bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Nitric Oxide (NO)-Sensing Repressor NsrR of
Neisseria meningitidis
Has a Compact Regulon of Genes Involved in NO Synthesis and Detoxification
Authors: Heurlier Karin , Thomson Melanie J. , Aziz Naveed , Moir James W. B. 
Published: February 2008

ABSTRACT

We have analyzed the extent of regulation by the nitric oxide (NO)-sensitive repressor NsrR from
Neisseria meningitidis
MC58, using microarray analysis. Target genes that appeared to be regulated by NsrR, based on a comparison between an
nsrR
mutant and a wild-type strain, were further investigated by quantitative real-time PCR, revealing a very compact set of genes, as follows:
norB
(encoding NO reductase),
dnrN
(encoding a protein putatively involved in the repair of nitrosative damage to iron-sulfur clusters),
aniA
(encoding nitrite reductase),
nirV
(a putative nitrite reductase assembly protein), and
mobA
(a gene associated with molybdenum metabolism in other species but with a frame shift in
N. meningitidis
). In all cases, NsrR acts as a repressor. The NO protection systems
norB
and
dnrN
are regulated by NO in an NsrR-dependent manner, whereas the NO protection system cytochrome
c
′ (encoded by
cycP
) is not controlled by NO or NsrR, indicating that
N. meningitidis
expresses both constitutive and inducible NO protection systems. In addition, we present evidence to show that the anaerobic response regulator FNR is also sensitive to NO but less so than NsrR, resulting in complex regulation of promoters such as
aniA
, which is controlled by both FNR and NsrR:
aniA
was found to be maximally induced by intermediate NO concentrations, consistent with a regulatory system that allows expression during denitrification (in which NO accumulates) but is down-regulated as NO approaches toxic concentrations.
Dissection of Ammonium Uptake Systems inCorynebacterium glutamicum: Mechanism of Action and Energetics of AmtA and AmtB
Authors: Walter Britta , Küspert Melanie , Ansorge Daniel , Krämer Reinhard , Burkovski Andreas 
Published: February 2008

ABSTRACTCorynebacterium glutamicumhas two different Amt-type proteins. While AmtB has a low substrate affinity and is not saturable up to 3 mM methylammonium, AmtA has a high substrate affinity and mediates saturable, membrane potential-dependent transport, resulting in a high steady-state accumulation of methylammonium, even in the absence of metabolic trapping.
Identification and Characterization of an Archaeon-Specific Riboflavin Kinase
Authors: Mashhadi Zahra , Zhang Hong , Xu Huimin , White Robert H. 
Published: February 2008

ABSTRACTThe riboflavin kinase inMethanocaldococcus jannaschiihas been identified as the product of the MJ0056 gene. Recombinant expression of the MJ0056 gene inEscherichia coliled to a large increase in the amount of flavin mononucleotide (FMN) in theE. colicell extract. The unexpected features of the purified recombinant enzyme were its use of CTP as the phosphoryl donor and the absence of a requirement for added metal ion to catalyze the formation of FMN. Identification of this riboflavin kinase fills another gap in the archaeal flavin biosynthetic pathway. Some divalent metals were found to be potent inhibitors of the reaction. The enzyme represents a unique CTP-dependent family of kinases.
Functional Characterization and Mutagenesis of the Proposed Behavioral Sensor TlpD of
Helicobacter pylori
Authors: Schweinitzer Tobias , Mizote Tomoko , Ishikawa Naohiro , Dudnik Alexey , Inatsu Sakiko , Schreiber Sören , Suerbaum Sebastian , Aizawa Shin-Ichi , Josenhans Christine 
Published: February 2008

ABSTRACT

Helicobacter pylori
requires flagellar motility and chemotaxis to establish and maintain chronic infection of the human stomach. The pH gradient in the stomach mucus is essential for bacterial orientation and guides the bacterium toward a narrow layer of the mucus, suggesting that
H. pylori
is capable of energy sensing or taxis. In the present study,
H. pylori
wild-type behavior in a temporal swimming assay could be altered by electron transport inhibitors, indicating that a connection between metabolism and behavior exists. In order to elucidate mechanisms of behavioral responses of
H. pylori
related to energy sensing, we investigated the phenotypes of single and multiple mutants of the four proposed chemotaxis sensor proteins. All sensor mutants were motile, but they diverged in their behavior in media supporting different energy yields. One proposed intracellular sensor, TlpD, was crucial for behavioral responses of
H. pylori
in defined media which did not permit growth and led to reduced bacterial energy levels. Suboptimal energetic conditions and inhibition of electron transport induced an increased frequency of stops and direction changes in the wild type but not in
tlpD
mutants. Loss of metabolism-dependent behavior in
tlpD
mutants could be reversed by complementation but not by electron donors bypassing the activity of the electron transport chain, in contrast to the case for the wild type. TlpD, which apparently lacks transmembrane domains, was detected both in the bacterial cytoplasm and at the bacterial periphery. The proposed energy sensor TlpD was found to mediate a repellent tactic response away from conditions of reduced electron transport.
Lethality of suicide methods
Authors: Elnour A A , Harrison J 
Published: February 2008

Objectives:To (a) quantify the lethality of suicide methods used in Australia in the period 1 July 1993 to 30 June 2003, (b) examine method-specific case fatality by age and sex, and (c) identify changes in case fatality during the study period.Methods:Two sources of data on episodes of self-harm in Australia were used, mortality and hospital separation data. Double counting of cases recorded in both sources was controlled by omitting fatal hospital cases from estimates of episodes of self-harm.Results:Overall case fatality was 12%. For each suicide method, case fatality was higher in males and older age groups. Firearms were the most lethal suicide means (90%) followed by hanging (83%). Rates of suicide involving firearms declined over time, and those involving hanging rose. Case fatality for firearm cases changed little over time, but declined for self-harm by hanging/suffocation, poisoning, sharp objects, and crashing a motor vehicle.Conclusions:This study (Australia) and two others (USA) show differences in method-specific lethality by gender and age. This study adds the finding of changes in lethality over time. Understanding of suicidality in populations, on which prevention efforts depend, requires explanation of these findings.
Conspicuity and bicycle crashes: preliminary findings of the Taupo Bicycle Study
Authors: Thornley S J , Woodward A , Langley J D , Ameratunga S N , Rodgers A 
Published: February 2008

Objective:To describe the methods, characteristics of participants, and report on the preliminary findings of a longitudinal study of cyclists.Design:Web-based survey to establish a cohort of cyclists.Setting:Participants in the largest mass-participation bicycle event in New Zealand, the Wattyl Lake Taupo Cycle Challenge.Participants:2469 riders who had enrolled online in the 2006 Wattyl Lake Taupo Cycle Challenge.Main outcome measures:Self-reported crashes in preceding 12 months.Results:Of 5653 eligible riders, 2469 (44%) completed the study questionnaire. Mean age was 44 years, 73% were male, and the average number of kilometers cycled per week in the preceding 12 months was 130. The annual incidence of crashes leading to injury that disrupted usual daily activities for at least 24 h was 0.5 per cyclist/year. About one-third of these crashes resulted in presentation to a health professional. The mean number of days absent from work attributable to bicycle crashes was 0.39 per cyclist/year. After adjustment for potential confounders and exposure (kilometers cycled per year), the rate of days off work from bicycle crash injury was substantially lower among riders who reported always wearing fluorescent colors (multivariate incidence rate ratio 0.23, 95% CI 0.09 to 0.59).Conclusions:Low cyclist conspicuity may increase the risk of crash-related injury and subsequent time off work. Increased use of high-visibility clothing is a simple intervention that may have a large impact on the safety of cycling.
Case-control study of acute renal failure in patients with cystic fibrosis in the UK
Authors: Smyth A , Lewis S , Bertenshaw C , Choonara I , McGaw J , Watson A 
Published: February 2008

Background:There has been a recent increase in the number of reported cases of acute renal failure (ARF) in cystic fibrosis (CF). A case-control study was conducted to determine the factors which are associated with an increased risk of ARF.Methods:24 cases of confirmed ARF were identified in patients with CF from 20 UK CF centres presenting between 1997 and 2004. Using the UK CF database, sex- and age-matched controls were identified. Risk factors were analysed by conditional logistic regression and Mantel-Haenszel analysis.Results:21 of the 24 patients with ARF had received an aminoglycoside at the time of their episode of ARF or in the preceding week compared with only 3 of 42 controls during the same time period (OR 81.8, 95% CI 4.7 to 1427, p<0.001). In the year before the episode of ARF, significantly more cases than controls had received gentamicin (19/24 cases vs 1/42 controls, p<0.001). The numbers receiving tobramycin were similar (9/24 cases vs 16/42 controls, p = 0.9). A known risk factor for renal impairment (prior renal disease, acute dehydration or long-term treatment with a nephrotoxic drug) was present in 18/24 cases and 7/42 controls (OR 24.0, 95% CI 3.1 to 186.6, p = 0.002).Conclusions:In patients with CF the use of an intravenous aminoglycoside is a risk factor for ARF; gentamicin is more nephrotoxic than tobramycin. Most patients who develop ARF have a risk factor which necessitates withholding aminoglycosides or more closely monitoring their use.
Alterations in Gemin5 Expression Contribute to Alternative mRNA Splicing Patterns and Tumor Cell Motility
Authors: Lee Jong Heun , Horak Christine E. , Khanna Chand , Meng Zhaojing , Yu Li Rong , Veenstra Timothy D. , Steeg Patricia S. 
Published: February 2008

Abstract
The role of Gemin5 in alternative mRNA splicing, tumor cell motility, and proteomic instability was investigated. Isotope Capture Affinity Tag proteomic analysis was conducted on MDA-MB-435 tumor cells transfected with either a control vector (C-100) or the Nm23-H1 metastasis suppressor (H1-177). Ingenuity pathway analysis revealed that RNA posttranscriptional processing was the most prominent class of differentially expressed proteins. Within this category, overexpression of Acinus1, Poly(a) binding protein, HNRPA2B1, Bop1, and Gemin5 was confirmed in less metastatic H1-177 cells. Overexpression of the latter four proteins was also observed in the lower metastatic antisense Ezrin transfectant of a murine osteosarcoma model system, confirming the general relevance of the trends. Gemin5, a component of the spliceosomal complex, was chosen for further study. Analysis of global mRNA splicing by SpliceArray chips revealed that 16 genes were differentially spliced in C-100 compared with H1-177 cells; transient transfection of gemin5 into C-100 cells restored the splice pattern to that of H1-177 cells. Alternative splicing patterns for the engulfment and cell motility 1 and thrombospondin 4 genes were confirmed by semiquantitative reverse transcription-PCR. Gemin5 overexpression coordinately reduced C-100 cell motility by 50%, and siRNA-mediated reduction of Gemin5 expression increased the motility of H1-177 cells by 2-fold (P &lt; 0.004). The data provide the first demonstration that alterations in the expression of a spliceosome protein can effect both specific splicing events and tumor cell motility. The data also show that changes in mRNA splicing patterns accompany metastatic progression, which may contribute to proteome instability. [Cancer Res 2008;68(3):639–44]
Inhibition of Endoplasmic Reticulum Stress–Induced Apoptosis of Melanoma Cells by the ARC Protein
Authors: Chen Li Hua , Jiang Chen Chen , Watts Ralph , Thorne Rick F. , Kiejda Kelly A. , Zhang Xu Dong , Hersey Peter 
Published: February 2008

Abstract
We have shown previously that most melanoma cell lines are insensitive to endoplasmic reticulum (ER) stress–induced apoptosis, but resistance can be reversed through activation of caspase-4 by inhibition of the MEK/ERK pathway. We report in this study that apoptosis was induced by the ER stress inducer thapsigargin or tunicamycin via a caspase-8–mediated pathway in the melanoma cell line Me1007, although the MEK/ERK pathway was activated in this cell line. The high sensitivity of Me1007 to ER stress–induced apoptosis was associated with low expression levels of the apoptosis repressor with caspase recruitment domain (ARC) protein that was expressed at relatively high levels in the resistant melanoma cell lines. Transfection of cDNA encoding ARC into Me1007 cells inhibited both caspase-8 activation and apoptosis induced by thapsigargin or tunicamycin. In contrast, inhibition of ARC by small interfering RNA knockdown sensitized the resistant melanoma cell lines to ER stress–induced apoptosis, which was inhibitable by blockage of caspase-8 activation. Both exogenous and endogenous ARC seemed to predominantly locate to the cytoplasm and mitochondria and could be coimmunoprecipitated with caspase-8. Taken together, ER stress can potentially activate multiple apoptosis signaling pathways in melanoma cells in a context-dependent manner. Whereas the MEK/ERK signaling pathway plays an important role in inhibiting ER stress–induced caspase-4 activation, ARC seems to be critical in blocking activation of casapse-8 in melanoma cells subjected to ER stress. [Cancer Res 2008;68(3):834–42]
Antiangiogenic Therapy with Mammalian Target of Rapamycin Inhibitor RAD001 (Everolimus) Increases Radiosensitivity in Solid Cancer
Authors: Manegold Philipp C. , Paringer Carmen , Kulka Ulrike , Krimmel Klaus , Eichhorn Martin E. , Wilkowski Ralf , Jauch Karl-Walter , Guba Markus , Bruns Christiane J. 
Published: February 2008

Abstract
Purpose: Radiotherapy exerts direct antivascular effects in tumors and also induces a proangiogenic stress response in tumor cells via the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (mTOR) pathway. Therefore, the combination of radiotherapy and antiangiogenic therapy with mTOR inhibitor RAD001 (Everolimus) might exert additive/synergistic effects on tumor growth.
Experimental Design: Effects of radiation combined with mTOR inhibitor RAD001 were studied on proliferation of murine colon cancer CT-26, human pancreatic cancer L3.6pl, and human umbilical vascular endothelial cells in vitro. In vivo tumor growth of subcutaneous colon cancer CT 26 and orthotopic pancreatic cancer L3.6pl was assessed after fractionated radiotherapy (5 × 2 or 5 × 4 Gy) with or without the addition of the mTOR inhibitor RAD001. RAD001 (1.5 mg/kg/d) was administered until the end of experiments beginning before or after radiotherapy.
Results: A single dose of 2 Gy reduced in vitro proliferation of L3.6pl (−16%), CT-26 (−70%), and human umbilical vascular endothelial cells (HUVEC; −72%). The mTOR inhibitor RAD001 (10 ng/mL) suppressed proliferation of HUVEC (−83%), L3.6pl (−8%), and CT-26 (−82%). Combination of even low concentrations of 0.01 ng/mL RAD001 and 0.25 Gy radiation significantly reduced proliferation of HUVECs (−57%), whereas additive effects of RAD001 and radiation on tumor cells were seen only at the highest concentrations tested. In vivo, RAD001 introduced before radiotherapy (5 × 2 Gy) improved tumor growth control in mice (L3.6pl: 326 mm3 versus 1144 mm3; CT-26: 210 mm3 versus 636 mm3; P &lt; 0.05 versus control). RAD001 turned out to possess a dose-modifying effect on radiotherapy.
Conclusion: Endothelial cells seem to be most sensitive to combination of mTOR inhibition and radiotherapy. Additive tumor growth delay using the mTOR inhibitor RAD001 and radiotherapy in vivo therefore might rely on combined antiangiogenic and antivascular effects.
Inhibition of IκB Kinase Subunit 2 in Cutaneous T-Cell Lymphoma Down-Regulates Nuclear Factor-κB Constitutive Activation, Induces Cell Death, and Potentiates the Apoptotic Response to Antineoplastic Chemotherapeutic Agents
Authors: Sors Aurore , Jean-Louis Francette , Bégué Elodie , Parmentier Laurent , Dubertret Louis , Dreano Michel , Courtois Gilles , Bachelez Hervé , Michel Laurence 
Published: February 2008

AbstractPurpose: A key molecular feature of cutaneous T-cell lymphomas (CTCL) is the constitutive activation of the nuclear factor-κB (NF-κB) transcription factor. We investigated in vitro the effects on CTCL survival and chemoresistance of a specific inhibition of IκB kinase subunit 2 (IKK2).Experimental Design: Selective IKK2 inhibition was carried out by transfection of SeAx and MyLa CTCL lines with an inactive form of IKK2 and by exposing these lines and tumor cells from 10 patients with Sézary syndrome (SS) to AS602868, a new IKK2 inhibitor. The constitutive nuclear translocation of NF-κB was analyzed by electrophoretic mobility shift assay and confocal microscopy. Apoptosis was determined by Annexin V/propidium iodide–positive staining and mitochondrial transmembrane potential alterations as well as poly(ADP-ribose)polymerase cleavage. The expression of Bcl-2 family oncoproteins and survivin was studied by immunoblotting.Results: Specific IKK2 inhibition resulting from transfection or from incubation with AS602868 allowed a down-regulation of NF-κB transcriptional activity. As shown by electrophoretic mobility shift assay and apoptosis assays, AS602868 down-regulated the nuclear translocation of NF-κB and induced a potent apoptotic response in CTCL lines and in tumor cells from patients with SS while preserving the viability of both peripheral blood lymphocytes from healthy donors and of nonmalignant T cells from SS patients. Moreover, CTCL death induction by conventional antineoplastic agents etoposide and vincristine was potentiated by AS602868. Finally, AS602868-induced apoptosis of CTCL cells was associated with an up-regulation of Bax dimers and a decrease of survivin.Conclusion: These results indicate that IKK2 inhibition represents a promising strategy for the treatment of advanced stages of CTCL.
A Single-Nucleotide Polymorphism in the Aromatase Gene Is Associated with the Efficacy of the Aromatase Inhibitor Letrozole in Advanced Breast Carcinoma
Authors: Colomer Ramon , Monzo Mariano , Tusquets Ignasi , Rifa Juli , Baena José M. , Barnadas Agusti , Calvo Lourdes , Carabantes Francisco , Crespo Carmen , Muñoz Montserrat , Llombart Antonio , Plazaola Arrate , Artells Rosa , Gilabert Monstsrrat , Lloveras Belen , Alba Emilio 
Published: February 2008

Abstract
Purpose: To evaluate the efficacy of treatment with the aromatase inhibitor letrozole in breast cancer patients segregated with respect to DNA polymorphisms of the aromatase gene CYP19.
Patients and Methods: Postmenopausal patients (n = 67) with hormone receptor–positive metastatic breast cancer were treated with the aromatase inhibitor letrozole. PCR allelic discrimination was used to examine three single-nucleotide polymorphisms (SNP) in DNA obtained from breast carcinoma tissue. Two SNPs analyzed (rs10046 and rs4646) were located in the 3′ untranslated region and one (rs727479) was in the intron of the aromatase CYP19 gene. The primary end point of treatment efficacy was time to progression (TTP).
Results: Median age was 62 years and median number of metastatic sites was 2. Observed allelic SNP frequencies were rs10046, 71%; rs4646, 46%; and rs727479, 63%. Of the 67 patients, 65 were evaluable for efficacy. Median TTP was 12.1 months. We observed no relationship between TTP and the rs10046 or rs727479 variants. In contrast, we found that TTP was significantly improved in patients with the rs4646 variant, compared with the wild-type gene (17.2 versus 6.4 months; P = 0.02).
Conclusion: In patients with hormone receptor–positive metastatic breast cancer treated with the aromatase inhibitor letrozole, the presence of a SNP in the 3′ untranslated region of the CYP19 aromatase gene is associated with improved treatment efficacy. Testing for the CYP19 rs4646 SNP as a predictive tool for breast cancer patients on antiaromatase therapy deserves prospective evaluation.
The role of TRPV6 in breast carcinogenesis
Authors: Bolanz Katrin A. , Hediger Matthias A. , Landowski Christopher P. 
Published: February 2008

AbstractTRPV6 is an endothelial calcium entry channel that is strongly expressed in breast adenocarcinoma tissue. In this study, we further confirmed this observation by analysis of breast cancer tissues, which indicated that TRPV6 mRNA expression was up-regulated between 2-fold and 15-fold compared with the average in normal breast tissue. Whereas TRPV6 is expressed in the cancer tissue, its role as a calcium channel in breast carcinogenesis is poorly understood. Therefore, we investigated how TRPV6 affects the viability, apoptosis, and calcium transport in the breast cancer cell line T47D. Hormones can also affect the tumor development; hence, we determined the effects of estradiol, progesterone, and 1,25-vitamin D on TRPV6 transcription. Interestingly, the estrogen receptor antagonist tamoxifen reduced expression of TRPV6 and is able to inhibit its calcium transport activity (IC50, 7.5 μmol/L). The in vitro model showed that TRPV6 can be regulated by estrogen, progesterone, tamoxifen, and 1,25-vitamin D and has a large influence on breast cancer cell proliferation. Moreover, the effect of tamoxifen on cell viability was enhanced when TRPV6 expression was silenced with small interfering RNA. TRPV6 may be a novel target for the development of calcium channel inhibitors to treat breast adenocarcinoma expressing TRPV6. [Mol Cancer Ther 2008;7(2):271–9]
In vivooptical imaging of human lymphoma xenograft using a library-derived peptidomimetic against α4β1 integrin
Authors: Peng Li , Liu Ruiwu , Andrei Mirela , Xiao Wenwu , Lam Kit S. 
Published: February 2008

AbstractIncreasing literature suggests that cell adhesion molecule α4β1 integrin plays a pivotal role in autoimmune diseases and cancer development. Noninvasive visualization of α4β1 integrin in vivo will facilitate the understanding of its involvement in disease progression and development of targeted therapies. Due to the lack of high-affinity targeting ligands, molecular imaging of α4β1 integrin is much less explored than that of αvβ3 and αvβ5 integrins. We have recently reported using the one bead–one compound combinatorial library method to identify a peptidomimetic, LLP2A, that preferentially binds to activated α4β1 integrin. Here, we described the use of LLP2A-Cy5.5 conjugate as an in vivo optical imaging probe in a human lymphoma xenograft model. This univalent LLP2A-Cy5.5 conjugate retained the binding activity and specificity to α4β1 integrin as shown by cell binding assays using α4β1-positive Molt-4 T-leukemia cells. The subcutaneous Molt-4 tumor was clearly visualized from 1 to 24 h after tail vein injection of the conjugate. Direct imaging and confocal microscopic examination of excised tumors and organs confirmed the accumulation of LLP2A in tumors and revealed very little or no uptake in normal organs except for lymph nodes. Kidney uptake was high when the whole organ was scanned but it was negative when examined microscopically, suggesting that LLP2A bound to the renal tubules loosely. Tumor uptake of LLP2A-Cy5.5 conjugate was blocked by excess unlabeled LLP2A. This study showed that the combinatorial chemical library-derived peptidomimetic LLP2A can be easily developed into an optical imaging probe for noninvasively monitoring of activated α4β1 integrin in vivo. [Mol Cancer Ther 2008;7(2):432–7]