bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Basis for Vancomycin-Enhanced Cephalosporin Susceptibility in Vancomycin-Resistant Enterococci Revealed Using Counterselection with Dominant-Negative Thymidylate Synthase
Authors: Kristich Christopher J. , Djorić Dušanka , Little Jaime L. 
Published: December 2013

ABSTRACT

Antibiotic-resistant enterococci are major causes of hospital-acquired infections. All enterococci are intrinsically resistant to most cephalosporins, antibiotics in the beta-lactam family that impair peptidoglycan synthesis by inactivating the transpeptidases responsible for cross-linking. In addition, clinical isolates of enterococci often possess acquired resistance to vancomycin, a glycopeptide antibiotic that impairs peptidoglycan biosynthesis by a mechanism distinct from that of the beta-lactams, namely, by binding to the
d
-Ala-
d
-Ala termini found in peptidoglycan precursors to prevent their utilization by biosynthetic transglycosylases. Antimicrobial synergism between vancomycin and beta-lactams against vancomycin-resistant enterococci was originally described decades ago, but the genetic basis for synergy has remained unknown. Because a complete understanding of the mechanism underlying synergy between vancomycin and beta-lactams might suggest new targets or strategies for therapeutic intervention against antibiotic-resistant enterococci, we explored the genetic basis for synergy between vancomycin and cephalosporins in
Enterococcus faecalis
. To do so, we developed a counterselection strategy based on a dominant-negative mutant of thymidylate synthase and implemented this approach to create a panel of mutants in vancomycin-resistant
E. faecalis
. Our results confirm that vancomycin promotes synergy by inducing expression of the
van
resistance genes, as a mutant in which the
van
genes are expressed in the absence of vancomycin exhibits susceptibility to cephalosporins. Further, we show that peptidoglycan precursors substituted with
d
-Ala-
d
-Lac are not required for vancomycin-enhanced cephalosporin sensitivity. Instead, production of the
d
,
d
-carboxypeptidase VanY
B
is both necessary and sufficient to dramatically sensitize
E. faecalis
to cephalosporins.
Antenatal melatonin as an antioxidant in human pregnancies complicated by fetal growth restriction—a phase I pilot clinical trial: study protocol
Authors: Alers Nicole O , Jenkin Graham , Miller Suzanne L , Wallace Euan M 
Published: December 2013

BackgroundFetal growth restriction complicates about 5% of pregnancies and is commonly caused by placental dysfunction. It is associated with increased risks of perinatal mortality and short-term and long-term morbidity, such as cerebral palsy. Chronic in utero hypoxaemia, inflammation and oxidative stress are likely culprits contributing to the long-term neurological sequelae of fetal growth restriction. In this regard, we propose that melatonin, a powerful antioxidant, might mitigate morbidity and/or mortality associated with fetal growth restriction. Melatonin has an excellent biosafety profile and crosses the placenta and blood–brain barrier. We present the protocol for a phase I clinical trial to investigate the efficacy of maternal oral melatonin administration in women with a pregnancy complicated by fetal growth restriction.Methods and analysisThe proposed trial is a single-arm, open-label clinical trial involving 12 women. Severe, early onset fetal growth restriction will be diagnosed by an estimated fetal weight ≤10th centile in combination with abnormal fetoplacental Doppler studies, occurring before 34 weeks of pregnancy. Baseline measurements of maternal and fetal well-being, levels of oxidative stress and ultrasound and Doppler measurements will be obtained at the time of diagnosis of fetal growth restriction. Women will then start melatonin treatment (4 mg) twice daily until birth. The primary outcomes are the levels of oxidative stress in the maternal and fetal circulation and placenta. Secondary outcomes are fetoplacental Doppler studies (uterine artery, umbilical artery middle cerebral artery and ductus venosus), fetal biometry, fetal biophysical profile and a composite determination of neonatal outcome. A historical cohort of gestational-matched fetal growth restriction and a healthy pregnancy cohort will be used as comparators.Ethics and disseminationEthical approval has been obtained from Monash Health Human Research Ethics Committee B (HREC12133B). Data will be presented at international conferences and published in peer-reviewed journals.Trial registration numberClinical Trials, protocol registration system:NCT01695070.
Predictive Factors of Contralateral Paratracheal Lymph Node Metastasis in Papillary Thyroid Cancer: Prospective Multicenter Study
Authors: Eun Young Gyu , Lee Young Chan , Kwon Kee Hwan 
Published: December 2013

ObjectiveTo analyze patterns of central lymph node (LN) metastasis to specific compartments in the neck and predictive factors of contralateral paratracheal LN metastasis in patients who underwent prophylactic bilateral central LN dissection for papillary thyroid cancer (PTC).Study DesignProspective study.SettingMultitertiary centers.Subjects and MethodsOne hundred forty consecutive patients underwent total thyroidectomy and prophylactic bilateral central LN dissection for unilateral PTC without evidence of central LN metastatic disease based on preoperative ultrasound imaging. The central LN compartment was divided into prelaryngeal, ipsilateral/contralateral paratracheal, and pretracheal regions. The patterns of central LN metastasis and clinicopathologic variables for predicting contralateral metastasis were analyzed.ResultsFifty‐one (36.4%) of 140 patients had nodal involvement in the central compartment. Twelve (23.5%) patients had ipsilateral paratracheal LN metastasis, 17 (33.3%) had ipsilateral paratracheal and pretracheal LN metastasis, 14 (27.5%) had bilateral paratracheal LN metastasis, 9 (17.6%) had pretracheal‐only LN metastasis, and 8 (15.7%) had prelaryngeal LN metastasis. Ipsilateral paratracheal LN metastasis was found to independently predict contralateral paratracheal LN metastasis in patients without central LN metastatic disease.ConclusionsContralateral paratracheal LN metastasis is associated with ipsilateral paratracheal LN metastasis. This information may help to determine the optimal extent of prophylactic central LN dissection in patients with PTC.
Washing older blood units before transfusion reduces plasma iron and improves outcomes in experimental canine pneumonia
Authors: Cortés-Puch Irene , Wang Dong , Sun Junfeng , Solomon Steven B. , Remy Kenneth E. , Fernandez Melinda , Feng Jing , Kanias Tamir , Bellavia Landon , Sinchar Derek , Perlegas Andreas , Solomon Michael A. , Kelley Walter E. , Popovsky Mark A. , Gladwin Mark T. , Kim-Shapiro Daniel B. , Klein Harvey G. , Natanson Charles 
Published: December 2013

Key PointsWashing older blood before transfusion reduces plasma iron, improving outcomes from established infection in canines. In contrast, washing fresh blood before transfusion increases in vivo plasma CFH release, worsening outcomes.
Comparison of remission criteria in a tumour necrosis factor inhibitor treated rheumatoid arthritis longitudinal cohort: patient global health is a confounder
Authors: Balogh Emese , Madruga Dias Joao , Orr Carl , Mullan Ronan , Harty Len , FitzGerald Oliver , Gallagher Phil , Molloy Miriam , O’Flynn Eileen , Kelly Alexia , Minnock Patricia , O’Neill Madeline , Moore Louise , Murray Mairead , Fearon Ursula , Veale Douglas J 
Published: December 2013

Abstract
Introduction
Our objectives were to assess the frequency and sustainability of American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) and Disease Activity Score (DAS)28(4v)–C-reactive protein (CRP) remission 12 months after the initiation of tumour necrosis factor inhibitor (TNFi) therapy in a rheumatoid arthritis (RA) cohort.

Methods
Data were collected of 273 biologic naive RA patients at baseline, then 3, 6 and 12 months post-TNFi therapy. Remission status was calculated using DAS28(4v)-CRP <2.6 and ACR/EULAR Boolean criteria. Response was scored using EULAR criteria.

Results
Mean (range) patient age was 59.9 (7.2-85.4) years with disease duration of 13.4 (1.0-52.0) years. Responder status maintained from 3–12 months (86%, 82.4%), laboratory/clinical parameters (erythrocyte sedimentation rate (ESR), CRP, patient global health (PGH), DAS28(4v)-CRP) also showed sustained improvement (P < 0.05). DAS28 remission was reached by 102 subjects at 1 year, 27 patients were in Boolean remission, but 75 missed it from the DAS28 remission group. Patients in remission were younger (P = 0.041) with lower baseline tender joint count (TJC)28 and PGH than those not in remission (P = 0.001, P = 0.047). DAS28 remission patients were older (P = 0.026) with higher 12 months PGH and subsequently higher DAS28 than Boolean remission patients (P < 0.0001). Patients not achieving Boolean remission due to missing one subcriteria most frequently missed PGH ≤1 criteria (79.8%).

Conclusions
Only 10% of this TNFi treated cohort achieved remission according to the new ACR/EULAR criteria, which requires lower disease activity. More stringent criteria may ensure further resolution of disease activity and better longterm radiographic outcome, which supports earlier intervention with biologic therapy in RA.
Randomized Phase III Study of Erlotinib Versus Observation in Patients With No Evidence of Disease Progression After First-Line Platin-Based Chemotherapy for Ovarian Carcinoma: A European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group, and Gynecologic Cancer Intergroup Study
Authors: Vergote Ignace B. , Jimeno Antonio , Joly Florence , Katsaros Dionyssios , Coens Corneel , Despierre Evelyn , Marth Christian , Hall Marcia , Steer Christopher B. , Colombo Nicoletta , Lesoin Anne , Casado Antonio , Reinthaller Alexander , Green John , Buck Martin , Ray-Coquard Isabelle , Ferrero Annamaria , Favier Laure , Reed Nick Simon , Curé Hervé , Pujade-Lauraine Eric 
Published: December 2013

Purpose This trial evaluated the efficacy of maintenance erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, after first-line chemotherapy. Patients and Methods Eligible patients had high-risk International Federation of Gynecology and Obstetrics stage I or stage II to IV epithelial ovarian, primary peritoneal, or fallopian tube cancer and were not selected for EGFR expression. All patients underwent first-line platinum-based chemotherapy (CT) and showed no signs of progression at the end of CT. Patients were randomly assigned to maintenance erlotinib 150 mg orally daily for 2 years or to observation. EGFR immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and mutation analyses were performed in 318 patients. Results Between October 2005 and February 2008, 835 patients were randomly assigned (median follow-up, 51 months). Twenty-six percent of the patients stopped erlotinib as a result of adverse effects (of these, 67% were due to rash). For erlotinib and observation, respectively, the median progression-free survival was 12.7 and 12.4 months (hazard ratio [HR], 1.05; 95% CI, 0.90 to 1.23), and the median overall survival was 50.8 and 59.1 months (HR, 0.99; 95% CI, 0.81 to 1.20 months), respectively. No subgroup could be identified with improved effect of erlotinib, based on IHC or FISH for EGFR, or mutations in genes related to the EGFR pathway, or on rash during erlotinib therapy. However, patients with a positive FISH EGFR score had a worse overall survival (46.1 months) than those with a negative score (67.0 months; HR, 1.56; 95% CI, 1.01 to 2.40; P = .044). Global health/quality-of-life scores showed a significant difference during the first year (P = .0102) in favor of the observation arm. Conclusion Maintenance erlotinib after first-line treatment in ovarian cancer did not improve progression-free or overall survival.
Temperate shelf water dispersal by Australian boundary currents: Implications for population connectivity
Authors: Coleman Melinda A. , Feng Ming , Roughan Moninya , Cetina‐Heredia Paulina , Connell Sean D. 
Published: December 2013

Lay AbstractBoundary currents have been recognized as potential causes of spatial variation in the ocean because of their role in physical transport. In this study we used particle tracking methods in an ocean circulation model to determine the effect of multiple boundary currents on connectivity around temperate Australia during the austral winter. Our results demonstrated that oceanographic connectivity was asymmetric around Australia, having greater eastward connectivity due to more favorable ocean boundary currents during this season. We compared connectivity patterns with genetic data from an important marine species, the kelp, Ecklonia radiata, which have more genetic similarity between the west and south coasts of Australia, with the east coast, likely due to predominantly eastward dispersal in currents. Boundary current connectivity was linked to genetic connectivity of kelp on multigeneration time scales and the nature of these relationships varied among the three boundary current systems according to current strength.
Global Analysis of Serine/Threonine and Tyrosine Protein Phosphatase Catalytic Subunit Genes inNeurospora crassaReveals Interplay Between Phosphatases and the p38 Mitogen-Activated Protein Kinase
Authors: Ghosh Arit , Servin Jacqueline A , Park Gyungsoon , Borkovich Katherine A 
Published: December 2013

AbstractProtein phosphatases are integral components of the cellular signaling machinery in eukaryotes, regulating diverse aspects of growth and development. The genome of the filamentous fungus and model organism Neurospora crassa encodes catalytic subunits for 30 protein phosphatase genes. In this study, we have characterized 24 viable N. crassa phosphatase catalytic subunit knockout mutants for phenotypes during growth, asexual development, and sexual development. We found that 91% of the mutants had defects in at least one of these traits, whereas 29% possessed phenotypes in all three. Chemical sensitivity screens were conducted to reveal additional phenotypes for the mutants. This resulted in the identification of at least one chemical sensitivity phenotype for 17 phosphatase knockout mutants, including novel chemical sensitivities for two phosphatase mutants lacking a growth or developmental phenotype. Hence, chemical sensitivity or growth/developmental phenotype was observed for all 24 viable mutants. We investigated p38 mitogen-activated protein kinase (MAPK) phosphorylation profiles in the phosphatase mutants and identified nine potential candidates for regulators of the p38 MAPK. We demonstrated that the PP2C class phosphatase pph-8 (NCU04600) is an important regulator of female sexual development in N. crassa. In addition, we showed that the Δcsp-6 (ΔNCU08380) mutant exhibits a phenotype similar to the previously identified conidial separation mutants, Δcsp-1 and Δcsp-2, that lack transcription factors important for regulation of conidiation and the circadian clock.
A Genetic Screen for Functional Partners of Condensin in Fission Yeast
Authors: Robellet Xavier , Fauque Lydia , Legros Pénélope , Mollereau Esther , Janczarski Stéphane , Parrinello Hugues , Desvignes Jean-Pierre , Thevenin Morgane , Bernard Pascal 
Published: December 2013

AbstractMitotic chromosome condensation is a prerequisite for the accurate segregation of chromosomes during cell division, and the conserved condensin complex a central player of this process. However, how condensin binds chromatin and shapes mitotic chromosomes remain poorly understood. Recent genome-wide binding studies showing that in most species condensin is enriched near highly expressed genes suggest a conserved link between condensin occupancy and high transcription rates. To gain insight into the mechanisms of condensin binding and mitotic chromosome condensation, we searched for factors that collaborate with condensin through a synthetic lethal genetic screen in the fission yeast Schizosaccharomyces pombe. We isolated novel mutations affecting condensin, as well as mutations in four genes not previously implicated in mitotic chromosome condensation in fission yeast. These mutations cause chromosome segregation defects similar to those provoked by defects in condensation. We also identified a suppressor of the cut3-477 condensin mutation, which largely rescued chromosome segregation during anaphase. Remarkably, of the five genes identified in this study, four encode transcription co-factors. Our results therefore provide strong additional evidence for a functional connection between chromosome condensation and transcription.
Association Study between IL-1β−511 C/T Polymorphism and Obsessive-Compulsive Disorder (OCD) in Chinese Han Population
Authors: Bo Yongli , Liu Shiguo , Yin Yingying , Wang Zusen , Cui Jiajia , Zong Jinbao , Zhang Xinhua , Li Xingang 
Published: December 2013

Aim: This study investigated the potential association between Obsessive-Compulsive Disorder (OCD) and a functional polymorphism of IL-1β−511 C/T in Chinese Han population. Methods: The authors genotyped the IL-1β−511 C/T of 241 OCD patients and 444 healthy control subjects and then performed a case-control association analysis. Results: No difference was found in IL-1β−511 C/T genotypic and allelic frequencies between OCD cases and controls (χ2 = 0.501, df = 2, P = 0.78 by genotype; χ2 = 0.487, df = 1, P = 0.49 by allele). Conclusion: IL-1β−511 polymorphism may not play a major role in the genetic predisposition to OCD in Chinese Han population. Given that this is an early investigation of this gene in OCD, further studies are required to draw firm conclusions.
Adoptively Transferred Immune T Cells Eradicate Established Tumors despite Cancer-Induced Immune Suppression
Authors: Arina Ainhoa , Schreiber Karin , Binder David C. , Karrison Theodore G. , Liu Rebecca B. , Schreiber Hans 
Published: December 2013

Abstract
Myeloid-derived CD11b+Gr1+ suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are considered a major obstacle for effective adoptive T cell therapy. Myeloid cells suppress naive T cell proliferation ex vivo and can prevent the generation of T cell responses in vivo. We find, however, that adoptively transferred immune T cells eradicate well-established tumors in the presence of MDSCs and TAMs, which are strongly immunosuppressive ex vivo. These MDSCs and TAMs were comparable in numbers and immunosuppressive capacity among different tumor models. Longitudinal microscopy of tumors in vivo revealed that after T cell transfer, tumor vasculature and cancer cells disappeared simultaneously. During T cell–mediated tumor destruction, the tumor stroma contained abundant myeloid cells (mainly TAMs) that retained their suppressive properties. Preimmunized but not naive mice resisted immune suppression caused by an unrelated tumor burden, supporting the idea that in vivo, myeloid immunosuppressive cells can suppress naive but not memory T cell responses.
IFN-γ–Mediated Induction of an Apical IL-10 Receptor on Polarized Intestinal Epithelia
Authors: Kominsky Douglas J. , Campbell Eric L. , Ehrentraut Stefan F. , Wilson Kelly E. , Kelly Caleb J. , Glover Louise E. , Collins Colm B. , Bayless Amanda J. , Saeedi Bejan , Dobrinskikh Evgenia , Bowers Brittelle E. , MacManus Christopher F. , Müller Werner , Colgan Sean P. , Bruder Dunja 
Published: December 2013

Abstract
Cytokines secreted at sites of inflammation impact the onset, progression, and resolution of inflammation. In this article, we investigated potential proresolving mechanisms of IFN-γ in models of inflammatory bowel disease. Guided by initial microarray analysis, in vitro studies revealed that IFN-γ selectively induced the expression of IL-10R1 on intestinal epithelia. Further analysis revealed that IL-10R1 was expressed predominantly on the apical membrane of polarized epithelial cells. Receptor activation functionally induced canonical IL-10 target gene expression in epithelia, concomitant with enhanced barrier restitution. Furthermore, knockdown of IL-10R1 in intestinal epithelial cells results in impaired barrier function in vitro. Colonic tissue isolated from murine colitis revealed that levels of IL-10R1 and suppressor of cytokine signaling 3 were increased in the epithelium and coincided with increased tissue IFN-γ and IL-10 cytokines. In parallel, studies showed that treatment of mice with rIFN-γ was sufficient to drive expression of IL-10R1 in the colonic epithelium. Studies of dextran sodium sulfate colitis in intestinal epithelial-specific IL-10R1–null mice revealed a remarkable increase in disease susceptibility associated with increased intestinal permeability. Together, these results provide novel insight into the crucial and underappreciated role of epithelial IL-10 signaling in the maintenance and restitution of epithelial barrier and of the temporal regulation of these pathways by IFN-γ.
Autophagy Induction by SIRT6 through Attenuation of Insulin-like Growth Factor Signaling Is Involved in the Regulation of Human Bronchial Epithelial Cell Senescence
Authors: Takasaka Naoki , Araya Jun , Hara Hiromichi , Ito Saburo , Kobayashi Kenji , Kurita Yusuke , Wakui Hiroshi , Yoshii Yutaka , Yumino Yoko , Fujii Satoko , Minagawa Shunsuke , Tsurushige Chikako , Kojima Jun , Numata Takanori , Shimizu Kenichiro , Kawaishi Makoto , Kaneko Yumi , Kamiya Noriki , Hirano Jun , Odaka Makoto , Morikawa Toshiaki , Nishimura Stephen L. , Nakayama Katsutoshi , Kuwano Kazuyoshi 
Published: December 2013

Abstract
Cigarette smoke (CS)–induced cellular senescence has been implicated in the pathogenesis of chronic obstructive pulmonary disease, and SIRT6, a histone deacetylase, antagonizes this senescence, presumably through the attenuation of insulin-like growth factor (IGF)-Akt signaling. Autophagy controls cellular senescence by eliminating damaged cellular components and is negatively regulated by IGF-Akt signaling through the mammalian target of rapamycin (mTOR). SIRT1, a representative sirtuin family, has been demonstrated to activate autophagy, but a role for SIRT6 in autophagy activation has not been shown. Therefore, we sought to investigate the regulatory role for SIRT6 in autophagy activation during CS-induced cellular senescence. SIRT6 expression levels were modulated by cDNA and small interfering RNA transfection in human bronchial epithelial cells (HBECs). Senescence-associated β-galactosidase staining and Western blotting of p21 were performed to evaluate senescence. We demonstrated that SIRT6 expression levels were decreased in lung homogenates from chronic obstructive pulmonary disease patients, and SIRT6 expression levels correlated significantly with the percentage of forced expiratory volume in 1 s/forced vital capacity. CS extract (CSE) suppressed SIRT6 expression in HBECs. CSE-induced HBEC senescence was inhibited by SIRT6 overexpression, whereas SIRT6 knockdown and mutant SIRT6 (H133Y) without histone deacetylase activity enhanced HBEC senescence. SIRT6 overexpression induced autophagy via attenuation of IGF-Akt-mTOR signaling. Conversely, SIRT6 knockdown and overexpression of a mutant SIRT6 (H133Y) inhibited autophagy. Autophagy inhibition by knockdown of ATG5 and LC3B attenuated the antisenescent effect of SIRT6 overexpression. These results suggest that SIRT6 is involved in CSE-induced HBEC senescence via autophagy regulation, which can be attributed to attenuation of IGF-Akt-mTOR signaling.