bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Macrophage Inflammatory Protein 3α: Protein and Peptide Nuclear Magnetic Resonance Solution Structures, Dimerization, Dynamics, and Anti-Infective Properties
Authors: Chan David I. , Hunter Howard N. , Tack Brian F. , Vogel Hans J. 
Published: December 2007

ABSTRACT

Human macrophage inflammatory protein 3α (MIP-3α), also known as CCL20, is a 70-amino-acid chemokine which exclusively binds to chemokine receptor 6. In addition, the protein also has direct antimicrobial, antifungal, and antiviral activities. The solution structure of MIP-3α was solved by the use of two-dimensional homonuclear proton nuclear magnetic resonance (NMR). The structure reveals the characteristic chemokine fold, with three antiparallel β strands followed by a C-terminal α helix. In contrast to the crystal structures of MIP-3α, the solution structure was found to be monomeric. Another difference between the NMR and crystal structures lies in the angle of the α helix with respect to the β strands, which measure 69 and ∼56.5° in the two structures, respectively. NMR diffusion and pH titration studies revealed a distinct tendency for MIP-3α to form dimers at neutral pH and monomers at lower pH, dependent on the protonation state of His40. Molecular dynamics simulations of both the monomeric and the dimeric forms of MIP-3α supported the notion that the chemokine undergoes a change in helix angle upon dimerization and also highlighted the important hydrophobic and hydrogen bonding contacts made by His40 in the dimer interface. Moreover, a constrained N terminus and a smaller binding groove were observed in dimeric MIP-3α simulations, which could explain why monomeric MIP-3α may be more adept at receptor binding and activation. The solution structure of a synthetic peptide consisting of the last 20 residues of MIP-3α displayed a highly amphipathic α helix, reminiscent of various antimicrobial peptides. Antimicrobial assays with this peptide revealed strong and moderate bactericidal activities against
Escherichia coli
and
Staphylococcus aureus
, respectively. This confirms that the C-terminal α-helical region of MIP-3α plays a significant part in its broad anti-infective activity.
Systemic Pharmacokinetics of Rifaximin in Volunteers with Shigellosis
Authors: Taylor David N. , McKenzie Robin , Durbin Anna , Carpenter Colleen , Haake Robert , Bourgeois A. Louis 
Published: December 2007

ABSTRACT

Rifaximin is an oral antibiotic indicated for treatment of traveler's diarrhea. Rifaximin pharmacokinetics were evaluated in individuals challenged with
Shigella flexneri
. Peak plasma rifaximin concentrations were low after nine consecutive doses, and no accumulation was observed. Rifaximin serum levels were minimal and similar to those previously reported in studies of healthy volunteers.
Induction of
erm
(C) Expression by Noninducing Antibiotics
Authors: Bailey Marne , Chettiath Tobin , Mankin Alexander S. 
Published: December 2007

ABSTRACT

Ketolides, which represent the newest macrolide antibiotics, are generally perceived to be noninducers of inducible
erm
genes. In the study described in this paper we investigated the effects of several macrolide and ketolide compounds on the expression of the inducible
erm
(C) gene by
Escherichia coli
cells. Exposure to 14-member-ring macrolide drugs and to azithromycin led to a rapid and pronounced increase in the extent of dimethylation of Erm(C) target residue A2058 in 23S rRNA. When cells were incubated with subinhibitory concentrations of ketolides, the extent of A2058 dimethylation was also increased, albeit to a lower level and with kinetics slower than those observed with macrolides. The induction of
erm
(C) expression by ketolides was further confirmed by using a reporter construct which allows the colorimetric detection of induction in a disc diffusion assay. Most of the ketolides tested, including the clinically relevant compounds telithromycin and cethromycin, were able to induce the reporter expression, even though the induction occurred within a more narrow range of concentrations compared to the concentration range at which induction was achieved with the inducing macrolide antibiotics. No induction of the reporter expression was observed with 16-member-ring macrolide antibiotics or with a control drug, chloramphenicol. The deletion of three codons of the
erm
(C) leader peptide eliminated macrolide-dependent induction but left ketolide-dependent induction unchanged. We conclude that ketolides are generally capable of inducing
erm
genes. The narrow range of ketolide inducing concentrations, coupled with the slow rate of induction and the lower steady-state level of ribosome methylation, may mask this effect in MIC assays.
Participation of the Serine-RichEntamoeba histolyticaProtein in Amebic Phagocytosis of Apoptotic Host Cells
Authors: Teixeira Jose E. , Huston Christopher D. 
Published: December 2007

ABSTRACTEntamoeba histolyticais an intestinal ameba that causes dysentery and liver abscesses. Cytotoxicity and phagocytosis of host cells characterize invasiveE. histolyticainfection. Prior to phagocytosis of host cells,E. histolyticainduces apoptotic host cell death, using a mechanism that requires contact via an amebic galactose-specific lectin. However, lectin inhibition only partially blocks phagocytosis of already dead cells, implicating at least one additional receptor in phagocytosis. To identify receptors for engulfment of apoptotic cells, monoclonal antibodies againstE. histolyticamembrane antigens were screened for inhibition of phagocytosis. Of 43 antibodies screened, one blocked lectin-independent uptake of apoptotic cells, with >90% inhibition at a dose of 20 μg/ml (P< 0.0003 versus control). The same antibody also inhibited adherence to apoptotic lymphocytes and, to a lesser extent, adherence to and killing of viable lymphocytes. The antigen recognized by the inhibitory antibody was purified by affinity chromatography and identified by liquid chromatography-mass spectrometry as the serine-richE. histolyticaprotein (SREHP). Consistent with this, the inhibitory antibody bound to recombinant SREHP present in bacterial lysates on immunoblots. The SREHP is an abundant immunogenic surface protein of unclear function. The results of this unbiased antibody screen strongly implicate the SREHP as a participant inE. histolyticaphagocytosis and suggest that it may play an important role in adherence to apoptotic cells.
Predicting natural cavities in chalk
Authors: Edmonds C. N. 
Published: December 2007

Introduction

Chalk is a soluble carbonate rock with extensive karst development. Natural cavity occurrence initially appears to be random. In an area where the degree of influence of all cavity formational factors is similar, but dissolution is focused on one set of joints rather than another, then solution feature occurrence is perhaps random. This might be termed the ‘microscale’ view, measured at a scale of metres. However, if the pattern of natural cavity occurrence is considered at a ‘macroscale’ level, say measured in hundreds of metres or kilometres, then spatial patterns emerge suggesting dissolution is not as random as it might first appear.

Spatial characteristics of natural cavity occurrence on the Chalk

In order to analyse the spatial characteristics of natural cavity occurrence it was first necessary to collect as many records of solution feature occurrence as possible from published and unpublished sources including local authorities, Construction Industry Research and Information Association (CIRIA), Transport Research Laboratory (TRL), Building Research Establishment (BRE), National House Building Council (NHBC), the Environment Agency, water companies, and site investigation reports. Particular emphasis was placed on fieldwork to record new features revealed in a wide range of engineering works, road and motorway construction, and on visits to large numbers of working/disused chalk quarries and aggregate workings. A database of 2226 natural cavities was compiled, composed mainly of solution pipes, sinkholes (dolines) and swallow holes.
The spatially related database (each cavity location being recorded by National Grid Reference) was carefully scrutinized to determine
Geomorphological mapping
Authors: Lee E. M. 
Published: December 2007

There has been a long tradition of geomorphological mapping to support land use planning, especially in Poland (e.g. Klimaszewski 1956, 1961; Galon 1962) and France (e.g. Tricart 1965; for a history of geomorphological mapping in Europe, see Verstappen 1983). The Geological Society Working Party Report on maps and plans (Anon. 1972) identified examples of geomorphological mapping that could be of use to engineers. However, the value of the technique was best highlighted by its application to road projects in unstable terrain in Nepal and South Wales during the early 1970s (e.g. Brunsden et al. 1975a, b; Doornkamp et al. 1979; Jones et al. 1983). The techniques have also been successfully applied to dryland problems (e.g. Brunsden et al. 1979; Bush et al. 1980, Doornkamp et al 1980; Cooke et al. 1982, 1985; Jones et al. 1986), soil erosion (e.g. Morgan 1995) and river management (e.g. Doornkamp 1982; Richards et al. 1987). Despite these applications, BS5930, Code of Practice for Site Investigations (British Standards Institution 1981), contains little reference to geomorphological maps (Griffiths & Marsh 1986) and the technique remains a marginal skill practised by a few experienced engineering geomorphologists. Examples of good mapping practice can be found within the references cited in this paper.
The style and format of a geomorphological map needs to reflect the nature of the environment and the problems that need to be addressed. The following are some of the more common types of map.
Segment linkage and the state of stress in transtensional transfer zones: field examples from the Pannonian Basin
Authors: Fodor L. I. 
Published: December 2007

Abstract
Metre- to kilometre-scale en échelon strike-slip faults were mapped at the 1:10 000 scale in the Gánt mining area of the Vértes Hills in central Hungary. Good exposures allow detailed observation of brittle structures within the transfer zones of the overstepping fault segments. The strike-slip segments are subvertical to steeply dipping, with a rake of 20–30° accommodating a noticeable dip-slip. Displacement transfer between strike-slip faults was achieved through transtensional relay ramps, which represent a specific type of transfer zone. The breaching faults are oblique-normal or pure normal types. Their strike, dip and the obliquity of their striae change systematically. This occurred in order to accommodate extension across the relay ramp. Low-angle connecting faults occur at a high angle to the main fault, and form preferentially when the striae approach the orientation of the strike of the main fault. Slip vectors on the main and secondary connecting fault planes are subparallel, so defining a coherently moving hanging wall. A stress-inversion method was applied for the main fault segments, which characterize a state of stress of regional significance. Calculations were performed for the whole data-sets, including data for the guided connecting faults of the transtensional relay ramps, even though, in theory, stress inversion is not realistic for faults with a guided slip. Indeed, calculations gave a state of stress that is differs from that of the regional stress state. The results should be a warning to geologists that fault geometry has to be clarified in overstepping fault arrays before using the data-set for fault-slip inversion.
Activation of Tumor-Specific CD8+ T Cells after Intratumoral Ad5-TRAIL/CpG Oligodeoxynucleotide Combination Therapy
Authors: VanOosten Rebecca L. , Griffith Thomas S. 
Published: December 2007

AbstractCD8+ T-cell activation via cross-presentation of antigens from apoptotic tumor cells is controversial. Dendritic cells capture naturally shed tumor antigens and cross-present them to CD8+ T cells; unfortunately, the frequency of activated CD8+ T cells is often too low to mount an effective response against the tumor. By increasing the amount of antigen for presentation, a larger T-cell response can be theoretically elicited. We used a recombinant adenovirus encoding full-length murine tumor necrosis factor–related apoptosis-inducing ligand (Ad5-mTRAIL) to induce tumor cell apoptosis, and when given intratumorally to mice bearing experimental renal cell carcinoma (Renca) tumors, Ad5-mTRAIL minimally prolonged survival and induced a low level of CTL activity. To enhance dendritic cell efficiency, an immunostimulatory CpG oligodeoxynucleotide (CpG ODN) was combined with Ad5-mTRAIL. This combination therapy significantly augmented in vivo antigen-specific T-cell proliferation and CTL activity, as well as prolonged survival of Renca tumor-bearing mice. Interestingly, depletion of CD4+ or CD25+ cells before therapy further enhanced survival and in vivo CTL activity. In addition, tumor-free mice depleted of CD4+ cells were also able to reject a subsequent challenge of Renca cells, but not MHC-matched RM-11 prostate tumor cells, demonstrating the existence of immunologic memory. These results collectively show that local treatment with Ad5-mTRAIL and CpG ODN can augment tumor antigen cross-presentation resulting in T-cell proliferation, enhanced CTL activity, and increased animal survival. [Cancer Res 2007;67(24):11980–90]
Discovery of Epigenetically Silenced Genes by Methylated DNA Immunoprecipitation in Colon Cancer Cells
Authors: Jacinto Filipe V. , Ballestar Esteban , Ropero Santiago , Esteller Manel 
Published: December 2007

Abstract
CpG island promoter hypermethylation of tumor suppressor genes is a common hallmark of human cancer, and new large-scale epigenomic technologies might be useful in our attempts to define the complete DNA hypermethylome of tumor cells. Here, we report a functional search for hypermethylated CpG islands using the colorectal cancer cell line HCT-116, in which two major DNA methyltransferases, DNMT1 and DNMT3b, have been genetically disrupted (DKO cells). Using methylated DNA immunoprecipitation methodology in conjunction with promoter microarray analyses, we found that DKO cells experience a significant loss of hypermethylated CpG islands. Further characterization of these candidate sequences shows CpG island promoter hypermethylation and silencing of genes with potentially important roles in tumorigenesis, such as the Ras guanine nucleotide-releasing factor (RASGRF2), the apoptosis-associated basic helix-loop transcription factor (BHLHB9), and the homeobox gene (HOXD1). Hypermethylation of these genes occurs in premalignant lesions and accumulates during tumorigenesis. Thus, our results show the usefulness of DNMT genetic disruption strategies combined with methylated DNA immunoprecipitation in searching for unknown hypermethylated candidate genes in human cancer that might aid our understanding of the biology of the disease and be of potential translational use. [Cancer Res 2007;67(24):11481–6]
A novel, potent, and specific ephrinA1-based cytotoxin against EphA2 receptor–expressing tumor cells
Authors: Wykosky Jill , Gibo Denise M. , Debinski Waldemar 
Published: December 2007

AbstractWe have previously shown that the EphA2 receptor tyrosine kinase is overexpressed in glioblastoma multiforme (GBM) and represents a novel, attractive therapeutic target for the treatment of brain tumors. Here, we have developed an EphA2-targeted agent, ephrinA1-PE38QQR, a novel cytotoxin composed of ephrinA1, a ligand for EphA2, and PE38QQR, a mutated form of Pseudomonas aeruginosa exotoxin A. EphrinA1-PE38QQR showed potent and dose-dependent killing of GBM cells overexpressing the EphA2 receptor in cell viability and clonogenic survival assays, with an average IC50 of ∼10−11 mol/L. The conjugate was also highly effective in killing breast and prostate cancer cells overexpressing EphA2. The cytotoxic effect of ephrinA1-PE38QQR was specific, as it was neutralized by an excess of EphA2 ligands. Moreover, normal human endothelial cells and breast cancer cells that do not overexpress EphA2, as well as GBM cells that have down-regulated EphA2, were not susceptible to the cytotoxin. EphrinA1-PE38QQR–mediated cytotoxicity induced caspase-dependent apoptosis, which was, however, not responsible for cell death in response to the conjugate. In addition, the conjugate elicited no changes in the activity of survival pathways such as phosphoinositide 3-kinase, measured by AKT phosphorylation. This is the first attempt to create a cytotoxic therapy using any of the ephrin ligands of either class (A or B) conjugated to a bacterial toxin. EphrinA1-PE38QQR is very potent and specific, produces cell death that is caspase independent, and forms the basis for the further development of clinically applicable EphA2-targeted cytotoxins. [Mol Cancer Ther 2007;6(12):3208–18]
Introducing a Partitioning Mechanism for PAHs into the Community Multiscale Air Quality Modeling System and Its Application to Simulating the Transport of Benzo(a)pyrene over Europe
Authors: Aulinger Armin , Matthias Volker , Quante Markus 
Published: December 2007

Abstract
Into the Community Multiscale Air Quality modeling system (CMAQ) that is widely used for simulating the transport and fate of air pollutants, a new module was inserted that accounts for the partitioning of semivolatile organic compounds—in particular, polycyclic organic hydrocarbons (PAHs)—between the gaseous and the particulate phases. This PAH version of CMAQ can at this time be applied to substances that are predominantly associated with particles and can be assumed to be inert, as is the case for benzo(a)pyrene [B(a)P]. The model was set up for Europe on a grid with 54-km cell width with a nest of 18-km gridcell width located around the North Sea to simulate ambient air concentrations and depositions of B(a)P in January, April, July, and October 2000. To evaluate the quality of the simulation results, daily and monthly mean concentrations were compared with measurements from six monitoring stations. The typical ratio of modeled to measured values is circa 4 (median), which—with respect to both measurement and simulation uncertainties and problems involved when comparing measurements with simulations—proved that the PAH version of CMAQ is suitable to simulate the fate and transport of B(a)P over Europe and can serve as a starting point for models for other PAHs that additionally consider degradation.
Conserved and divergent patterns of expression of DAZL, VASA and OCT4 in the germ cells of the human fetal ovary and testis
Authors: Anderson Richard A , Fulton Norma , Cowan Gillian , Coutts Shona , Saunders Philippa TK 
Published: December 2007

AbstractBackgroundGerm cells arise from a small group of cells that express markers of pluripotency including OCT4. In humans formation of gonadal compartments (cords in testis, nests in ovary) takes place during the 1st trimester (6–8 weeks gestation). In the 2nd trimester germ cells can enter meiotic prophase in females whereas in males this does not occur until puberty. We have used qRTPCR, Westerns and immunohistochemical profiling to determine which of the germ cell subtypes in the human fetal gonads express OCT4, DAZL and VASA, as these have been shown to play an essential role in germ cell maturation in mice.ResultsOCT4 mRNA and protein were detected in extracts from both 1st and 2nd trimester ovaries and testes. In ovarian extracts a marked increase in expression of VASA and DAZL mRNA and protein occurred in the 2nd trimester. In testicular extracts VASA mRNA and protein were low/undetectable in 1st trimester and increased in the 2nd trimester whereas the total amount of DAZL did not seem to change. During the 1st trimester, germ cells were OCT4 positive but did not express VASA. These results are in contrast to the situation in mice where expression of Vasa is initiated in Oct4 positive primordial germ cells as they enter the gonadal ridge. In the 2nd trimester germ cells with intense cytoplasmic staining for VASA were present in both sexes; these cells were OCT4 negative. DAZL expression overlapped with both OCT4 and VASA and changed from the nuclear to the cytoplasmic compartment as cells became OCT4-negative. In males, OCT4-positive and VASA-positive subpopulations of germ cells coexisted within the same seminiferous cords but in the ovary there was a distinct spatial distribution of cells with OCT4 expressed by smaller, peripherally located, germ cells whereas DAZL and VASA were immunolocalised to larger (more mature) centrally located cells.ConclusionOCT4,DAZLandVASAare expressed by human fetal germ cells but their patterns of expression are temporally and spatially distinct. In the 1st trimester OCT4 was detected in most germ cells. In the 2nd trimester the onset of expression ofVASAwas associated with the formation of oocytes and spermatogonia both of which were OCT-4 negative. Relocation of DAZL from nucleus to cytoplasm paralleled the down regulation of OCT4 and the onset of expression of VASA. These data reveal similarities between the expression of key regulatory proteins within germ cells as they mature in male and female fetal human gonads suggesting that in the female these maturational changes are not determined by entry into meiosis.
Biological characterization of two xenografts derived from human CUPs (carcinomas of unknown primary)
Authors: Lequin Delphine , Fizazi Karim , Toujani Saloua , Souquère Sylvie , Mathieu Marie-Christine , Hainaut Pierre , Bernheim Alain , Praz Françoise , Busson Pierre 
Published: December 2007

Abstract

Background
Carcinomas of unknown primary site (CUP) are epithelial malignancies revealed by metastatic lesions in the absence of any detectable primary tumor. Although they often adopt an aggressive clinical pattern, their basic biology remains poorly understood. Laboratory research on their biology have been hampered so far by the absence of cell lines representative of CUPs.

Methods
We attempted xenografts of CUP clinical specimens in immunodeficient mice and subsequent in vitro culture of transplanted malignant cells. Whenever possible, malignant xenografted or cultured cells were characterized by microsatellite genotyping, immunohistology, electron microscopy, multifish chromosome analysis and search of TP 53 gene mutations.

Results
Successful xenografts were achieved in 2 cases out of 4. One of them (Capi1) was lost after 3 passages whereas the other one (Capi3) has been adapted to in vitro culture and is currently available to the scientific community with reliable identification based on microsatellite genotyping. Both Capi1 and Capi3 have histological characteristics of adenocarcinomas and display intense expression of EMA, CEA and cytokeratin 7. Multifish chromosome analysis demonstrated a translocation involving chromosomes 4 and 21 in both specimens. Distinct rare missense mutations of the TP53 gene were detected in Capi1 (codon 312) and Capi3 (codon 181); the codon 181 mutation is consistent with a previously reported similar finding in a small series of CUP specimens. Finally, intense membrane expression of c-kit was recorded in Capi3.

Conclusion
Our data suggest that xenografted tumors can be obtained from a substantial fraction of CUP clinical specimens. The hypothesis of a preferential association of CUPs with TP 53 mutations of codon 181 deserves further investigations. The Capi3 cell line will be a useful tool for assessment of novel c-kit inhibitors.