bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuroprotective Effects of Calmodulin Peptide 76‐121aa: Disruption of Calmodulin Binding to Mutant Huntingtin
Authors: Dudek Nichole L. , Dai Ying , Muma Nancy A.
Published: March 2009

Huntington's disease (HD) is a neurodegenerative disease caused by mutant huntingtin protein containing an expanded polyglutamine tract, which may cause abnormal protein–protein interactions such as increased association with calmodulin (CaM). We previously demonstrated in HEK293 cells that a peptide containing amino acids 76‐121 of CaM (CaM‐peptide) interrupted the interaction between CaM and mutant huntingtin, reduced mutant huntingtin‐induced cytotoxicity and reduced transglutaminase (TG)‐modified mutant huntingtin. We now report that adeno‐associated virus (AAV)‐mediated expression of CaM‐peptide in differentiated neuroblastoma SH‐SY5Y cells, stably expressing an N‐terminal fragment of huntingtin containing 148 glutamine repeats, significantly decreases the amount of TG‐modified huntingtin and attenuates cytotoxicity. Importantly, the effect of the CaM‐peptide shows selectivity, such that total TG activity is not significantly altered by expression of CaM‐peptide nor is the activity of another CaM‐dependent enzyme, CaM kinase II.In vitro, recombinant exon 1 of huntingtin with 44 glutamines (htt‐exon1‐44Q) binds to CaM‐agarose; the addition of 10 µM of CaM‐peptide significantly decreases the interaction of htt‐exon1‐44Q and CaM but not the binding between CaM and calcineurin, another CaM‐binding protein. These data support the hypothesis that CaM regulates TG‐catalyzed modifications of mutant huntingtin and that specific and selective disruption of the CaM‐huntingtin interaction is potentially a new target for therapeutic intervention in HD.
Highlights from the perspectives in melanoma XII conference
Authors: Kirkwood John M. , Eggermont Alexander
Published: March 2009

The following meeting highlights are from the Perspectives in Melanoma XII conference, held in Scheveningen/The Hague, the Netherlands, on October 2–4, 2008. Selected reviews are included but further discussions of these and other presentations are posted at http://www.MelanomaCare.org.
Preoperative topical cyclopentolate can be omitted when using intracameral lidocaine in phacoemulsification surgery
Authors: Lundberg Björn , Behndig Anders
Published: March 2009

Purpose:  To evaluate the mydriatic effect of topical cyclopentolate 1% when combined with topical phenylephrine 10% and intracameral lidocaine 1% in phacoemulsification cataract surgery.

Methods:  We performed a prospective, double‐masked, randomized trial including 20 patients with age‐related cataract, who were scheduled for unilateral phacoemulsification and intraocular lens (IOL) implantation. Patients were given either two drops of phenylephrine 10% at 30 mins and 15 mins prior to surgery (group 1), or two drops each of cyclopentolate 1% and phenylephrine 10% at the same time points (group 2). All patients were also given lidocaine 1% intracamerally at the beginning of the procedure. Intraoperative pupil sizes were assessed from video‐recordings.

Results:  Initially, pupil sizes were significantly smaller in group 1 (4.8 ± 1.2 mm versus 6.5 ± 1.4 mm; p = 0.0098), but the lidocaine injection increased the pupil sizes in group 1 significantly, so that pupil sizes in both groups were equalized throughout the surgical procedure.

Conclusions:  Preoperative topical cyclopentolate does not enhance mydriasis in phacoemulsification surgery when using intracameral lidocaine and can be omitted when intracameral lidocaine is used.
ELECTROKINETIC STUDIES OF MINERALS IN AQUEOUS SOLUTIONS THROUGH ELECTROACOUSTIC MEASUREMENT
Authors: RAO FENG , SONG SHAOXIAN , LOPEZ-VALDIVIESO ALEJANDRO
Published: March 2009

Electrokinetic property of various minerals in aqueous solutions has been studied through electroacoustic measurement in the present work. This study was carried out on the particles of calcite ( CaCO 3), magnetite ( Fe 3 O 4), quartz ( SiO 2), and galena ( PbS ) in an aqueous NaCl solution. Electrophoretic measurement was also applied to magnetite and quartz particles for the comparison of the two methods. The experimental results have shown that the point of zero charges (PZCs) of calcite, magnetite, and galena were at pH 12.5, 3.8 and 2.8, respectively, while no PZC for quartz appeared in the pH range of 1.5–11. The electroacoustic and electrophoretic measurements have obtained the same PZC and similar curves of zeta potential vs pH for magnetite and quartz particles in aqueous solutions. In addition, it has been found that a specific adsorption of Na + cation was applied to magnetite surfaces in aqueous solutions if the electrolyte ( NaCl ) concentration in the solution is high enough, leading the isoelectric point to shift rightward. This observation might be more remarkable in electroacoustic measurement than electrophoretic measurement.
Trastuzumab-Induced HER Reprogramming in “Resistant” Breast Carcinoma Cells
Authors: Narayan Murli , Wilken Jason A. , Harris Lyndsay N. , Baron Andre T. , Kimbler Kimberly D. , Maihle Nita J.
Published: March 2009

Although trastuzumab (Herceptin) is an important advance in the treatment of breast cancer, a significant proportion of patients do not respond to trastuzumab either alone or in combination with chemotherapy. In this study, we observe that epidermal growth factor receptor (EGFR) and HER3 expression is substantially increased after long-term trastuzumab exposure of HER2-positive breast carcinoma–derived cell lines that show primary resistance to trastuzumab. Furthermore, long-term trastuzumab exposure of trastuzumab-resistant cell lines induces de novo sensitivity to the EGFR-targeted agents gefitinib or cetuximab in two of three cell lines accompanied by increased EGFR expression. Together, these results indicate that primary trastuzumab resistance is not synonymous with lack of responsiveness to trastuzumab and, importantly, suggest that trastuzumab priming may sensitize trastuzumab-resistant tumors to other HER family-directed therapeutics. [Cancer Res 2009;69(6):2191–4]
Endothelin-1 Stimulates Lymphatic Endothelial Cells and Lymphatic Vessels to Grow and Invade
Authors: Spinella Francesca , Garrafa Emirena , Di Castro Valeriana , Rosanò Laura , Nicotra Maria Rita , Caruso Arnaldo , Natali Pier Giorgio , Bagnato Anna
Published: March 2009

The lymphatic vasculature is essential for tissue fluid homeostasis and cancer metastasis, although the molecular mechanisms involved remain poorly characterized. Endothelin-1 (ET-1) axis plays a crucial role in angiogenesis and tumorigenesis. Here, we first report that ET-1 acts as a lymphangiogenic mediator. We performed in vitro and in vivo studies and show that lymphatic endothelial cells produce ET-1, ET-3, and express the endothelin B receptor (ETBR). In these cells, ET-1 promotes proliferation, invasiveness, vascular-like structures formation, and phosphorylation of AKT and p42/44 mitogen-activated protein kinase through ETBR. In normoxic conditions, ET-1 is also able to up-regulate the expression of vascular endothelial growth factor (VEGF)-C, VEGF receptor-3, and VEGF-A, and to stimulate hypoxia-inducible factor (HIF)-1α expression similarly to hypoxia. Moreover, HIF-1α silencing by siRNA desensitizes VEGF-C and VEGF-A production in response to ET-1 or hypoxia, implicating HIF-1α/VEGF as downstream signaling molecules of ET-1 axis. Double immunofluorescence analysis of human lymph nodes reveals that lymphatic vessels express ETBR together with the lymphatic marker podoplanin. Furthermore, a Matrigel plug assay shows that ET-1 promotes the outgrowth of lymphatic vessels in vivo. ETBR blockade with the specific antagonist, BQ788, inhibits in vitro and in vivo ET-1–induced effects, demonstrating that ET-1 through ETBR directly regulates lymphatic vessel formation and by interacting with the HIF-1α–dependent machinery can amplify the VEGF-mediated lymphatic vascularization. Our results suggest that ET-1 axis is indeed a new player in lymphangiogenesis and that targeting pharmacologically ETBR and related signaling cascade may be therapeutically exploited in a variety of diseases including cancer. [Cancer Res 2009;69(6):2669–76]
Identification of Ligand-Induced Proteolytic Cleavage and Ectodomain Shedding of VEGFR-1/FLT1 in Leukemic Cancer Cells
Authors: Rahimi Nader , Golde Todd E. , Meyer Rosana D.
Published: March 2009

Vascular endothelial growth factor receptor-1/fms-related tyrosine kinase 1 (VEGFR-1/FLT1) is expressed as a membrane-bound receptor tyrosine kinase and as an alternatively spliced soluble protein (sVEGFR-1) containing the 1-6 IgG-like domain of its ectodomain. sVEGFR-1 is known as a naturally occurring inhibitor of angiogenesis and as a surrogate marker for cancer progression; it is also linked to pregnancy-induced hypertension called preeclampsia and to avascularity of normal cornea. It remains an open question whether alternative mRNA splicing is the only mechanism by which sVEGFR-1 is generated. In this study, we show that in leukemic cancer cells, PlGF and VEGF-A both induce tyrosine phosphorylation of VEGFR-1 and render it susceptible to ectodomain shedding, resulting in the generation of sVEGFR-1 and an intracellular cytoplasmic fragment. Activation of protein kinase C and tumor necrosis factor-α–converting enzyme family metalloproteases are critically required for the occurrence of sVEGFR-1. Following the removal of the ectodomain, the remnant of VEGFR-1 remains attached to the membrane, and the activity of γ-secretase/presenilin is required for its release from the cell membrane. We propose that sVEGFR-1 produced via ectodomain shedding plays a prominent role in the VEGF receptor system by antagonizing VEGF receptor signaling by acting as a dominant-negative form and/or forming a nonsignaling dimerizing complex with VEGF receptors. [Cancer Res 2009;69(6):2607–14]
Epigenetic Regulation of c-ROS Receptor Tyrosine Kinase Expression in Malignant Gliomas
Authors: Jun Hyun Jung , Woolfenden Steve , Coven Shanie , Lane Keara , Bronson Roderick , Housman David , Charest Alan
Published: March 2009

The proto-oncogene tyrosine kinase c-ROS is an orphan receptor whose normal expression pattern is tightly spatio-temporally restricted during development. In glioma, c-ROS mRNA expression is frequently ectopically up-regulated. In this study, we determined by immunohistochemical means that c-ROS receptor protein is present in 25% of low-grade and 30% of malignant glioma tumor samples from tissue microarrays. We then explored the molecular basis for the up-regulation of c-ROS expression in these tumors. We identified and characterized the c-ROS gene promoter region and report that the ectopic expression of c-ROS in tumors is tied to hypomethylation of a CpG island in the c-ROS promoter. Bisulfite sequencing analysis in glioma tumor samples revealed that demethylation of the CpG island (−384 to −132 bp) correlated with c-ROS expression. Moreover, c-ROS expression could be activated by treatment of c-ROS–negative cells with the demethylating agent 5-aza-2′-deoxycytidine. These results establish a strong link between c-ROS promoter demethylation and gain of c-ROS expression and function in glioma. Our data suggest that epigenetic activation of c-ROS represents an important oncogenic mechanism for glioma initiation and progression and suggest that cautionary measures in the clinical use of 5-aza-dC for the treatment of glioma be taken into consideration. [Cancer Res 2009;69(6):2180–4]
Identification of CD20 C-Terminal Deletion Mutations Associated with Loss of CD20 Expression in Non-Hodgkin's Lymphoma
Authors: Terui Yasuhito , Mishima Yuji , Sugimura Natsuhiko , Kojima Kiyotsugu , Sakurai Takuma , Mishima Yuko , Kuniyoshi Ryoko , Taniyama Akiko , Yokoyama Masahiro , Sakajiri Sakura , Takeuchi Kengo , Watanabe Chie , Takahashi Shunji , Ito Yoshinori , Hatake Kiyohiko
Published: March 2009

Purpose: Rituximab is commonly incorporated into CD20-positive B-cell lymphoma therapy to improve response and prognosis. With increasing use, resistance to rituximab is a continuing concern, but CD20 mutation as a cause of resistance has not previously been reported.

Experimental Design: Freshly collected lymphoma cells from 50 patients with previously untreated or relapsed/resistant non-Hodgkin's B-cell lymphomas (diffuse large B cell, n = 22; follicular, n = 7; mucosa associated lymphoid tissue, n = 16; chronic lymphocytic leukemia, n = 2; small lymphocytic lymphoma, n = 1; lymphoplasmacytic, n = 1; mantle cell lymphoma, n = 1) were assessed for CD20 expression by flow cytometry, and CD20 gene sequencing was done on extracted DNA.

Results: CD20 mutations were found in 11 (22.0%) of 50 patients and could be grouped as C-terminal deletion (8.0%), early termination (10.0%), and extracellular domain (2.0%) or transmembrane domain (2.0%) mutations. The mean fluorescence intensity of CD20 on fresh lymphoma cells was significantly lower for the C-terminal deletion mutation [3.26; 95% confidence interval (95% CI), 0.09-6.89] compared with wild type (30.8; 95% CI, 22.4-39.2; P < 0.05). In contrast, early termination mutations did not show significant differences in CD20 expression compared with wild type (19.5; 95% CI, 10.7-28.4; P > 0.05).

Conclusions: It is possible that C-terminal deletion mutations of CD20 may be related to relapse/resistance after rituximab therapy. These mutations should be examined in patients showing progression of disease after partial remission.
Heterogeneity of the MYCN Oncogene in Neuroblastoma
Authors: Theissen Jessica , Boensch Marc , Spitz Ruediger , Betts David , Stegmaier Sabine , Christiansen Holger , Niggli Felix , Schilling Freimut , Schwab Manfred , Simon Thorsten , Westermann Frank , Berthold Frank , Hero Barbara
Published: March 2009

Purpose: MYCN amplification is an important therapy-stratifying marker in neuroblastoma. Fluorescence in situ hybridization with signal detection on the single-cell level allows a critical judgement of MYCN intratumoral heterogeneity.

Experimental Design: The MYCN status was investigated by fluorescence in situ hybridization at diagnosis and relapse. Heterogeneity was defined as the simultaneous presence of amplified cells (≥5 cells per slide) and nonamplified cells within one tumor or sequential change of the amplification status during the course of the disease. Likewise, heterogeneity can be detected between primary tumor and metastasis.

Results: From 1,341 patients analyzed, 1,071 showed no amplification, 250 showed homogeneous amplification, and 20 patients showed MYCN heterogeneity. Of the patients with heterogeneity, 12 of 20 had clusters of MYCN amplifications, 3 of 20 had amplified single cells, 3 of 20 showed MYCN amplifications in the bone marrow but not in the primary tumor, and 2 of 20 acquired MYCN amplification during the course of the disease. All stage 4 patients were treated according to high-risk protocols; 7 of 8 later progressed. Four patients with localized disease were treated according to high-risk protocol because of MYCN-amplified clusters; 1 of 4 later progressed. One patient treated with mild chemotherapy experienced progression. Seven patients with localized/4S disease underwent no chemotherapy: 4 of 5 patients with MYCN heterogeneity at diagnosis remained disease-free, and 1 of 5 experienced local progression. Two patients had normal MYCN status at diagnosis but acquired MYCN amplification during the course of the disease.

Conclusion: MYCN heterogeneity is rare. Our results suggest that small amounts of MYCN-amplified cells are not correlated to adverse outcomes. More patients with heterogeneity are warranted to clarify the role of MYCN heterogeneity for risk classification.
Tumor-Targeted Nanomedicines: Enhanced Antitumor Efficacy In vivo of Doxorubicin-Loaded, Long-Circulating Liposomes Modified with Cancer-Specific Monoclonal Antibody
Authors: ElBayoumi Tamer A. , Torchilin Vladimir P.
Published: March 2009

Purpose: The efficacy of drug delivery systems can be enhanced by making them target specific via the attachment of various ligands. We attempted to enhance tumor accumulation and therapeutic effect of doxorubicin-loaded, long-circulating, polyethylene glycol–coated liposomes (Doxil, ALZA Corp.) by coupling to their surface the anticancer monoclonal antibody (mAb) 2C5 with nucleosome-restricted activity that can recognize the surface of various tumors but not normal cells and specifically targets pharmaceutical carriers to tumor cells in vitro and in vivo. Following earlier in vitro results with various cancer cell lines, the mAb 2C5 liposomes were studied in vivo versus plain and nonspecific-IgG liposomes.

Experimental Design: Antibody coupling to Doxil was done via the “postinsertion” technique. Using 111In-labeled liposomes, the tissue biodistribution and pharmacokinetic profile were studied, as well as their accumulation in tumors in mice, followed by the whole-body γ-scintigraphic imaging. Therapeutic efficacy of mAb 2C5–targeted Doxil versus nonspecific IgG–modified and original Doxil controls was followed by registering live tumor growth and determining tumor weights upon mice sacrifice.

Results: mAb 2C5–targeted liposomes showed enhanced accumulation in tumors, and the in vivo therapeutic activity of the mAb 2C5–Doxil treatment was found to be significantly superior, resulting in final tumor weights of only 25% to 40% compared with all Doxil control treatments, when tested against the s.c. primary murine tumors of 4T1 and C26 and human PC3 tumor in nude mice.

Conclusions: Our results showed the remarkable capability of 2C5-targeted Doxil to specifically deliver its cargo into various tumors, significantly increasing the efficacy of therapy.
Estrogen-related receptor-α antagonist inhibits both estrogen receptor–positive and estrogen receptor–negative breast tumor growth in mouse xenografts
Authors: Chisamore Michael J. , Wilkinson Hilary A. , Flores Osvaldo , Chen J. Don
Published: March 2009

Estrogen-related receptors (ERR) are orphan members of the nuclear receptor superfamily most closely related to estrogen receptors (ER). Although ERα is a successful target for treating breast cancer, there remains an unmet medical need especially for estrogen-independent breast cancer. Although estradiol is not an ERR ligand, ER and ERR share many commonalities and overlapping signaling pathways. An endogenous ERR ligand has not been identified; however, novel synthetic ERRα subtype–specific antagonists have started to emerge. In particular, we recently identified a novel compound, N-[(2Z)-3-(4,5-dihydro-1,3-thiazol-2-yl)-1,3-thiazolidin-2-yl idene]-5H dibenzo[a,d][7]annulen-5-amine (termed compound A) that acts specifically as an ERRα antagonist. Here, we show that compound A inhibited cell proliferation in ERα-positive (MCF-7 and T47D) and ERα-negative (BT-20 and MDA-MD-231) breast cancer cell lines. Furthermore, we report the differential expression of 83 genes involved in ERRα signaling in MCF-7 and BT-20 breast cancer cell lines. We show that compound A slowed tumor growth in MCF-7 and BT-20 mouse xenograft models, and displayed antagonistic effects on the uterus. Furthermore, a subset of genes involved in ERRα signaling in vitro were evaluated and confirmed in vivo by studying uterine gene expression profiles from xenograft mice. These results suggest for the first time that inhibition of ERRα signaling via a subtype-specific antagonist may be an effective therapeutic strategy for ER-positive and ER-negative breast cancers. [Mol Cancer Ther 2009;8(3):672–81]
Claudin-7 Regulates EpCAM-Mediated Functions in Tumor Progression
Authors: Nübel Tobias , Preobraschenski Julia , Tuncay Hüseyin , Weiss Tobias , Kuhn Sebastian , Ladwein Markus , Langbein Lutz , Zöller Margot
Published: March 2009

EpCAM has been described as a therapeutically relevant tumor marker. We noted an interaction between EpCAM and the tight junction protein claudin-7 and here explored the nature of this interaction and its effect on EpCAM-mediated functions. The interaction between EpCAM and claudin-7 was defined in HEK293 cells transfected with rat claudin-7 and EpCAM cDNA. Deletions of the epidermal growth factor–like and the thyroglobin repeat domains of EpCAM or the cytoplasmic domain of EpCAM or claudin-7 did not prevent the EpCAM-claudin-7 association. A chimeric EpCAM molecule with an exchange of the cytoplasmic and transmembrane domains and an EpCAM molecule with point mutations in an AxxxG motif in the transmembrane region do not associate with claudin-7. HEK cells and the rat pancreatic tumor line BSp73AS, transfected with (mutated) EpCAM and claudin-7 cDNA, revealed that the association of both molecules severely alters the functional activity of EpCAM. Claudin-7–associated EpCAM is recruited into tetraspanin-enriched membrane microdomains (TEM). The TEM-located claudin-7-EpCAM complex supports proliferation accompanied by sustained extracellular signal–regulated kinase-1/2 phosphorylation, up-regulation of antiapoptotic proteins, and drug resistance, but not EpCAM-mediated cell-cell adhesion. Enhanced motility may be supported by colocalization of claudin-7 with actin bundles, which is only seen in EpCAM-claudin-7–expressing cells. The EpCAM-claudin-7 complex strongly promotes tumorigenicity, accelerates tumor growth, and supports ascites production and thymic metastasis formation.

High expression of the tumor marker EpCAM is frequently associated with poor prognosis, which could well rely on the EpCAM-claudin-7 association that prohibits EpCAM-mediated cell-cell adhesion but promotes migration, proliferation, apoptosis resistance, and tumorigenicity. (Mol Cancer Res 2009;7(3):285–99)
Do Autistic Traits Play a Role in the Bullying of Obsessive-Compulsive Disorder and Social Phobia Sufferers?
Authors: Bejerot S. , Mörtberg E.
Published: March 2009

Background: Social phobia and obsessive-compulsive disorder (OCD) share several similarities: both are categorized as anxiety disorders, avoidant personality disorder and depression are common in both, they have a similar age of onset and course, and both disorders respond to treatments with serotonin reuptake inhibitors and cognitive behavioural therapy. However, OCD and social phobia differ in respect to their relation to autism spectrum disorders (ASD; i.e. Asperger’s syndrome, autism, pervasive disorder not otherwise specified). Findings that suggest a link between OCD and ASD have no parallel in social phobia. Moreover, obsessive-compulsive, paranoid and schizotypal personality disorders are prevalent in OCD and in ASD, but not in social phobia. Individuals with ASD are known to be frequent targets of bullying. We hypothesised that individuals with autistic traits would have been frequent targets for bullies during their childhood, as opposed to people without such traits. Methods: Adult patients with social phobia (n = 63) or OCD (n = 65) were assessed regarding autistic traits, and interviewed about being bullied at school. A reference group (n = 551) responded to questions about being bullied. Results: There was a significant difference in the prevalence of being bullied between OCD (50%), social phobia patients (20%) and the reference group (27%). Autistic traits were more common in OCD than in social phobia. A history of being bullied was related to autistic traits among patients. Conclusions: Falling victim to bullying is not a random event. Autistic traits, i.e. low social skills, may be a predictor of being bullied in school. The high rate of bullying victims in persons who later develop OCD is suggested to be related to the overlap between OCD and ASD.
Monozygotic Twins Discordant for Dandy-Walker Malformation
Authors: Li Dong-Zhi , Liao Can
Published: March 2009

Dandy-Walker malformation is a congenital brain abnormality involving the fourth ventricle and cerebellum. We report on a case of twins discordant for this disorder diagnosed in the second trimester of gestation. The twin pregnancy was revealed to be monozygotic using DNA investigation. To our knowledge, this is the first time monozygotic twins discordant for Dandy-Walker malformation have been described.
Differential Effects of Ceramide on Cell Viability and Extracellular Matrix Remodeling in Keratinocytes and Fibroblasts
Authors: Philips N. , Tuason M. , Chang T. , Lin Y. , Tahir M. , Rodriguez S.G.
Published: March 2009

Ceramides are used in skin care and treatment of dermatological diseases. Cell viability and extracellular matrix (ECM) remodeling are important parameters in skin health. Skin photoaging, from exposure to ultraviolet radiation, is associated with epidermal hyperplasia and dermal ECM atrophy caused by alterations in expression of matrixmetalloproteinases (MMPs), elastin and transforming growth factor-β (TGF-β). The purpose of this study was to determine the effects of c2-ceramide (ceramide) on the cell viability and expression of TGF-β, MMP-1 and elastin in cultured keratinocytes and fibroblasts. Ceramide inhibited keratinocyte cell viability by apoptosis and stimulated expression of elastin, MMP-1 and TGF-β, suggesting improved epidermal functioning by a TGF-β mechanism. Conversely, ceramide stimulated fibroblast cell growth at the lower concentrations and inhibited the expression of MMP-1, elastin and TGF-β, which indicates a predominantly beneficial effect in the prevention of photoaging-associated dermal alterationby TGF-β and non-TGF-β mechanisms. The regulation of MMP-1 expression by ceramide was transcriptionally mediated and via the activator protein-1 sequence in both keratinocytes and fibroblasts. The study delineates the specific, though differential, beneficial effects of ceramide in the prevention of epidermal hyperplasia and dermal ECM remodeling, associated with photoaging.
Drought-Driven Changes in Lake Areas and Their Effects on the Surface Energy Balance of Minnesota’s Lake-Dotted Landscape
Authors: Plank Colin , Shuman Bryan
Published: March 2009

Open water within Minnesota constitutes 11 830 km2 and represents a significant proportion of the moisture available on the landscape. Because lakes absorb and store heat in the spring and summer, and release heat in the autumn and winter, they also play a significant role in surface energy budgets. Lake areas fluctuate significantly over time, and thus alter surface albedo and energy partitioning in the expanding and contracting lake margin. Observations of lake areas from the 1930s “Dust Bowl” drought were used to approximate the impact of changes in lake area and volume on surface energy budgets. A statewide map of lake area change constructed from historical aerial photos of 620 lakes shows trends in percent area changes that mimic trends in moisture balance. Based on the aerial photos and an analysis of lake bathymetries, the water volume removed from the land exposed around the lakes during the drought was 9.1 ± 3.0 × 109 m3. The total area of exposed land was 3300 ± 800 km2. Based on a balanced energy budget estimate, the transition from standing water to exposed land at lake margins accounted for 1.12 ± 0.31 × 1011 W of energy storage across the state. The decreased heat storage resulted in a statewide average storage flux anomaly of 0.50 ± 0.14 W m−2 with localized anomalies as high as 33.9 ± 7.1 W m−2. Large uncertainties exist, however, regarding the partitioning of the energy because of the wide range of potential albedo values for both land and water. As conditions warmed during the twentieth century, lake volumes have increased. Therefore, the assessment herein of the change in heat storage is relevant to comparisons of high regional temperatures in the 1930s and 2000s.
A Verified Estimation of the El Niño Index Niño-3.4 since 1877
Authors: Bunge Lucia , Clarke Allan J.
Published: March 2009

Decadal and longer time-scale variabilities of the best known El Niño–Southern Oscillation (ENSO) indexes are poorly correlated before 1950, and so knowledge of interdecadal variability and trend in ENSO indexes is dubious, especially before 1950. To address this problem, the authors constructed and compared physically related monthly ENSO indexes. The base index was El Niño index Niño-3.4, the sea surface temperature (SST) anomaly averaged over the equatorial box bounded by 5°N, 5°S, 170°W, and 120°W; the authors also constructed indexes based on the nighttime marine air temperature over the Niño-3.4 region (NMAT3.4) and an equatorial Southern Oscillation index (ESOI). The Niño-3.4 index used the “uninterpolated” sea surface temperature data from the Second Hadley Centre Sea Surface Temperature dataset (HadSST2), a dataset with smaller uncertainty and better geographical coverage than others. In constructing the index, data at each point for a given month were weighted to take into account the typical considerable spatial variation of the SST anomaly over the Niño-3.4 box as well as the number of observations at that point for that month. Missing monthly data were interpolated and “noise” was reduced by using the result that Niño-3.4 has essentially the same calendar month amplitude structure every year. This 12-point calendar month structure from April to March was obtained by an EOF analysis over the last 58 yr and then was fitted to the entire monthly time series using a least squares approach. Equivalent procedures were followed for NMAT3.4 and ESOI. The new ESOI uses Darwin atmospheric pressure in the west and is based on theory that allows for variations of the atmospheric boundary layer depth across the Pacific.

The new Niño-3.4 index was compared with NMAT3.4, the new ESOI, and with a record of δ18O from a coral at Palmyra, an atoll inside the region Niño-3.4 (Cobb et al.). Correlation coefficients between Niño-3.4 and the three monthly indexes mentioned above before 1950 are 0.84, 0.87, 0.73 and 0.93, 0.86, 0.73 for decadal time scales. These relatively high correlation coefficients between physically related but independent monthly time series suggest that this study has improved knowledge of low-frequency variability. All four indexes are consistent with a rise in Niño-3.4 SST and the weakening of the equatorial Pacific winds since about 1970.
Upper-Ocean Thermal Structure and the Western North Pacific Category 5 Typhoons. Part II: Dependence on Translation Speed
Authors: Lin I-I. , Pun Iam-Fei , Wu Chun-Chieh
Published: March 2009

Using new in situ ocean subsurface observations from the Argo floats, best-track typhoon data from the U.S. Joint Typhoon Warning Center, an ocean mixed layer model, and other supporting datasets, this work systematically explores the interrelationships between translation speed, the ocean’s subsurface condition [characterized by the depth of the 26°C isotherm (D26) and upper-ocean heat content (UOHC)], a cyclone’s self-induced ocean cooling negative feedback, and air–sea enthalpy fluxes for the intensification of the western North Pacific category 5 typhoons. Based on a 10-yr analysis, it is found that for intensification to category 5, in addition to the warm sea surface temperature generally around 29°C, the required subsurface D26 and UOHC depend greatly on a cyclone’s translation speed. It is observed that even over a relatively shallow subsurface warm layer of D26 ∼ 60–70 m and UOHC ∼ 65–70 kJ cm−2, it is still possible to have a sufficient enthalpy flux to intensify the storm to category 5, provided that the storm can be fast moving (typically Uh ∼ 7–8 m s−1). On the contrary, a much deeper subsurface layer is needed for slow-moving typhoons. For example at Uh ∼ 2–3 m s−1, D26 and UOHC are typically ∼115–140 m and ∼115–125 kJ cm−2, respectively. A new concept named the affordable minimum translation speed Uh_min is proposed. This is the minimum required speed a storm needs to travel for its intensification to category 5, given the observed D26 and UOHC. Using more than 3000 Argo in situ profiles, a series of mixed layer numerical experiments are conducted to quantify the relationship between D26, UOHC, and Uh_min. Clear negative linear relationships with correlation coefficients R = −0.87 (−0.71) are obtained as Uh_min = −0.065 × D26 + 11.1, and Uh_min = −0.05 × UOHC + 9.4, respectively. These relationships can thus be used as a guide to predict the minimum speed a storm has to travel at for intensification to category 5, given the observed D26 and UOHC.
Closed and Open-Ended Question Tools in a Telephone Survey About ``The Good Teacher''
Authors: Arnon Sara , Reichel Nirit
Published: March 2009

Combining diverse methods in a single study raises a problem: What should be done when the findings of one method of investigation conflict with those of another? We illustrate this problem using an example in which three study phases—quantitative, qualitative, and intervention—were applied. The findings coming from the quantitative phase did not fit those coming from the qualitative phase; there were discrepancies within the qualitative phase itself, and the findings coming from single-case evaluations of the intervention using standardized scales did not fit the findings derived from self-made scales. We explain these inconsistencies by way of the complementary approach: conflicting findings should be integrated, and consistency is restored by admitting complexity in the phenomenon under investigation.
Gram-positive bacteria enhance HIV-1 susceptibility in Langerhans cells, but not in dendritic cells, via Toll-like receptor activation
Authors: Ogawa Youichi , Kawamura Tatsuyoshi , Kimura Tetsuya , Ito Masahiko , Blauvelt Andrew , Shimada Shinji
Published: March 2009

Although numerous studies have shown a higher risk of acquiring HIV infection in the presence of other sexually transmitted diseases, the biologic mechanisms responsible for enhanced HIV acquisition are unclear. Because Langerhans cells (LCs) are suspected to be the initial HIV targets after sexual exposure, we studied whether microbial components augment HIV infection in LCs by activating Toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD) pattern recognition receptors. We found that TLR1/2 and TLR2/6 agonists dramatically enhanced both HIV susceptibility and replication in immature monocyte-derived LCs, whereas TLR3-5, TLR7-9, and NOD1,2 agonists did not significantly affect HIV infection. The same infection-enhancing effects were observed when LCs were incubated with other related bacterial components as well as with whole Gram+ bacteria. In resident LCs in human skin, TLR2 agonists also significantly increased HIV susceptibility. By contrast, TLR2 agonists and related bacterial components decreased HIV susceptibility in monocyte-derived dendritic cells (DCs). We found that TLR2 activation of LCs, but not DCs, resulted in a significant down-regulation of APOBEC3G, which is a cellular restriction factor for HIV. Given these data, we hypothesize that ligation of TLR2 by Gram+ bacterial products may underlie enhanced sexual transmission of HIV that occurs with concomitant bacterial sexually transmitted disease infections.
Common susceptibility alleles are unlikely to contribute as strongly as the FV and ABO loci to VTE risk: results from a GWAS approach
Authors: Trégouët David-Alexandre , Heath Simon , Saut Noémie , Biron-Andreani Christine , Schved Jean-François , Pernod Gilles , Galan Pilar , Drouet Ludovic , Zelenika Diana , Juhan-Vague Irène , Alessi Marie-Christine , Tiret Laurence , Lathrop Mark , Emmerich Joseph , Morange Pierre-Emmanuel
Published: March 2009

Venous thromboembolism (VTE) is a complex disease that has a major genetic component of risk. To identify genetic factors that may modify the risk of VTE, we conducted a genome-wide association study by analyzing approximately 317 000 single nucleotide polymorphisms (SNPs) in 453 VTE cases and 1327 controls. Only 3 SNPs located in the FV and ABO blood group genes were found associated with VTE at a genome-wide significant level of 1.7 × 10−7. Detailed analysis of these SNPs in additional cohorts of more than 1700 cases and 1400 controls revealed that the association observed at the FV locus was the result of the increased risk mediated by the FV Leiden mutation, whereas O and A2 blood groups were found to be at lower risk for VTE. Apart from the FV and ABO loci, no other locus was found strongly associated with VTE. However, using this large cohort of subjects, we were able to replicate the mild effects of 2 nonsynonymous SNPs, rs1613662 in GP6 and rs13146272 in CYP4V2, recently suspected to be associated with VTE.
Quarantine for pandemic influenza control at the borders of small island nations
Authors: Nishiura Hiroshi , Wilson Nick , Baker Michael G
Published: March 2009

Background

Although border quarantine is included in many influenza pandemic plans, detailed guidelines have yet to be formulated, including considerations for the optimal quarantine length. Motivated by the situation of small island nations, which will probably experience the introduction of pandemic influenza via just one airport, we examined the potential effectiveness of quarantine as a border control measure.

Methods

Analysing the detailed epidemiologic characteristics of influenza, the effectiveness of quarantine at the borders of islands was modelled as the relative reduction of the risk of releasing infectious individuals into the community, explicitly accounting for the presence of asymptomatic infected individuals. The potential benefit of adding the use of rapid diagnostic testing to the quarantine process was also considered.

Results

We predict that 95% and 99% effectiveness in preventing the release of infectious individuals into the community could be achieved with quarantine periods of longer than 4.7 and 8.6 days, respectively. If rapid diagnostic testing is combined with quarantine, the lengths of quarantine to achieve 95% and 99% effectiveness could be shortened to 2.6 and 5.7 days, respectively. Sensitivity analysis revealed that quarantine alone for 8.7 days or quarantine for 5.7 days combined with using rapid diagnostic testing could prevent secondary transmissions caused by the released infectious individuals for a plausible range of prevalence at the source country (up to 10%) and for a modest number of incoming travellers (up to 8000 individuals).

Conclusion

Quarantine at the borders of island nations could contribute substantially to preventing the arrival of pandemic influenza (or at least delaying the arrival date). For small island nations we recommend consideration of quarantine alone for 9 days or quarantine for 6 days combined with using rapid diagnostic testing (if available).
Characterization of STAT3 activation and expression in canine and human osteosarcoma
Authors: Fossey Stacey L , Liao Albert T , McCleese Jennifer K , Bear Misty D , Lin Jiayuh , Li Pui-Kai , Kisseberth William C , London Cheryl A
Published: March 2009

Background

Dysregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a key participant in tumor cell survival, proliferation, and metastasis and is often correlated with a more malignant tumor phenotype. STAT3 phosphorylation has been demonstrated in a subset of human osteosarcoma (OSA) tissues and cell lines. OSA in the canine population is known to exhibit a similar clinical behavior and molecular biology when compared to its human counterpart, and is often used as a model for preclinical testing of novel therapeutics. The purpose of this study was to investigate the potential role of STAT3 in canine and human OSA, and to evaluate the biologic activity of a novel small molecule STAT3 inhibitor.

Methods

To examine STAT3 and Src expression in OSA, we performed Western blotting and RT-PCR. OSA cells were treated with either STAT3 siRNA or small molecule Src (SU6656) or STAT3 (LLL3) inhibitors and cell proliferation (CyQUANT), caspase 3/7 activity (ELISA), apoptosis (Western blotting for PARP cleavage) and/or viability (Wst-1) were determined. Additionally, STAT3 DNA binding after treatment was determined using EMSA. Expression of STAT3 targets after treatment was demonstrated with Western blotting, RT-PCR, or gel zymography.

Results

Our data demonstrate that constitutive activation of STAT3 is present in a subset of canine OSA tumors and human and canine cell lines, but not normal canine osteoblasts. In both canine and human OSA cell lines, downregulation of STAT3 activity through inhibition of upstream Src family kinases using SU6656, inhibition of STAT3 DNA binding and transcriptional activities using LLL3, or modulation of STAT3 expression using siRNA, all resulted in decreased cell proliferation and viability, ultimately inducing caspase-3/7 mediated apoptosis in treated cells. Furthermore, inhibition of either Src or STAT3 activity downregulated the expression of survivin, VEGF, and MMP2, all known transcriptional targets of STAT3.

Conclusion

These data suggest that STAT3 activation contributes to the survival and proliferation of human and canine OSA cells, thereby providing a potentially promising target for therapeutic intervention. Future investigational trials of LLL3 in dogs with spontaneous OSA will help to more accurately define the role of STAT3 in the clinical setting.
From back number aesthetics to new expression: James Gibbons Huneker's New Cosmopolis
Authors: Fagg John
Published: March 2009

James Gibbons Huneker was an influential cultural critic in the decades around 1900. His idiosyncratic style has lead to his work being somewhat overlooked. This article relates Huneker's collection of New York travel sketches, New Cosmopolis (1915), to other examples of literary impressionism, and specifically to the work of J.K. Huysmans, Stephen Crane and Henry James. It then argues that New Cosmopolis moves beyond the aestheticism and detached analysis of the impressionistic literary sketch towards a more subjective, engaged form of city writing. This led Huneker to an urban aesthetic and to an embrace of cosmopolitanism comparable to the ideas celebrated in Paul Rosenfeld's Port of New York (1924). Rosenfeld argues that the writers and artists he profiles, including Randolph Bourne, Alfred Stieglitz and William Carlos Williams, represent a flowering of new expression in America. Huneker's relationship to these modern, progressive figures is, in part, attributable to his tendency towards spontaneous, idiosyncratic and highly subjective statements and his recognition of the visceral sensory experiences provided by New York's tango halls, movie theatres and Coney Island roller coasters.
Two Distinct Mechanisms Mediate Acute μ-Opioid Receptor Desensitization in Native Neurons
Authors: Dang Vu C. , Napier Ian A. , Christie MacDonald J.
Published: March 2009

Sustained stimulation of G-protein coupled receptors (GPCRs) leads to rapid loss of receptor function (acute desensitization). For many GPCRs including the μ-opioid receptor (MOR), an accepted mechanism for acute desensitization is through G-protein coupled receptor kinase (GRKs) mediated phosphorylation of the receptor, which facilitates the binding of β-arrestins (βarrs) to the receptor and then promotes endocytosis. However, the mechanism(s) that mediate acute desensitization have not yet been well defined in native neurons. This study used whole-cell patch clamp recording of G-protein coupled inward-rectifying potassium (GIRK) currents to assay MOR function and identify mechanisms of acute MOR desensitization in locus ceruleus (LC) neurons. The rate and extent of MOR desensitization were unaffected by βarr-2 knock-out. Disruption of GRK2 function via inhibitory peptide introduced directly into neurons also failed to affect desensitization in wild type or βarr-2 knock-outs. Inhibition of ERK1/2 activation alone had little effect on acute desensitization. However, when both GRK2-βarr-2 and ERK1/2 functions were disrupted simultaneously, desensitization of MOR was nearly abolished. Together, these results suggest that acute desensitization of MOR in native LC neurons is determined by at least two molecular pathways, one involving GRK2 and βarr-2, and a parallel pathway mediated by activated ERK1/2.
The Dipeptidyl-Peptidase-Like Protein DPP6 Determines the Unitary Conductance of Neuronal Kv4.2 Channels
Authors: Kaulin Yuri A. , De Santiago-Castillo José A. , Rocha Carmen A. , Nadal Marcela S. , Rudy Bernardo , Covarrubias Manuel
Published: March 2009

The neuronal subthreshold-operating A-type K+current regulates electrical excitability, spike timing, and synaptic integration and plasticity. The Kv4 channels underlying this current have been implicated in epilepsy, regulation of dopamine release, and pain plasticity. However, the unitary conductance (γ) of neuronal somatodendritic A-type K+channels composed of Kv4 pore-forming subunits is larger (∼7.5 pS) than that of Kv4 channels expressed singly in heterologous cells (∼4 pS). Here, we examined the putative novel contribution of the dipeptidyl-peptidase-like protein-6 DPP6-S to the γ of native [cerebellar granule neuron (CGN)] and reconstituted Kv4.2 channels. Coexpression of Kv4.2 proteins with DPP6-S was sufficient to match the γ of native CGN channels; and CGN Kv4 channels fromdpp6knock-out mice yielded a γ indistinguishable from that of Kv4.2 channels expressed singly. Moreover, suggesting electrostatic interactions, charge neutralization mutations of two N-terminal acidic residues in DPP6-S eliminated the increase in γ. Therefore, DPP6-S, as a membrane protein extrinsic to the pore domain, is necessary and sufficient to explain a fundamental difference between native and recombinant Kv4 channels. These observations may help to understand the molecular basis of neurological disorders correlated with recently identified human mutations in thedpp6gene.
Variable Threshold of Trigeminal Cold-Thermosensitive Neurons Is Determined by a Balance between TRPM8 and Kv1 Potassium Channels
Authors: Madrid Rodolfo , de la Peña Elvira , Donovan-Rodriguez Tansy , Belmonte Carlos , Viana Félix
Published: March 2009

Molecular determinants of threshold differences among cold thermoreceptors are unknown. Here we show that such differences correlate with the relative expression ofIKD, a current dependent onShaker-like Kv1 channels that acts as an excitability brake, andITRPM8, a cold-activated excitatory current. Neurons responding to small temperature changes have high functional expression of TRPM8 (transient receptor potential cation channel, subfamily M, member 8) and low expression ofIKD. In contrast, neurons activated by lower temperatures have a lower expression of TRPM8 and a prominentIKD. Otherwise, both subpopulations have nearly identical membrane and firing properties, suggesting that they belong to the same neuronal pool. Blockade ofIKDshifts the threshold of cold-sensitive neurons to higher temperatures and augments cold-evoked nocifensive responses in mice. Similar behavioral effects ofIKDblockade were observed in TRPA1−/−mice. Moreover, only a small percentage of trigeminal cold-sensitive neurons were activated by TRPA1 agonists, suggesting that TRPA1 does not play a major role in the detection of low temperatures by uninjured somatic cold-specific thermosensory neurons under physiological conditions. Collectively, these findings suggest that innocuous cooling sensations and cold discomfort are signaled by specific low- and high-threshold cold thermoreceptor neurons, differing primarily in their relative expression of two ion channels having antagonistic effects on neuronal excitability. Thus, although TRPM8 appears to function as a critical cold sensor in the majority of peripheral sensory neurons, the expression of Kv1 channels in the same terminals seem to play an important role in the peripheral gating of cold-evoked discomfort and pain.