bluuebunny/crossref_metadata_2025 huggingface dataset:
Fatal Epstein-Barr Virus Primo Infection in a 25-Year-Old Man Treated with Azathioprine for Crohn's Disease
Authors: N'Guyen Y. , Andreoletti L. , Patey M. , Lecoq-Lafon C. , Cornillet P. , Léon A. , Jaussaud R. , Fieschi C. , Strady C.
Published: February 2009

We report a case of Epstein-Barr virus (EBV) primo infection with the development of successive infectious mononucleosis, hemophagocytic lymphohistiocytosis, and B-cell lymphoproliferative disorder in a patient treated with azathioprine for Crohn's disease. This case report suggests that specific EBV-related clinical and virological management should be considered when treating a patient with inflammatory bowel disease with azathioprine.
Evaluation of Different RNA Extraction Methods and Storage Conditions of Dried Plasma or Blood Spots for Human Immunodeficiency Virus Type 1 RNA Quantification and PCR Amplification for Drug Resistance Testing
Authors: Monleau Marjorie , Montavon Céline , Laurent Christian , Segondy Michel , Montes Brigitte , Delaporte Eric , Boillot François , Peeters Martine
Published: February 2009

The development and validation of dried sample spots as a method of specimen collection are urgently needed in developing countries for monitoring of human immunodeficiency virus (HIV) infection. Our aim was to test some crucial steps in the use of dried spots, i.e., viral recovery and storage over time. Moreover, we investigated whether dried plasma and blood spots (DPS and DBS, respectively) give comparable viral load (VL) results. Four manual RNA extraction methods from commercial HIV type 1 (HIV-1) VL assays—a QIAamp minikit (Qiagen), the Abbott Molecular sample preparation system, the Nuclisens assay (bioMarieux), and High Pure viral nucleic acid kit (Roche Applied Science)—were compared for VL quantification and PCR amplification for genotypic drug resistance testing on dried spots from spiked plasma and residual samples from HIV-1 patients (n= 47; median VL, 4.13 log10copies/ml). RNA recovery from DPS was efficient using Nuclisens extraction (median difference, 0.03 log10copies/ml) and slightly underestimated using the Abbott Molecular sample preparation system (median difference, 0.35 log10copies/ml). PCR amplification results were in concordance. Measurements from DBS overestimated VL for plasma, with VL results showing <3.7 log10copies/ml. VL was stable for up to 3 months in spiked DPS stored at 20°C but for only 1 month at 37°C. A faster decline was observed in PCR efficiency: DPS could be stored for 1 week at 37°C and for 1 month at 20°C. In conclusion, the RNA extraction method is an important factor in obtaining reliable RNA quantification and PCR amplification of HIV-1 on DPS/DBS. DBS could be used as an alternative for DPS depending on HIV RNA cutoffs for virological failure. VL measurements remain stable over a longer period than do PCR amplification results.
Intranasal Administration of Alpha Interferon Reduces Seasonal Influenza A Virus Morbidity in Ferrets
Authors: Kugel Daniela , Kochs Georg , Obojes Karola , Roth Joachim , Kobinger Gary P. , Kobasa Darwyn , Haller Otto , Staeheli Peter , von Messling Veronika
Published: February 2009

The type I interferon (IFN) response represents one of the first lines of defense against influenza virus infections. In this study, we assessed the protective potential of exogenous IFN-α against seasonal and highly pathogenic influenza viruses in ferrets. Intranasal treatment with IFN-α several hours before infection with the H1N1 influenza A virus strain A/USSR/90/77 reduced viral titers in nasal washes at least 100-fold compared to mock-treated controls. IFN-treated animals developed only mild and transient respiratory symptoms, and the characteristic fever peak seen in mock-treated ferrets 2 days after infection was not observed. Repeated application of IFN-α substantially increased the protective effect of the cytokine treatment. IFN-α did not increase survival after infection with the highly pathogenic H5N1 avian influenza A virus strain A/Vietnam/1203/2004. However, viral titers in nasal washes were significantly reduced at days 1 and 3 postinfection. Our study shows that intranasal application of IFN-α can protect ferrets from seasonal influenza viruses, which replicate mainly in the upper respiratory tract, but not from highly pathogenic influenza viruses, which also disseminate to the lung. Based on these results, a more intensive evaluation of IFN-α as an emergency drug against pandemic influenza A is warranted.
Noncytotoxic Suppression of Human Immunodeficiency Virus Type 1 Transcription by Exosomes Secreted from CD8+T Cells
Authors: Tumne Ashwin , Prasad Varsha Shridhar , Chen Yue , Stolz Donna B. , Saha Kunal , Ratner Deena M. , Ding Ming , Watkins Simon C. , Gupta Phalguni
Published: February 2009

CD8+T cells display a noncytotoxic activity that suppresses transcription of human immunodeficiency virus type 1 (HIV-1) in an antigen-independent and major histocompatibility complex-unrestricted manner. To date, the precise cellular and molecular factors mediating this CD8+T-cell effector function remain unsolved. Despite evidence indicating the dependence of the activity on cell-cell contact, the possibility of a membrane-mediated activity that represses transcription from the viral promoter remains unexplored. We therefore investigated whether this inhibition of HIV-1 transcription might be elicited by a membrane-bound determinant. Using a CD8+T-cell line displaying potent noncytotoxic HIV-1 suppression activity, we have identified a membrane-localized HIV-1-suppressing activity that is concomitantly secreted as 30- to 100-nm endosome-derived tetraspanin-rich vesicles known as exosomes. Purified exosomes from CD8+T-cell culture supernatant noncytotoxically suppressed CCR5-tropic (R5) and CXCR4-tropic (X4) replication of HIV-1 in vitro through a protein moiety. Similar antiviral activity was also found in exosomes isolated from two HIV-1-infected subjects. The antiviral exosomes specifically inhibited HIV-1 transcription in both acute and chronic models of infection. Our results, for the first time, indicate the existence of an antiviral membrane-bound factor consistent with the hallmarks defining noncytotoxic CD8+T-cell suppression of HIV-1.
Genetic risk factors for anterior cruciate ligament ruptures:COL1A1gene variant
Authors: Posthumus M , September A V , Keegan M , O’Cuinneagain D , Van der Merwe W , Schwellnus M P , Collins M
Published: February 2009

Background:

Anterior cruciate ligament (ACL) ruptures are considered the most severe injury sustained in sports. Although various intrinsic and extrinsic risk factors have been identified, the exact aetiology of the injury is not yet fully understood. Recently, the gene encoding for the α1 chain of type I collagen (COL1A1) has been shown to be associated with cruciate ligament ruptures and shoulder dislocations.

Objective:

To determine whether the functional Sp1 binding site polymorphism within intron 1 of theCOL1A1gene is associated specifically with ACL ruptures in an independent population.

Methods:

117 Caucasian participants with surgically diagnosed ACL ruptures, and 130 Caucasian physically active controls without any history of previous ligament or tendon injuries were recruited for this case–control genetic association study. All participants were genotyped for theCOL1A1Sp1 binding site polymorphism (G/T; rs1800012).

Results:

The rare TT genotype was significantly (p = 0.031, OR = 0.08, 95% CI <0.01 to 1.46) under-represented in the ACL group (0 out of 117, 0%), compared with the controls (6 out of 130, 4.6%).

Conclusion:

The TT genotype of theCOL1A1Sp1 binding site polymorphism was significantly under-represented in South African participants with ACL ruptures. We propose that this sequence variant be the first specific genetic element to be included in multifactorial models developed to understand the aetiology and risk factors for ACL rupture.
Magnetic Characteristics of Massive Sulfide Ore Bodies near Sudbury, Canada
Authors: Schwarz E. J.
Published: February 2009

The type of pyrrhotite, the direction and intensity of the natural remanent magnetization, and the anisotropy of the susceptibility have been determined for samples (101) of massive sulfides from the Strathcona, Falconbridge, Little Stobie, and Copper Cliff North Mines. The results are mutually consistent and indicate an appreciable positive anomaly over Copper Cliff North, weak anomalies over Little Stobie and Falconbridge, and very low magnetic relief over Strathcona. The aeromagnetic maps show a 100γ positive anomaly over Copper Cliff North, and a weak positive anomaly over Falconbridge, but no anomaly over the other deposits. The Falconbridge and Little Stobie deposits on the South Range occur at the base of the irruptive and contain a very high proportion of the magnetic Fe7S8, while the Copper Cliff North Mine, which is situated in a N-S trending offset, also contains appreciable quantities of nonmagnetic Fe9S10. The distribution of the Fe7S8 and the shape of the deposits with respect to the local geomagnetic field, suggest that the ore deposits on the South Range of the irruptive are more likely to produce marked anomalies than those on the North Range. However, on a detailed scale, deposits at the base of the irruptive on the North Range (Strathcona Mine) also contain very high proportions of Fe7S8, which could give rise to significant local anomalies, in a detailed survey on the surface, or in the mines. Further testing in other areas is required to establish the usefulness of studies of this type with the objective of finding guides for the selection of magnetic anomalies of interest in exploration.
Age of Inactive Alluvial Fans—Bow River Valley, Alberta
Authors: Roed M. A. , Wasylyk D. G.
Published: February 2009

Prominent inactive alluvial fans, which characterize parts of the Bow River valley, Banff National Park, Alberta, were deposited in a distinct interval of 'post-glacial' time. The fans were nearly completely formed before Altithermal time 6000 years B.P., as indicated by the occurrence of Mazama ash in the upper part of one of the fan deposits. This information indicates that a large landslide at Johnston Creek occurred within the same interval of time.
On the Origin and Deformation of the Fleur de Lys Metaconglomerate, Appalachian Fold Belt, Northwest Newfoundland
Authors: Wit Maarten J. de
Published: February 2009

The results of a study of a deformed metaconglomerate from the Fleur de Lys Supergroup, which occupies the northwest metamorphic zone of the Appalachian–Caledonian orogen in northwest Newfoundland, are described.This Eocambrian conglomerate unconformably overlies a Precambrian basement complex and has previously been interpreted as a glacial deposit. Sedimentological evidence does not support such an interpretation, and the present study shows the conglomerate to be of probable fluviatile origin.The deformation of the deposit, reflected in the state of finite strain of the clasts, is clearly inhomogeneous on all scales. The clasts range from nondeformed to intensely deformed and their shapes vary from oblale to prolate ellipsoids. The finite strain is thought to be due to buckling and three-dimensional differential flattening at the basement-conglomerate interface.
K–Ar isochron age and paleomagnetism of diabase along the trans-Avalon aeromagnetic lineament—evidence of Late Triassic rifting in Newfoundland
Authors: Hodych J. P. , Hayatsu A.
Published: February 2009

A prominent aeromagnetic lineament crosses the Avalon Peninsula of Newfoundland from 46°50.4′N, 53°45.9′W to 47°22.1′N, 52°30.0′W. It is shown to be at least partly caused by diabase dikes of Late Triassic and possibly Early Jurassic age which are probably related to the Shelburne diabase dike and the North Mountain basalt, both of Nova Scotia. All are thought to have resulted from rifting which preceded opening of the Atlantic.Unmetamorphosed diabase was found at three sites along the trans-Avalon aeromagnetic lineament: as narrow sills at site 1 (46°58.0′N, 53°25.4′W), as a narrow dike at site 2 (47°4.7′N, 53°7.6′W), and as large angular boulders at site 3 (47°11.0′N, 52°52.2′W).For sites 1 and 2, analyses of seven diabase samples fall on a single K–Ar isochron whose intercept on the 40Ar/36Ar axis is at 215 ± 45 and whose slope gives a Late Triassic age of 201.1 ± 2.6 Ma. Analyses of two diabase samples from the Shelburne dike fall close to this isochron suggesting a similar age. Paleomagnetism adds support; the virtual paleopole measured for sites 1 and 2, using 12 oriented diabase samples demagnetized in 300 Oe (23 880 A/m) alternating field (AF), falls at 87.8°E, 72.9°N (dp = 3.0°, dm = 4.3°), close to the virtual paleopole reported for the Shelburne dike.For site 3, analyses of two samples fall on the K–Ar isochron reported for the North Mountain basalt, tentatively suggesting that the intrusion at site 3 occurred about 10 Ma later than at sites 1and 2.
A new younginid (Reptilia: Eosuchia) from the Upper Permian of Madagascar
Authors: Currie Philip J.
Published: February 2009

Acerosodontosaurus piveteaui, a new genus and species of primitive diapsid reptile of the Family Younginidae, is based upon a partial skull and partial skeleton from Upper Permian strata of the République Démocratique de Madagascar. Morphologically, Acerosodontosaurus is closer to Youngina than any other known early diapsid. It can be distinguished from Youngina by a higher maxillary tooth count, a broader skull in the antorbital region, a broader puboischiatic plate, and a longer iliac blade. The type specimen is more mature than known specimens of Youngina, and furnishes anatomical information not reported in other younginid specimens.
Hydrochemistry of a dolomite karst: the Bruce Peninsula of Ontario
Authors: Cowell D. W. , Ford D. C.
Published: February 2009

Surface and subsurface waters on the Bruce Peninsula, Ontario, were sampled and analysed for Ca2+, Mg2+, pH, HCO3−; partial pressure of CO2(PCO2), and saturation states with respect to calcite (SIc) and dolomite (SId) were calculated. A total of 250 samples representing six hydrochemical environments were collected. These environments are (1) Georgian Bay and Lake Huron, (2) inland lakes, (3) rivers and streams, (4) wetlands, (5) conduit-flow springs, and (6) diffuse-flow springs. The seasonal behaviour and chemical separation of these waters are examined.Except for Georgian Bay and Lake Huron the waters of the peninsula are very hard, ranging from 180–320 ppm Ca2+ plus Mg2+ (as CaCO3), and display increasing hardness as the summer season progresses. Surface recharge and conduit-flow springs are generally saturated with respect to calcite and dolomite. Only diffuse-flow springs, which are among the hardest of waters, are commonly undersaturated. These waters are also the easiest to distinguish chemically and results of a linear discriminant function analysis suggest other waters of the peninsula to be of one class.
EFFECTS OF CORRELATION BETWEEN REAL AND IMAGINARY PARTS OF THE QUADRATIC PUMP NOISE ON THE INTENSITY FLUCTUATION OF A SINGLE-MODE LASER SYSTEM
Authors: ZHAO G. H. , XIANG Y. L. , MEI D. C.
Published: February 2009

The effects of the correlations between real and imaginary parts of the quadratic pump noise on the normalized intensity correlation function and the associated relaxation time of a single-mode laser model were investigated. The expressions of the intensity correlation function C(s) and the relaxation time Tc were derived. Based on numerical computations, we found that Tc monotonously increases as the strength λp of correlation between the real and imaginary parts of quadratic pump noise increases and the larger λp value is, the slower C(s) decays. The presence of correlations between the real and imaginary parts of the quadratic pump noise causes the intensity fluctuation to increase.
CFD MODELING OF THE STEADY-STATE MOMENTUM AND OXYGEN TRANSPORT IN A BIOREACTOR THAT IS DRIVEN BY AN AERIAL ROTATING DISK
Authors: LIOW K. Y. S. , TAN B. T. , THOUAS G. A. , THOMPSON M. C.
Published: February 2009

This work considers the momentum transport and mass transfer of O 2 in a novel aerial rotating disk bioreactor (RDB) for animal cell or tissue culture. Specifically, this design uses a rotating lid placed above the surface of the culture medium to provide a stirring mechanism, which has potential benefits of enhanced gas transfer, reducing possible contamination, and better access to the culture medium below. The aim of this study is to use CFD to characterize the flow field, shear stresses, and oxygen profiles at a range of Reynolds number that lies within the laminar flow regime. Ultimately, such data will aid the development of an aerial RDB for tumor progression. Numerical simulation is used whereby the two-phase flow, comprising air as the gaseous phase, and water as the aqueous phase, is obtained by solving the unsteady, axisymmetric, incompressible Navier Stokes equation. Having obtained an accurate flow field, a species transport equation is then used to predict the oxygen transfer from the gaseous phase to the aqueous phase. Results are presented for a rotation Reynolds number (Re) range that corresponds to the impeller speed range of 60 to 240 rpm. While the flow is primarily swirl-dominant, it is found that the secondary flow in the aqueous region consists of a single recirculation pattern. As the oxygen transfer in the aqueous phase is mainly driven by convection, there is a clear depletion of oxygen at the center of the recirculation region. Shear stress distributions along the bottom stationary wall indicate a shift in the peak towards the external cylinder wall with increasing Re.
MY ARCHITECTURE: A KNOWLEDGE REPRESENTATION META-MODEL FOR SOFTWARE ARCHITECTURE
Authors: SMEDA ADEL , OUSSALAH MOURAD , KHAMMACI TAHAR
Published: February 2009

In this article we show how knowledge representation techniques can be applied to software architecture. We define a representation model for software architecture concepts. The model is based on MY model (meta modeling in Y), which is a knowledge engineering methodology. It represents software architecture concepts using three branches: component, connector, and architecture. The component branch represents concepts that are related to computations, the connector branch represents concepts that are related to interactions, and the architecture branch represents concepts that are related to the structure and the topology of the system described. We think that such a representation of architecture concepts aids in improving reusability not only at the implementation level, but also at the description level. The model assigns a hierarchical library for the four software architecture conceptual levels (meta-meta architecture level, meta architecture level, architecture level, application level).
ANISOTROPIC METAMATERIALS FOR FIELD ENHANCEMENT AND NEGATIVE INDEX APPLICATIONS
Authors: FIDDY M. A. , INGEL R. P. , SCHENK J. O.
Published: February 2009

1D highly anisotropic periodic structures can exhibit very large internal field enhancements and positive spectral phase slopes. The field enhancement can lead to significant external fields radiating from the structure close to frequencies at which the spectral phase slope changes sign and where an effective negative index regime can occur.
LONG RANGE SURFACE PLASMON DEVICES DESIGN USING SUBWAVELENGTH METAL GRATING
Authors: WU ZHI , HAUS JOSEPH W. , ZHAN QIWEN , NELSON ROBERT L.
Published: February 2009

In this paper we review a new electro-optic devices design strategy using long range surface plasmon (LRSP) excitation along subwavelength metal grating. It is shown that LRSP can be excited on extremely thin subwavelength metal grating embedded in symmetric dielectric ambient. Due to coupling and propagation of LRSP between the metal grating nanowires, a super-narrow reflection dip can be obtained. Compared with conventional LRSP along metal thin film, much narrower resonance is achieved through decreased damping from the existence of large dielectric gaps between the grating nanowires. This interesting phenomenon can be used to design electro-optics devices with improved performance. Examples of electro-optic modulator design with lower insertion loss and low operating voltage and spectral notch filter design with very narrow spectral width will be shown. Its application in refractive index sensing is also discussed.
THE THIRD- AND FIFTH-ORDER NONLINEAR REFRACTION IN THE SINGLE- AND DOUBLE-SIDED TMAF/PSS ELECTROSTATIC SELF-ASSEMBLY FILMS
Authors: OUYANG QIUYUN , ZHANG XUERU , SONG YINGLIN
Published: February 2009

The nonlinear refraction in the single- and double-sided 40-bilayer TMAF/PSS electrostatic self-assembly films were measured by closed-aperture Z-scan technique with picosecond laser pulses (with duration of 40 ps at 532 nm). The materials contain a positively charged material trifluoroacetic acid (TFA) salt of amino-substitute methanofullerene derivative monoadduct fullerene (TMAF) and a negatively charged material ploy (sodium 4-styrenesulfon ate) (PSS). The experimental results show that under the conditions of the peak intensity I0 = 7.0 GW/cm2, both the single- and double-sided films demonstrate third- and fifth-order non-linearities, and the fifth-order non-linearity has greater contribution to the nonlinear refraction than the third-order nonlinearity. The theoretical fittings also prove that the nonlinear refraction coefficients both γ and η are almost the same for the same materials no matter what the measurements are from the single- or the double-sided films.
Single-Molecule Approaches to Stochastic Gene Expression
Authors: Raj Arjun , van Oudenaarden Alexander
Published: February 2009

Both the transcription of mRNAs from genes and their subsequent translation into proteins are inherently stochastic biochemical events, and this randomness can lead to substantial cell-to-cell variability in mRNA and protein numbers in otherwise identical cells. Recently, a number of studies have greatly enhanced our understanding of stochastic processes in gene expression by utilizing new methods capable of counting individual mRNAs and proteins in cells. In this review, we examine the insights that these studies have yielded in the field of stochastic gene expression. In particular, we discuss how these studies have played in understanding the properties of bursts in gene expression. We also compare the array of different methods that have arisen for single mRNA and protein detection, highlighting their relative strengths and weaknesses. In conclusion, we point out further areas where single-molecule techniques applied to gene expression may lead to new discoveries.
Angiotensin II inhibits the Na+-K+ pump via PKC-dependent activation of NADPH oxidase
Authors: White Caroline N. , Figtree Gemma A. , Liu Chia-Chi , Garcia Alvaro , Hamilton Elisha J. , Chia Karin K. M. , Rasmussen Helge H.
Published: February 2009

The sarcolemmal Na+-K+ pump, pivotal in cardiac myocyte function, is inhibited by angiotensin II (ANG II). Since ANG II activates NADPH oxidase, we tested the hypothesis that NADPH oxidase mediates the pump inhibition. Exposure to 100 nmol/l ANG II increased superoxide-sensitive fluorescence of isolated rabbit ventricular myocytes. The increase was abolished by pegylated superoxide dismutase (SOD), by the NADPH oxidase inhibitor apocynin, and by myristolated inhibitory peptide to ε-protein kinase C (εPKC), previously implicated in ANG II-induced Na+-K+ pump inhibition. A role for εPKC was also supported by an ANG II-induced increase in coimmunoprecipitation of εPKC with the receptor for the activated kinase and with the cytosolic p47 phox subunit of NADPH oxidase. ANG II decreased electrogenic Na+-K+ pump current in voltage-clamped myocytes. The decrease was abolished by SOD, by the gp91ds inhibitory peptide that blocks assembly and activation of NADPH oxidase, and by εPKC inhibitory peptide. Since colocalization should facilitate NADPH oxidase-dependent regulation of the Na+-K+ pump, we examined whether there is physical association between the pump subunits and NADPH oxidase. The α1-subunit coimmunoprecipitated with caveolin 3 and with membrane-associated p22 phox and cytosolic p47 phox NADPH oxidase subunits at baseline. ANG II had no effect on α1/caveolin 3 or α1/p22 phox interaction, but it increased α1/p47 phox coimmunoprecipitation. We conclude that ANG II inhibits the Na+-K+ pump via PKC-dependent NADPH oxidase activation.
Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes
Authors: Ndisang Joseph Fomusi , Lane Nina , Jadhav Ashok
Published: February 2009

In type 2 diabetes (T2D), postprandial and fasting hyperglycemia are important predictors of cardiovascular diseases; however, few drugs are currently available to simultaneously suppress these conditions. Here, we report an enduring antidiabetic effect of the heme oxygenase (HO) inducer hemin on Goto-Kakizaki rats (GK), a nonobese insulin-resistant T2D model. HO breaks down the heme-moiety-generating antioxidants (biliverdin/bilirubin and ferritin) and carbon monoxide, which stimulate insulin secretion. Hemin induces HO-1 to potentiate HO activity and the HO-derived products. Chronically applied hemin (30 mg/kg ip) for a month reduced and maintained fasting glucose at physiological levels for 3 mo. Before therapy, glucose levels were 9.3 ± 0.3 mmol/l ( n = 14). At 1, 2, and 3 mo posttherapy, we recorded 6.7 ± 0.13, 5.9 ± 0.2, and 7.2 ± 0.2 mmol/l, respectively. Hemin was also effective against postprandial hyperglycemia (14.6 ± 1.1 vs. 7.5 ± 0.4 mmol/l; n = 14; P < 0.01), and the effect remained sustained for 3 mo after therapy. The reduction of hyperglycemia was accompanied by enhanced HO-1, HO activity, and cGMP of the soleus muscle, alongside increased plasma bilirubin, ferritin, SOD, total antioxidant capacity, and insulin levels, whereas markers/mediators of oxidative stress like urinary-8-isoprostane and soleus muscle nitrotyrosine, NF-κB, and activator protein-1 and -2 were abated. Furthermore, inhibitors of insulin signaling including soleus muscle glycogen synthase kinase-3 and JNK were reduced, while the insulin-sensitizing adipokine, adiponectin, alongside AMPK were increased. Correspondingly, hemin improved glucose tolerance, suppressed insulin intolerance, reduced insulin resistance, and overturned the inability of insulin to enhance glucose transporter 4, a protein required for glucose uptake. Hemin also upregulated HO-1/HO activity and cGMP and lowered glucose in euglycemic Sprague-Dawley control rats albeit less intensely, suggesting greater selectivity of the HO system in diabetic conditions. In conclusion, reduced oxidative stress alongside the concomitant and paradoxical enhancement of insulin secretion and insulin-sensitizing pathways may account for the 3-mo-enduring antidiabetic effect. The synergistic interaction among HO, adiponectin, and GLUT4 may be explored against insulin-resistant diabetes.
Reappraisal of the intravenous glucose tolerance index for a simple assessment of insulin sensitivity in mice
Authors: Pacini Giovanni , Ahrén Maria , Ahrén Bo
Published: February 2009

Mice are increasingly used in studies where measuring insulin sensitivity (IS) is a common procedure. The glucose clamp is labor intensive, cannot be used in large numbers of animals, cannot be repeated in the same mouse, and has been questioned as a valid tool for IS in mice; thus, the minimal model with 50-min intravenous glucose tolerance test (IVGTT) data was adapted for studies in mice. However, specific software and particular ability was needed. The aim of this study was to establish a simple procedure for evaluating IS during IVGTT in mice (CSI). IVGTTs ( n = 520) were performed in NMRI and C57BL/6J mice (20–25g). After glucose injection (1 g/kg), seven samples were collected for 50 min for glucose and insulin measurements, analyzed with a minimal model that provided the validated reference IS (SI). By using the regression CSI = α1 + α2 × KG/AUCD, where KG is intravenous glucose tolerance index and AUCd is the dynamic area under the curve, IS was calculated in 134 control animals randomly selected (regression CSI vs. SI: r = 0.66, P < 0.0001) and yielded α1 = 1.93 and α2 = 0.24. KG is the slope of log (glucose5-20) and AUCD is the mean dynamic area under insulin curve in the IVGTT. By keeping fixed α1 and α2, CSI was validated in 143 control mice (4.7 ± 0.2 min·μU−1·ml−1, virtually identical to SI: 4.7 ± 0.3, r = 0.89, P < 0.0001); and in 123 mice in different conditions: transgenic, addition of neuropeptides, incretins, and insulin (CSI: 6.0 ± 0.4 vs. SI: 6.1 ± 0.4, r = 0.94, P < 0.0001). In the other 120 animals, CSI revealed its ability to segregate different categories, as does SI. This easily usable formula for calculating CSI overcomes many experimental obstacles and may be a simple alternative to more complex procedures when large numbers of mice or repeated experiments in the same animals are required.
Nonshivering thermogenesis without interscapular brown adipose tissue involvement during conditioned fear in the rat
Authors: Marks Andrew , Vianna Daniel M. L. , Carrive Pascal
Published: February 2009

As with other forms of psychological stress, conditioned fear causes an increase in body temperature. The mechanisms underlying this stress-induced hyperthermia are not well understood, but previous research suggests that nonshivering thermogenesis might contribute, as it does during cold exposure. The major source of nonshivering thermogenesis in the rat is brown adipose tissue (BAT), and the largest BAT deposit in that species is in the interscapular area just below the skin. BAT is also under sympathetic control via β-adrenoceptors. If BAT contributes to fear-induced hyperthermia, then the interscapular skin should warm up faster than other skin areas, and this response should be suppressed by the β-adrenoceptor antagonist, propranolol. We tested this noninvasively by infrared thermography. In conscious rats, 30 min of contextual fear caused hyperthermia (as indicated by a +1.5°C increase in lumbar back skin temperature) and increased the difference in temperature between interscapular and lumbar back skin (TiScap − TBack) by +1°C. Propranolol (10 mg/kg ip) completely abolished this hyperthermia; however, the TiScap-TBack increase was not reduced. In contrast, exposure to cold air (4°C) induced a +2.7°C increase in TiScap-TBack, which was reduced to +1°C after propranolol. The results show that conditioned fear-induced hyperthermia is of nonshivering origin and mediated by β-adrenoceptors, but interscapular BAT does not contribute to it and does not appear to be activated, either.
C-reactive protein and cardiac vagal activity following resistance exercise training in young African-American and white men
Authors: Heffernan Kevin S. , Jae Sae Young , Vieira Victoria J. , Iwamoto Gary A. , Wilund Kenneth R. , Woods Jeffrey A. , Fernhall Bo
Published: February 2009

African Americans have a greater prevalence of hypertension and diabetes compared with white Americans, and both autonomic dysregulation and inflammation have been implicated in the etiology of these disease states. The purpose of this study was to examine the cardiac autonomic and systemic inflammatory response to resistance training in young African-American and white men. Linear (time and frequency domain) and nonlinear (sample entropy) heart rate variability, baroreflex sensitivity, tonic and reflex vagal activity, and postexercise heart rate recovery were used to assess cardiac vagal modulation. C-reactive protein (CRP) and white blood cell count were used as inflammatory markers. Twenty two white and 19 African-American men completed 6 wk of resistance training followed by 4 wk of exercise detraining (Post 2). Sample entropy, tonic and reflex vagal activity, and heart rate recovery were increased in white and African-American men following resistance training ( P < 0.05). Following detraining (Post 2), sample entropy, tonic and reflex vagal activity, and heart rate recovery returned to baseline values in white men but remained above baseline in African-American men. While there were no changes in white blood cell count or CRP in white men, these inflammatory markers decreased in African-American men following resistance training, with reductions being maintained following detraining ( P < 0.05). In conclusion, resistance training improves cardiac autonomic function and reduces inflammation in African-American men, and these adaptations remained after the cessation of training. Resistance training may be an important lifestyle modification for improving cardiac autonomic health and reducing inflammation in young African-American men.
Adaptive plasticity of killifish (Fundulus heteroclitus) embryos: dehydration-stimulated development and differential aquaporin-3 expression
Authors: Tingaud-Sequeira Angèle , Zapater Cinta , Chauvigné François , Otero David , Cerdà Joan
Published: February 2009

Embryos of the marine killifish Fundulus heteroclitus are adapted to survive aerially. However, it is unknown if they are able to control development under dehydration conditions. Here, we show that air-exposed blastula embryos under saturated relative humidity were able to stimulate development, and hence the time of hatching was advanced with respect to embryos continuously immersed in seawater. Embryos exposed to air at later developmental stages did not hatch until water was added, while development was not arrested. Air-exposed embryos avoided dehydration probably because of their thickened egg envelope, although it suffered significant evaporative water loss. The potential role of aquaporins as part of the embryo response to dehydration was investigated by cloning the aquaporin-0 (FhAqp0), -1a (FhAqp1a), and -3 (FhAqp3) cDNAs. Functional expression in Xenopus laevis oocytes showed that FhaAqp1a was a water-selective channel, whereas FhAqp3 was permeable to water, glycerol, and urea. Expression of fhaqp0 and fhaqp1a was prominent during organogenesis, and their mRNA levels were similar between water- and air-incubated embryos. However, fhaqp3 transcripts were highly and transiently accumulated during gastrulation, and the protein product was localized in the basolateral membrane of the enveloping epithelial cell layer and in the membrane of ingressing and migrating blastomers. Interestingly, both fhaqp3 transcripts and FhAqp3 polypeptides were downregulated in air-exposed embryos. These data demonstrate that killifish embryos respond adaptively to environmental desiccation by accelerating development and that embryos are able to transduce dehydration conditions into molecular responses. The reduced synthesis of FhAqp3 may be one of these mechanisms to regulate water and/or solute transport in the embryo.
Sensitivity Analysis to Select the Most Influential Risk Factors in a Logistic Regression Model
Authors: Hussain Jassim N.
Published: February 2009

The traditional variable selection methods for survival data depend on iteration procedures, and control of this process assumes tuning parameters that are problematic and time consuming, especially if the models are complex and have a large number of risk factors. In this paper, we propose a new method based on the global sensitivity analysis (GSA) to select the most influential risk factors. This contributes to simplification of the logistic regression model by excluding the irrelevant risk factors, thus eliminating the need to fit and evaluate a large number of models. Data from medical trials are suggested as a way to test the efficiency and capability of this method and as a way to simplify the model. This leads to construction of an appropriate model. The proposed method ranks the risk factors according to their importance.
The Effect of Isotopic Composition on the Uncertainty of Routine Metal Mass Concentration Measurements in Ambient Air
Authors: Brown Richard J. C. , Goddard Sharon L. , Brown Andrew S. , Yardley Rachel E.
Published: February 2009

The main sources of uncertainty encountered during the analysis of the mass concentration of metals in ambient air as part of the operation of the UK Heavy Metals Monitoring Network are presented. It is observed that the uncertainty contribution from possible variation in the isotopic composition of the sample depends on the element in question, but can be significant (e.g., for Pb, Cd, and Hg). The working curve method for the ICP-MS analysis of metals in solution, with a low resolution, high throughput instrument measuring at onem/zratio per element, relies on the relative abundance of the isotopes under consideration being the same in both the sample and the calibration solution. Calculation of the uncertainty in this analysis assumes that the isotopic composition variation within the sample and calibration solution is limited to a defined range. Therefore, in order to confirm the validity of this quantification methodology and its uncertainty budget, the isotopic composition of the calibration standards used for quantification has been determined. The results of this analysis are presented here.
EVI1 Impairs Myelopoiesis by Deregulation of PU.1 Function
Authors: Laricchia-Robbio Leopoldo , Premanand Kavitha , Rinaldi Ciro R. , Nucifora Giuseppina
Published: February 2009

EVI1 is an oncogene inappropriately expressed in the bone marrow (BM) of ∼10% of myelodysplastic syndrome (MDS) patients. This disease is characterized by severe anemia and multilineage myeloid dysplasia that are thought to be a major cause of mortality in MDS patients. We earlier reported on a mouse model that constitutive expression of EVI1 in the BM led to fatal anemia and myeloid dysplasia, as observed in MDS patients, and we subsequently showed that EVI1 interaction with GATA1 blocks proper erythropoiesis. Whereas this interaction could provide the basis for the erythroid defects in EVI1-positive MDS, it does not explain the alteration of myeloid differentiation. Here, we have examined the expression of several genes activated during terminal myelopoiesis in BM cells and identified a group of them that are altered by EVI1. A common feature of these genes is their regulation by the transcription factor PU.1. We report here that EVI1 interacts with PU.1 and represses the PU.1-dependent activation of a myeloid promoter. EVI1 does not seem to inhibit PU.1 binding to DNA, but rather to block its association with the coactivator c-Jun. After mapping the PU.1-EVI1 interaction sites, we show that an EVI1 point mutant, unable to bind PU.1, restores the activation of PU.1-regulated genes and allows a normal differentiation of BM progenitors in vitro. [Cancer Res 2009;69(4):1633–42]
DDB1-CUL4 and MLL1 Mediate Oncogene-Induced p16INK4a Activation
Authors: Kotake Yojiro , Zeng Yaxue , Xiong Yue
Published: February 2009

The induction of cellular senescence by oncogenic signals acts as a barrier to cellular transformation and is attained, in part, by the elevation of the p16INK4a tumor suppressor gene. p16 expression is repressed epigenetically by Polycomb, but how p16 is induced is not known. We report here that the p16 locus is H3K4-methylated in highly expressing cells. H3K4 methyltransferase MLL1 directly binds to and is required, along with its core component RbBP5, for the induction of p16 by oncogenic Ras. We further show that damaged DNA binding protein DDB1 and CUL4, which assemble distinct E3 ubiquitin ligases by recruiting various WD40 proteins, act upstream of MLL1-mediated H3K4 methylation. We showed that CUL4A directly binds to p16 and that silencing DDB1 blocks Ras-induced p16 activation. Ras expression dissociates BMI1 from the p16 locus, whereas both CUL4 and MLL1 bind to the p16 locus similarly in both normal and oncogenic stimulated cells. These results suggest that DDB1-CUL4 and MLL1 complexes constitute a novel pathway that mediates p16 activation during oncogenic checkpoint response and is repressed by the polycomb repression complexes during normal growth of young cells. [Cancer Res 2009;69(5):1809–14]
Mesenchymal Stem Cells: Flip Side of the Coin
Authors: Mishra Pravin J. , Mishra Prasun J. , Glod John W. , Banerjee Debabrata
Published: February 2009

Tumor-associated fibroblasts or carcinoma-associated fibroblasts (CAF) play an important role in the growth of epithelial solid tumors. Although the cell type of origin of CAFs has not been conclusively established, it has been shown that they may be bone marrow derived. One side of the mesenchymal stem cell (MSC) coin is the well-accepted therapeutic potential of these cells for regenerative and immunomodulatory purposes. The ominous dark side is revealed by the recent work demonstrating that hMSCs may be a source of CAFs. In this review, we discuss the role of stromal cells in the tumor microenvironment and suggest that by exploring the in vitro/in vivo interplay between different cell types within the tumor milieu, strategies for improved tumor therapy can be developed. [Cancer Res 2009;69(4):1255–8]
Is Anticancer Drug Development Heading in the Right Direction?
Authors: Hambley Trevor W.
Published: February 2009

The success of molecularly targeted agents, such as imatinib, has led to expectations of a new era in anticancer drug development, and to a greatly increased focus on targeting as a strategy. However, the number of successes to date is small, and recent results suggest that the success of imatinib, for instance, in treating chronic myelogenous leukemia and gastrointestinal stromal tumor may be the exception rather than the rule. Here, we argue that the search for new anticancer agents needs to continue on as many fronts as possible, and not be focused on one strategy alone. [Cancer Res 2009;69(4):1259–62]
A Century of Deciphering the Control Mechanisms of Sex Steroid Action in Breast and Prostate Cancer: The Origins of Targeted Therapy and Chemoprevention
Authors: Jordan V. Craig
Published: February 2009

The origins of the story to decipher the mechanisms that control the growth of sex hormone–dependent cancers started more than 100 years ago. Clinical observations of the apparently random responsiveness of breast cancer to endocrine ablation (hormonal withdrawal) provoked scientific inquiries in the laboratory that resulted in the development of effective strategies for targeting therapy to the estrogen receptor (ER; or androgen receptor in the case of prostate cancer), the development of antihormonal treatments that dramatically enhanced patient survival, and the first successful testing of agents to reduce the risk of developing any cancer. Most importantly, elucidating the receptor-mediated mechanisms of sex steroid–dependent growth and the clinical success of antihormones has had broad implication in medicinal chemistry with the synthesis of new selective hormone receptor modulators for numerous clinical applications. Indeed, the successful translational research on the ER was the catalyst for the current strategy for developing targeted therapies to the tumor and the start of “individualized medicine.” During the past 50 years, ideas about the value of antihormones translated effectively from the laboratory to improve clinical care, improve national survival rates, and significantly reduced the burden of cancer. [Cancer Res 2009;69(4):1243–54]
Crocetin inhibits pancreatic cancer cell proliferation and tumor progression in a xenograft mouse model
Authors: Dhar Animesh , Mehta Smita , Dhar Gopal , Dhar Kakali , Banerjee Snigdha , Van Veldhuizen Peter , Campbell Donald R. , Banerjee Sushanta K.
Published: February 2009

Crocetin, a carotenoid compound derived from saffron, has long been used as a traditional ancient medicine against different human diseases including cancer. The aim of the series of experiments was to systematically determine whether crocetin significantly affects pancreatic cancer growth both in vitro and/or in vivo. For the in vitro studies, first, MIA-PaCa-2 cells were treated with crocetin and in these sets of experiments, a proliferation assay using H3-thymidine incorporation and flow cytometric analysis suggested that crocetin inhibited proliferation. Next, cell cycle proteins were investigated. Cdc-2, Cdc-25C, Cyclin-B1, and epidermal growth factor receptor were altered significantly by crocetin. To further confirm the findings of inhibition of proliferation, H3-thymidine incorporation in BxPC-3, Capan-1, and ASPC-1 pancreatic cancer cells was also significantly inhibited by crocetin treatment. For the in vivo studies, MIA-PaCa-2 as highly aggressive cells than other pancreatic cancer cells used in this study were injected into the right hind leg of the athymic nude mice and crocetin was given orally after the development of a palpable tumor. The in vivo results showed significant regression in tumor growth with inhibition of proliferation as determined by proliferating cell nuclear antigen and epidermal growth factor receptor expression in the crocetin-treated animals compared with the controls. Both the in vitro pancreatic cancer cells and in vivo athymic nude mice tumor, apoptosis was significantly stimulated as indicated by Bax/Bcl-2 ratio. This study indicates that crocetin has a significant antitumorigenic effect in both in vitro and in vivo on pancreatic cancer. [Mol Cancer Ther 2009;8(2):315–23]
A Genotype-Dependent Intermediate ECG Phenotype in Patients With Persistent Lone Atrial Fibrillation
Authors: Husser Daniela , Stridh Martin , Sörnmo Leif , Roden Dan M. , Darbar Dawood , Bollmann Andreas
Published: February 2009

Background—

Atrial fibrillation (AF) is heterogeneous at the clinical and molecular levels. Association studies have reported that common single-nucleotide polymorphisms in
KCNE1
and
SCN5A
may predispose to AF. In this study, we tested the hypothesis that specific AF-associated genotypes confer variation on the appearance of AF assessed by analysis of fibrillatory rate of the atria.

Methods and Results—

Twenty-six nonrelated patients (21 males, mean age 55�12 years) with persistent lone AF (median AF duration 5 weeks) not taking class I or III antiarrhythmic drugs were studied. Fibrillatory rate was obtained by spatiotemporal QRST cancellation and time-frequency analysis of the index surface ECG. Genotypes at the AF-associated loci in
KCNE1
(S38G) and
SCN5A
(H558R) were determined by direct DNA sequencing. The atrial fibrillatory rate was 418�50 fibrillations per minute (range, 336 to 521) in the study cohort. Carriers of the 38GG
KCNE1
genotype (n=13) had significantly lower fibrillatory rates (392�36 versus 443�49 fibrillations per minute,
P
=0.006) compared to those with GS or SS genotype (n=13). Six patients (23%) with fibrillatory rates >450 fibrillations per minute, all had either the GS or SS genotype (χ
2
P
=0.008). In contrast, both the heterozygeous and homozygeous
SCN5A
H558R polymorphism had no effect on fibrillatory rate. There were no significant associations between fibrillatory rate and clinical (age, gender, AF duration, drug treatment) or echocardiographic (left atrial diameter, left ventricular ejection fraction) variables. In multivariable regression analysis, the
KCNE1
S38G genotype (SS/GS coded 0, GG coded 1) was the only independent predictor of fibrillatory rate (β=−0.437,
P
=0.006) with a SE of the estimate of 44 fibrillations per minute.

Conclusions—

This study suggests that atrial fibrillatory rate obtained from the surface ECG is at least in part determined by
KCNE1
(S38G) genotype, implying that this variant exerts functional effects on atrial electrophysiology. This intermediate ECG phenotype may be useful for elaborating genetic influences on AF mechanisms and identifying subsets of patients for variability in AF susceptibility or response to therapies.