bluuebunny/crossref_metadata_2025_split huggingface dataset:
In VitroAntiviral Characteristics of HIV-1 Attachment Inhibitor BMS-626529, the Active Component of the Prodrug BMS-663068
Authors: Nowicka-Sans Beata , Gong Yi-Fei , McAuliffe Brian , Dicker Ira , Ho Hsu-Tso , Zhou Nannan , Eggers Betsy , Lin Pin-Fang , Ray Neelanjana , Wind-Rotolo Megan , Zhu Li , Majumdar Antara , Stock David , Lataillade Max , Hanna George J. , Matiskella John D. , Ueda Yasutsugu , Wang Tao , Kadow John F. , Meanwell Nicholas A. , Krystal Mark 
Published: May 2012

ABSTRACTBMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a novel small-molecule attachment inhibitor that targets HIV-1 gp120 and prevents its binding to CD4+T cells. The activity of BMS-626529 is virus dependent, due to heterogeneity within gp120. In order to better understand the anti-HIV-1 spectrum of BMS-626529 against HIV-1,in vitroactivities against a wide variety of laboratory strains and clinical isolates were determined. BMS-626529 had half-maximal effective concentration (EC50) values of <10 nM against the vast majority of viral isolates; however, susceptibility varied by >6 log10, with half-maximal effective concentration values in the low pM range against the most susceptible viruses. Thein vitroantiviral activity of BMS-626529 was generally not associated with either tropism or subtype, with few exceptions. Measurement of the binding affinity of BMS-626529 for purified gp120 suggests that a contributory factor to its inhibitory potency may be a relatively long dissociative half-life. Finally, in two-drug combination studies, BMS-626529 demonstrated additive or synergistic interactions with antiretroviral drugs of different mechanistic classes. These results suggest that BMS-626529 should be active against the majority of HIV-1 viruses and support the continued clinical development of the compound.
Rifapentine Is Not More Active than Rifampin against Chronic Tuberculosis in Guinea Pigs
Authors: Dutta Noton K. , Illei Peter B. , Peloquin Charles A. , Pinn Michael L. , Mdluli Khisimuzi E. , Nuermberger Eric L. , Grosset Jacques H. , Karakousis Petros C. 
Published: May 2012

ABSTRACT

Rifamycins are key sterilizing drugs in the current treatment of active tuberculosis (TB). Daily dosing of rifapentine (P), a potent rifamycin with high intracellular accumulation, in place of rifampin (R) in the standard antitubercular regimen significantly shortens the duration of treatment needed to prevent relapse in a murine model of active TB. We undertook the current study to compare directly the activities of human-equivalent doses of P and R in a guinea pig model of chronic TB, in which bacilli are predominantly extracellular within human-like necrotic granulomas. Hartley strain guinea pigs were aerosol infected with ∼200 bacilli of
Mycobacterium tuberculosis
H37Rv, and treatment given 5 days/week was initiated 6 weeks later. R at 100 mg/kg of body weight and P at 100 mg/kg were given orally alone or in combination with isoniazid (H) at 60 mg/kg and pyrazinamide (Z) at 300 mg/kg. Culture-positive relapse was assessed in subgroups of guinea pigs after completion of 1 and 2 months of treatment. Human-equivalent doses of R and P showed equivalent bactericidal activity when used alone and in combination therapy. In guinea pigs treated with rifampin, isoniazid, and pyrazinamide (RHZ) or PHZ, microbiological relapse occurred in the lungs of 8/10 animals treated for 1 month and in 0/10 animals treated for 2 months. Substitution of P for R in the standard antitubercular regimen did not shorten the time to cure in this guinea pig model of chronic TB. Data from ongoing clinical trials comparing the activity of these two drugs are awaited to determine the relevance of the guinea pig TB model in preclinical drug screening.
The Order Bacillales Hosts Functional Homologs of the Worrisome
cfr
Antibiotic Resistance Gene
Authors: Hansen Lykke H. , Planellas Mercè H. , Long Katherine S. , Vester Birte 
Published: May 2012

ABSTRACT

The
cfr
gene encodes the Cfr methyltransferase that methylates a single adenine in the peptidyl transferase region of bacterial ribosomes. The methylation provides resistance to several classes of antibiotics that include drugs of clinical and veterinary importance. This paper describes a first step toward elucidating natural residences of the worrisome
cfr
gene and functionally similar genes. Three
cfr
-like genes from the order
Bacillales
were identified from BLAST searches and cloned into plasmids under the control of an inducible promoter. Expression of the genes was induced in
Escherichia coli
, and MICs for selected antibiotics indicate that the
cfr
-like genes confer resistance to PhLOPSa (phenicol, lincosamide, oxazolidinone, pleuromutilin, and streptogramin A) antibiotics in the same way as the
cfr
gene. In addition, modification at A2503 on 23S rRNA was confirmed by primer extension. Finally, expression of the Cfr-like proteins was verified by SDS gel electrophoresis of whole-cell extracts. The work shows that
cfr
-like genes exist in the environment and that
Bacillales
are natural residences of
cfr
-like genes.
Impact of Cefepime Therapy on Mortality among Patients with Bloodstream Infections Caused by Extended-Spectrum-β-Lactamase-Producing Klebsiella pneumoniae and Escherichia coli
Authors: Chopra Teena , Marchaim Dror , Veltman Jennifer , Johnson Paul , Zhao Jing J. , Tansek Ryan , Hatahet Dania , Chaudhry Khawar , Pogue Jason M. , Rahbar Hiro , Chen Ting-Yi , Truong Thientu , Rodriguez Victor , Ellsworth Joseph , Bernabela Luigino , Bhargava Ashish , Yousuf Adnan , Alangaden George , Kaye Keith S. 
Published: May 2012

ABSTRACT

Extended-spectrum-β-lactamase (ESBL)-producing pathogens are associated with extensive morbidity and mortality and rising health care costs. Scant data exist on the impact of antimicrobial therapy on clinical outcomes in patients with ESBL bloodstream infections (BSI), and no large studies have examined the impact of cefepime therapy. A retrospective 3-year study was performed at the Detroit Medical Center on adult patients with BSI due to ESBL-producing
Klebsiella pneumoniae
or
Escherichia coli
. Data were collected from the medical records of study patients at five hospitals between January 2005 and December 2007. Multivariate analysis was performed using logistic regression. One hundred forty-five patients with BSI due to ESBL-producing pathogens, including
K. pneumoniae
(83%) and
E. coli
(16.5%), were studied. The mean age of the patients was 66 years. Fifty-one percent of the patients were female, and 79.3% were African-American. Fifty-three patients (37%) died in the hospital, and 92 survived to discharge. In bivariate analysis, the variables associated with mortality (
P
< 0.05) were presence of a rapidly fatal condition at the time of admission, use of gentamicin as a consolidative therapeutic agent, and presence of one or more of the following prior to culture date: mechanical ventilation, stay in the intensive care unit (ICU), and presence of a central venous catheter. In multivariate analysis, the predictors of in-hospital mortality included stay in the intensive care unit (odds ratio [OR], 2.17; 95% confidence interval [CI], 0.98 to 4.78), presence of a central-line catheter prior to positive culture (OR, 2.33; 95% CI, 0.77 to 7.03), presence of a rapidly fatal condition at the time of admission (OR, 5.13; 95% CI, 2.13 to 12.39), and recent prior hospitalization (OR, 1.92; 95% CI, 0.83 to 4.09). When carbapenems were added as empirical therapy to the predictor model, there was a trend between empirical carbapenem therapy and decreased mortality (OR, 0.61; 95% CI, 0.26 to 1.50). When added to the model, receipt of empirical cefepime alone (
n
= 43) was associated with increased mortality, although this association did not reach statistical significance (OR, 1.66; 95% CI, 0.71 to 3.87). The median length of hospital stay was shorter for patients receiving empirical cefepime than for those receiving empirical or consolidated carbapenem therapy. In multivariate analysis, empirical therapy with cefepime for BSI due to an ESBL-producing pathogen was associated with a trend toward an increased mortality risk and empirical carbapenem therapy was associated with a trend toward decreased mortality risk.
Ehrlichia chaffeensis TRP32 Interacts with Host Cell Targets That Influence Intracellular Survival
Authors: Luo Tian , McBride Jere W. 
Published: May 2012

ABSTRACT

Ehrlichia chaffeensis
is an obligately intracellular bacterium that exhibits tropism for mononuclear phagocytes and survives by evading host cell defense mechanisms. Recently, molecular interactions of
E. chaffeensis
tandem repeat proteins 47 and 120 (TRP47 and -120) and the eukaryotic host cell have been described. In this investigation, yeast two-hybrid analysis demonstrated that an
E. chaffeensis
type 1 secretion system substrate, TRP32, interacts with a diverse group of human proteins associated with major biological processes of the host cell, including protein synthesis, trafficking, degradation, immune signaling, cell signaling, iron metabolism, and apoptosis. Eight target proteins, including translation elongation factor 1 alpha 1 (EF1A1), deleted in azoospermia (DAZ)-associated protein 2 (DAZAP2), ferritin light polypeptide (FTL), CD63, CD14, proteasome subunit beta type 1 (PSMB1), ring finger and CCCH-type domain 1 (RC3H1), and tumor protein p53-inducible protein 11 (TP53I11) interacted with TRP32 as determined by coimmunoprecipitation assays, colocalization with TRP32 in HeLa and THP-1 cells, and/or RNA interference. Interactions between TRP32 and host targets localized to the
E. chaffeensis
morulae or in the host cell cytoplasm adjacent to morulae. Common or closely related interacting partners of
E. chaffeensis
TRP32, TRP47, and TRP120 demonstrate a molecular convergence on common cellular processes and molecular cross talk between
Ehrlichia
TRPs and host targets. These findings further support the role of TRPs as effectors that promote intracellular survival.
VirK Is a Periplasmic Protein Required for Efficient Secretion of Plasmid-Encoded Toxin from Enteroaggregative Escherichia coli
Authors: Tapia-Pastrana Gabriela , Chavez-Dueñas Lucia , Lanz-Mendoza Humberto , Teter Ken , Navarro-García Fernando 
Published: May 2012

ABSTRACT

Despite the autotransporter (AT) moniker, AT secretion appears to involve the function of periplasmic chaperones. We identified four periplasmic proteins that specifically bound to plasmid-encoded toxin (Pet), an AT produced by enteroaggregative
Escherichia coli
(EAEC). These proteins include the 17-kDa Skp chaperone and the 37-kDa VirK protein. We found that the
virK
gene is present in different
Enterobacteriaceae
. VirK bound to misfolded conformations of the Pet passenger domain, but it did not bind to the folded passenger domain or to the β domain of Pet. Assays with an EAECΔ
virK
mutant and its complemented version showed that, in the absence of VirK, Pet was not secreted but was instead retained in the periplasm as proteolytic fragments. In contrast, Pet was secreted from a Δ
skp
mutant. VirK was not required for the insertion of porin proteins into the outer membrane but assisted with insertion of the Pet β domain into the outer membrane. Loss of VirK function blocked the EAEC-mediated cytotoxic effect against HEp-2 cells. Thus, VirK facilitates the secretion of the AT Pet by maintaining the passenger domain in a conformation that both avoids periplasmic proteolysis and facilitates β-domain insertion into the outer membrane.
Effects of bird ingestion on seed germination of Vaccinium cylindraceum (Ericaceae), an endemic species of the Azores archipelago1This article is part of a Special Issue entitled “A tribute to Sam Vander Kloet FLS: Pure and applied research from blueberries to heathland ecology”.
Authors: Pereira M.J. , Mourato C. 
Published: May 2012

In this paper we investigate the effects of bird ingestion on Vaccinium cylindraceum Smith seed germination characteristics and the effect of a lack of bird dispersal on seed germination in the field. To test the effect of bird ingestion on seed germination, we carried out laboratory germination trials using ingested seeds and manually depulped seeds. To test the effect of a lack of bird dispersal on seed germination, we carried out germination trials using intact fruits above or under a cap of dead leaves under field conditions. The number of damaged seeds per fruit differed between species. Nearly 92% and 70% of the seeds ingested by, respectively, Erithacus rubecula and Turdus merula passed intact through the birds’ digestive tracts, and the germination characteristics of these seeds were not significantly affected. Only 16% of the seeds ingested passed intact through the digestive tract of Fringilla coelebs , and the germination ability of these seeds was significantly reduced. Uncovered intact berries in the field cracked, exposing the seeds to light, thus resulting in 18% of germination. Our results suggest that E. rubecula, T. merula, and F. coelebs can act as seed dispersers of V. cylindraceum. Also, V. cylindraceum seeds do not need to be ingested to germinate, but seed germination is enhanced as a consequence of seed exposure to light.
Beyond botany to genetic resource preservation: the S.P. Vander Kloet Vaccinium collections1This article is part of a Special Issue entitled “A tribute to Sam Vander Kloet FLS: Pure and applied research from blueberries to heathland ecology”.
Authors: Hummer Kim E. , Jamieson Andrew R. , Newell Ruth E. 
Published: May 2012

Sam P. Vander Kloet, botanist, traveled the world examining and obtaining specimens to redefine infrageneric taxonomic units within Vaccinium L., family Ericaceae. Besides his botanical treatises, his legacy includes herbarium voucher specimens and ex situ genetic resource collections including a seed bank and living plant collections at the Agriculture and Agri-Food Canada Research Centre, Kentville, Nova Scotia, Canada; the K.C. Irving Environmental Science Centre and Harriet Irving Botanical Gardens, Acadia University, Wolfville, Nova Scotia, Canada; the Canadian Clonal Genebank, Harrow, Ontario, Canada; and the US Department of Agriculture, Agricultural Research Service, National Clonal Germplasm Repository, Corvallis, Oregon, United States. Sam P. Vander Kloet’s collections include representatives of wild Ericaceae with special emphasis on collections of North American and subtropical endemic Vaccinium species. These reference collections are significant and represent a lifetime of dedicated research. Representatives of his heritage collections have now been deposited not only in American genebanks (in Canada and the United States) but also in the World Genebank in Svalbard, Norway, for long term conservation and future evaluation of Vaccinium for the service of humanity. The bequest of his wild collected germplasm will continue to be available to facilitate utilization of an extended Vaccinium gene pool for development and breeding throughout the world.
Floral volatile composition of four species of Vaccinium1This article is part of a Special Issue entitled “A tribute to Sam Vander Kloet FLS: Pure and applied research from blueberries to heathland ecology”.
Authors: Forney Charles F. , Javorek Steven K. , Jordan Michael A. , Vander Kloet Sam P. 
Published: May 2012

The floral volatile composition of four species of Vaccinium was profiled to asses the diversity of the floral chemistry within this genus. Flowers of Vaccinium angustifolium Aiton, Vaccinium varingiaefolium Miq., Vaccinium arboreum Marsh., and Vaccinium poasanum Donn. Sm. were sampled from three or more plants, and volatiles were collected and analyzed by gas chromatography – mass spectroscopy. A total of 45 volatile compounds were detected in the air (headspace) surrounding flowers including 40 from V. angustifolium, 34 for V. varingiaefolium, 37 for V. arboreum, and 17 for V. poasanum. Of the volatile compounds identified, 34 were terpenoids, 6 were benzoids and phenylpropanoids, 4 were aliphatics, and 1 was a miscellaneous cyclic compound. Terpenoids accounted for 98%, 80%, 76%, and 67% of the total volatiles for V. angustifolium, V. varingiaefolium, V. arboreum, and V. poasanum, respectively. The most abundant volatile compound emitted from the flowers of each species was α-pinene for V. angustifolium (23%) and V. arboreum (63%), methyl benzoate for V. varingiaefolium (18%), and ethyl benzene for V. poasanum (21%). Substantial variation was observed in the floral volatile composition of these four Vaccinium species, which may reflect their diverse ecological origins.
Antiglycation activity of Vaccinium spp. (Ericaceae) from the Sam Vander Kloet collection for the treatment of type II diabetes1This article is part of a Special Issue entitled “A tribute to Sam Vander Kloet FLS: Pure and applied research from blueberries to heathland ecology”.
Authors: Ferrier Jonathan , Djeffal Sabrina , Morgan Holly Porter , Vander Kloet Sam P. , Redžić Sulejman , Cuerrier Alain , Balick Michael J. , Arnason John T. 
Published: May 2012

In this report, the inhibition of advanced glycation endproducts (AGEs) by extracts of leaves from a collection of six, mainly tropical, Vaccinium L. spp. (Ericaceae) was examined. Indigenous Peoples have used Vaccinium species to treat symptoms of type I and II diabetes. Sustained hyperglycaemia, often associated with diabetes, facilitates crosslinking of sugars with proteins, producing AGEs. AGEs are a therapeutic target since they are responsible for many diabetes symptoms and contribute to ageing and the development of atherosclerosis, kidney, vascular, and neurological diseases. Vaccinium barandanum S. Vidal, Vaccinium consanguineum Klotzsch, Vaccinium gaultheriifolium (Griff.) Hook. f. ex C.B. Clarke, Vaccinium poasanum Donn. Sm., Vaccinium tonkinense Dop, and Disterigma rimbachii (A.C. Sm.) Luteyn (outgroup) were collected from Sam Vander Kloet’s common garden collection. Ethanolic extracts of leaves of these Vaccinium spp. were potent inhibitors of AGEs. Vaccinium and outgroup species extracts tested in an AGE inhibition assay demonstrated concentration dependent inhibition, with a half maximal inhibitory concentration (IC50) ranging from 4.2 to 16.2 µg·mL–1. Phenolic content ranged from 258 to 626 (µg quercetin equivalents·mg extract–1). Activity and phenolic content show that these tropical accessions have a higher phenolic content (p < 0.001, t test) and AGE inhibition (p < 0.03, t test) than six temperate species from our collections in eastern North America. Significant relationships were found between IC50 and latitude of geographic origin.
A formalized, taxonomy-driven approach to cross-layer application adaptation
Authors: Popescu Razvan , Staikopoulos Athanasios , Brogi Antonio , Liu Peng , Clarke Siobhán 
Published: May 2012

Advances in pervasive technology have made it possible to consider large-scale application types that potentially span heterogeneous organizations, technologies, and device types. This class of application will have a multilayer architecture, where each layer is likely to use languages and technologies appropriate to its own concerns. An example application is a geographically large-scale crisis management system. Typically, such applications are required to dynamically adapt their behavior based on current circumstances, with adaptations potentially affecting all layers of the application. The complexities involved in dynamically adapting multilayer applications will significantly benefit from formal approaches to its specification.
This article presents a new methodology for flexible, multilayer application adaptation, with layer-specific adaptation solution templates bound to application mismatches that are organized into hierarchical taxonomies. Templates can be linked either through direct invocations or through adaptation events, supporting flexible cross-layer adaptation. The methodology illustrates the use of different formalisms for different elements of its specification. In particular, we combine semiformal metamodeling techniques for the system model specification with formal Petri nets, which are used to capture template matchmaking using reachability analysis. This work demonstrates how existing formalisms can be used for the specification of a generic adaptation model for pervasive applications.
The Next Challenge in Cancer Immunotherapy: Controlling T-Cell Traffic to the Tumor
Authors: Abastado Jean-Pierre 
Published: May 2012

Abstract
One of the steps that limits the efficacy of T-cell–based immunotherapy of cancer is T-cell access to the tumor. We recently showed that several chemotherapeutic drugs induce intratumoral expression of chemokines that attract effector T cells. Moreover, in a cohort of patients with melanoma who had been treated with dacarbazine, one of the most frequently used chemotherapies for metastatic melanoma, tumor response to the treatment correlated with intratumoral expression of T-cell–attracting chemokines and with T-cell infiltration. These findings reveal the possibility of developing novel systemic strategies aimed at improving T-cell homing to tumors. Such strategies, used alone or in combination with adoptive T-cell therapies or therapeutic cancer vaccines, may prove to be more efficient in prolonging patient survival. Cancer Res; 72(9); 2159–61. ©2012 AACR.
Common PIK3CA Mutants and a Novel 3′ UTR Mutation Are Associated with Increased Sensitivity to Saracatinib
Authors: Arcaroli John J. , Quackenbush Kevin S. , Powell Rebecca W. , Pitts Todd M. , Spreafico Anna , Varella-Garcia Marileila , Bemis Lynne , Tan Aik Choon , Reinemann Jaclyn M. , Touban Basel M. , Dasari Arvind , Eckhardt S. Gail , Messersmith Wells A. 
Published: May 2012

Abstract
Purpose: Dysregulation of the phosphoinositide 3-kinase (PI3K) and Src signaling pathways commonly occur in colorectal cancer. Mutations in the PIK3CA gene are associated with an increase in severity of disease and worse clinical outcomes. Elevated levels of Src have been identified in premalignant lesions and are suggested to play a central role in tumor progression. Because these pathways appear to enhance tumor growth and metastasis, molecularly targeted agents for both pathways are currently being evaluated in early-phase clinical trials.
Experimental Design: We used colorectal cancer cell lines and a patient-derived explant model to investigate the efficacy of saracatinib. Mutations in the PIK3CA were evaluated to examine the association between mutations in the PIK3CA gene and sensitivity to saracatinib.
Results: We have identified a subset of patients with a PIK3CA (exon 9 and 20) mutation with increased sensitivity to saracatinib. A novel 3′ untranslated region (UTR) mutation was also shown to be associated with increased sensitivity to saracatinib and have a reduced affinity for miR-520a and miR-525a. Importantly, we show that Src inhibition reduces the interaction between Src and p85, subsequently decreasing Akt-dependent signaling.
Conclusion: These results indicate that a personalized approach in targeting Src in PIK3CA-mutant patients with colorectal cancers may prove effective in a subset of patients with this genetic alteration. Clin Cancer Res; 18(9); 2704–14. ©2012 AACR.