bluuebunny/crossref_metadata_2025_split huggingface dataset:
Type III Secretion Is Essential for the Rapidly Fatal Diarrheal Disease Caused by Non-O1, Non-O139 Vibrio cholerae
Authors: Shin Ok S. , Tam Vincent C. , Suzuki Masato , Ritchie Jennifer M. , Bronson Roderick T. , Waldor Matthew K. , Mekalanos John J. 
Published: June 2011

ABSTRACT

Cholera is a severe diarrheal disease typically caused by O1 serogroup strains of
Vibrio cholerae
. The pathogenicity of all pandemic
V. cholerae
O1 strains relies on two critical virulence factors: cholera toxin, a potent enterotoxin, and toxin coregulated pilus (TCP), an intestinal colonization factor. However, certain non-O1, non-O139
V. cholerae
strains, such as AM-19226, do not produce cholera toxin or TCP, yet they still cause severe diarrhea. The molecular basis for the pathogenicity of non-O1, non-O139
V. cholerae
has not been extensively characterized, but many of these strains encode related type III secretion systems (TTSSs). Here, we used infant rabbits to assess the contribution of the TTSS to non-O1, non-O139
V. cholerae
pathogenicity. We found that all animals infected with wild-type AM-19226 developed severe diarrhea even more rapidly than rabbits infected with
V. cholerae
O1. Unlike
V. cholerae
O1 strains, which do not damage the intestinal epithelium in rabbits or humans, AM-19226 caused marked disruptions of the epithelial surface in the rabbit small intestine. TTSS proved to be essential for AM-19226 virulence in infant rabbits; an AM-19226 derivative deficient for TTSS did not elicit diarrhea, colonize the intestine, or induce pathological changes in the intestine. Deletion of either one of the two previously identified or two newly identified AM-19226 TTSS effectors reduced but did not eliminate AM-19226 pathogenicity, suggesting that at least four effectors contribute to this strain’s virulence. In aggregate, our results suggest that the TTSS-dependent virulence in non-O1, non-O139
V. cholerae
represents a new type of diarrheagenic mechanism.

IMPORTANCE
Cholera, which is caused by
Vibrio cholerae
, is an important cause of diarrheal disease in many developing countries. The mechanisms of virulence of nonpandemic strains that can cause a diarrheal illness are poorly understood. AM-19226, like several other pathogenic, nonpandemic
V. cholerae
strains, carries genes that encode a type III secretion system (TTSS), but not cholera toxin (CT) or toxin coregulated pilus (TCP). In this study, we used infant rabbits to study AM-19226 virulence. Infant rabbits orally inoculated with this strain rapidly developed a fatal diarrheal disease, which was accompanied by marked disruptions of the intestinal epithelium. This strain’s TTSS proved essential for its pathogenicity, and there was no diarrhea, intestinal pathology, or colonization in rabbits infected with a TTSS mutant. The effector proteins translocated by the TTSS all appear to contribute to AM-19226 virulence. Thus, our study provides insight into
in vivo
mechanisms by which a novel TTSS contributes to diarrheal disease caused by nonpandemic strains of
V. cholerae
.
Impact of pelleted diets with different mineral compositions on the crown size of mandibular cheek teeth and mandibular relative density in degus (Octodon degus)
Authors: Jekl V. , Gumpenberger M. , Jeklova E. , Hauptman K. , Stehlik L. , Knotek Z. 
Published: June 2011

The impact of pelleted diets with different mineral compositions on the crown size of the mandibular cheek teeth, as well as the mandibular bone and cheek teeth density, in degus (Octodon degus) was investigated. A total of 28 animals were randomly divided into four groups and fed different calcium or phosphorous dietary content, in the presence or absence of UV light, for 14 months. Dental radiographs and CT images of the head were taken, and the crown size of premolar and molar teeth was recorded. Apical and coronal crown elongation of all cheek teeth and significantly smaller relative cheek teeth and mandibular densities were recorded in degus fed a high‐phosphorus diet with an improper calcium:phosphorus ratio. A diet with a calcium:phosphorus ratio of 1:1 was also responsible for the rapid development of dental disease with subsequent severe health impairment.
The Calabrian Stage, Pleistocene highstand in Malta: a new marker for unravelling the Late Neogene and Quaternary history of the islands
Authors: Pedley Martyn 
Published: June 2011

Abstract:

The Late Neogene and Quaternary sedimentary record within the Maltese islands is very fragmentary and has generally been ignored by sedimentologists. Local stratigraphies for parts of the Quaternary have been erected from vertebrate remains contained in Quaternary cave and fissure deposits of the islands. However, no coherent correlation scheme has been proposed in which to encompass them. The situation is exacerbated by the absence of datable fossils within the majority of Quaternary deposits. Considerable progress in resolving these problems is, however, possible if recourse is made to the post-Messinian (Late Miocene) erosion features evidenced in the topography of the islands. In particular, a hitherto unrecognized marine erosion surface, the San Leonardo Marine Abrasion Surface, is described and dated by reference to the marine deposits (San Leonardo Beds) lying directly above it and similarities to contemporaneous SE Sicily marine deposits. This provides an end-Calabrian Stage (Emilian Sub-Stage) base line upon which to hang fragmentary information on later events that have shaped the topography of the Maltese islands. From this it can be confirmed that a tectonic deformation event spanning latest Messinian to mid- Pliocene times uplifted the islands and reactivated previously incipient graben systems. This deformation episode is shown to have ceased within the islands well before the early Calabrian (before
c
. 1.6 Ma). Subsequent minor regional uplift and eustacy together with subaerial weathering processes have been the principal agents in shaping the islands. Collectively, these processes have prevented terrestrial animal migrations into the Maltese islands from North Africa since Messinian times. However, the infrequent re-establishment of a marine lowstand isthmus virtually linking Malta with SE Sicily has permitted opportunistic animal migrations into the islands and the presence of these greatly aids in dating the sedimentological events.
Uplift and lateritization history of the Çaldağ ophiolite in the context of Neo-Tethyan ophiolite obduction and uplift: implications for the Cenozoic weathering history of western Anatolia
Authors: Tavlan Metin , Thorne Robert , Herrington Richard Jeremy 
Published: June 2011

Abstract:

The Çaldağ ophiolite, in the Bornova Flysch Zone, is a fragment of Neo-Tethys in the Aegean province, western Turkey. The Bornova Flysch Zone is probably of Cretaceous age, and is locally covered by Early Eocene sediments of the Başlamış Formation that show the first evidence of exposure of ultramafic rocks. Field mapping confirms eight tectonic events correlated with the published regional history. The Çaldağ ophiolite would have been exposed to weathering only from the Mid-Palaeocene to the Late Miocene and from the Mid-Pliocene until the present. This weathering has resulted in the formation of an average
c
. 69 m thick oxide-dominated Ni-laterite. Biological, palaeoecological and isotopic records indicate favourable conditions for weathering, comparable with those of regions in which laterites form today. These data suggest that tropical to subtropical climatic conditions dominated through most of the Cenozoic; the Palaeocene–Eocene was significantly warmer than the Oligo-Miocene. Combining the exhumation history with the available climate data better constrains the periods suitable for laterite formation with implications for laterite formation regionally. The data indicate a possible total period of 50 Ma when laterite formation was possible, yet the profile measured at Çaldağ is indicative of either a shorter period of actual weathering or partial erosion of the formed profile.
Brittle tectonic reconstruction of palaeo-extension inherited from Mesozoic rifting in West Zagros (Kermanshah, Iran)
Authors: Navabpour Payman , Angelier Jacques , Barrier Eric 
Published: June 2011

Abstract:
The present-day Zagros mountain belt of SW Iran corresponds to the former Arabian passive continental margin of the southern Neo-Tethyan basin, which existed since a Permian–Triassic rifting episode and underwent later collisional deformation in mid- to late Cenozoic time. In West Zagros, the Kermanshah Radiolarian Trough, separated from the Neo-Tethyan basin by the narrow continental platform of the Bisotun Limestone, resulted from the Triassic–Jurassic rifting of the passive margin. Brittle tectonic analyses of syndepositional normal fault slip data have been undertaken to study the extensional history of the passive margin in terms of palaeostress reconstruction. Dominant east–west trends of the inherited rift-related normal faults in West Zagros indicate an approximately north–south trend of extension that prevailed during the entire Mesozoic syn- to post-rift evolution of the radiolarian trough. This extension characterizes a stretched continental margin similar to the present-day passive margin of the British Isles. Considering the structural pattern of the inherited basement faults, as revealed by the present-day earthquake focal mechanisms, an oblique crustal stretching model is proposed for the rifting process.
The Furongian (late Cambrian) Steptoean Positive Carbon Isotope Excursion (SPICE) in Avalonia
Authors: Woods Mark A. , Wilby Philip R. , Leng Melanie J. , Rushton Adrian W.A. , Williams Mark 
Published: June 2011

Abstract:

The Steptoean Positive Carbon Isotope Excursion (SPICE) of earliest late Cambrian (Furongian) age is identified in England. The excursion is found within a
c
. 145 m thick siliciclastic succession within the middle and higher part of the Outwoods Shale Formation of Warwickshire, and reaches a maximum δ
13
C
org
amplitude of 4.1‰ at values of −25.6‰. Biostratigraphical data show that the excursion occupies the greater part of the
Olenus
Biozone, an equivalent of the
Glyptagnostus reticulatus
Biozone that marks the base of the Furongian and coeval base of the Steptoean in North America. The amplitude of the excursion approaches that recorded in limestone-dominated Laurentian successions, and is greater than that recently documented for organic-rich mudstones of palaeocontinental Baltica in southern Sweden. A minor positive excursion above the SPICE may equate with a similar excursion recognized in Siberia. The SPICE in the Outwoods Shale Formation seems closely linked to the widely recognized early Furongian eustatic sea-level rise. There is no evidence in the English succession for slightly later regression, elsewhere considered coincident with the peak of the excursion and pivotal to some previous models explaining the SPICE.

Supplementary material:

Analytical results, including total organic carbon (TOC) values for each sample, are available at
www.geolsoc.org.uk/SUP18455
.
Hafnium isotope record of the Ancient Gneiss Complex, Swaziland, southern Africa: evidence for Archaean crust–mantle formation and crust reworking between 3.66 and 2.73 Ga
Authors: Zeh Armin , Gerdes Axel , Millonig Leo 
Published: June 2011

Abstract:

Combined U–Pb and Lu–Hf isotope analyses of zircons from 16 tonalite–trondjemite–granodiorite (TTG) gneiss and granite samples from Swaziland reveal that the oldest rocks of the Ancient Gneiss Complex in southern Africa formed by reworking of Early Archaean or perhaps Late Hadean crust at 3.66 Ga, and that new crust was extracted from a depleted mantle source during Palaeoarchaean events between 3.54 and 3.32 Ga. This interpretation is supported by εHf
t
of −1.6 ± 2.0 obtained from 3.66 Ga TTG gneisses, corresponding to hafnium model ages between 3.77 ± 0.18 Ga, for a presumed Hadean–Early Archaean chondritic mantle, and 4.08 ± 0.18 Ga, for a presumed Hadean depleted mantle reservoir, with the first model age being the most likely in the light of recent data from worldwide sources. Furthermore, it is reflected by superchondritic εHf
t
up to +2.2 ± 2.0 for TTGs formed at 3.54, 3.45 and 3.32 Ga. The new datasets additionally show that the Palaeoarchaean crust formed between 3.54 and 3.32 Ga was intensely reworked afterwards, without significant addition of depleted mantle derived material, during orogenic and intracratonic melting processes at 3.23, 3.1 and 2.7 Ga. This is well reflected by an array of decreasing εHf
t
from +2.2 to −7.2 between 3.3 and 2.7 Ga, which can be forced by
176
Lu/
177
Hf of 0.0113, which is similar to that of present-day average continental crust, and might result from lower crust zircon fractionation during Archaean crust reworking.

Supplementary material:

Results of
in situ
U–Pb and Lu–Hf isotope zircon analyses and concordia diagrams are available at
www.geolsoc.org.uk/SUP18465
.
The diversity of flow structures in felsic dykes
Authors: Tian Ye , Shan Yehua 
Published: June 2011

Abstract:
Numerous structures and textures, which can be related to magma flow, were observed in felsic dykes intruding late Mesozoic granitoid plutons in the Jiaodong peninsula, in eastern Shandong province, eastern China. These flow structures may be classified into two categories, interior and peripheral. The former group includes magmatic bands, various types of folds (e.g. injection, sheath, similar and disharmonic folds), rotation of phenocrysts, magmatic foliation or lineation, and crenulation, whereas the latter includes hot tool marks and quarrying structures. Magmatic banding resulted from shearing of mingled magma during magma flow in the dykes. The magma seemed to flow rapidly, probably triggering turbulence in some thick dykes. Interaction at the contact between the hot, moving magma and the cold, stationary wallrock sometimes produced the peripheral structures. A few measurements of hot tool marks and of magmatic lineation reveal a roughly horizontal flow of magma within these dykes. For the dominant NE–SW-striking dyke set in the Laoshan granitoid pluton, the felsic magma probably ascended on or to the SW of the pluton to feed the dyke swarm, and then flowed laterally to drive the horizontal propagation of dykes.
EGF61 Polymorphism Predicts Complete Pathologic Response to Cetuximab-Based Chemoradiation Independent of KRAS Status in Locally Advanced Rectal Cancer Patients
Authors: Hu-Lieskovan Siwen , Vallbohmer Daniel , Zhang Wu , Yang Dongyun , Pohl Alexander , Labonte Melissa J. , Grimminger Peter P. , Hölscher Arnulf H. , Semrau Robert , Arnold Dirk , Dellas Kathrin , Debucquoy Annelies , Haustermans Karin , Machiels Jean-Pascal H. , Sempoux Christine , Rödel Claus , Bracko Matej , Velenik Vaneja , Lenz Heinz-Josef 
Published: June 2011

Abstract
Background: Cetuximab has shown significant clinical activity in metastatic colon cancer. However, cetuximab-containing neoadjuvant chemoradiation has not been shown to improve tumor response in locally advanced rectal cancer patients in recent phase I/II trials. We evaluated functional germline polymorphisms of genes involved in epidermal growth factor receptor pathway, angiogenesis, antibody-dependent cell-mediated cytotoxicity, DNA repair, and drug metabolism, for their potential role as molecular predictors for clinical outcome in locally advanced rectal cancer patients treated with preoperative cetuximab-based chemoradiation.
Methods: 130 patients (74 men and 56 women) with locally advanced rectal cancer (4 with stage II, 109 with stage III, and 15 with stage IV, 2 unknown) who were enrolled in phase I/II clinical trials treated with cetuximab-based chemoradiation in European cancer centers were included. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor samples and genotyping was done by using PCR-RFLP assays. Fisher's exact test was used to examine associations between polymorphisms and complete pathologic response (pCR) that was determined by a modified Dworak classification system (grade III vs. grade IV: complete response).
Results: Patients with the epidermal growth factor (EGF) 61 G/G genotype had pCR of 45% (5/11), compared with 21% (11/53) in patients heterozygous, and 2% (1/54) in patients homozygous for the A/A allele (P &lt; 0.001). In addition, this association between EGF 61 G allele and pCR remained significant (P = 0.019) in the 59 patients with wild-type KRAS.
Conclusion: This study suggested EGF A+61G polymorphism to be a predictive marker for pCR, independent of KRAS mutation status, to cetuximab-based neoadjuvant chemoradiation of patients with locally advanced rectal cancer. Clin Cancer Res; 17(15); 5161–9. ©2011 AACR.
To DNA or not to DNA? That Is the Question, When It Comes to Molecular Subtyping for the Clinic!
Authors: Smeets Serge J. , Harjes Ulrike , van Wieringen Wessel N. , Sie Daoud , Brakenhoff Ruud H. , Meijer Gerrit A. , Ylstra Bauke 
Published: June 2011

AbstractGenome-wide RNA expression profiling has yielded tumor subtypes with strong predictive or prognostic value for a wide variety of cancers. Recently, for breast cancer two RNA expression classifiers have been adopted by the World Health Organization (WHO) and approved by the Food and Drug Administration (FDA). Also on the basis of DNA copy number profiles, tumor subtypes with different prognosis have been described, but have not yet led to clinical implementation. The genomic revolution caused by next generation sequencing of DNA samples presents additional mutation, balanced translocations, single-nucleotide polymorphisms (SNP), and copy neutral loss of heterozygosity data simultaneously. We foresee a further boost of the potential of DNA profiling in the clinic when these multidimensional DNA factors will be implemented. Here we evaluate the current stratification power with DNA copy numbers. In a training and validation approach using data of 400 published breast cancer samples, we show that a DNA copy number classifier accurately classifies RNA expression subtypes. We consider this an important step forward for clinical implementation of genomic subtyping using DNA and discuss the extra dimensions upcoming techniques will bring to the DNA palette. Clin Cancer Res; 17(15); 4959–64. ©2011 AACR.
Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin
Authors: Bhagwat Shripad V. , Gokhale Prafulla C. , Crew Andrew P. , Cooke Andy , Yao Yan , Mantis Christine , Kahler Jennifer , Workman Jennifer , Bittner Mark , Dudkin Lorina , Epstein David M. , Gibson Neil W. , Wild Robert , Arnold Lee D. , Houghton Peter J. , Pachter Jonathan A. 
Published: June 2011

AbstractThe phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR is a clinically validated target. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, metabolism, proliferation, and survival. Rapamycin and its analogues partially inhibit mTOR through allosteric binding to mTORC1, but not mTORC2, and have shown clinical utility in certain cancers. Here, we report the preclinical characterization of OSI-027, a selective and potent dual inhibitor of mTORC1 and mTORC2 with biochemical IC50 values of 22 nmol/L and 65 nmol/L, respectively. OSI-027 shows more than 100-fold selectivity for mTOR relative to PI3Kα, PI3Kβ, PI3Kγ, and DNA-PK. OSI-027 inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo. OSI-027 and OXA-01 (close analogue of OSI-027) potently inhibit proliferation of several rapamycin-sensitive and -insensitive nonengineered and engineered cancer cell lines and also, induce cell death in tumor cell lines with activated PI3K–AKT signaling. OSI-027 shows concentration-dependent pharmacodynamic effects on phosphorylation of 4E-BP1 and AKT in tumor tissue with resulting tumor growth inhibition. OSI-027 shows robust antitumor activity in several different human xenograft models representing various histologies. Furthermore, in COLO 205 and GEO colon cancer xenograft models, OSI-027 shows superior efficacy compared with rapamycin. Our results further support the important role of mTOR as a driver of tumor growth and establish OSI-027 as a potent anticancer agent. OSI-027 is currently in phase I clinical trials in cancer patients. Mol Cancer Ther; 10(8); 1394–406. ©2011 AACR.
KIAA0101 Interacts with BRCA1 and Regulates Centrosome Number
Authors: Kais Zeina , Barsky Sanford H. , Mathsyaraja Haritha , Zha Alicia , Ransburgh Derek J.R. , He Gang , Pilarski Robert T. , Shapiro Charles L. , Huang Kun , Parvin Jeffrey D. 
Published: June 2011

Abstract
To find genes and proteins that collaborate with BRCA1 or BRCA2 in the pathogenesis of breast cancer, we used an informatics approach and found a candidate BRCA interactor, KIAA0101, to function like BRCA1 in exerting a powerful control over centrosome number. The effect of KIAA0101 on centrosomes is likely direct, as its depletion does not affect the cell cycle, KIAA0101 localizes to regions coincident with the centrosomes, and KIAA0101 binds to BRCA1. We analyzed whether KIAA0101 protein is overexpressed in breast cancer tumor samples in tissue microarrays, and we found that overexpression of KIAA0101 correlated with positive Ki67 staining, a biomarker associated with increased disease severity. Furthermore, overexpression of the KIAA0101 gene in breast tumors was found to be associated with significantly decreased survival time. This study identifies KIAA0101 as a protein important for breast tumorigenesis, and as this factor has been reported as a UV repair factor, it may link the UV damage response to centrosome control. Mol Cancer Res; 9(8); 1091–9. ©2011 AACR.
Enhancing Mitochondrial Respiration Suppresses Tumor Promoter TPA-Induced PKM2 Expression and Cell Transformation in Skin Epidermal JB6 Cells
Authors: Wittwer Jennifer A. , Robbins Delira , Wang Fei , Codarin Sarah , Shen Xinggui , Kevil Christopher G. , Huang Ting-Ting , Van Remmen Holly , Richardson Arlan , Zhao Yunfeng 
Published: June 2011

Abstract
Differentiated cells primarily metabolize glucose for energy via the tricarboxylic acid cycle and oxidative phosphorylation, but cancer cells thrive on a different mechanism to produce energy, characterized as the Warburg effect, which describes the increased dependence on aerobic glycolysis. The M2 isoform of pyruvate kinase (PKM2), which is responsible for catalyzing the final step of aerobic glycolysis, is highly expressed in cancer cells and may contribute to the Warburg effect. However, whether PKM2 plays a contributing role during early cancer development is unclear. In our studies, we have made an attempt to elucidate the effects of varying mitochondrial respiration substrates on skin cell transformation and expression of PKM2. Tumorigenicity in murine skin epidermal JB6 P+ (promotable) cells was measured in a soft agar assay using 12-O-tetradecanoylphorbol-13-acetate (TPA) as a tumor promoter. We observed a significant reduction in cell transformation upon pretreatment with the mitochondrial respiration substrate succinate or malate/pyruvate. We observed that increased expression and activity of PKM2 in TPA-treated JB6 P+ cells and pretreatment with succinate or malate/pyruvate suppressed the effects. In addition, TPA treatment also induced PKM2 whereas PKM1 expression was suppressed in mouse skin epidermal tissues in vivo. In comparison with JB6 P+ cells, the nonpromotable JB6 P− cells showed no increase in PKM2 expression or activity upon TPA treatment. Knockdown of PKM2 using a siRNA approach significantly reduced skin cell transformation. Thus, our results suggest that PKM2 activation could be an early event and play a contributing role in skin tumorigenesis. Cancer Prev Res; 4(9); 1476–84. ©2011 AACR.