bluuebunny/crossref_metadata_2025_split huggingface dataset:
In Silico
Prediction and Experimental Evaluation of Furanoheliangolide Sesquiterpene Lactones as Potent Agents against Trypanosoma brucei rhodesiense
Authors: Schmidt Thomas J. , Da Costa Fernando B. , Lopes Norberto P. , Kaiser Marcel , Brun Reto 
Published: October 2013

ABSTRACT

As a continuation of our earlier study on the
in vitro
antiprotozoal activity of 40 natural sesquiterpene lactones (STLs), we extended the set of tested compounds from our laboratories to 59. On the basis of this extended data set, further enriched by literature data for 10 compounds tested under the same conditions, our quantitative structure-activity relationship (QSAR) analyses for activity against
T. brucei rhodesiense
(etiologic agent of human African trypanosomiasis, or sleeping sickness) were continued, and the QSAR model thus obtained with 69 structures was used to predict the activity of a virtual library of 1,750 STL structures. As a major result from these calculations, furanoheliangolide-type compounds, a subclass of STLs hitherto untested against
T. brucei rhodesiense
, were predicted to have an exceptionally high level of
in vitro
activity. Four representative compounds of this type, goyazensolide, 4,5-dihydro-2′,3′-epoxy-15-deoxygoyazensolide, budlein A, and 4,15-isoatriplicolide tiglate, were therefore tested. They displayed 50% inhibitory concentrations (IC
50
s) of 0.07, 0.20, 0.07, and 0.015 μM, respectively, so that the
in silico
prediction was experimentally confirmed. 4,15-Isoatriplicolide tiglate is the most potent STL against
T. b. rhodesiense
found. Furanoheliangolide STLs were thus identified as interesting leads against this parasite which deserve more detailed investigations.
Potent Sub-MIC Effect of GSK1322322 and Other Peptide Deformylase Inhibitors on
In Vitro
Growth of Staphylococcus aureus
Authors: Butler Deborah , Chen Dongzhao , O'Dwyer Karen , Lewandowski Thomas , Aubart Kelly , Zalacain Magdalena 
Published: October 2013

ABSTRACT

Peptide deformylase (PDF), a clinically unexploited antibacterial target, plays an essential role in protein maturation. PDF inhibitors, therefore, represent a new antibiotic class with a unique mode of action that provides an alternative therapy for the treatment of infections caused by drug-resistant pathogens, including methicillin-resistant
Staphylococcus aureus
(MRSA). GSK1322322 is a novel PDF inhibitor that is in phase II clinical development for the treatment of lower respiratory tract and skin infections. We have discovered that PDF inhibitors can prevent
S. aureus
in vitro
growth for up to 6 h at concentrations 8- to 32-fold below their MICs. This phenomenon seems specific to PDF inhibitors, as none of the antimicrobial agents with alternative mechanisms of action tested show such a potent and widespread effect. It also appears limited to
S. aureus
, as PDF inhibitors do not show such an inhibition of growth at sub-MIC levels in
Streptococcus pneumoniae
or
Haemophilus influenzae
. Analysis of the effect of GSK1322322 on the early growth of 100 randomly selected
S. aureus
strains showed that concentrations equal to or below 1/8× MIC inhibited growth of 91% of the strains tested for 6 h, while the corresponding amount of moxifloxacin or linezolid only affected the growth of 1% and 6% of strains, respectively. Furthermore, the sub-MIC effect demonstrated by GSK1322322 appears more substantial on those strains at the higher end of the MIC spectrum. These effects may impact the clinical efficacy of GSK1322322 in serious infections caused by multidrug-resistant
S. aureus
.
Oxantel Disrupts Polymicrobial Biofilm Development of Periodontal Pathogens
Authors: Dashper Stuart , O'Brien-Simpson Neil , Liu Sze Wei , Paolini Rita , Mitchell Helen , Walsh Katrina , D'Cruze Tanya , Hoffmann Brigitte , Catmull Deanne , Zhu Ying , Reynolds Eric 
Published: October 2013

ABSTRACT

Bacterial pathogens commonly associated with chronic periodontitis are the spirochete
Treponema denticola
and the Gram-negative, proteolytic species
Porphyromonas gingivalis
and
Tannerella forsythia
. These species rely on complex anaerobic respiration of amino acids, and the anthelmintic drug oxantel has been shown to inhibit fumarate reductase (Frd) activity in some pathogenic bacteria and inhibit
P. gingivalis
homotypic biofilm formation. Here, we demonstrate that oxantel inhibited
P. gingivalis
Frd activity with a 50% inhibitory concentration (IC
50
) of 2.2 μM and planktonic growth of
T. forsythia
with a MIC of 295 μM, but it had no effect on the growth of
T. denticola
. Oxantel treatment caused the downregulation of six
P. gingivalis
gene products and the upregulation of 22 gene products. All of these genes are part of a regulon controlled by heme availability. There was no large-scale change in the expression of genes encoding metabolic enzymes, indicating that
P. gingivalis
may be unable to overcome Frd inhibition. Oxantel disrupted the development of polymicrobial biofilms composed of
P. gingivalis
,
T. forsythia
, and
T. denticola
in a concentration-dependent manner. In these biofilms, all three species were inhibited to a similar degree, demonstrating the synergistic nature of biofilm formation by these species and the dependence of
T. denticola
on the other two species. In a murine alveolar bone loss model of periodontitis oxantel addition to the drinking water of
P. gingivalis
-infected mice reduced bone loss to the same level as the uninfected control.
Complete Genome Sequence of an H12N8 Avian Influenza Virus Isolated from Wild Bird Feces in Hunan East Dongting Lake National Nature Reserve
Authors: Zhang Hong , Li Zi , Yang Hao , Liu Yunzhi , Li Fangcai , Wang Lijie , Li Xiaodan , Zhu Yun , Cai Yahui , Bai Zhiyong , Yi Feiyue , Shu Yuelong 
Published: October 2013

ABSTRACT
An H12N8 subtype avian influenza virus (AIV) was isolated from a wild bird in China in 2011. It is the first report of isolation of the H12N8 subtype AIV in Asia. Phylogenetic analysis results suggested it is a reassortant, and all eight gene segments belong to the Eurasian gene pool.
Maternal Infection with Schistosoma japonicum Induces a Profibrotic Response in Neonates
Authors: McDonald Emily A. , Cheng Ling , Jarilla Blanca , Sagliba Marianne J. , Gonzal Annaliza , Amoylen Amabelle J. , Olveda Remigio , Acosta Luz , Baylink David , White Eric S. , Friedman Jennifer F. , Kurtis Jonathan D. 
Published: October 2013

ABSTRACTThe global burden of schistosomiasis is significant, with fibrosis a major associated morbidity and the primary cause of mortality. We have previously shown that schistosomiasis during pregnancy upregulates proinflammatory cytokines in the cord blood. In this study, we extend these findings to include a large panel of fibrosis-associated markers. We developed a multiplex bead-based assay to measure the levels of 35 proteins associated with fibrosis. Cord blood from 109 neonates born to mothers residing in an area ofSchistosoma japonicumendemicity was assessed for these molecules. Ten mediators were elevated in the cord blood from schistosome-infected pregnancies, including insulin-like growth factor 1 (IGF-1), tumor growth factor β1 (TGF-β1), connective tissue growth factor (CTGF), procollagen I carboxy-terminal propeptide (PICP), amino-telopeptide of type 1 collagen (ICTP), collagen VI, desmosine, matrix metalloproteinase 2 (MMP-2), tissue inhibitor of metalloproteinases 1 (TIMP-1), and TIMP-4. Many of these were also positively correlated with preterm birth (PICP, ICTP, MMP-2, TGF-β1, desmosine, CTGF, TIMP-1). In addition, birth weight was 168 g lower for infants with detectable levels of CTGF than for those with CTGF levels below the level of detection. Maternal schistosomiasis results in upregulation of fibrosis-associated proteins in the cord blood of the neonate, a subset of which are also associated with adverse birth outcomes. As the first report of fibrosis-associated molecules altered in the newborn of infected mothers, this study has broad implications for the health of the fetus, stretching from gestation to adulthood.
Testing for sexually transmitted infections among students: a discrete choice experiment of service preferences
Authors: Llewellyn Carrie D , Sakal Chloe , Lagarde Mylene , Pollard Alex , Miners Alec H 
Published: October 2013

ObjectivesTo assess preferences among students for sexually transmitted infection (STI) testing services, with a view to establishing strength of preference for different service attributes.DesignOnline discrete choice experiment (DCE) questionnaire.SettingSouth East of England.ParticipantsA convenience sample of 233 students from two universities.OutcomesAdjusted ORs in relation to service characteristics.ResultsThe study yielded 233 responses. Respondents’ ages ranged from 16 to 34 years with a mean age of 22 years. Among this sample, the respondents demonstrated strong preferences for a testing service which provided tests for all STIs including syphilis, herpes and HIV (OR 4.1; 95% CI 3.36 to 4.90) and centres staffed by a doctor or nurse with specialist knowledge of STIs (OR 2.1; 95% CI 1.78 to 2.37). Receiving all test results, whether positive or negative, was also significantly preferable to not being notified when tests were all negative (‘no news is good news’; OR 1.3; 95% CI 1.16 to 1.5). The length of time waiting for an appointment and the method by which results are received were not significant service characteristics in terms of preferences. Patient level characteristics such as age, sex and previous testing experience did not predict the likelihood of testing.ConclusionsThis study demonstrates that of the examined attributes, university students expressed the strongest preference for a comprehensive testing service. The next strongest preferences were for being tested by specialist STI staff and receiving negative as well as positive test results. However, it remains unclear how strong these preferences are in relation to characteristics which were not part of the study design and whether or not they are cost-effective.
Persistent long-standing illness and non-drinking over time, implications for the use of lifetime abstainers as a control group
Authors: Ng Fat Linda , Cable Noriko , Marmot MG , Shelton Nicola 
Published: October 2013

BackgroundNon-drinkers are shown to have worse health than moderate drinkers in later life. We examine the preceding health status of non-drinkers in early adulthood, and secondly whether persistent poor health is associated with persistent non-drinking.MethodsUsing two prospective British birth cohort studies established in 1958 (National Child Development Study (NCDS)) and in 1970 (British Cohort Study (BCS)), participants who reported ‘never’ or ‘never had an alcoholic drink’ to drinking status questions in successive waves from 23 to 26 years in the NCDS/BCS were derived as ‘lifetime abstainers’. Logistic regression on the odds of being a lifetime abstainer was carried out on changes in limiting long-standing illness (LLSI) in the NCDS and long-standing illness (LSI) in the BCS, adjusting for sex, education, poor psychosocial health, marital and parental status.ResultsParticipants with an LLSI in consecutive waves since 23 years had 4.50 times the odds of someone who did not have an LLSI of being a lifetime abstainer at 33 years (95% CI 1.99 to 10.18) and 7.02 times the odds at 42 years (2.39 to 20.66) after adjusting for all factors. Similarly, in the BCS, having an LSI in consecutive waves resulted in higher odds of being a lifetime abstainer at 30 years (OR 2.80, 1.88 to 4.18) and 34 years (OR 3.33, 2.01 to 5.53).ConclusionsPersistent LSI was associated with remaining a non-drinker across adulthood. Studies comparing the health outcomes of moderate drinkers to lifetime abstainers that do not account for pre-existing poor health may overestimate the better health outcomes from moderate alcohol consumption.
TRAPEZIECTOMY WITH LIGAMENT RECONSTRUCTION AND TENDON INTERPOSITION: A MINIMUM 10-YEAR FOLLOW-UP
Authors: Vinycomb Toby , Crock John 
Published: October 2013

Purpose: To investigate the long-term (> 10 yrs) outcomes of trapeziectomy with ligament reconstruction and tendon interposition (LRTI). Methods: We reviewed 15 cases of trapeziectomy with LRTI performed for the treatment trapeziometacarpal osteoarthritis. Mean follow up was 13.5 yrs (range, 10.5–17.5 yrs). We assessed a number of subjective and objective outcomes. A good outcome was a participant who did not require revision surgery, was satisfied with the outcome of their surgery and did not experience rest pain. Results: No patients had revision surgery and only two patients were unsatisfied or very unsatisfied with the outcome of their surgery. Pain with activity was the strongest predictor of participant satisfaction. Discussion: Approximately half the participants in this study experienced good long-term outcomes. Some participants were experiencing long-term symptoms, particularly pain, despite reporting that they are satisfied with the outcome of their surgery. Alternative techniques should be investigated that provide superior long-term outcomes.
Provenance, diagenesis and reservoir quality of the Upper Triassic Wolfville Formation, Bay of Fundy, Nova Scotia, Canada
Authors: Kettanah Yawooz A. , Kettanah Muhammad Y. , Wach Grant D. 
Published: October 2013

Abstract

The reservoir characterization and provenance of the Wolfville Formation were investigated using petrography, heavy minerals and microprobe analysis of tourmaline and garnet. Sandstone samples were taken from exposures at Rainy Cove and Cambridge Cove, and from the subsurface at Chinampas N-37 well beneath the Bay of Fundy. The surface and subsurface rocks have differences in their relative content and/or type of detritus, cement and heavy minerals (opaques, garnet, scheelite, tourmaline, rutile, apatite and others). These sandstones have continental block provenance in the subsurface rocks and recycled orogen provenance in the exposures. The main sources of the exposed Wolfville Formation sediments were the Palaeozoic rocks of the Meguma Supergroup, South Mountain Batholith, Horton and Windsor groups; meanwhile the subsurface sandstones might have been derived from the same sources or the Avalon Terrane and/or Gondwana. The sandstones were deposited during early stages of rifting post-dating earlier Palaeozoic collision orogenies that culminated with the Appalachian orogeny. The exposures of Wolfville Formation have low porosity (
c.
6%) that diminishes to negligible in the subsurface. The Wolfville Formation has a considerable thickness beneath the Bay of Fundy where it overlies the Horton Bluff Formation, Meguma and/or Avalon terranes. However, its reservoir potential is not encouraging.
Temporal relations between mineral deposits and global tectonic cycles
Authors: Cawood Peter A. , Hawkesworth Chris J. 
Published: October 2013

Abstract
Mineral deposits are heterogeneously distributed in both space and time, with variations reflecting tectonic setting, evolving environmental conditions, as in the atmosphere and hydrosphere, and secular changes in the Earth's thermal history. The distribution of deposit types whose settings are tied to plate margin processes (e.g. orogenic gold, volcanic-hosted massive sulphide, Mississippi valley type Pb–Zn deposits) correlates well with the supercontinent cycle, whereas deposits related to intra-cratonic settings and mantle-driven igneous events, such as Ni–Cu–PGE deposits, lack a clear association. The episodic distribution of deposits tied to the supercontinent cycle is accentuated by selective preservation and biasing of rock units and events during supercontinent assembly, a process that encases the deposit within the assembled supercontinent and isolates it from subsequent removal and recycling at plate margins.
Phase Transition in Long‐Range Percolation on Bipartite Hierarchical Lattices
Authors: Shang Yilun 
Published: October 2013

We propose a family of bipartite hierarchical lattice of order N governed by a pair of parameters ℓ and γ. We study long‐range percolation on the bipartite hierarchical lattice where any edge (running between vertices of unlike bipartition sets) of length k is present with probability pk = 1 − exp(−αβ−k), independently of all other edges. The parameter α is the percolation parameter, while β describes the long‐range nature of the model. The model exhibits a nontrivial phase transition in the sense that a critical value αc ∈ (0, ∞) if and only if ℓ ≥ 1, 1 ≤ γ ≤ N − 1, and β ∈ (N, N2). Moreover, the infinite component is unique when α > αc.
GLI1 Interferes with the DNA Mismatch Repair System in Pancreatic Cancer through BHLHE41-Mediated Suppression of MLH1
Authors: Inaguma Shingo , Riku Miho , Hashimoto Mitsuyoshi , Murakami Hideki , Saga Shinsuke , Ikeda Hiroshi , Kasai Kenji 
Published: October 2013

Abstract
The mismatch repair (MMR) system is indispensable for the fidelity of DNA replication, the impairment of which predisposes to the development and progression of many types of cancers. To date, GLI1 transcription factor, a key molecule of the Hedgehog signaling pathway, has been shown to regulate the expression of several genes crucial for a variety of cancer cell properties in many types of cancers, including pancreatic ductal adenocarcinoma (PDAC), but whether GLI1 could control the MMR system was not known. Here, we showed that GLI1 and GLI2 indirectly suppressed the expression of MLH1 in PDAC cells. Through GLI1 target gene screening, we found that GLI1 and GLI2 activated the expression of a basic helix-loop-helix type suppressor BHLHE41/DEC2/SHARP1 through a GLI-binding site in the promoter. Consistent with a previous report that BHLHE41 suppresses the MLH1 promoter activity, we found that the activation of GLI1 led to the BHLHE41-dependent suppression of MLH1, and a double knockdown of GLI1 and GLI2 conversely increased the MLH1 protein in PDAC cells. Using TALEN-based modification of the MLH1 gene, we further showed that GLI1 expression was indeed associated with an increased tolerance to a methylating agent, methylnitrosourea cooperatively with a lower copy number status of MLH1. Finally, GLI1 expression was immunohistochemically related positively with BHLHE41 and inversely with MLH1 in PDAC cells and precancerous lesions of the pancreas. On the basis of these results, we propose that GLI1 depresses the MMR activity and might contribute to the development and progression of PDAC. Cancer Res; 73(24); 7313–23. ©2013 AACR.
The Janus Kinases Inhibitor AZD1480 Attenuates Growth of Small Cell Lung Cancers In Vitro and In Vivo
Authors: Lee Jih-Hsiang , Park Kang-Seo , Alberobello Anna Teresa , Kallakury Bhaskar , Weng Meng-Tzu , Wang Yisong , Giaccone Giuseppe 
Published: October 2013

Abstract
Purpose: The prognosis of small cell lung cancer (SCLC) is poor, and there has been very little progress in the medical treatment of SCLC in the past two decades. We investigated the potential of Janus-activated kinases (JAK) inhibitor, AZD1480, for treatment of SCLC in vitro and in vivo.
Experimental Design: JAK1 and JAK2 were inhibited by AZD1480 or siRNAs, and the effect of inhibition of JAK gene family on SCLC cell viability was evaluated. The effect of AZD1480 on cell-cycle distribution and apoptosis induction was studied. Antitumor effects of AZD1480 in tumor xenografts were assessed.
Results: AZD1480 significantly inhibited growth of six out of 13 SCLC cells with IC50s ranging from 0.73 to 3.08 μmol/L. Knocking down of JAK2 and JAK1 inhibited proliferation of Jak2-positive/Jak1-negative H82 cells and Jak1-positive/Jak2-negative GLC4 cells, respectively. Treatment of SCLC cells with AZD1480 for 24 hours resulted in an increase of 4N DNA content and histone 3 serine 10 phosphorylation, indicative of G2–M phase arrest. Moreover, SCLCs underwent apoptosis after AZD1480 treatment as exemplified by the downregulation of MCL1, the accumulation of cleaved caspase 3, cleaved PARP, and increase of annexin-V–positive cells. Finally, xenograft experiments showed that AZD1480 attenuated the growth of H82 and GLC4 tumors in mice, and we observed stronger apoptosis as well as decreased CD31-positive endothelial cells in H82 and GLC4 xenografts upon AZD1480 treatment.
Conclusions: JAK inhibitor AZD1480 attenuated growth of SCLC cells in vitro and in vivo. Clinical development of anti-JAKs therapies in SCLC warrants further investigation. Clin Cancer Res; 19(24); 6777–86. ©2013 AACR.
Peroxisome Proliferator–Activated Receptor δ Agonist GW1516 Attenuates Diet-Induced Aortic Inflammation, Insulin Resistance, and Atherosclerosis in Low-Density Lipoprotein Receptor Knockout Mice
Authors: Bojic Lazar A. , Burke Amy C. , Chhoker Sanjiv S. , Telford Dawn E. , Sutherland Brian G. , Edwards Jane Y. , Sawyez Cynthia G. , Tirona Rommel G. , Yin Hao , Pickering J. Geoffrey , Huff Murray W. 
Published: October 2013

Objective—
The peroxisome proliferator–activated receptor (PPAR) δ regulates systemic lipid homeostasis and inflammation. However, the ability of PPARδ agonists to improve the pathology of pre-established lesions and whether PPARδ activation is atheroprotective in the setting of insulin resistance have not been reported. Here, we examine whether intervention with a selective PPARδ agonist corrects metabolic dysregulation and attenuates aortic inflammation and atherosclerosis.

Approach and Results—

Low-density lipoprotein receptor knockout mice were fed a chow or a high-fat, high-cholesterol (HFHC) diet (42% fat, 0.2% cholesterol) for 4 weeks. For a further 8 weeks, the HFHC group was fed either HFHC or HFHC plus GW1516 (3 mg/kg per day). GW1516 significantly attenuated pre-established fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia, as well as glucose and insulin intolerance. GW1516 intervention markedly reduced aortic sinus lesions and lesion macrophages, whereas smooth muscle α-actin was unchanged and collagen deposition enhanced. In aortae, GW1516 increased the expression of the PPARδ-specific gene
Adfp
but not PPARα- or γ-specific genes. GW1516 intervention decreased the expression of aortic proinflammatory M1 cytokines, increased the expression of the anti-inflammatory M2 cytokine
Arg1
, and attenuated the
iNos
/
Arg1
ratio. Enhanced mitogen-activated protein kinase signaling, known to induce inflammatory cytokine expression in vitro, was enhanced in aortae of HFHC-fed mice. Furthermore, the HFHC diet impaired aortic insulin signaling through Akt and forkhead box O1, which was associated with elevated endoplasmic reticulum stress markers CCAAT-enhancer-binding protein homologous protein and 78kDa glucose regulated protein. GW1516 intervention normalized mitogen-activated protein kinase activation, insulin signaling, and endoplasmic reticulum stress.

Conclusions—
Intervention with a PPARδ agonist inhibits aortic inflammation and attenuates the progression of pre-established atherosclerosis.