bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic and Biochemical Characterization of a Novel Metallo-β-Lactamase, TMB-1, from an Achromobacter xylosoxidans Strain Isolated in Tripoli, Libya
Authors: El Salabi Allaaeddin , Borra Pardha Saradhi , Toleman Mark A. , Samuelsen Ørjan , Walsh Timothy R. 
Published: January 2012

ABSTRACT

An
Achromobacter xylosoxidans
strain from the Tripoli central hospital produced a unique metallo-β-lactamase, designated TMB-1, which is related to DIM-1 (62%) and GIM-1 (51%).
bla
TMB-1
was embedded in a class 1 integron and located on the chromosome. The TMB-1 β-lactamase has lower
k
cat
values than both DIM-1 and GIM-1 with cephalosporins and carbapenems. The

K
m

values were more similar to those of GIM-1 than those of DIM-1, with the overall
k
cat
/

K
m

values being lower than those for GIM-1 and DIM-1.
Antigen 85C Inhibition Restricts Mycobacterium tuberculosis Growth through Disruption of Cord Factor Biosynthesis
Authors: Warrier Thulasi , Tropis Marielle , Werngren Jim , Diehl Anne , Gengenbacher Martin , Schlegel Brigitte , Schade Markus , Oschkinat Hartmut , Daffe Mamadou , Hoffner Sven , Eddine Ali Nasser , Kaufmann Stefan H. E. 
Published: January 2012

ABSTRACTThe antigen 85 (Ag85) protein family, consisting of Ag85A, -B, and -C, is vital forMycobacterium tuberculosisdue to its role in cell envelope biogenesis. The mycoloyl transferase activity of these proteins generates trehalose dimycolate (TDM), an envelope lipid essential forM. tuberculosisvirulence, and cell wall arabinogalactan-linked mycolic acids. Inhibition of these enzymes through substrate analogs hinders growth of mycobacteria, but a link to mycolic acid synthesis has not been established. In this study, we characterized a novel inhibitor of Ag85C, 2-amino-6-propyl-4,5,6,7-tetrahydro-1-benzothiophene-3-carbonitrile (I3-AG85). I3-AG85 was isolated from a panel of four inhibitors that exhibited structure- and dose-dependent inhibition ofM. tuberculosisdivision in broth culture. I3-AG85 also inhibitedM. tuberculosissurvival in infected primary macrophages. Importantly, it displayed an identical MIC against the drug-susceptible H37Rv reference strain and a panel of extensively drug-resistant/multidrug-resistantM. tuberculosisstrains. Nuclear magnetic resonance analysis indicated binding of I3-AG85 to Ag85C, similar to its binding to the artificial substrate octylthioglucoside. Quantification of mycolic acid-linked lipids of theM. tuberculosisenvelope showed a specific blockade of TDM synthesis. This was accompanied by accumulation of trehalose monomycolate, while the overall mycolic acid abundance remained unchanged. Inhibition of Ag85C activity also disrupted the integrity of theM. tuberculosisenvelope. I3-AG85 inhibited the division of and reduced TDM synthesis in anM. tuberculosisstrain deficient in Ag85C. Our results indicate that Ag85 proteins are promising targets for novel antimycobacterial drug design.
Anti-Human Immunodeficiency Virus Type 1 Activity of Novel 6-Substituted 1-Benzyl-3-(3,5-Dimethylbenzyl)Uracil Derivatives
Authors: Ordonez Paula , Hamasaki Takayuki , Isono Yohei , Sakakibara Norikazu , Ikejiri Masahiro , Maruyama Tokumi , Baba Masanori 
Published: January 2012

ABSTRACTNonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) are important components of current combination therapies for human immunodeficiency virus type 1 (HIV-1) infection. In screening of chemical libraries, we found 6-azido-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AzBBU) and 6-amino-1-benzyl-3-(3,5-dimethylbenzyl)uracil (AmBBU) to be highly active and selective inhibitors of HIV-1 replicationin vitro. To determine the resistance profiles of these compounds, we conducted a long-term culture of HIV-1-infected MT-4 cells with escalating concentrations of each compound. After serial passages of the infected cells, escape viruses were obtained, and they were more than 500-fold resistant to the uracil derivatives compared to the wild type. Sequence analysis was conducted for RT of the escape viruses at passages 12 and 24. The amino acid mutation Y181C in the polymerase domain of RT was detected for all escape viruses. Docking studies using the crystal structure of RT showed that AmBBU requires the amino acid residues Leu100, Val106, Tyr181, and Trp229 for exerting its inhibitory effect on HIV-1. Four additional amino acid changes (K451R, R461K, T468P, and D471N) were identified in the RNase H domain of RT; however, their precise role in the acquisition of resistance is still unclear. In conclusion, the initial mutation Y181C seems sufficient for the acquisition of resistance to the uracil derivatives AzBBU and AmBBU. Further studies are required to determine the precise role of each mutation in the acquisition of HIV-1 resistance.
Involvement of the Mannose Receptor and p38 Mitogen-Activated Protein Kinase Signaling Pathway of the Microdomain of the Integral Membrane Protein after Enteropathogenic Escherichia coli Infection
Authors: Liu Zhihua , Ma Yanlei , Moyer Mary Pat , Zhang Peng , Shi Chenzhang , Qin Huanlong 
Published: January 2012

ABSTRACTThe microdomain of the integral membrane protein (MIMP) has been shown to adhere to mucin and to antagonize the adhesion of enteropathogenicEscherichia coli(EPEC) to epithelial cells; however, the mechanism has not been fully elucidated. In this study, we further identified the receptor of MIMP on NCM460 cells and investigated the mechanism (the p38 mitogen-activated protein kinase [MAPK] pathway) following the interaction of MIMP and its corresponding receptor, mannose receptor. We first identified the target receptor of MIMP on the surfaces of NCM460 cells using immunoprecipitation-mass spectrometry technology. We also verified the mannose receptor and examined the degradation and activation of the p38 MAPK signaling pathway. The results indicated that MIMP adhered to NCM460 cells by binding to the mannose receptor and inhibited the phosphorylation of p38 MAPK stimulated after EPEC infection via inhibition of the Toll-like receptor 5 pathway. These findings indicated that MIMPs relieve the injury of NCM460 cells after enteropathogenicE. coliinfection through the mannose receptor and inhibition of the p38 MAPK signaling pathway, both of which may therefore be potential therapeutic targets for intestinal diseases, such as inflammatory bowel disease.
Association between the Haptoglobin and Heme Oxygenase 1 Genetic Profiles and Soluble CD163 in Susceptibility to and Severity of Human Malaria
Authors: Mendonça Vitor R. R. , Luz Nívea F. , Santos Nadja J. G. , Borges Valéria M. , Gonçalves Marilda S. , Andrade Bruno B. , Barral-Netto Manoel 
Published: January 2012

ABSTRACTIntravascular hemolysis is a hallmark event in the immunopathology of malaria that results in increased systemic concentrations of free hemoglobin (Hb). The oxidation of Hb by free radicals causes the release of heme, which amplifies inflammation. To circumvent the detrimental effects of free heme, hosts have developed several homeostatic mechanisms, including the enzyme haptoglobin (Hp), which scavenges cell-free Hb, the monocyte receptor CD163, which binds to Hb-Hp complexes, and heme oxygenase-1 (HO-1), which degrades intracellular free heme. We tested the association between these three main components of the host response to hemolysis and susceptibility to malaria in a Brazilian population. The genetic profiles of theHMOX1andHpgenes and the plasma levels of a serum inflammatory marker, the soluble form of the CD163 receptor (sCD163), were studied in 264 subjects, including 78 individuals with symptomatic malaria, 106 individuals with asymptomatic malaria, and 80 uninfected individuals. We found that long (GT)nrepeats in the microsatellite polymorphism region of theHMOX1gene, theHp2allele, and theHp2.2genotype were associated with symptomatic malaria. Moreover, increased plasma concentrations of heme, Hp, HO-1, and sCD163 were associated with susceptibility to malaria. The validation of these results could support the development of targeted therapies and aid in reducing the severity of malaria.
Microevolution in
fimH
Gene of Mucosa-Associated Escherichia coli Strains Isolated from Pediatric Patients with Inflammatory Bowel Disease
Authors: Iebba Valerio , Conte Maria Pia , Lepanto Maria Stefania , Di Nardo Giovanni , Santangelo Floriana , Aloi Marina , Totino Valentina , Checchi Monica Proietti , Longhi Catia , Cucchiara Salvatore , Schippa Serena 
Published: January 2012

ABSTRACT

Several studies reported increased numbers of mucosa-associated
Escherichia coli
strains in patients with inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC). The majority of
E. coli
strains possess type 1 fimbriae, whose tip fibrillum protein, FimH, naturally undergoes amino acid replacements, an important process in the adaptation of commensal
E. coli
strains to environmental changes, like those observed in IBD and urinary tract infections. In this study, we analyzed mutational patterns in the
fimH
gene of 52 mucosa-associated
E. coli
strains isolated from IBD and non-IBD pediatric patients, in order to investigate microevolution of this genetic trait. FimH-positive strains were also phylogenetically typed and tested for their adhesive ability on Caco-2 cells. Specific FimH alleles for each grouping feature were found. Mutations G66S and V27A were related to CD, while mutations A242V, V163A, and T74I were attributed to UC. Otherwise, the G66S, N70S, and S78N mutations were specifically attributed to B2/D phylogroups. The N70S and A119V mutations were related to adhesive
E. coli
strains. Phylogroup B2, adhesive, and IBD
E. coli
strains showed a higher site substitution rate (SSR) in the
fimH
gene, together with a higher number of mutations. The degree of naïve mucosal inflammation was related to specific FimH alleles. Moreover, we could suggest that the V27A mutation is pathoadaptive for the CD intestinal habitat, while we could also suggest that both the N70S and S78N mutations are related to the more virulent
E. coli
B2 phylogroup. In conclusion, we found some FimH variants that seem to be more involved than others in the evolution of IBD pathogenesis.
Characterization of a Novel Inactivated Salmonella enterica Serovar Enteritidis Vaccine Candidate Generated Using a Modified cI857/λ PR/GeneEExpression System
Authors: Jawale Chetan V. , Chaudhari Atul A. , Jeon Byung Woo , Nandre Rahul M. , Lee John Hwa 
Published: January 2012

ABSTRACTA new strategy to develop an effective vaccine is essential to control food-borneSalmonella entericaserovar Enteritidis infections. Bacterial ghosts (BGs), which are nonliving, Gram-negative bacterial cell envelopes, are generated by expulsion of the cytoplasmic contents from bacterial cells through controlled expression using the modified cI857/λ PR/geneEexpression system. In the present study, the pJHL99 lysis plasmid carrying the mutated lambda pR37-cI857 repressor and PhiX174 lysis geneEwas constructed and transformed inS. Enteritidis to produce a BG. Temperature induction of the lysis gene cassette at 42°C revealed quantitative killing ofS. Enteritidis. TheS. Enteritidis ghost was characterized using scanning and transmission electron microscopy to visualize the transmembrane tunnel structure and loss of cytoplasmic materials, respectively. The efficacy of the BG as a vaccine candidate was evaluated in a chicken model using 60 10-day-old chickens, which were divided into four groups (n= 15), A, B, C, and D. Group A was designated as the nonimmunized control group, whereas the birds in groups B, C, and D were immunized via the intramuscular, subcutaneous, and oral routes, respectively. The chickens from all immunized groups showed significant increases in plasma IgG and intestinal secretory IgA levels. The lymphocyte proliferation response and CD3+CD4+and CD3+CD8+T cell subpopulations were also significantly increased in all immunized groups. The data indicate that both humoral and cell-mediated immune responses are robustly stimulated. Based on an examination of the protection efficacy measured by observations of gross lesions in the organs and bacterial recovery, the candidate vaccine can provide efficient protection against virulent challenge.
Hyperinduction of Host Beta Interferon by a Listeria monocytogenes Strain Naturally Overexpressing the Multidrug Efflux Pump MdrT
Authors: Schwartz Kierstyn T. , Carleton Joshua D. , Quillin Sarah J. , Rollins Stuart D. , Portnoy Daniel A. , Leber Jess H. 
Published: January 2012

ABSTRACT

Many pathogens regulate or modify their immune-stimulating ligands to avoid detection by their infected hosts.
Listeria monocytogenes
, a facultative intracellular bacterial pathogen, interacts with multiple components of mammalian innate immunity during its infection cycle. During replication within the cytosol of infected cells,
L. monocytogenes
utilizes two multidrug efflux pumps, MdrM and MdrT, to secrete the small nucleic acid second messenger cyclic-di-AMP (c-di-AMP). Host recognition of c-di-AMP triggers the production of type I interferons, including beta interferon (IFN-β), which, surprisingly, promote
L. monocytogenes
virulence. In this study, we have examined the capacity of multiple laboratory and clinical isolates of
L. monocytogenes
to stimulate host production of IFN-β. We have identified the
L. monocytogenes
strain LO28 as able to hyperinduce IFN-β production in infected cells ∼30-fold more than the common laboratory clone
L. monocytogenes
strain 10403S. Genomic analyses determined that LO28 contains a naturally occurring loss-of-function allele of the transcriptional regulator BrtA and correspondingly derepresses expression of MdrT. Surprisingly, while derepression of MdrT resulted in hyperstimulation of IFN-β, it results in significant attenuation in multiple mouse models of infection. While type I interferons may promote
L. monocytogenes
virulence, this study demonstrates that unregulated expression of the c-di-AMP-secreting efflux pump MdrT significantly restricts virulence
in vivo
by an unknown mechanism.
Chlamydia muridarum T Cell Antigens and Adjuvants That Induce Protective Immunity in Mice
Authors: Yu Hong , Karunakaran Karuna P. , Jiang Xiaozhou , Shen Caixia , Andersen Peter , Brunham Robert C. 
Published: January 2012

ABSTRACTMajor impediments to aChlamydiavaccine lie in discovering T cell antigens and polarizing adjuvants that stimulate protective immunity. We previously reported the discovery of three T cell antigens (PmpG, PmpF, and RplF) via immunoproteomics that elicited protective immunity in the murine genital tract infection model againstChlamydiainfection after adoptive transfer of antigen-pulsed dendritic cells. To expand the T cell antigen repertoire necessary for aChlamydiavaccine, we evaluated 10 newChlamydiaT cell antigens discovered via immunoproteomics in addition to the 3 antigens reported earlier as a molecular subunit vaccine. We first tested five adjuvants, including three cationic liposome formulations (dimethyldioctadecylammonium bromide-monophosphoryl lipid A [DDA-MPL], DDA-trehalose 6,6′-dibehenate [DDA-TDB {CAF01}], and DDA-monomycolyl glycerol [DDA-MMG {CAF04}]), Montanide ISA720–CpG-ODN1826, and alum using the PmpG protein as a model T cell antigen in the mouse genital tract infection model. The results showed that the cationic liposomal adjuvants DDA-MPL and DDA-TDB elicited the best protective immune responses, characterized by multifunctional CD4+T cells coexpressing gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), and reduced infection by more than 3 logs. Using DDA-MPL as an adjuvant, we found that 7 of 13ChlamydiaT cell antigens (PmpG, PmpE, PmpF, Aasf, RplF, TC0420, and TC0825) conferred protection better than or equal to that of the reference vaccine antigen, major outer membrane protein (MOMP). Pools of membrane/secreted proteins, cytoplasmic proteins, and hypothetical proteins were tested individually or in combination. Immunization with combinations protected as well as the best individual protein in that combination. The T cell antigens and adjuvants discovered in this study are of further interest in the development of a molecularly definedChlamydiavaccine.
Connecting Two (or Less) Dots
Authors: Shahaf Dafna , Guestrin Carlos 
Published: January 2012

Finding information is becoming a major part of our daily life. Entire sectors, from Web users to scientists and intelligence analysts, are increasingly struggling to keep up with the larger and larger amounts of content published every day. With this much data, it is often easy to miss the big picture.
In this article, we investigate methods for automatically connecting the dots---providing a structured, easy way to navigate within a new topic and discover hidden connections. We focus on the news domain: given two news articles, our system automatically finds a coherent chain linking them together. For example, it can recover the chain of events starting with the decline of home prices (January 2007), and ending with the health care debate (2009).
We formalize the characteristics of a good chain and provide a fast search-driven algorithm to connect two fixed endpoints. We incorporate user feedback into our framework, allowing the stories to be refined and personalized. We also provide a method to handle partially-specified endpoints, for users who do not know both ends of a story. Finally, we evaluate our algorithm over real news data. Our user studies demonstrate that the objective we propose captures the users’ intuitive notion of coherence, and that our algorithm effectively helps users understand the news.
Loss of TGF-β Responsiveness in Prostate Stromal Cells Alters Chemokine Levels and Facilitates the Development of Mixed Osteoblastic/Osteolytic Bone Lesions
Authors: Li Xiaohong , Sterling Julie A. , Fan Kang-Hsien , Vessella Robert L. , Shyr Yu , Hayward Simon W. , Matrisian Lynn M. , Bhowmick Neil A. 
Published: January 2012

Abstract
Loss of TGF-β type II receptor (TβRII, encoded by Tgfbr2) expression in the prostate stroma contributes to prostate cancer initiation, progression, and invasion. We evaluated whether TβRII loss also affected prostate cancer bone metastatic growth. Immunohistologic analysis revealed that TβRII expression was lost in cancer-associated fibroblasts in human prostate cancer bone metastatic tissues. We recapitulated the human situation with a conditional stromal Tgfbr2 knockout (Tgfbr2-KO) mouse model. Conditioned media from primary cultured Tgfbr2-KO or control Tgfbr2-flox prostatic fibroblasts (koPFCM or wtPFCM, respectively) were applied to C4-2B prostate cancer cells before grafting the cells tibially. We found that koPFCM promoted prostate cancer cell growth in the bone and development of early mixed osteoblastic/osteolytic bone lesions. Furthermore, the koPFCM promoted greater C4-2B adhesion to type-I collagen, the major component of bone matrix, compared to wtPFCM-treated C4-2B. Cytokine antibody array analysis revealed that koPFCM had more than two-fold elevation in granulocyte colony-stimulating factor and CXCL1, CXCL16, and CXCL5 expression relative to wtPFCM. Interestingly, neutralizing antibodies of CXCL16 or CXCL1 were able to reduce koPFCM-associated C4-2B type-I collagen adhesion to that comparable with wtPFCM-mediated adhesion. Collectively, our data indicate that loss of TGF-β responsiveness in prostatic fibroblasts results in upregulation of CXCL16 and CXCL1 and that these paracrine signals increase prostate cancer cell adhesion in the bone matrix. These microenvironment changes at the primary tumor site can mediate early establishment of prostate cancer cells in the bone and support subsequent tumor development at the metastatic site. Mol Cancer Res; 10(4); 494–503. ©2012 AACR.
THE EXPOSURE OF AZEF, A MODERN "JUDAS": FACTS AND LEGENDS
Authors: GEIFMAN ANNA 
Published: January 2012

Abstract<title> Summary </title>
Many intricate details about the Azef affair remain unclear, but until new evidence is found, it is possible to challenge at least one currently accepted legend associated with it, namely, the revolutionaries' claim that Lopukhin helped them to expose Azef out of an altruistic love of truth. There are serious reasons to believe that the radicals used coercion to force the former director of the Police Department to supply them with evidence against Azef. This immediately transforms Lopukhin from an ally of the radicals into their victim, and demonstrates once again that any new evaluation of the events surrounding the Azef affair must not rely solely upon the version presented by Burtsev and the SRs, even in seemingly insignificant details.68
The shock of the master spy's exposure was so tremendous that the PSR never fully recovered from the terrible wound the Azef affair inflicted upon it. Indeed, this wound proved mortal for the party's Combat Organization, and drastically reduced the terrorist activities of the revolutionary camp in general. With terror discredited as a revolutionary tool and the combatants demoralized, never again did the PSR possess adequate strength to mount political assassinations against the leading statesmen of autocratic Russia—assassinations that could have drastically altered the course of Russian history.
Color vision is strongly associated with retinal thinning in multiple sclerosis
Authors: Villoslada Pablo , Cuneo Ami , Gelfand Jeffrey , Hauser Stephen L , Green Ari 
Published: January 2012

Objectives: Multiple Sclerosis (MS) frequently causes injury to the anterior visual pathway (AVP), impairing quality of life due to visual dysfunction. Development of biomarkers in MS is a high priority and both low-contrast visual acuity (LCVA) and time-domain optical coherence tomography (TD-OCT) have been proposed as candidates for this purpose. We sought to assess whether psychophysical assessments of color vision are similarly correlated with structural measures of AVP injury, and therefore augment measures of visual disability in MS. Methods: We studied the association between high-contrast visual acuity (HCVA), LCVA, color vision (Hardy–Rand–Rittler plates (HRR) and Lanthony D15 tests) and OCT, using both high-resolution spectral-domain OCT (SD-OCT; Spectralis, Heidelberg Engineering, Germany) and TD-OCT (Stratus, Carl Zeiss, US) in a cohort of 213 MS patients (52 with previous optic neuritis) and 47 matched controls in a cross-sectional study. Results: We found that MS patients have impairments in HCVA and LCVA ( p < 0.001) but that they suffer from even more profound abnormalities in color discrimination ( p < 0.0001). We found strong correlation between color vision and SD-OCT measures of retinal nerve fiber layer (RNFL) thickness (average RNFL, r = 0.594, p < 0.001) and papillomacular bundle thickness ( r = −0.565, p < 0.001). The correlation between OCT scores and functional visual impairments of all types was much stronger for SD-OCT than for TD-OCT. Conclusion: Our results indicate that color vision is highly correlated with these OCT scores when compared with traditional measures of visual acuity. Also we found that SD-OCT is superior to TD-OCT for detecting anterior visual pathway damage in MS. This makes both color-visual measures and SD-OCT strong candidate biomarkers of disease progression.