bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complete Nucleotide Sequence of Two Multidrug-Resistant IncR Plasmids from Klebsiella pneumoniae
Authors: Compain Fabrice , Frangeul Lionel , Drieux Laurence , Verdet Charlotte , Brisse Sylvain , Arlet Guillaume , Decré Dominique 
Published: April 2014

ABSTRACT

We report here the complete nucleotide sequence of two IncR replicons encoding multidrug resistance determinants, including β-lactam (
bla
DHA-1
,
bla
SHV-12
), aminoglycoside (
aphA1
,
strA
,
strB
), and fluoroquinolone (
qnrB4
,
aac6′-1b-cr
) resistance genes. The plasmids have backbones that are similar to each other, including the replication and stability systems, and contain a wide variety of transposable elements carrying known antibiotic resistance genes. This study confirms the increasing clinical importance of IncR replicons as resistance gene carriers.
Strain Types and Antimicrobial Resistance Patterns of Clostridium difficile Isolates from the United States, 2011 to 2013
Authors: Tickler Isabella A. , Goering Richard V. , Whitmore Joseph D. , Lynn Ashley N. W. , Persing David H. , Tenover Fred C. 
Published: April 2014

ABSTRACT

We determined the PCR ribotypes and antimicrobial susceptibility patterns of 508 toxigenic
Clostridium difficile
isolates collected between 2011 and 2013 from 32 U.S. hospitals. Of the 29 PCR ribotypes identified, the 027 strain type was the most common (28.1%), although the rates varied by geographic region. Ribotype 014/020 isolates appear to be emerging. Clindamycin and moxifloxacin resistances (36.8% and 35.8%, respectively) were the most frequent resistance phenotypes observed. Reduced susceptibility to vancomycin was observed in 39.1% of 027 isolates.
Akt Inhibitor MK2206 Prevents Influenza pH1N1 Virus Infection
In Vitro
Authors: Denisova Oxana V. , Söderholm Sandra , Virtanen Salla , Von Schantz Carina , Bychkov Dmitrii , Vashchinkina Elena , Desloovere Jens , Tynell Janne , Ikonen Niina , Theisen Linda L. , Nyman Tuula A. , Matikainen Sampsa , Kallioniemi Olli , Julkunen Ilkka , Muller Claude P. , Saelens Xavier , Verkhusha Vladislav V. , Kainov Denis E. 
Published: April 2014

ABSTRACT

The influenza pH1N1 virus caused a global flu pandemic in 2009 and continues manifestation as a seasonal virus. Better understanding of the virus-host cell interaction could result in development of better prevention and treatment options. Here we show that the Akt inhibitor MK2206 blocks influenza pH1N1 virus infection
in vitro
. In particular, at noncytotoxic concentrations, MK2206 alters Akt signaling and inhibits endocytic uptake of the virus. Interestingly, MK2206 is unable to inhibit H3N2, H7N9, and H5N1 viruses, indicating that pH1N1 evolved specific requirements for efficient infection. Thus, Akt signaling could be exploited further for development of better therapeutics against pH1N1 virus.
Cysteine Protease Activity of Feline Tritrichomonas foetus Promotes Adhesion-Dependent Cytotoxicity to Intestinal Epithelial Cells
Authors: Tolbert M. K. , Stauffer S. H. , Brand M. D. , Gookin J. L. 
Published: April 2014

ABSTRACTTrichomonads are obligate protozoan parasites most renowned as venereal pathogens of the reproductive tract of humans and cattle. Recently, a trichomonad highly similar to bovine venerealTritrichomonas foetusbut having a unique tropism for the intestinal tract was recognized as a significant cause of colitis in domestic cats. Despite a high prevalence, worldwide distribution, and lack of consistently effective drugs for treatment of the infection, the cellular mechanisms ofT. foetuspathogenicity in the intestinal tract have not been examined. The aims of this study were to determine the pathogenic effect of felineT. foetuson porcine intestinal epithelial cells, the dependence ofT. foetuspathogenicity on adhesion ofT. foetusto the intestinal epithelium, and the identity of mediators responsible for these effects. Using anin vitrococulture approach to model felineT. foetusinfection of the intestinal epithelium, these studies demonstrate thatT. foetuspromotes a direct contact-dependent activation of intestinal epithelial cell apoptosis signaling and progressive monolayer destruction. Moreover, these pathological effects were demonstrated to be largely dependent onT. foetuscell-associated cysteine protease activity. Finally,T. foetuscysteine proteases were identified as enabling cytopathic effects by promoting adhesion ofT. foetusto the intestinal epithelium. The present studies are the first to examine the cellular mechanisms of pathogenicity ofT. foetustoward the intestinal epithelium and support further investigation of the cysteine proteases as virulence factorsin vivoand as potential therapeutic targets for ameliorating the pathological effects of intestinal trichomonosis.
Mechanism of Asp24 Upregulation in Brucella abortus Rough Mutant with a Disrupted O-Antigen Export System and Effect of Asp24 in Bacterial Intracellular Survival
Authors: Tian Mingxing , Qu Jing , Han Xiangan , Ding Chan , Wang Shaohui , Peng Daxin , Yu Shengqing 
Published: April 2014

ABSTRACTWe previously showed thatBrucella abortusrough mutant strain 2308 ΔATP(called the ΔrfbEmutant in this study) exhibits reduced intracellular survival in RAW264.7 cells and attenuated persistence in BALB/c mice. In this study, we performed microarray analysis to detect genes with differential expression between the ΔrfbEmutant and wild-type strain S2308. Interestingly, acid shock protein 24 gene (asp24) expression was significantly upregulated in the ΔrfbEmutant compared to S2308, as confirmed by quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. Further studies using additional strains indicated that the upregulation ofasp24occurred only in rough mutants with disrupted O-antigen export system components, including the ATP-binding protein generfbE(bab1_0542) and the permease generfbD(bab1_0543), while the ΔwboArough mutant (which lacks an O-antigen synthesis-related glycosyltransferase) and the RB51 strain (a vaccine strain with the rough phenotype) showed no significant changes inasp24expression compared to S2308. In addition, abolishing the intracellular O-antigen synthesis of the ΔrfbEmutant by deleting thewboAgene (thereby creating the ΔrfbEΔwboAdouble-knockout strain) recoveredasp24expression. These results indicated thatasp24upregulation is associated with intracellular O-antigen synthesis and accumulation but not with the bacterial rough phenotype. Further studies indicated thatasp24upregulation in the ΔrfbEmutant was associated neither with bacterial adherence and invasion nor with cellular necrosis on RAW264.7 macrophages. However, proper expression of theasp24gene favors intracellular survival ofBrucellain RAW264.7 cells and HeLa cells during an infection. This study reveals a novel mechanism forasp24upregulation inB. abortusmutants.
Undecidability of Propositional Separation Logic and Its Neighbours
Authors: Brotherston James , Kanovich Max 
Published: April 2014

In this article, we investigate the logical structure of memory models of theoretical and practical interest. Our main interest is in “the logic behind a fixed memory model”, rather than in “a model of any kind behind a given logical system”. As an effective language for reasoning about such memory models, we use the formalism of separation logic. Our main result is that for any concrete choice of heap-like memory model, validity in that model is
undecidable
even for purely propositional formulas in this language.

The main novelty of our approach to the problem is that we focus on validity in specific, concrete memory models, as opposed to validity in general classes of models.
Besides its intrinsic technical interest, this result also provides new insights into the nature of their decidable fragments. In particular, we show that, in order to obtain such decidable fragments, either the formula language must be severely restricted or the valuations of propositional variables must be constrained.
In addition, we show that a number of propositional systems that approximate separation logic are undecidable as well. In particular, this resolves the open problems of decidability for Boolean BI and Classical BI.
Moreover, we provide one of the simplest undecidable propositional systems currently known in the literature, called “Minimal Boolean BI”, by combining the purely positive implication-conjunction fragment of Boolean logic with the laws of multiplicative *-conjunction, its unit and its adjoint implication, originally provided by intuitionistic multiplicative linear logic. Each of these two components is individually decidable: the implication-conjunction fragment of Boolean logic is co-NP-complete, and intuitionistic multiplicative linear logic is NP-complete.
All of our undecidability results are obtained by means of a direct encoding of Minsky machines.
The RAD51-Stimulatory Compound RS-1 Can Exploit the RAD51 Overexpression That Exists in Cancer Cells and Tumors
Authors: Mason Jennifer M. , Logan Hillary L. , Budke Brian , Wu Megan , Pawlowski Michal , Weichselbaum Ralph R. , Kozikowski Alan P. , Bishop Douglas K. , Connell Philip P. 
Published: April 2014

Abstract
RAD51 is the central protein that catalyzes DNA repair via homologous recombination, a process that ensures genomic stability. RAD51 protein is commonly expressed at high levels in cancer cells relative to their noncancerous precursors. High levels of RAD51 expression can lead to the formation of genotoxic RAD51 protein complexes on undamaged chromatin. We developed a therapeutic approach that exploits this potentially toxic feature of malignancy, using compounds that stimulate the DNA-binding activity of RAD51 to promote cancer cell death. A panel of immortalized cell lines was challenged with the RAD51-stimulatory compound RS-1. Resistance to RS-1 tended to occur in cells with higher levels of RAD54L and RAD54B, which are Swi2/Snf2-related translocases known to dissociate RAD51 filaments from dsDNA. In PC3 prostate cancer cells, RS-1–induced lethality was accompanied by the formation of microscopically visible RAD51 nuclear protein foci occurring in the absence of any DNA-damaging treatment. Treatment with RS-1 promoted significant antitumor responses in a mouse model, providing proof-of-principle for this novel therapeutic strategy. Cancer Res; 74(13); 3546–55. ©2014 AACR.
Evaluating TBK1 as a Therapeutic Target in Cancers with Activated IRF3
Authors: Muvaffak Asli , Pan Qi , Yan Haiyan , Fernandez Rafael , Lim Jongwon , Dolinski Brian , Nguyen Thi T. , Strack Peter , Wu Stephen , Chung Rossana , Zhang Weiqun , Hulton Chris , Ripley Steven , Hirsch Heather , Nagashima Kumiko , Wong Kwok-Kin , Jánne Pasi A. , Seidel-Dugan Cynthia , Zawel Leigh , Kirschmeier Paul T. , Middleton Richard E. , Morris Erick J. , Wang Yan 
Published: April 2014

Abstract
TBK1 (TANK-binding kinase 1) is a noncanonical IκB protein kinase that phosphorylates and activates downstream targets such as IRF3 and c-Rel and, mediates NF-κB activation in cancer. Previous reports demonstrated synthetic lethality of TBK1 with mutant KRAS in non–small cell lung cancer (NSCLC); thus, TBK1 could be a novel target for treatment of KRAS-mutant NSCLC. Here, the effect of TBK1 on proliferation in a panel of cancer cells by both genetic and pharmacologic approaches was evaluated. In KRAS-mutant cancer cells, reduction of TBK1 activity by knockdown or treatment with TBK1 inhibitors did not correlate with reduced proliferation in a two-dimensional viability assay. Verification of target engagement via reduced phosphorylation of S386 of IRF3 (pIRF3S386) was difficult to assess in NSCLC cells due to low protein expression. However, several cell lines were identified with high pIRF3S386 levels after screening a large panel of cell lines, many of which also harbor KRAS mutations. Specifically, a large subset of KRAS-mutant pancreatic cancer cell lines was uncovered with high constitutive pIRF3S386 levels, which correlated with high levels of phosphorylated S172 of TBK1 (pTBK1S172). Finally, TBK1 inhibitors dose-dependently inhibited pIRF3S386 in these cell lines, but this did not correlate with inhibition of cell growth. Taken together, these data demonstrate that the regulation of pathways important for cell proliferation in some NSCLC, pancreatic, and colorectal cell lines is not solely dependent on TBK1 activity.
Implications: TBK1 has therapeutic potential under certain contexts and phosphorylation of its downstream target IRF3 is a biomarker of TBK1 activity.
Visual Overview: http://mcr.aacrjournals.org/content/12/7/1055/F1.large.jpg.
Mol Cancer Res; 12(7); 1055–66. ©2014 AACR.
Efficient Induction of Antitumor Immunity by Synthetic Toll-like Receptor Ligand–Peptide Conjugates
Authors: Zom Gijs G. , Khan Selina , Britten Cedrik M. , Sommandas Vinod , Camps Marcel G.M. , Loof Nikki M. , Budden Christina F. , Meeuwenoord Nico J. , Filippov Dmitri V. , van der Marel Gijsbert A. , Overkleeft Hermen S. , Melief Cornelis J.M. , Ossendorp Ferry 
Published: April 2014

Abstract
Chemical conjugates comprising synthetic Toll-like receptor ligands (TLR-L) covalently bound to antigenic synthetic long peptides (SLP) are attractive vaccine modalities, which can induce robust CD8+ T-cell immune responses. Previously, we have shown that the mechanism underlying the power of TLR-L SLP conjugates is improved delivery of the antigen together with a dendritic cell activation signal. In the present study, we have expanded the approach to tumor-specific CD4+ as well as CD8+ T-cell responses and in vivo studies in two nonrelated aggressive tumor models. We show that TLR2-L SLP conjugates have superior mouse CD8+ and CD4+ T-cell priming capacity compared with free SLPs injected together with a free TLR2-L. Vaccination with TLR2-L SLP conjugates leads to efficient induction of antitumor immunity in mice challenged with aggressive transplantable melanoma or lymphoma. Our data indicate that TLR2-L SLP conjugates are suitable to promote integrated antigen-specific CD8+ and CD4+ T-cell responses required for the antitumor effects. Collectively, these data show that TLR2-L SLP conjugates are promising synthetic vaccine candidates for active immunotherapy against cancer. Cancer Immunol Res; 2(8); 756–64. ©2014 AACR.
Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma
Authors: Hodi F. Stephen , Lawrence Donald , Lezcano Cecilia , Wu Xinqi , Zhou Jun , Sasada Tetsuro , Zeng Wanyong , Giobbie-Hurder Anita , Atkins Michael B. , Ibrahim Nageatte , Friedlander Philip , Flaherty Keith T. , Murphy George F. , Rodig Scott , Velazquez Elsa F. , Mihm Martin C. , Russell Sara , DiPiro Pamela J. , Yap Jeffrey T. , Ramaiya Nikhil , Van den Abbeele Annick D. , Gargano Maria , McDermott David 
Published: April 2014

AbstractIpilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8+ and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7+/−/CD45RO+ cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade. Cancer Immunol Res; 2(7); 632–42. ©2014 AACR.
A memória em três atos: deslocamentos interdisciplinares
Authors: Dutra Eliana de Freitas 
Published: April 2014

Este texto pretende elaborar uma reflexão sobre a problemática do tempo, da memória e do esquecimento no campo do conhecimento histórico. Por essa via pretendemos contribuir para a discussão de como os historiadores tecem as formas atuais da história nas relações que estabelecem entre a história, o tempo e a memória, nas ligações que constroem entre o passado, o presente e o futuro, na sua tensão com os regimes de verdade da disciplina histórica, ou no seu inevitável trânsito nas fronteiras de outras disciplinas e formas de conhecimento, face às suas responsabilidades com a contemporaneidade.
Memória: tipos e mecanismos – achados recentes
Authors: Izquierdo Iván Antonio , Myskiw Jociane de Carvalho , Benetti Fernando , Furini Cristiane Regina Guerino 
Published: April 2014

Examinamos as definições e características gerais dos principais tipos de memórias de acordo com sua função, conteúdo e duração, as áreas cerebrais responsáveis por elas e os mecanismos moleculares sinápticos envolvidos na formação e extinção dos diversos tipos de memórias nessas áreas. Damos particular destaque a alguns aspectos de sua biologia, com alguma ênfase na memória de trabalho, na memória de curta duração e na memória de extinção, comentando os principais processos fisiológicos responsáveis por sua formação, evocação e extinção, assim como sobre sua modulação por sistemas cerebrais e periféricos. Encerramos com algumas recomendações para a manutenção das principais formas de memória.
Brasil, país do futebol?
Authors: Franco Júnior Hilário 
Published: April 2014

Como todo clichê, aquele que define o Brasil como o país do futebol contém algumas verdades e muitos exageros. É preciso examiná-lo criticamente. Verificar o que é que se entende por esse rótulo e analisar cada um de seus componentes de um ponto de vista histórico e comparativo. A conclusão revela, então, tanto sobre o futebol brasileiro quanto sobre o Brasil.
“The Covenant Made with David”: The King and the Kingdom in 2 Chronicles 21
Authors: Zimran Yisca 
Published: April 2014

Abstract
This article examines 2 Chronicles 21 and the description it provides of Jehoram of Judah’s reign, which diverges widely from the parallel in 2 Kings 8. Addressing some of the structural, substantive, and linguistic issues that arise from the text, it suggests that this chapter integrates two perspectives regarding Jehoram, each of which contain different details—that are nonetheless essentially interlinked. The proposal offered herein resolves some of the fundamental questions relating to the text, including the structure of the chapter and the duplications and meaning of the unique phrases it contains. The paper also discusses the Chronicler’s views concerning the family and Israelite kingship and the manner in which the promise to the house of David is presented in the chapter.
Biblical Hebrew šninɔ: A ‘Cautionary Tale’ of Root Identification
Authors: Vayntrub Jacqueline E. , Hardy Humphrey H. 
Published: April 2014

Abstract
The present study comprises a philological examination of the Biblical Hebrew term šninɔ. The contextual semantics, the ancient translations, and the re-identification of the verbal root ŠNN as a by-form of ŠNY ‘to recount’ demonstrate that šninɔ may be realigned as related to this root and translated as a ‘cautionary tale’.
„An dem Tag, als JHWH ihn rettete aus der Hand aller seiner Feinde und aus der Hand Sauls“ (Ps 18,1)
Authors: Weber Beat 
Published: April 2014

Abstract
Examining the arrangement of biographical notices in the titles of psalms ascribed to David reveals that these are not placed haphazardly. Their order and correlation conveys a message to the reader of the first two Davidic collections of psalms. There are two main horizons, one reflecting on the conflict between Saul and David (Pss 34; 52-59, followed by Ps 60 with national enemies), another reflecting on the conflict between David and Absalom (Ps 3-7; 63). The headings of Pss 18 (doubling 2 Sam 22) and Ps 51 (in connection with Ps 2 and 72) are of special hermeneutical significance, as they guide the reader’s understanding of such biographical information, signalling relationships between the headings of different psalms als well as back to the narrative of the Book of Samuel (1-2 Sam). In the midst of prayers in which David is struggling with enemies, Ps 18 foregrounds the salvation of JHWH “at the end.” Pss 2; 51 and 72 are interconnected by the common theme of the house of David and the prophetic voice of Nathan adressed twice to king David (2 Sam 7; 12).
Moderation of Summertime Heat Island Phenomena via Modification of the Urban Form in the Tokyo Metropolitan Area
Authors: Adachi Sachiho A. , Kimura Fujio , Kusaka Hiroyuki , Duda Michael G. , Yamagata Yoshiki , Seya Hajime , Nakamichi Kumiko , Aoyagi Toshinori 
Published: April 2014

AbstractThis study investigated the moderation of the urban heat island via changes in the urban form in the Tokyo metropolitan area (TMA). Two urban scenarios with the same population as that of the current urban form were used for sensitivity experiments: the dispersed-city and compact-city scenarios. Numerical experiments using the two urban scenarios as well as an experiment using the current urban form were conducted using a regional climate model coupled with a single-layer urban canopy model. The averaged nighttime surface air temperature in TMA increased by ~0.34°C in the dispersed-city scenario and decreased by ~0.1°C in the compact-city scenario. Therefore, the compact-city scenario had significant potential for moderating the mean areal heat-island effect in the entire TMA. Alternatively, in the central part of the TMA, these two urban-form scenarios produced opposite effects on the surface air temperature; that is, severe thermal conditions worsened further in the compact-city scenario because of the denser population. This result suggests that the compact-city form is not always appropriate for moderation of the urban-heat-island effect. This scenario would need to combine with other mitigation strategies, such as the additional greening of urban areas, especially in the central area. This study suggests that it is important to design a plan to adapt to higher urban temperatures, which are likely to ensue from future global warming and the urban heat island, from several perspectives; that is, designs should take into account not only climatological aspects but also impacts on urban inhabitants.