bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frequency Analysis Techniques for Identification of Viral Genetic Data
Authors: Trifonov Vladimir , Rabadan Raul 
Published: August 2010

ABSTRACT

Environmental metagenomic samples and samples obtained as an attempt to identify a pathogen associated with the emergence of a novel infectious disease are important sources of novel microorganisms. The low costs and high throughput of sequencing technologies are expected to allow for the genetic material in those samples to be sequenced and the genomes of the novel microorganisms to be identified by alignment to those in a database of known genomes. Yet, for various biological and technical reasons, such alignment might not always be possible. We investigate a frequency analysis technique which on one hand allows for the identification of genetic material without relying on alignment and on the other hand makes possible the discovery of nonoverlapping contigs from the same organism. The technique is based on obtaining signatures of the genetic data and defining a distance/similarity measure between signatures. More precisely, the signatures of the genetic data are the frequencies of
k
-mers occurring in them, with
k
being a natural number. We considered an entropy-based distance between signatures, similar to the Kullback-Leibler distance in information theory, and investigated its ability to categorize negative-sense single-stranded RNA (ssRNA) viral genetic data. Our conclusion is that in this viral context, the technique provides a viable way of discovering genetic relationships without relying on alignment. We envision that our approach will be applicable to other microbial genetic contexts, e.g., other types of viruses, and will be an important tool in the discovery of novel microorganisms.

IMPORTANCE
Multiple factors contribute to the emergence of novel infectious diseases. Implementation of effective measures against such diseases relies on the rapid identification of novel pathogens. Another important source of novel microorganisms is environmental metagenomic samples. The low costs and high throughput of sequencing technologies provide a method for the identification of novel microorganisms by sequence alignment. There are several obstacles to this method, as follows: our knowledge of biology is biased by an anthropomorphic view, microbial genomic material could be a minuscule fraction of the sample, the sequencing and enrichment technologies can be a source of errors and biases, and finally, microbes have high diversity and high evolutionary rates. As a result, novel microorganisms could have very low genetic similarity to already known genomes, and the identification by alignment could be computationally prohibitive. We investigate a frequency analysis technique which allows for the identification of novel genetic material without relying on alignment.
Emergence and Global Dissemination of Host-Specific
Streptococcus agalactiae
Clones
Authors: Sørensen Uffe B. Skov , Poulsen Knud , Ghezzo Claudia , Margarit Immaculada , Kilian Mogens 
Published: August 2010

ABSTRACT

To examine the global diversity of
Streptococcus agalactiae
(group B streptococci [GBS]) and to elucidate the evolutionary processes that determine its population genetics structure and the reported changes in host tropism and infection epidemiology, we examined a collection of 238 bovine and human isolates from nine countries on five continents. Phylogenetic analysis based on the sequences of 15 housekeeping genes combined with patterns of virulence-associated traits identified a genetically heterogeneous core population from which virulent lineages occasionally emerge as a result of recombination affecting major segments of the genome. Such lineages, like clonal complex 17 (CC17) and two distinct clusters of CC23, are exclusively adapted to either humans or cattle and successfully spread globally. The recent emergence and expansion of the human-associated and highly virulent sequence type 17 (ST17) could conceivably account, in part, for the increased prevalence of neonatal GBS infections after 1960. The composite structure of the
S. agalactiae
genome invalidates phylogenetic inferences exclusively based on multilocus sequence typing (MLST) data and thereby the previously reported conclusion that the human-associated CC17 emerged from the bovine-associated CC67.

IMPORTANCE
Group B streptococci (GBS) (
Streptococcus agalactiae
) have long been recognized as important causes of mastitis in cattle. After 1960, GBS also became the most prevalent cause of invasive and often fatal infections in newborns. At the same time, GBS are carried by a substantial proportion of healthy individuals. The aims of this study were to elucidate the genetic mechanisms that lead to diversification of the GBS population and to examine the relationship between virulence and host preference of evolutionary lineages of GBS. Genetic analysis of GBS isolates from worldwide sources demonstrated epidemic clones adapted specifically to either the human or bovine host. Such clones seem to emerge from a genetically heterogeneous core population as a result of recombination affecting major segments of the genome. Emergence and global spread of certain clones explain, in part, the change in epidemiology of GBS disease and may have implications for prevention.
Membrane Topology Mapping of the O-Antigen Flippase (Wzx), Polymerase (Wzy), and Ligase (WaaL) from Pseudomonas aeruginosa PAO1 Reveals Novel Domain Architectures
Authors: Islam Salim T. , Taylor Véronique L. , Qi Meng , Lam Joseph S. 
Published: August 2010

ABSTRACT

Biosynthesis of B-band lipopolysaccharide (LPS) in
Pseudomonas aeruginosa
follows the Wzy-dependent pathway, requiring the integral inner membrane proteins Wzx (O-antigen [O-Ag] flippase), Wzy (O-Ag polymerase), and WaaL (O-Ag ligase). For an important first step in deciphering the mechanisms of LPS assembly, we set out to map the membrane topology of these proteins. Random and targeted 3′
wzx
,
wzy
, and
waaL
truncations were fused to a
phoA
-
lacZα
dual reporter capable of displaying both alkaline phosphatase and β-galactosidase activity. The results from truncation fusion expression and the corresponding differential enzyme activity ratios allowed for the assignment of specific regions of the proteins to cytoplasmic, transmembrane (TM), or periplasmic loci. Protein orientation in the inner membrane was confirmed via C-terminal fusion to green fluorescent protein. Our data revealed unique TM domain properties in these proteins, particularly for Wzx, indicating the potential for a charged pore. Novel periplasmic and cytoplasmic loop domains were also uncovered, with the latter in Wzy and WaaL revealing tracts consistent with potential Walker A/B motifs.

IMPORTANCE
The opportunistic pathogen
Pseudomonas aeruginosa
synthesizes its virulence factor lipopolysaccharide via the Wzy-dependent pathway, requiring translocation, polymerization, and ligation of lipid-linked polysaccharide repeat units by the integral inner membrane proteins Wzx, Wzy, and WaaL, respectively. However, structural evidence to help explain the function of these proteins is lacking. Since membrane proteins are difficult to crystallize, topological mapping is an important first step in identifying exposed and membrane-embedded domains. We mapped the topologies of Wzx, Wzy, and WaaL from
P. aeruginosa
PAO1 by use of truncation libraries of a randomly fused C-terminal reporter capable of different enzyme activities in the periplasm and cytoplasm. Topology maps were created based directly on residue localization data, eliminating the bias associated with reliance on multiple topology prediction algorithms for initial generation of consensus transmembrane domain localizations. Consequently, we have identified novel periplasmic, cytoplasmic, and transmembrane domain properties that would help to explain the proposed functions of Wzx, Wzy, and WaaL.
Percutaneous transluminal angioplasty in a patient with vasospasm secondary to coccidioidal meningitis: case report and review of the literature
Authors: Hu Yin C , Newman C Benjamin , Bristol Ruth , McDougall Cameron G , Albuquerque Felipe C 
Published: August 2010

IntroductionCoccidioidomycosis is secondary to infection with fungal speciesCoccidioides immitisorCoccidioides posadasii.One consequence of extrapulmonary coccidioidomycosis dissemination is meningitis, which is associated with high rates of morbidity and mortality if left untreated. Intracranial vasospasm, although rarely described, can occur and may be a result of vasculitic or subacute fibrotic changes. We describe a case of successful percutaneous transluminal angioplasty (PTA) in a patient with severe vasospasm related to coccidioidal meningitis. This is the first report of this endovascular treatment used to treat coccidioidal vasospasm.Clinical presentationA patient with a history of pulmonary coccidioidomycosis presented with acute confusion, blurry vision and headache. Serology confirmed basilar meningitis and magnetic resonance angiography demonstrated severe symptomatic vasospasm.InterventionEmergent cerebral angiography confirmed severe vasospasm in the right middle cerebral artery and moderate vasospasm in the left middle cerebral artery. Successful PTA was performed under general anesthesia. The patient demonstrated postprocedural angiographic and clinical improvement.ConclusionWe report the first case of successful PTA performed to treat vasospasm related to coccidioidal meningitis. When vasospasm is clinically symptomatic, PTA is a safe and feasible procedure.
Trace element geochemistry of Nova Scotia (Canada) maple syrup
Authors: Greenough John D. , Fryer Brian J. , Mallory-Greenough Leanne 
Published: August 2010

Between 2000 and 2005, 50 sugar maple ( Acer saccharum Marshall, 1785) syrup samples from 16 producers in northern Nova Scotia, were analyzed (for 39 elements) using new techniques and inductively coupled plasma – mass spectrometry. Multidimensional scaling (exploratory statistics) using all samples and chemical data indicates that composition correlates with producer–woodlot, syrup colour (percent transmission), and processing (boiling alone versus reverse osmosis + boiling). Data are subdivided to explore these relationships. Using boiled samples (five producers, 21 samples), producers–woodlots are distinguished by high field-strength (Cr, Hf, and U), rare-earth (La, Pr, and Nd), chalcophile (Cu), alkaline earth (Ba, Ca), and especially alkali elements (Na, K, Rb, and Cs). On average, element concentrations are 1.6 times higher in darkest, boiled-only syrups (n = 6) compared with the lightest boiled syrups (same producers; n = 6). Apparently, dark syrups result from sap that contains low sugar content but similar element concentrations. More boiling to concentrate sugar causes caramelization, resulting in darker syrup and higher element concentrations. Averages for boiled and osmosis-processed syrups suggest that cations with small ionic radius and high charge (3+and 4+) are ∼1.6 times higher in boiled samples. These cations are partially lost by passing through the osmosis membrane. Based on boiled samples, water-soluble alkali metal cations with large ionic radius and low charge (+1) have high continental-crust-normalized concentrations (0.1 times), whereas insoluble cations with smaller ionic radius and higher charge (e.g., Hf, Th, REE) exhibit low (0.0001) concentrations. This pattern apparently reflects element solubility in soil water. Concentrations are ∼10 times those in Nova Scotia wine. Because ∼35 L of sap makes 1 L of syrup, the lower concentration factor in wine may reflect evapotranspiration concentration in grapes. Several elements in syrup (Sn, Cu, Pb, Zn), show producer-related concentration anomalies that probably reflect equipment (tanks, pumps, evaporators) used in processing.
The Theory of Reich's Fixed Point Theorem for Multivalued Operators
Authors: Lazăr Tania , Moţ Ghiocel , Petruşel Gabriela , Szentesi Silviu 
Published: August 2010

AbstractThe purpose of this paper is to present a theory of Reich's fixed point theorem for multivalued operators in terms of fixed points, strict fixed points, multivalued weakly Picard operators, multivalued Picard operators, data dependence of the fixed point set, sequence of multivalued operators and fixed points, Ulam-Hyers stability of a multivalued fixed point equation, well-posedness of the fixed point problem, and the generated fractal operator.
Secreted and Membrane-Bound Isoforms of Protease ADAM9 Have Opposing Effects on Breast Cancer Cell Migration
Authors: Fry Jessica L. , Toker Alex 
Published: August 2010

AbstractTumor cell migration is mediated by cell-autonomous signaling mechanisms as well as paracrine and autocrine factors secreted by activated stromal cells in the tumor microenvironment. Like other members of the ADAM (a disintegrin and metalloproteinase) family, the integrin-binding metalloproteinase ADAM9 modulates cell-cell and cell-matrix interactions as well as ectodomain shedding of cell surface receptors and ligands, thereby modifying intracellular and extracellular signaling. ADAM9 transcripts are alternatively spliced to express a transmembrane protein (ADAM9-L) and a secreted variant (ADAM9-S). In this study, we show that ADAM9-S promotes breast cancer cell migration in a manner requiring its metalloproteinase activity, whereas ADAM9-L suppresses cell migration independent of its metalloproteinase activity. Suppression of migration by ADAM9-L requires a functional disintegrin domain and integrin binding. Expression analysis revealed that both ADAM9 isoforms are expressed in breast cancer cell lines and tissues. Therefore, relative levels of membrane-tethered and secreted variants of ADAM9 are a key determinant in manifestation of aggressive migratory phenotypes associated with breast cancer progression. Cancer Res; 70(20); 8187–98. ©2010 AACR.
Matrix Metalloproteinase-9 Regulates Tumor Cell Invasion through Cleavage of Protease Nexin-1
Authors: Xu Danmei , McKee Chad M. , Cao Yunhong , Ding Yunchuan , Kessler Benedikt M. , Muschel Ruth J. 
Published: August 2010

Abstract
Matrix metalloproteinase-9 (MMP-9) expression is known to enhance the invasion and metastasis of tumor cells. In previous work based on a proteomic screen, we identified the serpin protease nexin-1 (PN-1) as a potential target of MMP-9. Here, we show that PN-1 is a substrate for MMP-9 and establish a link between PN-1 degradation by MMP-9 and regulation of invasion. PN-1 levels increased in prostate carcinoma cells after downregulation of MMP-9 and in tissues of MMP-9–deficient mice, consistent with PN-1 degradation by MMP-9. We identified three MMP-9 cleavage sites in PN-1 and showed that mutations in those sites made PN-1 more resistant to MMP-9. Urokinase plasminogen activator (uPA) is inhibited by PN-1. MMP-9 augmented uPA activity in the medium of PC3-ML cells by degrading PN-1. Prostate cancer cells, overexpressing PN-1 or treated with MMP-9 shRNA, had reduced cell invasion in Matrigel. PN-1 siRNA restored uPA activity and the invasive capacity. PN-1 mutated in the serpin inhibitory domain, the reactive center loop, failed to inhibit uPA and to reduce Matrigel invasion. This study shows a novel molecular pathway in which MMP-9 regulates uPA activity and tumor cell invasion through cleavage of PN-1. Cancer Res; 70(17); 6988–98. ©2010 AACR.
DNA Methylation Analysis Determines the High Frequency of Genic Hypomethylation and Low Frequency of Hypermethylation Events in Plasma Cell Tumors
Authors: Salhia Bodour , Baker Angela , Ahmann Gregory , Auclair Daniel , Fonseca Rafael , Carpten John 
Published: August 2010

Abstract
Multiple myeloma (MM) is a plasma cell malignancy of the bone marrow, which evolves from a premalignant stage called monoclonal gammopathy of undetermined significance (MGUS). In some patients, an intermediate stage referred to as smoldering multiple myeloma (SMM) is clinically recognized, with the full-bore malignancy termed MM. We conducted a study to assess differential CpG methylation at 1,500 genic loci during MM progression and profiled CD138+ plasma cells from MGUS, SMM, and MM specimens; human myeloma cell lines; and normal plasma cell (NPC) samples. We showed that the number of differentially methylated loci (DML) increased with tumor grade, and the vast majority were due to hypomethylation. Hierarchical clustering analysis revealed samples that coclustered tightly with NPC. These cases, referred to as “normal-like,” contained significantly fewer DML when compared with their non–normal-like counterparts and displayed overall methylation levels resembling NPC. This study represents one of the first methylome interrogation studies in MM and points toward global hypomethylation at genic CpG loci as an important and early mechanism driving myelomagenesis. Determining the set of critical genes and pathways based on the myeloma methylome is expected to lead to an improved understanding of biological mechanisms involved in myelomagenesis. Cancer Res; 70(17); 6934–44. ©2010 AACR.
Aminoflavone, a Ligand of the Aryl Hydrocarbon Receptor, Inhibits HIF-1α Expression in an AhR-Independent Fashion
Authors: Terzuoli Erika , Puppo Maura , Rapisarda Annamaria , Uranchimeg Badarch , Cao Liang , Burger Angelika M. , Ziche Marina , Melillo Giovanni 
Published: August 2010

Abstract
Aminoflavone (AF), the active component of a novel anticancer agent (AFP464) in phase I clinical trials, is a ligand of the aryl hydrocarbon receptor (AhR). AhR dimerizes with HIF-1β/AhR, which is shared with HIF-1α, a transcription factor critical for the response of cells to oxygen deprivation. To address whether pharmacologic activation of the AhR pathway might be a potential mechanism for inhibition of HIF-1, we tested the effects of AF on HIF-1 expression. AF inhibited HIF-1α transcriptional activity and protein accumulation in MCF-7 cells. However, inhibition of HIF-1α by AF was independent from a functional AhR pathway. Indeed, AF inhibited HIF-1α expression in AhR100 cells, in which the AhR pathway is functionally impaired, yet did not induce cytotoxicity, providing evidence that these effects are mediated by distinct signaling pathways. Moreover, AF was inactive in MDA-MB-231 cells, yet inhibited HIF-1α in MDA-MB-231 cells transfected with the SULT1A1 gene. AF inhibited HIF-1α mRNA expression by ∼50%. Notably, actinomycin-D completely abrogated the ability of AF to downregulate HIF-1α mRNA, indicating that active transcription was required for the inhibition of HIF-1α expression. Finally, AF inhibited HIF-1α protein accumulation and the expression of HIF-1 target genes in MCF-7 xenografts. These results show that AF inhibits HIF-1α in an AhR-independent fashion, and they unveil additional activities of AF that may be relevant for its further clinical development. Cancer Res; 70(17); 6837–48. ©2010 AACR.
HER-2 Signaling, Acquisition of Growth Factor Independence, and Regulation of Biological Networks Associated with Cell Transformation
Authors: Bollig-Fischer Aliccia , Dziubinski Michele , Boyer Alaina , Haddad Ramsi , Giroux Craig N. , Ethier Stephen P. 
Published: August 2010

Abstract
Activated oncogenes are the dominant drivers of malignant progression in human cancer, yet little is known about how the transformation from proto-oncogene to activated oncogene drives the expression of transformed phenotypes. An isogenic model of HER-2–mediated transformation of human mammary epithelial cells was used along with HER-2–amplified human breast cancers to investigate how HER-2 activation alters its properties as a signaling molecule and changes the networks of HER-2–regulated genes. Our results show that full oncogenic activation of HER-2 is the result of a transition in which activated HER-2 acquires dominant signaling properties that qualitatively alter the network of genes regulated by the activated oncogene compared with the proto-oncogene. Consequently, gene expression programs related to invasion, cell stress, and stemness become regulated by HER-2 in a manner not observed in nontransformed cells, even when HER-2 is overexpressed. Our results offer novel insights into biological processes that come under the control of HER-2 after it acquires full oncogenic potential. Cancer Res; 70(20); 7862–73. ©2010 AACR.
Interaction with Vascular Endothelium Enhances Survival in Primary Chronic Lymphocytic Leukemia Cells via NF-κB Activation andDe novoGene Transcription
Authors: Buggins Andrea G.S. , Pepper Chris , Patten Piers E.M. , Hewamana Saman , Gohil Satyen , Moorhead Jane , Folarin Najeem'deen , Yallop Deborah , Thomas N. Shaun B. , Mufti Ghulam J. , Fegan Chris , Devereux Stephen 
Published: August 2010

AbstractChronic lymphocytic leukemia (CLL) cells rapidly undergo apoptosis in vitro, suggesting that the in vivo microenvironment provides crucial antiapoptotic signals. Overexpression of the antiapoptotic proteins Bcl-2 and Mcl-1 is a hallmark of CLL, and their expression is further enhanced in the lymphoid tissues. However, the high levels of Mcl-1 found in peripheral blood samples, coupled with its short half-life, led us to hypothesize that it must be actively maintained in the peripheral circulation. Coculture of CLL cells with human vascular endothelial cells significantly enhanced tumor cell survival, an effect that was not observed with normal B cells. This was associated with elevated levels of the antiapoptotic proteins Bcl-2, Mcl-1, and Bcl-XL and marked increased expression of CD38 and CD49d, both of which are associated with clinically aggressive disease. Because CD38, CD49d, and some Bcl-2 family genes are transcriptional targets for NF-κB, we assessed NF-κB activation following coculture with endothelial cells. DNA binding of the NF-κB subunit Rel A was significantly increased and strongly correlated with changes in transcription of CD38, CD49d, BCL2, MCL1, and BCLXL, effects that were reversed by a peptide inhibitor of Rel A. These effects were not observed following coculture with nonendothelial cell lines. Therefore, CLL cells receive specific survival signals following interaction with endothelial cells mediated through the activation of NF-κB and the induction of downstream target genes. This type of interaction in the peripheral vasculature may explain the constitutive NF-κB activation and the overexpression of Bcl-2 family proteins commonly seen in this disease. Cancer Res; 70(19); 7523–33. ©2010 AACR.