bluuebunny/crossref_metadata_2025 huggingface dataset:
Ground‐Water Studies— Chicagoland Deep Tunnel System
Authors: Papadopulos Istavros S. , Larsen William R. , Neil Forrest C.
Published: July 2006

The Deep Tunnel System planned by the Metropolitan Sanitary District of Greater Chicago will provide flood and pollution control for the combined sewer areas of the Chicago region. Elements of the Deep Tunnel System that are of main concern to the ground‐water resources of the area are the conveyance tunnels and the mined storage reservoir which will convey and store polluted storm‐water overflows. The Silurian and the Cambrian‐Ordovician aquifers, in units of which these elements will be located, will be protected from any deleterious effects of the System by ensuring that a positive hydraulic head, causing an inward flow, is continuously maintained around the tunnels and the mined reservoir. In the Cambrian‐Ordovician aquifer, this necessitates1 that ground‐water levels are maintained by artificial recharge. Extensive ground‐water studies were conducted to (1) demonstrate the feasibility of aquifer protection by recharge, (2) determine the needed amounts of recharge water, and (3) estimate the seepage of ground water into the tunnels and mined res.ervoir. The studies included field investigations, analog computer analyses and office evaluation of the collected data and analog results. The results indicate that (1) the proposed aquifer protection is feasible, (2) the recharge requirements will vary from 1.4 mgd in 1976 to 6.0 mgd in 2010, (3) seepage into the tunnels will be small, in amounts that can be easily controlled.
Some Applications of Geophysical Well Logging to Basalt Hydrogeology
Authors: Crosby James W. , Anderson Jay V.
Published: July 2006

The application of borehole geophysics to study of basalt hydrogeology has been pursued at Washington State University for the past six years. Throughout this period much effort has been directed to redesign of commercial geophysical system components and development of expanded downhole capabilities. It has been demonstrated that composite logging techniques can be used to define the hydraulic regime of a well constructed in basalt. Certain of the logging measures, with further study, may become powerful tools for identifying anomalous conditions associated with pollutant dispersion in an aquifer. Positive correlations of basalt with the logging methods have not yet been made over distances greater than 20 miles. However, as improved logging density permits intermediate points of correlation to be established, further extensions are anticipated. Both major and minor log features of the basalts display varying degrees of lateral persistence. Because driller's logs are generally inadequate in describing subtleties of basalt geology, subsurface correlations are best made with geophysical logs. In areas with extensive surficial cover, the geophysical methods may prove to be a very practical method of determining basalt stratigraphy. Geophysical well logging offers to agencies charged with ground‐water management many opportunities for gaining new knowledge which have been largely neglected.
Mapping Ground Water by Using Electrical Resistivity with a Buried Current Sourcea
Authors: Merkel R. H. , Kaminski J. T.
Published: July 2006

Standard resistivity configurations lose resolution in regions where multiple geologic layering of high conductivity contrast occurs. To partially circumvent this problem an electrode configuration was used, which includes a current electrode at depth down a drill hole in a water field, to examine the possibility of delineating ground‐water flow channels. Results show the value of this technique in enhancing the electrical anomaly and hence determining structure. It was found that the ground water in this area flows primarily in fracture traces in the dolomite. Moreover, it was determined from well log synthesis that these fracture traces increase the effective porosity in the flow region by approximately ten percent.
Migration and Leaching of Metals from Old Mine Tailings Deposits
Authors: Galbraith James H. , Williams Roy E. , Siems Peter L.
Published: July 2006

Leaching of heavy metals by ground water passing through mine tailings is caused by the oxidation of sulfides through the action of microorganisms. The pH of the ground water entering the tailings system is reduced by mechanisms within the tailings system itself. Action of sulfide‐oxidizing and sulfur‐oxidizing bacteria causes the formation of sulfuric acid, thereby increasing the H+ and SO42− concentration within the system. Metal ions go into solution as metal sulfates, and the concentration of H2S increases by the interaction of H+ and S2− Increase in H2S creates an environment suitable for the growth of sulfate‐reducing bacteria which converts SO42− to S2− and simultaneously precipitates metal sulfides at a pH near 6.6. Decrease in pH with depth destroys sulfate‐reducing bacteria, and dissolution and leaching of the tailings increase.

Four lines of evidence demonstrate the presence of microorganisms in the tailings system: (1) Fe‐Mn concretions below the water table at Cataldo Mission Flats, (2) fixation of Na and K below the water table, (3) precipitation of sulfate salts on the surface of Cataldo Mission Flats, and (4) experiments on two sets of tailings samples, one from the surface which showed predominant aerobic activity and one from below the water table which showed predominant anaerobic activity. Where oxygen is sufficient, iron oxidizing bacteria oxidize Fe2+ to Fe3+ which forms an insoluble hydroxide. Consequently, very little iron is found in the ground water coming from the system. The combination of these mechanisms produces poor‐quality ground water with respect to metals.
Water Development on Tropic Volcanic Islands—Type Example: Hawaiia
Authors: Peterson Frank L.
Published: July 2006

Despite rainfalls which commonly exceed 200 inches per year in the mountainous portions of many of the islands in the Hawaiian chain, most streams in the islands are very flashy, and only a few carry water throughout the year. This is owing to the extremely permeable nature of the volcanic rocks and soils which make up the Hawaiian islands, and, in fact, the permeability of some of the younger volcanic rocks is so great that virtually no runoff occurs. As a result, development of reliable year‐round sources of surface water is difficult especially on the leeward portions of the islands. Furthermore, surface storage is difficult because of the high infiltration capacities of the rock and soil cover. Consequently, development of ground water provides the most abundant and the most reliable source of water supply for these islands. Three modes of fresh ground‐water occurrence may be distinguished: perched, dike‐confined, and basal. Although perched and dike‐confined ground water are of considerable local importance, the basal ground‐water body is by far the most widely developed and most important source of fresh ground water for these islands.
A Traditional Method of Ground‐Water Utilisation in the Middle East
Authors: Beaumont Peter
Published: July 2006

In the Middle East ground water has been used by man for at least 10,000 years, so that cultivation could be practised in arid regions. One of the most unusual ways of obtaining ground water is by means of qanats, which are small man‐made tunnels carrying water by gravity flow from beneath the water table to the ground surface. In Iran and Afghanistan in particular, many complex qanat systems are found supplying water to regions with very low precipitation totals, which are thus able to support locally intensive human settlement. At the present time in those areas close to the larger urban centres qanats are being replaced by pumped wells as the major suppliers of ground water.
Rapid Recharge in a Limestone Aquifer
Authors: Fox I. A. , Rushton K. R.
Published: July 2006

The introduction of an infiltration mechanism called rapid recharge assists in the mathematical modelling of large seasonal variations in the response of the confined portion of a limestone aquifer. Such modelling employs the technique of using an interactive analogue‐digital computer, together with a new method of utilising standard hydrological input data.
A Mathematical Model Study of Fresh‐Water Lenses
Authors: Chidley Thomas R. E. , Lloyd John W.
Published: July 2006

An analysis of the unsteady flow in a fresh‐water lens on a small tropical island is developed using the Ghyben‐Herzberg relationship to determine the lens thickness. An alternative view of the problem to that most commonly given is presented. Results are shown for some lenses on Grand Cayman Island in the Caribbean Sea. The aquifer material is a micro‐karst limestone. The chief result of engineering significance is that the conventional steady‐state analysis is shown to be a sound basis for estimating the long‐term yield if drought sequences are not long.
EFFICIENCY AND FARM SIZE IN WESTERN CAPE GRAPE PRODUCTION: POOLING SMALL DATASETS
Authors: Conradie Beatrice , Cookson Graham , Thirtle Colin
Published: July 2006

A stochastic frontier is fitted to two panels of wine grape farms (34 in Robertson and 36 in Worcester) for 2003 and 2004 and a cross section of 37 table grape farms in De Doorns for 2004 only. The panel of wine grape farms is the best model as tests show that De Doorns is different. Output is explained by land, labour and machinery and efficiency is affected by labour quality, age and education of the farmer, location, the percentage of non‐bearing vines and expenditures on electricity for irrigation. There is evidence of a small degree of increasing returns to scale.
COLLECTIVE ACTION IN SMALLHOLDER ORGANIC FARMING: A STUDY OF THE EZEMVELO FARMERS' ORGANIZATION IN KWAZULU‐NATAL
Authors: Gadzikwa L , Lyne Mc , Hendriks Sl
Published: July 2006

This study analyses the Ezemvelo Farmers' Organisation (EFO), a certified organic smallholder group in KwaZulu‐Natal province (South Africa), as an institution to improve smallholder access to a niche market by reducing unit production and transaction costs in the supply chain. Using a multinomial logit model, results suggest that EFO is more likely to survive if it continues to secure fully subsidised information, transport, fencing, and certification services for its members, and if it improves the benefits of participating by synchronising harvest and delivery dates, negotiating price discounts for organic inputs, and by maintaining an office with telephone, fax and postal services.
Stage‐dependent foraging in breeding black‐legged kittiwakes Rissa tridactyla: distinguishing behavioural responses to intrinsic and extrinsic factors
Authors: M. Humphreys Elizabeth , Wanless Sarah , M. Bryant David
Published: July 2006

Different phases of the annual cycle in birds and mammals are often associated with characteristic and recurrent foraging behaviours. The extent to which stage‐dependent changes in foraging behaviour are caused by intrinsic or extrinsic factors is unclear. We controlled for the effects of extrinsic factors by synchronising groups of incubating and chick‐rearing black‐legged kittiwakes Rissa tridactyla. Synchrony amongst incubators and rearers was achieved experimentally by switching eggs between nests. Behavioural responses to the treatment varied between the sexes. Male kittiwakes with prolonged‐incubation made fewer foraging trips but of greater duration compared to those rearing chicks resulting in no change in the time spent on trips between the two groups. Females with prolonged‐incubation carried out fewer trips than those rearing chicks but trip duration did not differ between the two stages which resulted in prolonged‐incubating birds spending a lower percentage time on trips. In contrast, foraging ranges did not differ between prolonged‐incubation and chick‐rearing birds for either sex. This suggests that extrinsic factors, such as food availability and distribution determine kittiwake foraging locations and ranges, whereas intrinsic factors, reflected in parental duties, constrain nest attendance. Female prolonged‐incubators invested lower levels of parental effort, in terms of daily energy expenditure, compared to chick‐rearers whereas males did not show stage‐related differences in energy expenditure. This provides evidence that incubation could be an energetically cheaper stage although under normal conditions this difference may be masked by temporal variation in environmental factors. We conclude that while conditions differ between the incubation and chick rearing stages for kittiwakes at this colony, they are not the main factors prompting changes in stage‐related foraging patterns. Intrinsic factors such as sex differences, or behaviours required for each stage of the annual cycle, rather than extrinsic factors related to seasonal environments, are likely to be the main proximate cause of recurring changes in behaviour between breeding stages.
Dynamic Material Behavior Modeling Using Internal State Variable Plasticity and Its Application in Hard Machining Simulations
Authors: Guo Y. B. , Wen Q. , Woodbury K. A.
Published: July 2006

Work materials experience large strains, high strain rates, high temperatures, and complex loading histories in machining. The problem of how to accurately model dynamic material behavior, including the adiabatic effect is essential to understand a hard machining process. Several conventional constitutive models have often been used to approximate flow stress in machining analysis and simulations. The empirical or semiempirical conventional models lack mechanisms for incorporating isotropic/kinematic hardening, recovery, and loading history effects. In this study, the material constants of AISI 52100 steel (62 HRc) were determined for both the Internal State Variable (ISV) plasticity model and the conventional Johnson-Cook (JC) model. The material constants were obtained by fitting the ISV and JC models using nonlinear least square methods to same baseline test data at different strains, strain rates, and temperatures. Both models are capable of modeling strain hardening and thermal softening phenomena. However, the ISV model can also accommodate the adiabatic and recovery effects, while the JC model is isothermal. Based on the method of design of experiment, FEA simulations and corresponding cutting tests were performed using the cutting tool with a 20 deg chamfer angle. The predicted chip morphology using the ISV model is consistent with the measured chips, while the JC model is not. The predicted temperatures can be qualitatively verified by the subsurface microstructure. In addition, the ISV model gave larger subsurface von Mises stress, plastic strain, and temperature compared with those by the JC model.
Material Characterization of NiTi Based Memory Alloys Fabricated by the Laser Direct Metal Deposition Process
Authors: Malukhin K. , Ehmann K.
Published: July 2006

Shape memory alloys (SMAs) are used in a wide variety of applications including medical stents, couplings, actuators, jointless monolithic structures for actuation and manipulation, etc. Due to the SMA’s poor machinability it is advantageous to use rapid prototyping (RP) techniques for the manufacturing of SMA structures. However, the influence of the RP process on the properties of the SMA is not fully explored yet. A laser based direct metal deposition (DMD) RP process was used in this work to manufacture NiTi SMA samples and to investigate their physical properties using optical microscopy, differential scanning calorimetry (DSC), chemical analysis with secondary ion mass spectrometry (SIMS), and energy dispersive x-ray spectrometry (EDS) with a scanning electron microscope (SEM). DSC analysis has shown that the thermally treated parts possess smooth and pronounced reversible martensite-austenite transformation peaks that are the prerequisite for the shape memory effect (SME) in SMAs. DSC has also shown that quenching affects the peaks. The density of the produced parts was close to the theoretical density of the material as determined by porosity measurements. Finally, SIMS depth profile analysis has shown very low amounts of contamination in the material manufactured by DMD. The major conclusion is that the DMD RP process can be used to manufacture high-quality SMA structures from SMA powders.
Application of Finite Deformation Theory to the Development of an Orthogonal Cutting Model—Part II: Experimental Investigation and Model Validation
Authors: Zheng Yuliu , Hu Xuefei , Sutherland John W.
Published: July 2006

In Part 1 of this paper, a continuum mechanics model of the orthogonal cutting process was developed based on finite deformation theory. In this part of the paper, constitutive equations for O1 and L6 tool steels are developed using the results from split Hopkinson pressure bar tests. Statistically designed orthogonal cutting experiments are conducted to secure process results across a range of cutting conditions. The continuum mechanics model established in Part 1 of this paper is used to simulate all the cutting tests. All the model outputs are calculated and compared with the corresponding cutting experiment results. Good agreement is observed between the model predictions and the experimental results. The continuum mechanics model is successfully used to predict the cutting force, shear angle, and temperature.
Machining a Micro/Meso Scale Structure Using a Minaturized Machine Tool by Using a Conventional Cutting Process
Authors: Lee J. H. , Park S. R. , Yang S. H.
Published: July 2006

Micro/meso scale parts, connectors, and couplers in optic communication and arbitrary 3D features are required in various fields of industry. In this paper, a miniaturized machine tool is developed to machine arbitrary 3D features in the micro/meso scale based on CNC and PC-NC technology. In the proposed system, a PI controller with antiwindup capability is adopted which helps micro/meso scale machining of components. For performance evaluation, a V groove and a 3D feature are machined using the proposed miniaturized machine tool.
Hydrogen Isotopes in Eocene River Gravels and Paleoelevation of the Sierra Nevada
Authors: Mulch Andreas , Graham Stephan A. , Chamberlain C. Page
Published: July 2006

We determine paleoelevation of the Sierra Nevada, California, by tracking the effect of topography on precipitation, as recorded in hydrogen isotopes of kaolinite exposed in gold-bearing river deposits from the Eocene Yuba River. The data, compared with the modern isotopic composition of precipitation, show that about 40 to 50 million years ago the Sierra Nevada stood tall (≥2200 meters), a result in conflict with proposed young surface uplift by tectonic and climatic forcing but consistent with the Sierra Nevada representing the edge of a pre-Eocene continental plateau.
Comment on "On the Regulation of Populations of Mammals, Birds, Fish, and Insects" IV
Authors: Peacock Elizabeth , Garshelis David L.
Published: July 2006

Sibly
et al
.'s (Reports, 22 July 2005, p. 607) contention that density dependence acts strongly on low-density animal populations irrespective of body size contradicts many long-term studies of large mammals. Their findings were distorted by harvest records, which may poorly reflect population trend. Omitting unreliable data, their massive data set is reduced to only one case for large mammals.
Nuclear Gene Indicates Coat-Color Polymorphism in Mammoths
Authors: Römpler Holger , Rohland Nadin , Lalueza-Fox Carles , Willerslev Eske , Kuznetsova Tatyana , Rabeder Gernot , Bertranpetit Jaume , Schöneberg Torsten , Hofreiter Michael
Published: July 2006

By amplifying the melanocortin type 1 receptor from the woolly mammoth, we can report the complete nucleotide sequence of a nuclear-encoded gene from an extinct species. We found two alleles and show that one allele produces a functional protein whereas the other one encodes a protein with strongly reduced activity. This finding suggests that mammoths may have been polymorphic in coat color, with both dark- and light-haired individuals co-occurring.
Decay of Endoplasmic Reticulum-Localized mRNAs During the Unfolded Protein Response
Authors: Hollien Julie , Weissman Jonathan S.
Published: July 2006

The unfolded protein response (UPR) allows the endoplasmic reticulum (ER) to recover from the accumulation of misfolded proteins, in part by increasing its folding capacity. Inositol-requiring enzyme–1 (IRE1) promotes this remodeling by detecting misfolded ER proteins and activating a transcription factor, X-box–binding protein 1, through endonucleolytic cleavage of its messenger RNA (mRNA). Here, we report that IRE1 independently mediates the rapid degradation of a specific subset of mRNAs, based both on their localization to the ER membrane and on the amino acid sequence they encode. This response is well suited to complement other UPR mechanisms because it could selectively halt production of proteins that challenge the ER and clear the translocation and folding machinery for the subsequent remodeling process.
Research productivity of the medical faculty at the American University of Beirut
Authors: Dakik H A , Kaidbey H , Sabra R
Published: July 2006

Objective

To analyse the quality and quantity of scientific publications of the medical faculty at the American University of Beirut (AUB) during a six year period (1996–2001)

Methods

The study included all faculty members in the medical school of AUB in the year 2001. A Medline search inclusive of the years 1996–2001 was done for each faculty member and a total number of 881 publications was obtained.

Results

The faculty consisted of 203 members. Their average productivity rate (mean (SD)) was 1.24 (1.38) publications/faculty member/year (PFY), with a mean impact factor of 2.69 (4.63). Eighteen per cent of the faculty did not have any publication in the six year study period, and only 20% had two or more publications per year. There was a significantly higher publication rate among newly recruited faculty members (0.93 (1.40) PFY for those appointed before 1990, 1.45 (1.24) PFY for those appointed during 1990–1995, and 1.67 (1.43) for those appointed after 1995, p = 0.007), and among those who are younger in age (p<0.01). Collaboration with international investigators resulted in more original publications than work done only at AUB (65% v 35%, p<0.001), and a higher journal impact factor for the publications (3.20 (3.85) v 1.71 (2.36), p<0.05).

Conclusions

This is one of the first studies that analyse the research productivity of the medical faculty in a university setting in a developing country. It shows a wide variation in the research productivity of the faculty members that seems to be related to individual as well as institutional characteristics. Further analysis is needed to define and characterise these factors.
Outpatient follow up appointments; Are we using the resources effectively?
Authors: Bromage S J , Napier-Hemy R D , Payne S R , Pearce I
Published: July 2006

Objective

British Association of Urological Surgeons (BAUS) guidelines and government initiatives have put pressure on the effective use of outpatient resources. Follow up appointments need to be carefully managed to ensure efficient use of available resources. The aim of this study was to audit outpatient follow up service with particular attention to the appropriateness of the appointments made.

Methods

All patients attending a general urology clinic were assessed by a form completed for each individual appointment. The source of the appointment and the time interval was recorded and each follow up appointment was judged to be either appropriate or inappropriate by the person giving the consultation. For those deemed to be inappropriate, justification was sought and the notes independently reviewed by a different clinician to verify this categorisation.

Results

Of 164 appointments made, 143 patients attended for follow up. A total of 131 appointments were considered to be appropriate (92%) with only 12 deemed by the consulting clinician to be inappropriate (8%). The commonest cause for an inappropriate appointment was failure to appreciate that follow up had already been arranged for a different date. There was no correlation between the source of the referral and an inappropriate referral.

Conclusion

This audit suggests an effective use of the outpatient follow up resource with respect to the appropriateness and timing of follow up consultations. Other areas of resource management such as default rates should be investigated in an attempt to improve the efficiency of a service.
Delayed recognition of congenital heart disease
Authors: Massin M M , Dessy H
Published: July 2006

Objective

The aim of this prospective study was to evaluate the proportion of children with delayed recognition of congenital heart disease (CHD).

Methods

Of the 744 children with CHD primarily diagnosed during a 10 year period in one hospital, the patients were identified where the diagnosis of CHD was established with a significant delay.

Results

Sixty six patients (8.9%) had delayed diagnosis of CHD. Among patients with cyanotic CHD, 10.4% (7 of 67 cases) were referred after they had initially been discharged home from the birth clinic. Among patients with acyanotic CHD, 8.7% (59 of 677) of all children and 35.1% (59 of 168) of the children who required surgery or interventional catheterisation were referred at an age where elective repair should have already been performed or needed immediate treatment because of their haemodynamic status. Of the 66 patients with delayed diagnosis, one infant with cor triatriatum died at admission because of delayed referral and 10 children had severe complications: preoperative cardiogenic shock in seven cases of aortic coarctation and one case of endocardial fibroelastosis, pulmonary hypertensive crisis in one child after delayed repair of a ventricular septal defect, and infectious endocarditis after dental care in a teenager with undiagnosed moderate aortic stenosis, who required Ross operation a few months later.

Discussion and conclusion

A substantial proportion of CHD was detected with relevant delay. In all cases of late diagnosis, clinical cardiac findings were present that should have alerted the physician on the possible presence of underlying CHD.
The Formation of TGN-to-Plasma-Membrane Transport Carriers
Authors: Bard Frédéric , Malhotra Vivek
Published: July 2006

In the trans-Golgi network (TGN), proteins are sorted for transport to the endosomes, plasma membrane, preceding Golgi cisternae, and endoplasmic reticulum. The formation of clathrin-coated vesicles for transport to the endosomes and of COP-I-coated vesicles for retrograde trafficking is fairly well characterized at the molecular level. We describe our current understanding of the TGN-to-cell-surface carriers, with a specific focus on the components involved in membrane fission. Inhibiting the fission machinery promotes growth of transport carriers into large tubules that remain attached to the TGN. Overactivating this machinery, on the other hand, vesiculates the TGN. To understand how membrane fission is regulated by cargo to form transport carriers yet prevents complete vesiculation of the TGN remains a daunting challenge. We discuss these issues with regard to TGN-to-cell-surface transport carriers.
Iron-Sulfur Protein Biogenesis in Eukaryotes: Components and Mechanisms
Authors: Lill Roland , Mühlenhoff Ulrich
Published: July 2006

Iron-sulfur (Fe/S) clusters require a complex set of proteins to become assembled and incorporated into apoproteins in a living cell. Researchers have described three distinct assembly systems in eukaryotes that are involved in the maturation of cellular Fe/S proteins. Mitochondria are central for biogenesis. They contain the ISC—the iron-sulfur cluster assembly machinery that was inherited from a similar system of eubacteria in evolution and is involved in biogenesis of all cellular Fe/S proteins. The basic principle of mitochondrial (and bacterial) Fe/S protein maturation is the synthesis of the Fe/S cluster on a scaffold protein before the cluster is transferred to apoproteins. Biogenesis of cytosolic and nuclear Fe/S proteins is facilitated by the cytosolic iron-sulfur protein assembly (CIA) apparatus. This process requires the participation of mitochondria that export a still unknown component via the ISC export machinery, including an ABC transporter.
Nucleoside reverse transcriptase inhibitors prevent HIV protease inhibitor-induced atherosclerosis by ubiquitination and degradation of protein kinase C
Authors: Bradshaw Emily L. , Li Xiang-An , Guerin Theresa , Everson William V. , Wilson Melinda E. , Bruce-Keller Annadora J. , Greenberg Richard N. , Guo Ling , Ross Stuart A. , Smart Eric J.
Published: July 2006

HIV protease inhibitors are important pharmacological agents used in the treatment of HIV-infected patients. One of the major disadvantages of HIV protease inhibitors is that they increase several cardiovascular risk factors, including the expression of CD36 in macrophages. The expression of CD36 in macrophages promotes the accumulation of cholesterol, the development of foam cells, and ultimately atherosclerosis. Recent studies have suggested that α-tocopherol can prevent HIV protease inhibitor-induced increases in macrophage CD36 levels. Because of the potential clinical utility of using α-tocopherol to limit some of the side effects of HIV protease inhibitors, we tested the ability of α-tocopherol to prevent ritonavir, a common HIV protease inhibitor, from inducing atherosclerosis in the LDL receptor (LDLR) null mouse model. Surprisingly, α-tocopherol did not prevent ritonavir-induced atherosclerosis. However, cotreatment with the nucleoside reverse transcriptase inhibitors (NRTIs), didanosine or D4T, did prevent ritonavir-induced atherosclerosis. Using macrophages isolated from LDLR null mice, we demonstrated that the NRTIs prevented the upregulation of CD36 and cholesterol accumulation in macrophages. Treatment of LDLR null mice with NRTIs promoted the ubiquitination and downregulation of protein kinase Cα (PKC). Previous studies demonstrated that HIV protease inhibitor activation of PKC was necessary for the upregulation of CD36. Importantly, the in vivo inhibition of PKC with chelerythrine prevented ritonavir-induced upregulation of CD36, accumulation of cholesterol, and the formation of atherosclerotic lesions. These novel mechanistic studies suggest that NRTIs may provide protection from one of the negative side effects associated with HIV protease inhibitors, namely the increase in CD36 levels and subsequent cholesterol accumulation and atherogenesis.
Involvement of stretch-activated cation channels in hypotonically induced insulin secretion in rat pancreatic β-cells
Authors: Takii Miki , Ishikawa Tomohisa , Tsuda Hidetaka , Kanatani Kazumitsu , Sunouchi Takaaki , Kaneko Yukiko , Nakayama Koichi
Published: July 2006

In isolated rat pancreatic β-cells, hypotonic stimulation elicited an increase in cytosolic Ca2+ concentration ([Ca2+]c) at 2.8 mM glucose. The hypotonically induced [Ca2+]c elevation was significantly suppressed by nicardipine, a voltage-dependent Ca2+ channel blocker, and by Gd3+, amiloride, 2-aminoethoxydiphenylborate, and ruthenium red, all cation channel blockers. In contrast, the [Ca2+]c elevation was not inhibited by suramin, a P2 purinoceptor antagonist. Whole cell patch-clamp analyses showed that hypotonic stimulation induced membrane depolarization of β-cells and produced outwardly rectifying cation currents; Gd3+ inhibited both responses. Hypotonic stimulation also increased insulin secretion from isolated rat islets, and Gd3+ significantly suppressed this secretion. Together, these results suggest that osmotic cell swelling activates cation channels in rat pancreatic β-cells, thereby causing membrane depolarization and subsequent activation of voltage-dependent Ca2+ channels and thus elevating insulin secretion.
Pathological shear stress directly regulates platelet αIIbβ3 signaling
Authors: Feng Shuju , Lu Xin , Reséndiz Julio C. , Kroll Michael H.
Published: July 2006

Integrin mechanotransduction is a ubiquitous biological process. Mechanical forces are transduced transmembranously by an integrin's ligand-bound extracellular domain through its β-subunit's cytoplasmic domain connected to the cytoskeleton. This often culminates in the activation of tyrosine kinases directing cell responses. The delicate balance between hemostasis and thrombosis requires exquisitely fine-tuned integrin function, and balance is maintained in vivo despite that the major platelet integrin αIIbβ3 is continuously subjected to frictional or shearing forces generated by laminar blood flow. To test the hypothesis that platelet function is regulated by the direct effects of mechanical forces on αIIbβ3, we examined αIIbβ3/cytoskeletal interactions in human platelets exposed to shear stress in a cone-plate viscometer. We observed that α-actinin, myosin heavy chain, and Syk coimmunoprecipitate with αIIbβ3 in resting platelets and that 120 dyn/cm2 shear stress leads to their disassociation from αIIbβ3. Shear-induced disassociation of α-actinin and myosin heavy chain from the β3 tail is unaffected by blocking von Willebrand factor (VWF) binding to glycoprotein (Gp) Ib-IX-V but abolished by blocking VWF binding to αIIbβ3. Syk's disassociation from β3 is inhibited when VWF binding to either GpIb-IX-V or αIIbβ3 is blocked. Shear stress-induced phosphorylation of SLP-76 and its association with tyrosine-phosphorylated adhesion and degranulation-promoting adapter protein are inhibited by blocking ligand binding to αIIbβ3 but not by blocking ligand binding to GpIb-IX-V. Chinese hamster ovary cells expressing αIIbβ3 with β3 truncated of its cytoskeletal binding domains demonstrate diminished shear-dependent adhesion and cohesion. These results support the hypothesis that shear stress directly modulates αIIbβ3 function and suggest that shear-induced αIIbβ3-mediated signaling contributes to the regulation of platelet aggregation by directing the release of constraining cytoskeletal elements from the β3-tail.
Differential expression of uterine calcium transporter 1 and plasma membrane Ca2+ATPase 1b during rat estrous cycle
Authors: Kim Hoe-Jin , Lee Geun-Shik , Ji Youn-Kyu , Choi Kyung-Chul , Jeung Eui-Bae
Published: July 2006

Calcium-related proteins include the calcium transporters 1 and 2 (CaT1 and CaT2), plasma membrane Ca2+-ATPase 1b (PMCA1b), and calbindin-D9k and -D28k. The expression of CaT1 and PMCA1b and their potential roles in the uterine tissue remain to be clarified. Thus, in the present study, the expression patterns of CaT1 and PMCA1b were examined to predict their roles in rat uterus during the estrous cycle. Both CaT1 and PMCA1b mRNAs were detected in rat uterus. Uterine CaT1 mRNA was highly expressed at diestrus compared with proestrus, whereas PMCA1b expression was not altered during the estrus cycle. To evaluate the sex steroids involved in uterine CaT1 mRNA regulation, 17β-estradiol (E2) and/or progesterone (P4) were injected into immature rats. Treatment with P4or E2plus P4resulted in an increase in CaT1 mRNA, but a synergetic effect of E2plus P4was not detected. Uterine CaT1 mRNA was induced by P4in a time- and dose-dependent manner, with maximal transcript detected 12 h after the final P4injection. Treatment with RU486, a progesterone receptor (PR) antagonist, completely blocked P4-induced CaT1 mRNA, indicating that P4regulates CaT1 mRNA expression via a PR-mediated pathway. In addition, CaT1 mRNA was expressed in uterine endometrium and glandular endometrium at diestrus in P4-treated rats. Together, these results suggest that CaT1 is regulated by P4at diestrus via a PR-dependent pathway.
Novel double-congenic strain reveals effects of spontaneously hypertensive rat chromosome 2 on specific lipoprotein subfractions and adiposity
Authors: Šeda Ondřej , Šedová Lucie , Liška František , Křenová Drahomíra , Prejzek Vratislav , Kazdová Ludmila , Tremblay Johanne , Hamet Pavel , Křen Vladimír
Published: July 2006

We have developed a new, double-congenic rat strain BN- Lx.SHR2, which carries two distinct segments of chromosome 2 introgressed from the spontaneously hypertensive rat strain (SHR) into the genetic background of congenic strain BN- Lx, which was previously shown to express variety of metabolic syndrome features. In 16-wk-old male rats of BN- Lx and BN- Lx.SHR2 strains, we compared their glucose tolerance and triacylglycerol and cholesterol concentrations in 20 lipoprotein subfractions and the lipoprotein particle sizes under conditions of feeding standard and high-sucrose diets. Introgression of two distinct SHR-derived chromosome 2 segments resulted in decreased adiposity together with aggravation of glucose intolerance in the double-congenic strain. The BN- Lx.SHR2 rats were more sensitive to sucrose-induced rise in triacylglycerolemia. Although the total cholesterol concentrations of the two strains were comparable after the standard diet and even lower in BN- Lx.SHR2 after sucrose feeding, detailed analysis revealed that under both dietary conditions, the double-congenic strain had significantly higher cholesterol concentrations in low-density lipoprotein fractions and lower high-density lipoprotein fractions. We established a new inbred model showing dyslipidemia and mild glucose intolerance without obesity, attributable to specific genomic regions. For the first time, the chromosome 2 segments of SHR origin are shown to influence other than blood pressure-related features of metabolic syndrome or to be involved in relevant nutrigenomic interactions.
Oncostatin M Induces Growth Arrest by Inhibition of Skp2, Cks1, and Cyclin A Expression and Induced p21 Expression
Authors: Halfter Hartmut , Friedrich Matthias , Resch Ansgar , Kullmann Michael , Stögbauer Florian , Ringelstein E. Bernd , Hengst Ludger
Published: July 2006

Oncostatin M has been characterized as a potent growth inhibitor for various tumor cells. Oncostatin M–treated glioblastoma cells cease proliferation and instigate astrocytal differentiation. The oncostatin M–induced cell cycle arrest in G1 phase is characterized by increased level of the cyclin-dependent kinase (CDK) inhibitory proteins p21Cip1/Waf1/Sdi1 and p27Kip1. Induction of p21 protein corresponds to increased mRNA level, whereas p27 accumulates due to increased stability of the protein. Interestingly, stabilization of p27Kip1 occurs even in S phase, showing that p27 stabilization is a direct consequence of oncostatin M signaling and not a result of the cell cycle arrest. Degradation of p27 in late G1 and S phase is initiated by the ubiquitin ligase complex SCF-Skp2/Cks1. Oncostatin M inhibits expression of two components of this E3 ligase complex (Skp2 and Cks1). Although combined overexpression of Skp2 and Cks1 rescues p27 degradation in S phase, it can not override p27 accumulation in G1 phase and cell cycle arrest by oncostatin M. In addition to increasing Cdk inhibitor level, oncostatin M also impairs cyclin A expression. Cyclin A mRNA and protein level decline shortly after oncostatin M addition. The accumulation of two CDK inhibitor proteins and the repression of cyclin A expression may explain the broad and potent antiproliferative effect of the cytokine. (Cancer Res 2006; 66(13): 6530-9)
Sustained Expression of Early Growth Response Protein-1 Blocks Angiogenesis and Tumor Growth
Authors: Lucerna Markus , Pomyje Jiri , Mechtcheriakova Diana , Kadl Alexandra , Gruber Florian , Bilban Martin , Sobanov Yuri , Schabbauer Gernot , Breuss Johannes , Wagner Oswald , Bischoff Markus , Clauss Matthias , Binder Bernd R. , Hofer Erhard
Published: July 2006

Transient induction of the transcription factor early growth response protein-1 (EGR-1) plays a pivotal role in the transcriptional response of endothelial cells to the angiogenic growth factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which are produced by most tumors and are involved in the angiogenic switch. We report here that sustained expression of EGR-1 by recombinant adenoviruses in endothelial cells, however, leads to the specific induction of potent feedback inhibitory mechanisms, including strong up-regulation of transcriptional repressors, negative cell cycle check point effectors, proteins with established antiangiogenic activity, and several proapoptotic genes. Sustained EGR-1 expression consistently leads to an antiangiogenic state characterized by an altered responsiveness to VEGF and bFGF and a striking inhibition of sprouting and tubule formation in vitro. Furthermore, EGR-1–expressing viruses potently inhibit cell invasion and vessel formation in the murine Matrigel model and repress tumor growth in a murine fibrosarcoma model. We propose that gene therapy involving sustained EGR-1 expression may constitute a novel therapeutic principle in the treatment of cancer due to the simultaneous induction of multiple pathways of antiangiogenesis, growth arrest, and apoptosis induction in proliferating cells leading to preferential inhibition of angiogenesis and tumor growth. (Cancer Res 2006; 66(13): 6708-13)
Tumors Face NO Problems?
Authors: Lancaster Jack R. , Xie Keping
Published: July 2006

The effect of nitric oxide (NO) synthase (NOS) II expression on cancer biology is unclear and difficult to define, with multiple reports of pro- and anti-cancer actions. Here we address the major factors that seem likely to account for these paradoxical behaviors, which include variability in NO production, heterogeneity in NO chemistry (and thus its cellular actions), and differential cellular responses. In addition, we suggest that a major determinant of the outcome of NO actions in the tumor environment is cellular adaptation/selection to the cytotoxic actions of NO. (Cancer Res 2006; 66(13): 6459-62)
Suppression of Lung Tumor Formation by the Regulatory Subunit of Ribonucleotide Reductase
Authors: Gautam Ashish , Bepler Gerold
Published: July 2006

The nucleotide metabolism enzyme ribonucleotide reductase is composed of a regulatory subunit (RRM1) and a catalytic subunit (RRM2). The RRM1 locus has frequent loss of heterozygosity in lung cancers, ectopic expression of RRM1 suppresses proliferation of ras-transformed mouse fibroblasts, and high levels of RRM1 expression are associated with a significant survival benefit in patients with lung cancer. In RRM1 transgenic human lung and colon cancer cell lines, we observed induction of G2 cell cycle arrest, apoptosis, and efficient DNA damage repair. We generated strains of RRM1 transgenic mice and found that carcinogen-induced lung tumor formation was significantly suppressed. The tumor suppression was more pronounced in strains with high levels of RRM1 expression than in those with low levels of expression. DNA damage repair capacity in transgenic animals was determined, and RRM1 transgenic animals repaired chemically induced DNA damage with greater efficiency than control animals. We conclude that the regulatory subunit of ribonucleotide reductase has tumor suppressor activity that is mediated through efficient DNA damage repair. (Cancer Res 2006; 66(13): 6497-502)
Inhibition of Histone Deacetylase Class I but not Class II Is Critical for the Sensitization of Leukemic Cells to Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Induced Apoptosis
Authors: Inoue Satoshi , Mai Antonello , Dyer Martin J.S. , Cohen Gerald M.
Published: July 2006

From work done largely on derived cell lines, it has been suggested that tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) might be a therapeutic target for many forms of malignancy. However, use of primary tumor cells, including chronic lymphocytic leukemic (CLL) cells, has shown inherent resistance to TRAIL. Although the molecular basis for this resistance remains unknown, treatment with histone deacetylase inhibitors (HDACi) often sensitizes resistant cells to TRAIL-induced apoptosis. We used structurally diverse HDACi to ascertain which HDAC needs to be inhibited for the sensitization. Inhibition of HDAC class I but not class II is required for sensitization to TRAIL-induced apoptosis of CLL cells and various cell lines. Using different HDACi together with small interfering RNA for HDAC1, HDAC2, HDAC3, and HDAC6, we report that inhibition of HDAC1 and HDAC2 but not HDAC3, HDAC6, and HDAC8 are primarily responsible for sensitization to TRAIL-induced apoptosis. Based on these data and our previous studies, we propose that a clinical trial in CLL is warranted using a combination of a selective HDACi that inhibits HDAC1 and/or HDAC2 together with a form of TRAIL that signals through TRAIL receptor 1. (Cancer Res 2006; 66(13): 6785-92)
Δ9-Tetrahydrocannabinol Inhibits Cell Cycle Progression in Human Breast Cancer Cells through Cdc2 Regulation
Authors: Caffarel María M. , Sarrió David , Palacios José , Guzmán Manuel , Sánchez Cristina
Published: July 2006

It has been proposed that cannabinoids are involved in the control of cell fate. Thus, these compounds can modulate proliferation, differentiation, and survival in different manners depending on the cell type and its physiopathologic context. However, little is known about the effect of cannabinoids on the cell cycle, the main process controlling cell fate. Here, we show that Δ9-tetrahydrocannabinol (THC), through activation of CB2 cannabinoid receptors, reduces human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis. In particular, THC arrests cells in G2-M via down-regulation of Cdc2, as suggested by the decreased sensitivity to THC acquired by Cdc2-overexpressing cells. Of interest, the proliferation pattern of normal human mammary epithelial cells was much less affected by THC. We also analyzed by real-time quantitative PCR the expression of CB1 and CB2 cannabinoid receptors in a series of human breast tumor and nontumor samples. We found a correlation between CB2 expression and histologic grade of the tumors. There was also an association between CB2 expression and other markers of prognostic and predictive value, such as estrogen receptor, progesterone receptor, and ERBB2/HER-2 oncogene. Importantly, no significant CB2 expression was detected in nontumor breast tissue. Taken together, these data might set the bases for a cannabinoid therapy for the management of breast cancer.(Cancer Res 2006; 66(13): 6615-21)