bluuebunny/crossref_metadata_2025_split huggingface dataset:
MmpL3 Is the Cellular Target of the Antitubercular Pyrrole Derivative BM212
Authors: La Rosa Valentina , Poce Giovanna , Canseco Julio Ortiz , Buroni Silvia , Pasca Maria Rosalia , Biava Mariangela , Raju Ravikiran M. , Porretta Giulio Cesare , Alfonso Salvatore , Battilocchio Claudio , Javid Babak , Sorrentino Flavia , Ioerger Thomas R. , Sacchettini James C. , Manetti Fabrizio , Botta Maurizio , De Logu Alessandro , Rubin Eric J. , De Rossi Edda 
Published: October 2011

ABSTRACT

The 1,5-diarylpyrrole derivative BM212 was previously shown to be active against multidrug-resistant clinical isolates and
Mycobacterium tuberculosis
residing within macrophages as well as against
Mycobacterium avium
and other atypical mycobacteria. To determine its mechanism of action, we identified the cellular target. Spontaneous
Mycobacterium smegmatis
,
Mycobacterium bovis
BCG, and
M. tuberculosis
H37Rv mutants that were resistant to BM212 were isolated. By the screening of genomic libraries and by whole-genome sequencing, we found that all the characterized mutants showed mutations in the
mmpL3
gene, allowing us to conclude that resistance to BM212 maps to the MmpL3 protein, a member of the MmpL (
m
ycobacterial
m
embrane
p
rotein,
l
arge) family. Susceptibility was unaffected by the efflux pump inhibitors reserpine, carbonylcyanide
m
-chlorophenylhydrazone, and verapamil. Uptake/efflux experiments with [
14
C]BM212 demonstrated that resistance is not driven by the efflux of BM212. Together, these data strongly suggest that the MmpL3 protein is the cellular target of BM212.
Enterobacterial Common Antigen Mutants of Salmonella enterica Serovar Typhimurium Establish a Persistent Infection and Provide Protection against Subsequent Lethal Challenge
Authors: Gilbreath Jeremy J. , Colvocoresses Dodds Jennifer , Rick Paul D. , Soloski Mark J. , Merrell D. Scott , Metcalf Eleanor S. 
Published: October 2011

ABSTRACTInfection withSalmonellaspp. is a significant source of disease globally. A substantial proportion of these infections are caused bySalmonella entericaserovar Typhimurium. Here, we characterize the role of the enterobacterial common antigen (ECA), a surface glycolipid ubiquitous among enteric bacteria, inS.Typhimurium pathogenesis. Construction of a defined mutation in the UDP-N-acetylglucosamine-1-phosphate transferase gene,wecA, in two clinically relevant strains ofS.Typhimurium, TML and SL1344, resulted in strains that were unable to produce ECA. Loss of ECA did not affect the gross cell surface ultrastructure, production of lipopolysaccharide (LPS), flagella, or motility. However, thewecAmutant strains were attenuated in both oral and intraperitoneal mouse models of infection (P< 0.001 for both routes of infection; log rank test), and virulence could be restored by complementation of thewecAgene intrans. Despite the avirulence of the ECA-deficient strains, thewecAmutant strains were able to persistently colonize systemic sites (spleen and liver) at moderate levels for up to 70 days postinfection. Moreover, immunization with thewecAmutant strains provided protection against a subsequent lethal oral or intraperitoneal challenge with wild-typeS.Typhimurium. Thus,wecAmutant (ECA-negative) strains ofSalmonellamay be useful as live attenuated vaccine strains or as vehicles for heterologous antigen expression.
Role of Toll Interleukin-1 Receptor (IL-1R) 8, a Negative Regulator of IL-1R/Toll-Like Receptor Signaling, in Resistance to Acute Pseudomonas aeruginosa Lung Infection
Authors: Véliz Rodriguez Tania , Moalli Federica , Polentarutti Nadia , Paroni Moira , Bonavita Eduardo , Anselmo Achille , Nebuloni Manuela , Mantero Stefano , Jaillon Sébastien , Bragonzi Alessandra , Mantovani Alberto , Riva Federica , Garlanda Cecilia 
Published: October 2011

ABSTRACTToll interleukin-1 receptor (IL-1R) 8 (TIR8), also known as single Ig IL-1 receptor (IL-R)-related molecule, or SIGIRR, is a member of the IL-1R-like family, primarily expressed by epithelial cells. Current evidence suggests that TIR8 plays a nonredundant role as a negative regulatorin vivounder different inflammatory conditions that are dependent on IL-R and Toll-like receptor (TLR) activation. In the present study, we examined the role of TIR8 in innate resistance to acute lung infections caused byPseudomonas aeruginosa, a Gram-negative pathogen responsible for life-threatening infections in immunocompromised individuals and cystic fibrosis patients. We show that Tir8 deficiency in mice was associated with increased susceptibility to acuteP. aeruginosainfection, in terms of mortality and bacterial load, and to exacerbated local and systemic production of proinflammatory cytokines (gamma interferon [IFN-γ], tumor necrosis factor alpha [TNF-α], IL-1β, and IL-6) and chemokines (CXCL1, CXCL2, and CCL2). It has been reported that host defense againstP. aeruginosaacute lung infection can be improved by blocking IL-1 since exaggerated IL-1β production may be harmful for the host in this infection. In agreement with these data, IL-1RI deficiency rescues the phenotype observed in Tir8-deficient mice: in Tir8−/−IL-1RI−/−double knockout mice we observed higher survival rates, enhanced bacterial clearance, and reduced levels of local and systemic cytokine and chemokine levels than in Tir8-deficient mice. These results suggest that TIR8 has a nonredundant effect in modulating the inflammation caused byP. aeruginosa, in particular, by negatively regulating IL-1RI signaling, which plays a major role in the pathogenesis of this infectious disease.
Two Zinc Uptake Systems Contribute to the Full Virulence of Listeria monocytogenes during Growth
In Vitro
and
In Vivo
Authors: Corbett David , Wang Jiahui , Schuler Stephanie , Lopez-Castejon Gloria , Glenn Sarah , Brough David , Andrew Peter W. , Cavet Jennifer S. , Roberts Ian S. 
Published: October 2011

ABSTRACT

We report here the identification and characterization of two zinc uptake systems, ZurAM and ZinABC, in the intracellular pathogen
Listeria monocytogenes
. Transcription of both operons was zinc responsive and regulated by the zinc-sensing repressor Zur. Deletion of either
zurAM
or
zinA
had no detectable effect on growth in defined media, but a double
zurAM zinA
mutant was unable to grow in the absence of zinc supplementation. Deletion of
zinA
had no detectable effect on intracellular growth in HeLa epithelial cells. In contrast, growth of the
zurAM
mutant was significantly impaired in these cells, indicating the importance of the ZurAM system during intracellular growth. Notably, the deletion of both
zinA
and
zurAM
severely attenuated intracellular growth, with the double mutant being defective in actin-based motility and unable to spread from cell to cell. Deletion of either
zurAM
or
zinA
had a significant effect on virulence in an oral mouse model, indicating that both zinc uptake systems are important
in vivo
and establishing the importance of zinc acquisition during infection by
L. monocytogenes
. The presence of two zinc uptake systems may offer a mechanism by which
L. monocytogenes
can respond to zinc deficiency within a variety of environments and during different stages of infection, with each system making distinct contributions under different stress conditions.
Efficient Search Engine Measurements
Authors: Bar-Yossef Ziv , Gurevich Maxim 
Published: October 2011

We address the problem of externally measuring aggregate functions over documents indexed by search engines, like corpus size, index freshness, and density of duplicates in the corpus. State of the art estimators for such quantities [Bar-Yossef and Gurevich 2008b; Broder et al. 2006] are biased due to inaccurate approximation of the so called “document degrees”. In addition, the estimators in Bar-Yossef and Gurevich [2008b] are quite costly, due to their reliance on rejection sampling.
We present new estimators that are able to overcome the bias introduced by approximate degrees. Our estimators are based on a careful implementation of an approximate importance sampling procedure. Comprehensive theoretical and empirical analysis of the estimators demonstrates that they have essentially no bias even in situations where document degrees are poorly approximated.

By avoiding the costly rejection sampling approach, our new importance sampling estimators are significantly more efficient than the estimators proposed in Bar-Yossef and Gurevich [2008b]. Furthermore, building on an idea from Broder et al. [2006], we discuss
Rao-Blackwellization
as a generic method for reducing variance in search engine estimators. We show that Rao-Blackwellizing our estimators results in performance improvements, without compromising accuracy.
GLIPR1 Suppresses Prostate Cancer Development through Targeted Oncoprotein Destruction
Authors: Li Likun , Ren Chengzhen , Yang Guang , Fattah Elmoataz Abdel , Goltsov Alexei A. , Kim Soo Mi , Lee Ju-Seog , Park Sanghee , Demayo Francesco J. , Ittmann Michael M. , Troncoso Patricia , Thompson Timothy C. 
Published: October 2011

Abstract
Downregulation of the proapoptotic p53 target gene glioma pathogenesis-related protein 1 (GLIPR1) occurs frequently in prostate cancer, but the functional meaning of this event is obscure. Here, we report the discovery of functional relationship between GLIPR1 and c-Myc in prostate cancer where c-Myc is often upregulated. We found that the expression of GLIPR1 and c-Myc were inversely correlated in human prostate cancer. Restoration of GLIPR1 expression in prostate cancer cells downregulated c-myc levels, inhibiting cell-cycle progression. Downregulation was linked to a reduction in β-catenin/TCF4-mediated transcription of the c-myc gene, which was caused by GLIPR1-mediated redistribution of casein kinase 1α (CK1α) from the Golgi apparatus to the cytoplasm where CK1α could phosphorylate β-catenin and mediate its destruction. In parallel, GLIPR1 also promoted c-Myc protein ubiquitination and degradation by glycogen synthase kinase-3α- and/or CK1α-mediated c-Myc phosphorylation. Notably, genetic ablation of the mouse homolog of Glipr1 cooperated with c-myc overexpression to induce prostatic intraepithelial neoplasia and prostate cancer. Together, our findings provide evidence for CK1α-mediated destruction of c-Myc and identify c-Myc S252 as a crucial CK1α phosphorylation site for c-Myc degradation. Furthermore, they reveal parallel mechanisms of c-myc downregulation by GLIPR1 that when ablated in the prostate are sufficient to drive c-Myc expression and malignant development. Cancer Res; 71(24); 7694–704. ©2011 AACR.
MicroRNA-30c-2* Expressed in Ovarian Cancer Cells Suppresses Growth Factor–Induced Cellular Proliferation and Downregulates the Oncogene BCL9
Authors: Jia Wei , Eneh Juliet O. , Ratnaparkhe Supriya , Altman Molly K. , Murph Mandi M. 
Published: October 2011

Abstract
MicroRNAs (miRNAs) are small noncoding RNAs that function as master regulators of posttranscriptional gene expression with each miRNA negatively regulating hundreds of genes. Lysophosphatidic acid (LPA) is a mitogenic lipid present within the ovarian tumor microenvironment and induces LPA receptor activation and intracellular signaling cascades like ERK/MAPK, leading to enhanced cellular proliferation. Here, we show that in SKOV-3 and OVCAR-3 cells, LPA stimulation at concentrations ranging from 1 nmol/L to 20 μmol/L for 30 to 60 minutes increases miR-30c-2*, and this effect is mediated through a combination of receptors because knock down of multiple LPA receptors is required for inhibition. The epidermal growth factor and platelet-derived growth factor also increase miR-30c-2* transcript expression, suggesting a broader responsive role for miR-30c-2*. Thus, we investigated the functional role of miR-30c-2* through ectopic expression of synthetic miRNA precursors of mature miRNA or antagomir transfection and observed that microRNA-30c-2* reduces, and the antagomir enhances, cell proliferation and viability in OVCAR-3, cisplatin-insensitive SKOV-3 and chemoresistant HeyA8-MDR cells. Ectopic expression of miR-30c-2* reduces BCL9 mRNA transcript abundance and BCL9 protein. Consistent with this observation, miR-30c-2* ectopic expression also reduced BCL9 luciferase reporter gene expression. In comparison with IOSE cells, all cancer cells examined showed increased BCL9 expression, which is consistent with its role in tumor progression. Taken together, this suggest that growth factor induced proliferation mediates a neutralizing response by significantly increasing miR-30c-2* which reduces BCL9 expression and cell proliferation in SKOV-3 and OVCAR-3 cells, likely as a mechanism to regulate signal transduction downstream. Mol Cancer Res; 9(12); 1732–45. ©2011 AACR.
Hypnic headache in children
Authors: Cerminara Caterina , Compagnone Eliana , Coniglio Antonella , Margiotta Milena , Curatolo Paolo , Villa Maria Pia , Parisi Pasquale 
Published: October 2011

Background: Hypnic headache (HH) is a rare, short-lasting headache occurring exclusively during sleep and usually affecting the elderly population. According to the ICHD-II diagnostic criteria, HH is characterized exclusively by sleep-related dull headache attacks, either lateralized or bilateral, a recurrence of >15 times per month and a persistence of pain >15 minutes after waking. No autonomic symptoms and no more than nausea, photophobia, or phonophobia are present. Cases: We report three children between 7 and 11 years old with HH features. The characteristics of our patient’s headache, with particular reference to the nocturnal pattern, the short duration and the absence of autonomic symptoms, lead us to consider the diagnosis of HH. Conclusions: Considering the very few cases of HH reported in paediatric age, our cases may expand the clinical spectrum of this disorder, suggesting a possible revision of the diagnostic criteria, with particular regard to the developmental age.
Mothers' satisfaction with referral hospital delivery service in Amhara Region, Ethiopia
Authors: Tayelgn Azmeraw , Zegeye Desalegn T , Kebede Yigzaw 
Published: October 2011

AbstractBackgroundA woman's satisfaction with the delivery service may have immediate and long-term effects on her health and subsequent utilization of the services. Providing satisfying delivery care increases service utilization. The objective of this study is to assess the satisfaction of mothers with referral hospitals' delivery service and identify some possible factors affecting satisfaction in Amhara region of Ethiopia.MethodsA hospital-based cross-sectional survey that involved an exit interview was conducted from September to November 2009 in three referral hospitals in Ethiopia. A total of 417 delivering mothers were enrolled in the study. Client satisfaction was measured using a survey instrument adopted from the Donabedian quality assessment framework. We collect data systematically from every other postnatal woman who delivered in the referral hospitals. Multivariate and binary logistic regression was applied to identify the relative effect of each explanatory variable on the outcome (satisfaction).ResultsThe proportion of mothers who were satisfied with delivery care in this study was 61.9%. Women's satisfaction with delivery care was associated with wanted status of the pregnancy, immediate maternal condition after delivery, waiting time to see the health worker, availability of waiting area, care providers' measure taken to assure privacy during examinations, and amount of cost paid for service.ConclusionsThe overall satisfaction of hospital delivery services in this study is found to be suboptimal. The study strongly suggests that more could be done to assure that services provided are more patient centered.
Histomorphometric and immunohistochemical analysis of infectious agents, T-cell subpopulations and inflammatory adhesion molecules in placentas from HIV-seropositive pregnant women
Authors: Baurakiades Emanuele , Martins Ana PC , Victor Moreschi N , Souza Camila DA , Abujamra Karla , Saito Augusto O , Mecatti Maíra C , Santos Mônica G , Pimentel Camilla R , Silva Larissa LG , Cruz Cristina R , de Noronha Lucia 
Published: October 2011

AbstractBackgroundThe aim of this study was to compare histomorphometric changes and the results of immunohistochemical tests for VCAM, ICAM-1, CD4 and CD8 in normal placentas from HIV-seropositive pregnant women.MethodsSamples of normal placentas were divided into 2 groups: healthy HIV-seronegative pregnant women (control group = C = 60) and HIV-seropositive women (experimental group = E = 57). Conventional histological sections were submitted to morphometric analysis and evaluated in terms of the immunohistochemical expression of ICAM-1, VCAM, CD4 and CD8.ResultsThe villi in group E were smaller than those in group C. The median for the CD8+ T cell count was higher in group E than in group C (p = 0.03). Immunohistochemical expression of ICAM-1 was observed in 57% of the cases in group E, compared with 21% of those in group C (p = 0.001). There was no difference in VCAM expression or CD4+ cell counts between groups and no correlation between the data for antiretroviral therapy and morphometric or immunohistochemical data.ConclusionsThe morphometric data showed that placentas of HIV-seropositive pregnant women tend to have smaller villi than those of seronegative women. In addition, immunohistochemical testing for infectious agents helped to identify cases that were positive for microorganisms (6/112) that routine pathological examination had failed to detect. The anti-p24 antibody had a limited ability to detect HIV viral protein in this study (2/57). Correlation of immunohistochemical expression of CD8+ T cells and ICAM-1 with the presence of HIV in the placenta revealed that those expressions can act as biomarkers of inflammatory changes. There was no correlation between the data for antiretroviral therapy and morphometric or immunohistochemical data.
Prostate Brachytherapy and Second Primary Cancer Risk: A Competitive Risk Analysis
Authors: Hinnen Karel A. , Schaapveld Michael , van Vulpen Marco , Battermann Jan. J. , van der Poel Henk , van Oort Inge M. , van Roermund Joep G.H. , Monninkhof Evelyn M. 
Published: October 2011

Purpose To assess the risk of second primary cancer (SPC) after [125I]iodine prostate cancer brachytherapy compared with prostatectomy and the general population. Patients and Methods In a cohort consisting of 1,888 patients with prostate cancer who received monotherapy with brachytherapy (n = 1,187; 63%) or prostatectomy (n = 701; 37%), SPC incidences were retrieved by linkage with the Dutch Cancer Registry. Standardized incidence rates (SIRs) and absolute excess risks (AERs) were calculated for comparison. Results A total of 223 patients were diagnosed with SPC, 136 (11%) after brachytherapy and 87 (12%) after prostatectomy, with a median follow-up of 7.5 years. The SIR for all malignancies, bladder cancer, and rectal cancer were 0.94 (95% CI, 0.78 to 1.12), 1.69 (95% CI, 0.98 to 2.70), and 0.90 (95% CI, 0.41 to 1.72) for brachytherapy and 1.04 (95% CI, 0.83 to 2.28), 1.82 (95% CI, 0.87 to 3.35), and 1.50 (95% CI, 0.68 to 2.85) for prostatectomy, respectively. Bladder SPC risk was significantly increased after brachytherapy for patients age 60 years or younger (SIR, 5.84; 95% CI, 2.14 to 12.71; AER, 24.03) and in the first 4 years of follow-up (SIR, 2.14; 95% CI, 1.03 to 3.94; AER, 12.24). Adjusted for age, the hazard ratio (brachytherapy v prostatectomy) for all SPCs combined was 0.87 (95% CI, 0.64 to 1.18). Conclusion Overall, we found no difference in SPC incidence between patients with prostate cancer treated with prostatectomy or brachytherapy. Furthermore, no increased tumor incidence was found compared with the general population. We observed a higher than expected incidence of bladder SPC after brachytherapy in the first 4 years of follow-up, probably resulting from lead time or screening bias. Because of power limitations, a small increased SPC risk cannot be formally excluded.
Impact of Early-Life Bisphenol A Exposure on Behavior and Executive Function in Children
Authors: Braun Joe M. , Kalkbrenner Amy E. , Calafat Antonia M. , Yolton Kimberly , Ye Xiaoyun , Dietrich Kim N. , Lanphear Bruce P. 
Published: October 2011

OBJECTIVES:To estimate the impact of gestational and childhood bisphenol A (BPA) exposures on behavior and executive function at 3 years of age and to determine whether child gender modified those associations.METHODS:We used a prospective birth cohort of 244 mothers and their 3-year-old children from the greater Cincinnati, Ohio, area. We characterized gestational and childhood BPA exposures by using the mean BPA concentrations in maternal (16 and 26 weeks of gestation and birth) and child (1, 2, and 3 years of age) urine samples, respectively. Behavior and executive function were measured by using the Behavior Assessment System for Children 2 (BASC-2) and the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P).RESULTS:BPA was detected in &gt;97% of the gestational (median: 2.0 μg/L) and childhood (median: 4.1 μg/L) urine samples. With adjustment for confounders, each 10-fold increase in gestational BPA concentrations was associated with more anxious and depressed behavior on the BASC-2 and poorer emotional control and inhibition on the BRIEF-P. The magnitude of the gestational BPA associations differed according to child gender; BASC-2 and BRIEF-P scores increased 9 to 12 points among girls, but changes were null or negative among boys. Associations between childhood BPA exposure and neurobehavior were largely null and not modified by child gender.CONCLUSIONS:In this study, gestational BPA exposure affected behavioral and emotional regulation domains at 3 years of age, especially among girls. Clinicians may advise concerned patients to reduce their exposure to certain consumer products, but the benefits of such reductions are unclear.
Atorvastatin for the Treatment of Plaque‐Type Psoriasis
Authors: Faghihi Toktam , Radfar Mania , Mehrabian Zohre , Ehsani Amir Hoshang , Hemami Mohsen Rezaei 
Published: October 2011

Study Objective. To explore the efficacy and safety of oral atorvastatin for the treatment of plaque‐type psoriasis.Design. Prospective, randomized, double‐blind, placebo‐controlled study.Setting. University‐affiliated psoriasis outpatient clinic in Iran.Patients. Forty‐two patients aged 16–60 years with a diagnosis of acute or chronic plaque‐type psoriasis with body surface area (BSA) involvement of greater than 10% were enrolled; 40 completed the study.Intervention. Oral atorvastatin 40 mg/day (20 patients) or placebo (20 patients) was administered for 12 weeks; patients' topical therapies with emollients, keratolytics, and/or class V corticosteroids were continued during the study period.Measurements and Main Results. The Psoriasis Area and Severity Index (PASI) and percentage BSA involvement were used to assess the efficacy of therapy. Mean ± SD baseline PASI scores were 7.42 ± 1.90 and 6.92 ± 1.76 in the atorvastatin and placebo groups, respectively. The primary outcomes were the degree of change in PASI scores and percentage BSA involvement from baseline to week 12. Significant improvement in psoriasis lesions was observed in both the atorvastatin and placebo groups (p<0.001 for both groups). A 75% improvement in PASI score (PASI 75) was achieved in 8 patients (40%) in the atorvastatin group and 7 patients (35%) in the placebo group. However, no statistically significant differences were noted between the two treatment groups in mean PASI score, percentage BSA involvement, and PASI 75. In terms of adverse effects, atorvastatin was well tolerated.Conclusion. Oral atorvastatin 40 mg/day was not associated with therapeutic benefit when given to patients with baseline PASI scores less than 12 who were also treated with standard topical therapies. Additional trials are needed to elucidate the place of statins for the treatment of psoriasis. A larger follow‐up study, as well as testing atorvastatin in patients with more intensive disease characterized by high PASI scores, is needed. Studies using higher atorvastatin doses or dose‐ranging studies should also be performed.