Rhino International, a UK‐registered charity, is working jointly with EAZA to develop and run the EAZA Rhino Campaign.
Husbandry and reproduction of Whitetip reef sharks Triaenodon obesus at Steinhart Aquarium, San Francisco
Authors: SCHALLER P.
Published: July 2006

At Steinhart Aquarium between December 2001 and July 2003 four litters of Whitetip reef sharks Triaenodon obesus were born to two ♀♀ producing at least 13 pups. Mean gestation period, estimated from the first appearance of mating wounds on the ♀ to parturition, was 387 ± 33·7 days (mean ± SD; n= 3). On three occasions, ♀♀ were caught and transferred from the exhibit to an isolation tank for the safety of both the pregnant ♀♀ and neonates. Ultrasound examination was carried out and blood samples taken during two pregnancies: at day 272 and day 288 of gestation for ♀1 and ♀2, respectively. An underwater video‐monitoring system recorded the birth of one litter of four pups. The total time from when the first pup's tail was observed emerging from the ♀'s cloaca to the full emergence of the final pup was 51 minutes: time between the full emergence of each pup was 10–13 minutes. Adult ♀♀ were returned to the exhibit on the day they gave birth and the mean time between parturition and next observed mating wounds was 95·7 ± 52·2 days (mean ± SD, range 57–155 days, n= 3).
Breeding and hand‐rearing Storm's storks Ciconia stormi at the Zoological Society of San Diego
Authors: MACE M. , RANGER W. , LEWINS E. , ATALLIAN D.‐M. , FARLEY M.
Published: July 2006

The Storm's stork Ciconia stormi is an Endangered Ciconiiforme from the inaccessible peat swamp forests and undisturbed freshwater habitats of Borneo, Sumatra, peninsular Malaysia and Thailand. The species is secretive so there are few published references describing its natural history. Two Storm's storks in 1993 and a further two in 1995 (four in total) were transferred from Zoo Negara, Malaysia, to the Zoological Society of San Diego, California, USA. One pair bred over a 4 year period and produced 34 eggs in 12 clutches: 12 chicks hatched, eight of which survived. This article describes the husbandry techniques and courtship for adult Storm's storks, and incubation (both by parents and in incubator), growth and development of chicks.
Hand‐rearing Greater flamingos Phoenicopterus ruber roseus for translocation from WWT Slimbridge to Auckland Zoo
Authors: BATTY M. , JARRETT N. S. , FORBES N. , BROWN M. J. , STANDLEY S. , RICHARDSON T. , OLIVER S. , IRELAND B. , CHALMERS K. P. , FRASER I.
Published: July 2006

Twenty Greater flamingo Phoenicopterus ruber roseus eggs, originating from a flock held at the Wildfowl & Wetlands Trust, Slimbridge, UK, were hatched in incubators. The chicks were hand‐reared in a pre‐export isolation facility before being successfully translocated to Auckland Zoo, New Zealand, at 33–71 days of age. At Auckland Zoo the flamingos were held in a quarantine facility for 30 days prior to being introduced to an enclosure on view to the public.
Husbandry and breeding of the Dibbler Parantechinus apicalis at Perth Zoo
Authors: LAMBERT C. , MILLS H.
Published: July 2006

The Dibbler Parantechinus apicalis is a small, carnivorous marsupial. Between 1996 and 1998 a recovery plan was initiated because the species is Endangered in its natural range. In 1997 Perth Zoo started breeding P. apicalis to study the behaviour of the species and to provide captive‐bred animals for a colony introduced to Escape Island, Jurien Bay, Australia. By 2001, 83 captive‐bred Dibblers and five wild‐born founders were released to this site. The husbandry protocols, reproductive behaviour, and birth and development of young P. apicalis are described in this article.
Review of the use of herb gardens and medicinal plants in primate exhibits in zoos
Authors: COUSINS D.
Published: July 2006

Primates in captivity have been observed eating plants with medicinal properties that grow naturally around their enclosures. In this way they appear to be self‐medicating, although this behaviour has not been scientifically proven. This article reviews the literature on the benefits of herbs and medicinal plants positioned in and around primate enclosures. There are some descriptions of the effectiveness of such plants for treating specific ailments, followed by details of the methods by which the primates have access to the plants; for example, within the enclosure, outside the enclosure but within arm's reach or in wiremesh‐covered troughs. The properties and active constituents of some herbs and medicinal plants are also given.
Cell-Directed Assembly of Lipid-Silica Nanostructures Providing Extended Cell Viability
Authors: Baca Helen K. , Ashley Carlee , Carnes Eric , Lopez Deanna , Flemming Jeb , Dunphy Darren , Singh Seema , Chen Zhu , Liu Nanguo , Fan Hongyou , López Gabriel P. , Brozik Susan M. , Werner-Washburne Margaret , Brinker C. Jeffrey
Published: July 2006

Amphiphilic phospholipids were used to direct the formation of biocompatible, uniform silica nanostructures in the presence of
Saccharomyces cerevisiae
and bacterial cell lines. The cell surfaces organize multilayered phospholipid vesicles that interface coherently with the silica host and help relieve drying stresses that develop with conventional templates. These host structures maintain cell accessibility, addressability, and viability in the absence of buffer or an external fluidic architecture. The cell surfaces are accessible and can be used to localize added proteins, plasmids, and nanocrystals. Prolonged cell viability combined with reporter protein expression enabled stand-alone cell-based sensing.
Genome of Rice Cluster I Archaea the Key Methane Producers in the Rice Rhizosphere
Authors: Erkel Christoph , Kube Michael , Reinhardt Richard , Liesack Werner
Published: July 2006

Rice fields are a global source of the greenhouse gas methane, which is produced by methanogenic archaea, and by methanogens of Rice Cluster I (RC-I) in particular. RC-I methanogens are not yet available in pure culture, and the mechanistic reasons for their prevalence in rice fields are unknown. We reconstructed a complete RC-I genome (3.18 megabases) using a metagenomic approach. Sequence analysis demonstrated an aerotolerant, H
2
/CO
2
-dependent lifestyle and enzymatic capacities for carbohydrate metabolism and assimilatory sulfate reduction, hitherto unknown among methanogens. These capacities and a unique set of antioxidant enzymes and DNA repair mechanisms as well as oxygen-insensitive enzymes provide RC-I with a selective advantage over other methanogens in its habitats, thereby explaining the prevalence of RC-I methanogens in the rice rhizosphere.
Parallel Declines in Pollinators and Insect-Pollinated Plants in Britain and the Netherlands
Authors: Biesmeijer J. C. , Roberts S. P. M. , Reemer M. , Ohlemüller R. , Edwards M. , Peeters T. , Schaffers A. P. , Potts S. G. , Kleukers R. , Thomas C. D. , Settele J. , Kunin W. E.
Published: July 2006

Despite widespread concern about declines in pollination services, little is known about the patterns of change in most pollinator assemblages. By studying bee and hoverfly assemblages in Britain and the Netherlands, we found evidence of declines (pre-versus post-1980) in local bee diversity in both countries; however, divergent trends were observed in hoverflies. Depending on the assemblage and location, pollinator declines were most frequent in habitat and flower specialists, in univoltine species, and/or in nonmigrants. In conjunction with this evidence, outcrossing plant species that are reliant on the declining pollinators have themselves declined relative to other plant species. Taken together, these findings strongly suggest a causal connection between local extinctions of functionally linked plant and pollinator species.
Comment on "Opposing Effects of Native and Exotic Herbivores on Plant Invasions"
Authors: Ricciardi Anthony , Ward Jessica M.
Published: July 2006

Parker
et al
. (Reports, 10 March 2006, p. 1459) showed that native herbivores suppress exotic plants more than native plants. Further analysis reveals that the effect of native herbivores is reduced on exotic plant species that are closely related to native species in the invaded region. Exotic plants may share traits with native congeners that confer similar resistance to resident herbivores.
Receptor Activation Alters Inner Surface Potential During Phagocytosis
Authors: Yeung Tony , Terebiznik Mauricio , Yu Liming , Silvius John , Abidi Wasif M. , Philips Mark , Levine Tim , Kapus Andras , Grinstein Sergio
Published: July 2006

The surface potential of biological membranes varies according to their lipid composition. We devised genetically encoded probes to assess surface potential in intact cells. These probes revealed marked, localized alterations in the charge of the inner surface of the plasma membrane of macrophages during the course of phagocytosis. Hydrolysis of phosphoinositides and displacement of phosphatidylserine accounted for the change in surface potential at the phagosomal cup. Signaling molecules such as K-Ras, Rac1, and c-Src that are targeted to the membrane by electrostatic interactions were rapidly released from membrane subdomains where the surface charge was altered by lipid remodeling during phagocytosis.
MICROTHREADING A MODEL FOR DISTRIBUTED INSTRUCTION-LEVEL CONCURRENCY
Authors: JESSHOPE CHRIS
Published: July 2006

This paper analyses the micro-threaded model of concurrency making comparisons with both data and instruction-level concurrency. The model is fine grain and provides synchronisation in a distributed register file, making it a promising candidate for scalable chip-multiprocessors. The micro-threaded model was first proposed in 1996 as a means to tolerate high latencies in data-parallel, distributed-memory multi-processors. This paper explores the model's opportunity to provide the simultaneous issue of instructions, required for chip multiprocessors, and discusses the issues of scalability with regard to support structures implementing the model and communication in supporting it. The model supports deterministic distribution of code fragments and dynamic scheduling of instructions from within those fragments. The hardware also recognises different classes of variables from the register specifiers, which allows the hardware to manage locality and optimise communication so that it is both efficient and scalable.
Muscarinic modulation of Cav2.3 (R-type) calcium channels is antagonized by RGS3 and RGS3T
Authors: Toro-Castillo Carmen , Thapliyal Ashish , Gonzalez-Ochoa Hector , Adams Brett A. , Meza Ulises
Published: July 2006

Ca2+influx through voltage-gated R-type (CaV2.3) Ca2+channels is important for hormone and neurotransmitter secretion and other cellular events. Previous studies have shown that CaV2.3 is both inhibited and stimulated through signaling mechanisms coupled to muscarinic ACh receptors. We previously demonstrated that muscarinic stimulation of CaV2.3 is blocked by regulator of G protein signaling (RGS) 2. Here we investigated whether muscarinic inhibition of CaV2.3 is antagonized by RGS3. RGS3 is particularly interesting because it contains a lengthy (∼380 residue) amino-terminal domain of uncertain physiological function. CaV2.3, M2muscarinic ACh receptors (M2R), and various deletion mutants of RGS3, including its native isoform RGS3T, were expressed in HEK293 cells, and agonist-dependent inhibition of CaV2.3 was quantified using whole cell patch-clamp recordings. Full-length RGS3, RGS3T, and the core domain of RGS3 were equally effective in antagonizing inhibition of CaV2.3 through M2R. These results identify RGS3 and RGS3T as potential physiological regulators of R-type Ca2+channels. Furthermore, they suggest that the signaling activity of RGS3 is unaffected by its extended amino-terminal domain. Confocal microscopy was used to examine the intracellular locations of four RGS3-enhanced green fluorescent protein fusion proteins. The RGS3 core domain was uniformly distributed throughout both cytoplasm and nucleus. By contrast, full-length RGS3, RGS3T, and the amino-terminal domain of RGS3 were restricted to the cytoplasm. These observations suggest that the amino terminus of RGS3 may serve to confine it to the cytoplasmic compartment where it can interact with cell surface receptors, heterotrimeric G proteins, and other signaling proteins.
Sequence analysis of the complete mitochondrial DNA in 10 commonly used inbred rat strains
Authors: Schlick Nancy E. , Jensen-Seaman Michael I. , Orlebeke Kimberly , Kwitek Anne E. , Jacob Howard J. , Lazar Jozef
Published: July 2006

Rat remains a major biomedical model system for common, complex diseases. The rat continues to gain importance as a model system with the completion of its full genomic sequence. Although the genomic sequence has generated much interest, only three complete sequences of the rat mitochondria exist. Therefore, to increase the knowledge of the rat genome, the entire mitochondrial genomes (16,307–16,315 bp) from 10 inbred rat strains (that are standard laboratory models around the world) and 2 wild rat strains were sequenced. We observed a total of 195 polymorphisms, 32 of which created an amino acid change (nonsynonymous substitutions) in 12 of the 13 protein coding genes within the mitochondrial genome. There were 11 single nucleotide polymorphisms within the tRNA genes, six in the 12S rRNA, and 12 in the 16S rRNA including 3 insertions/deletions. We found 14 single nucleotide polymorphisms and 2 insertion/deletion polymorphisms in the D-loop. The inbred rat strains cluster phylogenetically into three distinct groups. The wild rat from Tokyo grouped closely with five inbred strains in the phylogeny, whereas the wild rat from Milwaukee was not closely related to any inbred strain. These data will enable investigators to rapidly assess the potential impact of the mitochondria in these rats on the physiology and the pathophysiology of phenotypes studied in these strains. Moreover, these data provide information that may be useful as new animal models, which result in novel combinations of nuclear and mitochondrial genomes, are developed.
Palytoxin: exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis
Authors: Wattenberg Elizabeth V.
Published: July 2006

Palytoxin is a novel skin tumor promoter, which has been used to help probe the role of different types of signaling mechanisms in carcinogenesis. The multistage mouse skin model indicates that tumor promotion is an early, prolonged, and reversible phase of carcinogenesis. Understanding the molecular mechanisms underlying tumor promotion is therefore important for developing strategies to prevent and treat cancer. Naturally occurring tumor promoters that bind to specific cellular receptors have proven to be useful tools for investigating important biochemical events in multistage carcinogenesis. For example, the identification of protein kinase C as the receptor for the prototypical skin tumor promoter 12- O-tetradecanoylphorbol-13-acetate (TPA) (also called phorbol 12-myristate 13-acetate, PMA) provided key evidence that tumor promotion involves the aberrant modulation of signaling cascades that govern cell fate and function. The subsequent discovery that palytoxin, a marine toxin isolated from zoanthids (genus Palythoa), is a potent skin tumor promoter yet does not activate protein kinase C indicated that investigating palytoxin action could help reveal new aspects of tumor promotion. Interestingly, the putative receptor for palytoxin is the Na+,K+-ATPase. This review focuses on palytoxin-stimulated signaling and how palytoxin has been used to investigate alternate biochemical mechanisms by which important targets in carcinogenesis can be modulated.
Preparatory Activity in Premotor and Motor Cortex Reflects the Speed of the Upcoming Reach
Authors: Churchland Mark M. , Santhanam Gopal , Shenoy Krishna V.
Published: July 2006

Neurons in premotor and motor cortex show preparatory activity during an instructed-delay task. It has been suggested that such activity primarily reflects visuospatial aspects of the movement, such as target location or reach direction and extent. We asked whether a more dynamic feature, movement speed, is also reflected. Two monkeys were trained to reach at different speeds (“slow” or “fast,” peak speed being ∼50–100% higher for the latter) depending on target color. Targets were presented in seven directions and at two distances. Of 95 neurons with tuned delay-period activity, 95, 78, and 94% showed a significant influence of direction, distance, and instructed speed, respectively. Average peak modulations with respect to direction, distance and speed were 18, 10, and 11 spikes/s. Although robust, modulations of firing rate with target direction were not necessarily invariant: for 45% of neurons, the preferred direction depended significantly on target distance and/or instructed speed. We collected an additional dataset, examining in more detail the effect of target distance (5 distances from 3 to 12 cm in 2 directions). Of 41 neurons with tuned delay-period activity, 85, 83, and 98% showed a significant impact of direction, distance, and instructed speed. Statistical interactions between the effects of distance and instructed speed were common, but it was nevertheless clear that distance “tuning” was not in general a simple consequence of speed tuning. We conclude that delay-period preparatory activity robustly reflects a nonspatial aspect of the upcoming reach. However, it is unclear whether the recorded neural responses conform to any simple reference frame, intrinsic or extrinsic.
Origins of Cross-Orientation Suppression in the Visual Cortex
Authors: Li Baowang , Thompson Jeffrey K. , Duong Thang , Peterson Matthew R. , Freeman Ralph D.
Published: July 2006

The response of a neuron in striate cortex to an optimally oriented stimulus is suppressed by a superimposed orthogonal stimulus. The neural mechanism underlying this cross-orientation suppression (COS) may arise from intracortical or subcortical processes or from both. Recent studies of the temporal frequency and adaptation properties of COS suggest that depression at thalamo-cortical synapses may be the principal mechanism. To examine the possible role of synaptic depression in relation to COS, we measured the recovery time course of COS. We find it too rapid to be explained by synaptic depression. We also studied potential subcortical processes by measuring single cell contrast response functions for a population of LGN neurons. In general, contrast saturation is a consistent property of LGN neurons. Combined with rectifying nonlinearities in the LGN and spike threshold nonlinearities in visual cortex, contrast saturation in the LGN can account for most of the COS that is observed in the visual cortex.
Electron Paramagnetic Resonance Oxygen Images Correlate Spatially and Quantitatively with Oxylite Oxygen Measurements
Authors: Elas Martyna , Ahn Kang-Hyun , Parasca Adrian , Barth Eugene D. , Lee David , Haney Chad , Halpern Howard J.
Published: July 2006

Tumor oxygenation predicts cancer therapy response and malignant phenotype. This has spawned a number of oxymetries. Comparison of different oxymetries is crucial for the validation and understanding of these techniques. Electron paramagnetic resonance (EPR) imaging is a novel technique for providing quantitative high-resolution images of tumor and tissue oxygenation. This work compares sequences of tumor pO2 values from EPR oxygen images with sequences of oxygen measurements made along a track with an Oxylite oxygen probe. Four-dimensional (three spatial and one spectral) EPR oxygen images used spectroscopic imaging techniques to measure the width of a spectral line in each image voxel from a trityl spin probe (OX063, Amersham Health R&D) in the tissues and tumor of mice after spin probe injection. A simple calibration allows direct, quantitative translation of each line width to an oxygen concentration. These four-dimensional EPR images, obtained in 45 minutes from FSa fibrosarcomas grown in the legs of C3H mice, have a spatial resolution of ∼1 mm and oxygen resolution of ∼3 Torr. The position of the Oxylite track was measured within a 2-mm accuracy using a custom stereotactic positioning device. A total of nine images that involve 17 tracks were obtained. Of these, most showed good correlation between the Oxylite measured pO2 and a track located in the tumor within the uncertainties of the Oxylite localizability. The correlation was good both in terms of spatial distribution pattern and pO2 magnitude. The strong correlation of the two modalities corroborates EPR imaging as a useful tool for the study of tumor oxygenation.
High WT1 Expression Is Associated with Very Poor Survival of Patients with Osteogenic Sarcoma Metastasis
Authors: Srivastava Alok , Fuchs Bruno , Zhang Kunbo , Ruan Ming , Halder Chandralekha , Mahlum Eric , Weber Kristin , Bolander Mark E. , Sarkar Gobinda
Published: July 2006

Purpose: Although metastasis is the primary determinant of poor survival of patients with osteogenic sarcoma, some patients live much longer than others, indicating metastatic heterogeneity underlying survival outcome. The purpose of the investigation was to identify genes underlying survival outcome of patients with osteogenic sarcoma metastasis.

Experimental Design: We have used microarray to first compare mRNA expression between normal bone and osteogenic sarcoma specimens, identified genes overexpressed in osteogenic sarcoma, and compared expression of the selected gene between a poorly metastatic (SAOS) and two highly metastatic cell lines (LM8 and 143B). Finally, expression of the selected gene was assessed by immunostaining of osteogenic sarcoma samples with known survival outcome.

Results: Microarray analysis revealed 5.3-fold more expression of WT1 mRNA in osteogenic sarcoma compared with normal bone and >2-fold overexpression in 143B and LM8 cells compared with SAOS. Furthermore, WT1 mRNA was absent in normal bone (10 of 10) by reverse transcription-PCR but present in osteogenic sarcoma–derived cell lines (5 of 8). One hundred percent (42 of 42) of low-grade osteogenic sarcoma specimens expressed no WT1 as determined by immunostaining; however, 24% (12 of 49) of the high-grade specimens showed intense staining. Mean survival of patients with high-grade metastatic osteogenic sarcoma but low WT1 staining (27 of 37) was 96.5 ± 129.3 months, whereas mean survival of patients with high-grade metastatic osteogenic sarcoma having intense staining (10 of 37) was 18.3 ± 12.3 months (P > 0.0143). All splice variants of WT1 mRNA, including a hitherto unknown variant (lacking exons 4 and 5), were found to be expressed in osteogenic sarcoma.

Conclusion: WT1 seems to be associated with very poor survival of patients with osteogenic sarcoma metastasis.
Influence of Formulation Vehicle on Metronomic Taxane Chemotherapy: Albumin-Bound versus Cremophor EL–Based Paclitaxel
Authors: Ng Sylvia S.W. , Sparreboom Alex , Shaked Yuval , Lee Christina , Man Shan , Desai Neil , Soon-Shiong Patrick , Figg William D. , Kerbel Robert S.
Published: July 2006

Purpose: Low-dose metronomic chemotherapy treatments, especially when combined with ‘dedicated’ antiangiogenic agents, can induce significant antitumor activity without serious toxicity in various preclinical models. It remains unclear, however, whether some cytotoxic drugs are better suited for metronomic regimens than others. Paclitaxel appears to be a strong candidate for metronomic chemotherapy given its ability to inhibit endothelial cell functions relevant to angiogenesis in vitro at extraordinarily low concentrations and broad-spectrum antitumor activity. Clinically relevant concentrations of the formulation vehicle cremophor EL in Taxol, however, were previously reported to nullify the antiangiogenic effect of paclitaxel, the result of which would hamper its usefulness in metronomic regimens. We hypothesized that ABI-007, a cremophor EL–free, albumin-bound, 130-nm form of paclitaxel, could potentially alleviate this problem.

Experimental Design: The antiangiogenic activity of ABI-007 was assessed by multiple in vitro assays. The in vivo optimal dose of ABI-007 for metronomic chemotherapy was determined by measuring circulating endothelial progenitors in peripheral blood. The antitumor effects of metronomic and maximum tolerated dose ABI-007 and Taxol were then evaluated and compared in severe combined immunodeficient mice bearing human MDA-MD-231 breast cancer and PC3 prostate cancer xenografts.

Results: ABI-007 significantly inhibited rat aortic microvessel outgrowth, human endothelial cell proliferation, and tube formation. The optimal metronomic dose of ABI-007 was determined to be between 3 and 10 mg/kg. Metronomic ABI-007 but not Taxol, significantly suppressed tumor growth in both xenograft models. Furthermore, the antitumor effect of minimally toxic metronomic ABI-007 approximated that of the maximum tolerated dose of Taxol.

Conclusions: Our results underscore the influence of formulation vehicles on the selection of cytotoxic drugs for metronomic chemotherapy.
Chronic Oxaliplatin Resistance Induces Epithelial-to-Mesenchymal Transition in Colorectal Cancer Cell Lines
Authors: Yang Anthony D. , Fan Fan , Camp E. Ramsay , van Buren George , Liu Wenbiao , Somcio Ray , Gray Michael J. , Cheng Haiyun , Hoff Paulo M. , Ellis Lee M.
Published: July 2006

Purpose: Epithelial-to-mesenchymal transition (EMT) is a process whereby cells acquire molecular alterations that facilitate cell motility and invasion. In preliminary studies, we observed that oxaliplatin-resistant (OxR) colorectal cancer (CRC) cells underwent morphologic changes suggestive of a migratory phenotype, leading us to hypothesize that OxR CRC cells undergo EMT.

Experimental Design: The human CRC cell lines KM12L4 and HT29 were exposed to increasing doses of oxaliplatin to establish stable cell lines resistant to oxaliplatin. Migration and invasion were assessed by modified Boyden chamber assays. Morphologic and molecular changes characteristic of EMT were determined by immunofluorescence staining and Western blot analyses.

Results: The OxR cells showed phenotypic changes consistent with EMT: spindle-cell shape, loss of polarity, intercellular separation, and pseudopodia formation. KM12L4 and HT29 OxR cells exhibited an ∼8- to 15-fold increase in migrating and invading cells, respectively (P < 0.005 for both). Immunofluorescence staining of OxR cells revealed translocation of E-cadherin and β-catenin from their usual membrane-bound complex to the cytoplasm and nucleus, respectively. The OxR cells also had decreased expression of the epithelial adhesion molecules E-cadherin and plakoglobin and an increase in the mesenchymal marker vimentin. The KM12L4 OxR cells exhibited increased nuclear expression of Snail, an EMT-regulatory transcription factor, whereas the HT29 OxR cells exhibited an increase in nuclear expression of the EMT-associated transcription factor nuclear factor κB.

Conclusion: We hypothesize that induction of EMT may contribute to the decreased efficacy of therapy in chemoresistant CRC, as the tumor cells switch from a proliferative to invasive phenotype. Further understanding of the mechanisms of chemoresistance in CRC will enable improvements in chemotherapy for metastatic disease.