bluuebunny/crossref_metadata_2025 huggingface dataset:
Basin compartmentalization and drainage evolution during rift inversion: evidence from the Eastern Cordillera of Colombia
Authors: Silva A. , Mora A. , Caballero V. , Rodriguez G. , Ruiz C. , Moreno N. , Parra M. , Ramirez-Arias J. C. , Ibáñez M. , Quintero I.
Published: June 2013

The Cenozoic stratigraphic infill of hinterland and foreland basins in central Colombia holds the record of basin development during tectonic inversion of rift in the context of subduction orogenesis. A comprehensive review of detrital U–Pb geochronologic and thermochronologic data reveals that activation of interconnected fault systems in the hinterland Magdalena Valley and the Eastern Cordillera occurred coevally since Paleocene time. Longitudinal basins were fed by detritus shed from the Central Cordillera carried along axial drainage systems in open basins in times where slow deformation rates prevailed. Faster deformation since Oligocene resulted in the transient formation of internally drained basins. Differential along-strike exhumation and subsidence patterns in the Eastern Cordillera and the foredeep, respectively, document tectonic acceleration since late Miocene, which we attribute to superimposed collision of the Panama arc leading to oroclinal bending in the Cordillera. Our data documents that the inherited structural grain led to the formation of longitudinal drainage patterns, even in closed basins, which seem to be a general feature of early stages of inversion. We hypothesize that the presence of more humid climatic conditions and faster tectonic rates along the range’s eastern margin favoured the development of internally drained basins, as has also been shown in the Central Andes.

Supplementary material:

Methods details (zircon grains preparation, zircon U–Pb measurements, laboratory conditions and input constraints for AFT thermal modelling) and repository are available at
http://www.geolsoc.org.uk/SUP18628
AMPK couples plasma renin to cellular metabolism by phosphorylation of ACC1
Authors: Fraser Scott A. , Choy Suet-Wan , Pastor-Soler Núria M. , Li Hui , Davies Matthew R. P. , Cook Natasha , Katerelos Marina , Mount Peter F. , Gleich Kurt , McRae Jennifer L. , Dwyer Karen M. , van Denderen Bryce J. W. , Hallows Kenneth R. , Kemp Bruce E. , Power David A.
Published: June 2013

Salt reabsorption is the major energy-requiring process in the kidney, and AMP-activated protein kinase (AMPK) is an important regulator of cellular metabolism. Mice with targeted deletion of the β1-subunit of AMPK (AMPK-β1−/− mice) had significantly increased urinary Na+ excretion on a normal salt diet. This was associated with reduced expression of the β-subunit of the epithelial Na+ channel (ENaC) and increased subapical tubular expression of kidney-specific Na+-K+-2Cl− cotransporter 2 (NKCC2) in the medullary thick ascending limb of Henle. AMPK-β1−/− mice fed a salt-deficient diet were able to conserve Na+, but renin secretion increased 180% compared with control mice. Cyclooxygenase-2 mRNA also increased in the kidney cortex, indicating greater signaling through the macula densa tubular salt-sensing pathway. To determine whether the increase in renin secretion was due to a change in regulation of fatty acid metabolism by AMPK, mice with a mutation of the inhibitory AMPK phosphosite in acetyl-CoA carboxylase 1 [ACC1-knockin (KI)S79A mice] were examined. ACC1-KIS79A mice on a normal salt diet had no increase in salt loss or renin secretion, and expression of NKCC2, Na+-Cl− cotransporter, and ENaC-β were similar to those in control mice. When mice were placed on a salt-deficient diet, however, renin secretion and cortical expression of cyclooxygenase-2 mRNA increased significantly in ACC1-KIS79A mice compared with control mice. In summary, our data suggest that renin synthesis and secretion are regulated by AMPK and coupled to metabolism by phosphorylation of ACC1.
Directional information from neuronal ensembles in the primate orofacial sensorimotor cortex
Authors: Arce F. I. , Lee J.-C. , Ross C. F. , Sessle B. J. , Hatsopoulos N. G.
Published: June 2013

Neurons in the arm and orofacial regions of the sensorimotor cortex in behaving monkeys display directional tuning of their activity during arm reaching and tongue protrusion, respectively. While studies on population activity abound for the arm motor cortex, how populations of neurons from the orofacial sensorimotor cortex represent direction has never been described. We therefore examined and compared the directional information contained in the spiking activity of populations of single neurons recorded simultaneously from chronically implanted microelectrode arrays in the orofacial primary motor (MIo, N = 345) and somatosensory (SIo, N = 336) cortices of monkeys ( Macaca mulatta) as they protruded their tongue in different directions. Differential modulation to the direction of tongue protrusion was found in >60% of task-modulated neurons in MIo and SIo and was stronger in SIo ( P < 0.05). Moreover, mutual information between direction and spiking was significantly higher in SIo compared with MIo at force onset and force offset ( P < 0.01). Finally, the direction of tongue protrusion was accurately predicted on a trial-by-trial basis from the spiking activity of populations of MIo or SIo neurons by using a discrete decoder ( P < 0.01). The highly reliable decoding was comparable between MIo and SIo neurons. However, the temporal evolution of the decoding performance differed between these two areas: MIo showed late-onset, fast-rising, and phasic performance, whereas SIo exhibited early-onset, slow-rising, and sustained performance. Overall, the results suggest that both MIo and SIo are highly involved in representing the direction of tongue protrusion but they differ in the amplitude and temporal processing of the directional information distributed across populations of neurons.
SORCS1 contributes to the development of renal disease in rats and humans
Authors: Lazar Jozef , O'Meara Caitlin C. , Sarkis Allison B. , Prisco Sasha Z. , Xu Haiyan , Fox Caroline S. , Chen Ming-Huei , Broeckel Ulrich , Arnett Donna K. , Moreno Carol , Provoost Abraham P. , Jacob Howard J.
Published: June 2013

Many lines of evidence demonstrate that genetic variability contributes to chronic kidney disease susceptibility in humans as well as rodent models. Little progress has been made in discovering causal kidney disease genes in humans mainly due to genetic complexity. Here, we use a minimal congenic mapping strategy in the FHH (fawn hooded hypertensive) rat to identify Sorcs1 as a novel renal disease candidate gene. We investigated the hypothesis that genetic variation in Sorcs1 influences renal disease susceptibility in both rat and human. Sorcs1 is expressed in the kidney, and knocking out this gene in a rat strain with a sensitized genome background produced increased proteinuria. In vitro knockdown of Sorcs1 in proximal tubule cells impaired protein trafficking, suggesting a mechanism for the observed proteinuria in the FHH rat. Since Sorcs1 influences renal function in the rat, we went on to test this gene in humans. We identified associations between single nucleotide polymorphisms in SORCS1 and renal function in large cohorts of European and African ancestry. The experimental data from the rat combined with association results from different ethnic groups indicates a role for SORCS1 in maintaining proper renal function.
Comparison of the Direct Effects of Human Adipose- and Bone-Marrow-Derived Stem Cells on Postischemic Cardiomyoblasts in anIn VitroSimulated Ischemia-Reperfusion Model
Authors: Szepes Mónika , Benkő Zsolt , Cselenyák Attila , Kompisch Kai Michael , Schumacher Udo , Lacza Zsombor , Kiss Levente
Published: June 2013

Regenerative therapies hold a promising and exciting future for the cure of yet untreatable diseases, and mesenchymal stem cells are in the forefront of this approach. However, the relative efficacy and the mechanism of action of different types of mesenchymal stem cells are still incompletely understood. We aimed to evaluate the effects of human adipose- (hASC) and bone-marrow-derived stem cells (hBMSCs) and adipose-derived stem cell conditioned media (ACM) on the viability of cardiomyoblasts in anin vitroischemia-reperfusion (I-R) model. Flow cytometric viability analysis revealed that both cell treatments led to similarly increased percentages of living cells, while treatment with ACM did not (I-R model:12.13±0.75%; hASC:24.66±2.49%; hBMSC:25.41±1.99%; ACM:13.94±1.44%). Metabolic activity measurement (I-R model:0.065±0.033; hASC:0.652±0.089; hBMSC:0.607±0.059; ACM:0.225±0.013; arbitrary units) and lactate dehydrogenase assay (I-R model:0.225±0.006; hASC:0.148±0.005; hBMSC:0.146±0.004; ACM:0.208±0.009; arbitrary units) confirmed the flow cytometric results while also indicated a slight beneficial effect of ACM. Our results highlight that mesenchymal stem cells have the same efficacy when used directly on postischemic cells, and differences found between them in preclinical and clinical investigations are rather related to other possible causes such as their immunomodulatory or angiogenic properties.
Monitor, a Vibrotactile Aid for Environmental Perception: A Field Evaluation by Four People with Severe Hearing and Vision Impairment
Authors: Ranjbar Parivash , Stenström Ingeborg
Published: June 2013

Monitor is a portable vibrotactile aid to improve the ability of people with severe hearing impairment or deafblindness to detect, identify, and recognize the direction of sound‐producing events.
It transforms and adapts sounds to the frequency sensitivity range of the skin. The aid was evaluated in the field. Four females (44–54 years) with Usher Syndrome I (three with tunnel vision and one
with only light perception) tested the aid at home and in traffic in three different field studies: without Monitor, with Monitor with an omnidirectional microphone, and with Monitor with a directional microphone.
The tests were video‐documented, and the two field studies with Monitor were initiated after five weeks of training. The detection scores with omnidirectional and directional microphones were 100% for
three participants and above 57% for one, both in their home and traffic environments. In the home environment the identification scores with the omnidirectional microphone were 70%–97%
and 58%–95% with the directional microphone. The corresponding values in traffic were 29%–100% and 65%–100%, respectively. Their direction
perception was improved to some extent by both microphones. Monitor improved the ability of people with deafblindness to detect, identify, and recognize the direction of events producing sounds.
Extracellular Matrix Degradation and Tissue Remodeling in Periprosthetic Loosening and Osteolysis: Focus on Matrix Metalloproteinases, Their Endogenous Tissue Inhibitors, and the Proteasome
Authors: Syggelos Spyros A. , Aletras Alexios J. , Smirlaki Ioanna , Skandalis Spyros S.
Published: June 2013

The leading complication of total joint replacement is periprosthetic osteolysis, which often results in aseptic loosening of the implant, leading to revision surgery. Extracellular matrix degradation and connective tissue remodeling around implants have been considered as major biological events in the periprosthetic loosening. Critical mediators of wear particle-induced inflammatory osteolysis released by periprosthetic synovial cells (mainly macrophages) are inflammatory cytokines, chemokines, and proteolytic enzymes, mainly matrix metalloproteinases (MMPs). Numerous studies reveal a strong interdependence of MMP expression and activity with the molecular mechanisms that control the composition and turnover of periprosthetic matrices. MMPs can either actively modulate or be modulated by the molecular mechanisms that determine the debris-induced remodeling of the periprosthetic microenvironment. In the present study, the molecular mechanisms that control the composition, turnover, and activity of matrix macromolecules within the periprosthetic microenvironment exposed to wear debris are summarized and presented. Special emphasis is given to MMPs and their endogenous tissue inhibitors (TIMPs), as well as to the proteasome pathway, which appears to be an elegant molecular regulator of specific matrix macromolecules (including specific MMPs and TIMPs). Furthermore, strong rationale for potential clinical applications of the described molecular mechanisms to the treatment of periprosthetic loosening and osteolysis is provided.
Clinically Classified Periodontitis and Its Association in Patients with Preexisting Coronary Heart Disease
Authors: Chrysanthakopoulos Nikolaos A. , Chrysanthakopoulos Panagiotis A.
Published: June 2013

The aim of this retrospective study was to investigate possible associations
between clinically classified periodontitis as determined by assessing its
severity and diagnosed coronary heart disease in outpatients referred to a specialist
clinic for neurosurgery treatment. A total of 2,912 individuals were clinically
examined for periodontal disease experience by using probing pocket depth (PPD)
and clinical attachment loss (CAL). Socioeconomic, oral health behaviour, and
general health related information was collected by using a self-administered
questionnaire. Statistical analysis of the questionnaire items was performed by
using multivariate logistic regression analysis model. The results showed that the
occurrence of hypertension (OR=2.42, 95% CI = 1.52–3.84), smoking (OR=1.97, 95% CI = 1.25–3.11), classified periodontitis (OR=1.79, 95% CI = 1.15–2.77), and the high level of serum C-reactive protein (OR=1.74, 95% CI = 1.05–2.89) were significantly associated with the presence of coronary heart disease. These observations strengthen the role of some of the traditional causative risk factors for coronary heart disease while a significant association was recorded between diagnosed coronary heart disease and clinically classified periodontitis which is considered as a risk factor for coronary heart disease.
Multilevel Tunnelling Systems and Fractal Clustering in the Low‐Temperature Mixed Alkali‐Silicate Glasses
Authors: Jug Giancarlo , Paliienko Maksym
Published: June 2013

The thermal and dielectric anomalies of window‐type glasses at low temperatures (T < 1 K) are rather successfully explained by the two‐level systems (2LS) standard tunneling model (STM). However, the magnetic effects discovered in the multisilicate glasses in recent times, magnetic effects in the organic glasses, and also some older data from mixed (SiO2)1−x(K2O)x and (SiO2)1−x(Na2O)x glasses indicate the need for a suitable extension of the 2LS‐STM. We show that—not only for the magnetic effects, but also for the mixed glasses in the absence of a field—the right extension of the 2LS‐STM is provided by the (anomalous) multilevel tunnelling systems (ATS) proposed by one of us for multicomponent amorphous solids. Though a secondary type of TS, different from the standard 2LS, was invoked long ago already, we clarify their physical origin and mathematical description and show that their contribution considerably improves the agreement with the experimental data. In spite of dealing with low‐temperature properties, our work impinges on the structure and statistical physics of glasses at all temperatures.
The Impact of RFID Investment on Complex Product in Three-Level Assembly Supply Chain
Authors: Xu Wei , Lian Zhaotong , Yao Xifan
Published: June 2013

Motivated by the complex product with the feature about error-prone assembly system and supply chain inventory inaccuracy, this paper elaborates on the impact of information technology investment on complex product by establishing a three-stage supply chain model involving two suppliers, one manufacturer, and retailer which carried out Stackelberg games. In addition, it not only compares the manufacturer and the retailer’s optimal decision and maximum profit under the situation of the information asymmetry and free information sharing, but also analyzes their market behavior and changes in market performance. Meanwhile, it points out that the downstream in supply chain masters more information about market demands compared to the upstream one. The optimal cost threshold values of technology investment are also examined both for the centralized and the decentralized scenarios utilizing quantitative and modeling methods. By analyzing and comparing the optimal profit with or without investment on information technology, it establishes a supply chain coordination model which boosts the application of information technology. At the same time, it offers the conditions on which the upstream and downstream enterprises can coordinate with one another. The results of this paper have contributed significantly to making the price and ordering decisions on whether RFID should be adopted among members of the supply chain. Finally, we present numerical analyses, and several extensions of the model are considered as well.
Effects of Electromagnetic Fields on Osteogenesis of Human Alveolar Bone-Derived Mesenchymal Stem Cells
Authors: Lim KiTaek , Hexiu Jin , Kim Jangho , Seonwoo Hoon , Cho Woo Jae , Choung Pill-Hoon , Chung Jong Hoon
Published: June 2013

This study was performed to investigate the effects of extremely low frequency pulsed electromagnetic fields (ELF-PEMFs) on the proliferation and differentiation of human alveolar bone-derived mesenchymal stem cells (hABMSCs). Osteogenesis is a complex series of events involving the differentiation of mesenchymal stem cells to generate new bone. In this study, we examined not merely the effect of ELF-PEMFs on cell proliferation, alkaline phosphatase (ALP) activity, and mineralization of the extracellular matrix but vinculin, vimentin, and calmodulin (CaM) expressions in hABMSCs during osteogenic differentiation. Exposure of hABMSCs to ELF-PEMFs increased proliferation by 15% compared to untreated cells at day 5. In addition, exposure to ELF-PEMFs significantly increased ALP expression during the early stages of osteogenesis and substantially enhanced mineralization near the midpoint of osteogenesis within 2 weeks. ELF-PEMFs also increased vinculin, vimentin, and CaM expressions, compared to control. In particular, CaM indicated that ELF-PEMFs significantly altered the expression of osteogenesis-related genes. The results indicated that ELF-PEMFs could enhance early cell proliferation in hABMSCs-mediated osteogenesis and accelerate the osteogenesis.
A New Approach to Detect Epileptic Seizures in Electroencephalograms Using Teager Energy
Authors: Kamath Chandrakar
Published: June 2013

A Teager energy (TE) based approach to discriminate electroencephalogram signals corresponding to nonseizure (eyes open, eyes closed, or interictal) and seizure (ictal) intervals is proposed. Though a good number of contributions have been made for seizure detection, the challenges of unbalanced data (nonseizure and seizure events) and system computational efficiency still remain a challenge. It is reported in the literature that the seizures are characterized by abnormal sudden discharges in the brain which get manifested in the EEG recordings by frequency changes and increased amplitudes. Teager energy (TE) is capable of tracking such rapid changes in frequency as well as amplitude in the time domain. An important finding of this study is that the mean TE quantifier is largely independent of the window length and exhibits relative consistency when used as a relative measure for comparison. We compared the diagnostic capability of TE quantifier with those of Higuchi’s fractal dimension and sample entropy in discriminating nonseizure and seizure states in the EEGs and found that TE outperforms the other two nonlinear quantifiers. The result shows that the application of this method compares favorably with conventional classification methods in terms of performance and is well suited for real-time automatic epileptic seizure detection.
Complex Dynamical Behaviors in a Predator-Prey System with Generalized Group Defense and Impulsive Control Strategy
Authors: Li Shunyi
Published: June 2013

A predator-prey system with generalized group defense and impulsive control strategy is investigated. By using Floquet theorem and small amplitude perturbation skills, a local asymptotically stable prey-eradication periodic solution is obtained when the impulsive period is less than some critical value. Otherwise, the system is permanent if the impulsive period is larger than the critical value. By using bifurcation theory, we show the existence and stability of positive periodic solution when the pest eradication lost its stability. Numerical examples show that the system considered has more complicated dynamics, including (1) high-order quasiperiodic and periodic oscillation, (2) period-doubling and halving bifurcation, (3) nonunique dynamics (meaning that several attractors coexist), and (4) chaos and attractor crisis. Further, the importance of the impulsive period, the released amount of mature predators and the degree of group defense effect are discussed. Finally, the biological implications of the results and the impulsive control strategy are discussed.
MMP-3 Contributes to Nigrostriatal Dopaminergic Neuronal Loss, BBB Damage, and Neuroinflammation in an MPTP Mouse Model of Parkinson’s Disease
Authors: Chung Young Cheul , Kim Yoon-Seong , Bok Eugene , Yune Tae Young , Maeng Sungho , Jin Byung Kwan
Published: June 2013

The present study examined whether matrix metalloproteinase-3 (MMP-3) participates in the loss of dopaminergic (DA) neurons in the nigrostriatal pathway in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease with blood brain barrier (BBB) damage and infiltration of peripheral immune cells. Tyrosine hydroxylase (TH) immunostaining of brain sections from MPTP-treated mice showed that MPTP induced significant degeneration of nigrostriatal DA neurons. Moreover, FITC-labeled albumin detection and immunostaining revealed that MPTP caused damage to the BBB and increased the number of ED-1- and CD-3-immunopositive cells in the substantia nigra (SN). Genetic ablation of MMP-3 reduced the nigrostriatal DA neuron loss and improved motor function. This neuroprotective effect afforded by MMP-3 deletion was associated with the suppression of BBB disruption and a decrease in the number of ED-1- and CD-3-immunopositive cells in the SN. These data suggest that MMP-3 could play a crucial role in neurodegenerative diseases such as PD in which BBB damage and neuroinflammation are implicated.
Rossomyrmex, the Slave-Maker Ants from the Arid Steppe Environments
Authors: Ruano F. , Sanllorente O. , Lenoir A. , Tinaut A.
Published: June 2013

The host-parasite generaProformica-Rossomyrmexpresent four pairs of species with a very wide range of distribution from China to Southeastern Spain, from huge extended plains to the top of high mountains. Here we review (1) the published data on these pairs in comparison to other slave-makers; (2) the different dispersal ability in hosts and parasites inferred from genetics (chance of migration conditions the evolutionary potential of the species); (3) the evolutionary potential of host and parasite determining the coevolutionary process in each host-parasite system that we treat to define using cuticular chemical data. We find a lower evolutionary potential in parasites than in hosts in fragmented populations, where selective pressures give advantage to a limited female parasite migration due to uncertainty of locating a host nest. A similar evolutionary potential is detected for hosts and parasites when the finding of host nests is likely (i.e., in continuous and extended populations). Moreover, some level of local adaptation at CHC profiles between host and parasite exists independently of the kind of geographic distribution and the ability of dispersal of the different populations. Similarity at CHC profiles appears to be a trait imposed by natural selection for the interaction between hosts and slave-makers.
Minimally Modified LDL Upregulates Endothelin Type A Receptors in Rat Coronary Arterial Smooth Muscle Cells
Authors: Li Jie , Cao Lei , Xu Cang-Bao , Wang Jun-Jie , Cao Yong-Xiao
Published: June 2013

Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular disease. The present study investigated the effects of mmLDL on the expression of endothelin type A () receptors in coronary arteries. Rat coronary arteries were organ-cultured for 24 h. The contractile responses were recorded using a myographic system. receptor mRNA and protein expressions were determined using real-time PCR and western blotting, respectively. The results showed that organ-culturing in the presence of mmLDL enhanced the arterial contractility mediated by the receptor in a concentration-dependent and time-dependent manner. Culturing with mmLDL (10 μg/mL) for 24 h shifted the concentration-contractile curves toward the left significantly with increased of from control of and significantly increased receptor mRNA and protein levels. Inhibition of the protein kinase C, extracellular signal-related kinases 1 and 2 (ERK1/2), or NF-κB activities significantly attenuated the effects of mmLDL. The c-Jun N-terminal kinase inhibitor or the p38 pathway inhibitor, however, had no such effects. The results indicate that mmLDL upregulates the receptors in rat coronary arterial smooth muscle cells mainlyviaactivating protein kinase C, ERK1/2, and the downstream transcriptional factor, NF-κB.
Changes of PBP5 Gene Expression in Enterococcal Isolates from Renal Transplantation Recipients
Authors: Jarzembowski T. , Daca A. , Witkowski J. , Rutkowski B. , Gołębiewska J. , Dębska-Ślizień A.
Published: June 2013

The aim of the study was to evaluate changes in expression of PBP5 gene associated with immunosuppression. A linear locked nucleic acid (LNA) probe was used to measure resistance gene expression by the Flow-FISH method. Expression of the PBP5 gene measured by Flow-FISH was higher in enterococcal strains isolated from renal transplantation (RTx) recipients than in commensal strains. Additionally, in contrast to commensal strains in isolates from RTx patients, PBP5 gene expression was 17.45% higher in biofilms than in planktonic cells. Detailed comparison also showed that cyclosporine seemed to induce higher expression of PBP5 as compared to tacrolimus.
Predicting Subcontractor Performance Using Web‐Based Evolutionary Fuzzy Neural Networks
Authors: Ko Chien-Ho
Published: June 2013

Subcontractor performance directly affects project success. The use of inappropriate subcontractors may result in individual work delays, cost overruns, and quality defects throughout the project. This study develops web‐based Evolutionary Fuzzy Neural Networks (EFNNs) to predict subcontractor performance. EFNNs are a fusion of Genetic Algorithms (GAs), Fuzzy Logic (FL), and Neural Networks (NNs). FL is primarily used to mimic high level of decision‐making processes and deal with uncertainty in the construction industry. NNs are used to identify the association between previous performance and future status when predicting subcontractor performance. GAs are optimizing parameters required in FL and NNs. EFNNs encode FL and NNs using floating numbers to shorten the length of a string. A multi‐cut‐point crossover operator is used to explore the parameter and retain solution legality. Finally, the applicability of the proposed EFNNs is validated using real subcontractors. The EFNNs are evolved using 22 historical patterns and tested using 12 unseen cases. Application results show that the proposed EFNNs surpass FL and NNs in predicting subcontractor performance. The proposed approach improves prediction accuracy and reduces the effort required to predict subcontractor performance, providing field operators with web‐based remote access to a reliable, scientific prediction mechanism.
Asymptotic -Algebras from -Actions on Higher Rank Graphs
Authors: Yi Inhyeop
Published: June 2013

For a dynamical system arising from -action on a higher rank graph with finite vertex set, we show that the semidirect product of the asymptotic equivalence relation groupoid is essentially principal if and only if the -graph satisfies the aperiodic condition. Then we show that the corresponding asymptotic Ruelle algebra is simple if the graph is primitive with the aperiodic condition.
Vaginal Colonization bypapGAllele II+Escherichia coliIsolates from Pregnant and Nonpregnant Women as Predisposing Factor to Pyelonephritis
Authors: Al-Mayahie Sareaa Maseer Gatya
Published: June 2013

Vaginal (61) and fecal (61)Escherichia coliisolates from pregnant and nonpregnant women (18–45 years old) were surveyed forpapGalleles by PCR technique.papGallele II was the most prevalent among both vaginal (32.7%) and fecal (3.2%) isolates, whereas other alleles were found only among vaginal isolates (1.6% for alleles I and III and 3.2% for alleles II + III).papG+pregnant women's isolates did not differ significantly from those of nonpregnant in possession ofpapGallele II (90% versus 73.3%), whereas both (32.7%) differed significantly (P≤0.05) in comparison with fecal isolates (3.2%). The vast majority ofpapGallele II+vaginal isolates were clustered in group B2 (81.8%) and much less in group D (18.1%). Also, most of them were positive forfimH(100%),papC(100%),iucC(90.9%), andhly(72.7%), and about half of them were positive forsfa/foc(45.4%). In addition, the mean of VFs' gene possession was 3.5 (range from 2 to 5). It can be concluded that vaginal colonization bypapGallele II+E. coliis possibly one of the predisposing factors of both pregnant and nonpregnant women to pyelonephritis, but its potential may be modified by other factors especially host factors.
RG7116, a Therapeutic Antibody That Binds the Inactive HER3 Receptor and Is Optimized for Immune Effector Activation
Authors: Mirschberger Christian , Schiller Christian B. , Schräml Michael , Dimoudis Nikolaos , Friess Thomas , Gerdes Christian A. , Reiff Ulrike , Lifke Valeria , Hoelzlwimmer Gabriele , Kolm Irene , Hopfner Karl-Peter , Niederfellner Gerhard , Bossenmaier Birgit
Published: June 2013

The EGF receptor (EGFR) HER3 is emerging as an attractive cancer therapeutic target due to its central position in the HER receptor signaling network. HER3 amplifies phosphoinositide 3-kinase (PI3K)–driven tumorigenesis and its upregulation in response to other anti-HER therapies has been implicated in resistance to them. Here, we report the development and characterization of RG7116, a novel anti-HER3 monoclonal antibody (mAb) designed to block HER3 activation, downregulate HER3, and mediate enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) via glycoengineering of the Fc moiety. Biochemical studies and X-ray crystallography revealed that RG7116 bound potently and selectively to domain 1 of human HER3. Heregulin binding was prevented by RG7116 at concentrations more than 1 nmol/L as was nearly complete inhibition of HER3 heterodimerization and phosphorylation, thereby preventing downstream AKT phosphorylation. In vivo RG7116 treatment inhibited xenograft tumor growth up to 90% relative to controls in a manner accompanied by downregulation of cell surface HER3. RG7116 efficacy was further enhanced in combination with anti-EGFR (RG7160) or anti-HER2 (pertuzumab) mAbs. Furthermore, the ADCC potency of RG7116 was enhanced compared with the nonglycoengineered parental antibody, both in vitro and in orthotopic tumor xenograft models, where an increased median survival was documented. ADCC degree achieved in vitro correlated with HER3 expression levels on tumor cells. In summary, the combination of strong signaling inhibition and enhanced ADCC capability rendered RG7116 a highly potent HER3-targeting agent suitable for clinical development. Cancer Res; 73(16); 5183–94. ©2013 AACR.
The Association of High-Density Lipoprotein Cholesterol with Cancer Incidence in Type II Diabetes: A Case of Reverse Causality?
Authors: Morton Jamie , Ng Martin K.C. , Chalmers John , Woodward Mark , Mancia Giuseppe , Poulter Neil R. , Marre Michel , Cooper Mark E. , Zoungas Sophia ,   for the ADVANCE collaborative group
Published: June 2013

Background: Low high-density lipoprotein cholesterol (HDL-C) and type II diabetes are associated with an increased risk for cancer. Patients with type II diabetes typically have low HDL-C; however, the association between HDL-C and cancer has not been examined in this population.

Methods: A total of 11,140 patients with type II diabetes were followed for a median of 5 years. Cox proportional hazard models were used to assess the association between baseline HDL-C and risk of cancer incidence and cancer death, with adjustments made for potential confounders. To explore the possibility of reverse causation, analyses were repeated for the cancers occurring in the first and second halves of follow-up.

Results: Six hundred and ninety-nine patients developed cancer, with 48% occurring within the first half of follow-up. For every 0.4 mmol/L lower baseline HDL-C, there was a 16% higher risk of cancer [HR 1.16; 95% confidence interval (CI), 1.06–1.28; P = 0.0008] and cancer death (HR 1.16; 95% CI, 1.01–1.32; P = 0.03). After adjustment for confounding, the higher risk remained significant for cancer (adjusted HR 1.10; 95% CI, 1.00–1.22; P = 0.05) but not for cancer death (adjusted HR 1.08; 95% CI, 0.93–1.25; P = 0.31). The association was driven by cancers occurring within the first half of follow-up (adjusted HR 1.22; 95% CI, 1.05–1.41; P = 0.008) as no significant association was found between HDL-C and cancer in the second half of follow-up.

Conclusions: Low HDL-C is associated with cancer risk in patients with type II diabetes. However, this association may be explained by confounding and reverse causation.

Impact: HDL-C is not a risk factor for cancer in type II diabetes. Cancer Epidemiol Biomarkers Prev; 22(9); 1628–33. ©2013 AACR.
Serum Proteoglycans as Prognostic Biomarkers of Hepatocellular Carcinoma in Patients with Alcoholic Cirrhosis
Authors: Nault Jean-Charles , Guyot Erwan , Laguillier Christelle , Chevret Sylvie , Ganne-Carrie Nathalie , N'Kontchou Gisèle , Beaugrand Michel , Seror Olivier , Trinchet Jean-Claude , Coelho Jessica , Lasalle Philippe , Charnaux Nathalie , Delehedde Maryse , Sutton Angela , Nahon Pierre
Published: June 2013

Background: Proteoglycans are involved in neoangiogenesis and transduction of oncogenic signals, two hallmarks of carcinogenesis.

Methods: This study sought to assess the prognostic value of serum levels of three proteoglycans (endocan, syndecan-1, and glypican-3) and VEGF in 295 patients with alcoholic cirrhosis: 170 without hepatocellular carcinoma, 58 with early hepatocellular carcinoma, and 67 with advanced hepatocellular carcinoma at inclusion. We analyzed the association between proteoglycan levels and prognosis using Kaplan–Meier and Cox methods.

Results: Serum levels of the three proteoglycans and VEGF were increased in patients with advanced hepatocellular carcinoma compared with those without hepatocellular carcinoma or with early hepatocellular carcinoma. In multivariate analysis, high levels of serum endocan (>5 ng/mL) were independently associated with death [HR, 2.84; 95% confidence interval (CI,) 1.18–6.84; P = 0.02], but not with hepatocellular carcinoma occurrence, in patients without hepatocellular carcinoma at baseline. High serum endocan (>5 ng/mL) and syndecan-1 (>50 ng/mL) levels were significantly associated with greater risk of tumor recurrence (P = 0.025) in patients with early hepatocellular carcinoma treated by radiofrequency ablation. In patients with advanced hepatocellular carcinoma, high serum levels of endocan (P = 0.004) and syndecan-1 (P = 0.006) were significantly associated with less favorable overall survival. However, only a high level of serum syndecan-1 (>50 ng/mL) was independently associated with greater risk of death (HR, 6.21 95% CI, 1.90–20.30; P = 0.0025).

Conclusion: Serum endocan and syndecan-1 are easily assessable prognostic serum biomarkers of overall survival in alcoholic cirrhosis with and without hepatocellular carcinoma.

Impact: These new biomarkers will be useful to manage patients with hepatocellular carcinoma developed on alcoholic cirrhosis. Cancer Epidemiol Biomarkers Prev; 22(8); 1343–52. ©2013 AACR.
A Clinically Relevant Androgen Receptor Mutation Confers Resistance to Second-Generation Antiandrogens Enzalutamide and ARN-509
Authors: Joseph James D. , Lu Nhin , Qian Jing , Sensintaffar John , Shao Gang , Brigham Dan , Moon Michael , Maneval Edna Chow , Chen Isan , Darimont Beatrice , Hager Jeffrey H.
Published: June 2013

Despite the impressive clinical activity of the second-generation antiandrogens enzalutamide and ARN-509 in patients with prostate cancer, acquired resistance invariably emerges. To identify the molecular mechanisms underlying acquired resistance, we developed and characterized cell lines resistant to ARN-509 and enzalutamide. In a subset of cell lines, ARN-509 and enzalutamide exhibit agonist activity due to a missense mutation (F876L) in the ligand-binding domain of the androgen receptor (AR). AR F876L is sufficient to confer resistance to ARN-509 and enzalutamide in in vitro and in vivo models of castration-resistant prostate cancer (CRPC). Importantly, the AR F876L mutant is detected in plasma DNA from ARN-509–treated patients with progressive CRPC. Thus, selective outgrowth of AR F876L is a clinically relevant mechanism of second-generation antiandrogen resistance that can potentially be targeted with next-generation antiandrogens.

Significance: A missense mutation in the ligand-binding domain of the androgen receptor F876L confers resistance to the second-generation antiandrogens enzalutamide and ARN-509 in preclinical models of AR function and prostate cancer and is detected in plasma DNA from ARN-509–treated patients with progressive disease. These results chart a new path for the discovery and development of next-generation antiandrogens that could be coupled with a blood-based companion diagnostic to guide treatment decisions. Cancer Discov; 3(9); 1020–9. ©2013 AACR.

See related commentary by Nelson and Yegnasubramanian, p. 971

This article is highlighted in the In This Issue feature, p. 953
Computational Model to Probe Cellular Mechanics during Epithelial-Mesenchymal Transition
Authors: Vargas Diego A. , Bates Oliver , Zaman Muhammad H.
Published: June 2013

During the epithelial to mesenchymal transition (EMT), polarized cells in the epithelium can undergo a transformation characterized by the loss of cell-cell junctions and increased migratory activity into nonpolarized invasive cells. These cells adopt a mesenchymal shape and migrate into the basal lamina. Such transitions have been observed in developmental processes and have been linked to cancer cell metastasis. Most experimental studies on EMT search for molecular markers indicating an epithelial or mesenchymal conformation, focussing on afferent signaling pathways received by cells undergoing this transformation; however, these approaches are unable to track mechanical changes in the cell and the possible role this plays in EMT. In order to address this gap in our understanding, we have used a quantitative approach to study population level effects of single cell changes typically occurring during EMT. We have developed a computational model making use of the advantages of both single cell migratory models and agent-based cell population models to study the effect of cellular molecular processes in EMT. The disruption of a cell sheet representing the epithelium over a dense extracellular matrix (ECM) is simulated using interaction forces between different cells and between cells and discrete fibers representing the ECM. In our study, two different parameters were varied: protrusion force magnitude and E-cadherin (cell-cell junction) concentration. The cell population was tracked for 3 days and the number of cells that leave the layer, the depth of invasion, and the percentage of initial number of cells that remain in the layer (a measure of epithelium disruption) were monitored. Our studies suggest that having a high protrusion force or a reduction in cell-cell attachments is enough to cause EMT. Our results also demonstrate that the morphological progression in membrane disruption has an effect on the number of cells becoming invasive, with epithelial layers broken into clusters hindering the further exodus of cells. The results reveal the quantitative interplay between two key parameters involved in EMT and suggest potential avenues for further exploration of a systems level understanding of EMT.
Validation of a Parental Questionnaire to Identify Atopic Dermatitis in a Population-Based Sample of Children up to 2 Years of Age
Authors: von Kobyletzki L.B. , Berner A. , Carlstedt F. , Hasselgren M. , Bornehag C.G. , Svensson Å.
Published: June 2013

Background: Validated eczema questionnaires have been available for schoolchildren only, but the incidence of atopic dermatitis (AD) is highest during infancy. Objective: To validate a parental questionnaire to identify AD in children up to 2 years of age. Methods: Parents of 476 children answered a written questionnaire prior to an examination by a physician. Sensitivity, specificity, predictive values and test-retest reliability of the questionnaire were assessed. Results: A total of 245 (51%) girls and 231 (49%) boys, aged 1-24 months, with and without physician-diagnosed AD participated. Seventy-one children (15%) had physician-diagnosed AD. Validation of the questionnaire by comparisons with physicians' diagnoses showed a sensitivity of 0.87 (95% confidence interval, CI, 0.77-0.94) and a specificity of 0.98 (95% CI, 0.96-0.99). The positive predictive value was 0.90 (95% CI, 0.80-0.96) and the negative predictive value was 0.98 (95% CI, 0.96-0.99). Conclusion: The questionnaire identified AD in children aged 0-2 years with high accuracy.
A Kampo (Traditional Japanese Herbal) Medicine, Hochuekkito, Pretreatment in Mice Prevented Influenza Virus Replication Accompanied with GM-CSF Expression and Increase in Several Defensin mRNA Levels
Authors: Dan Katsuaki , Akiyoshi Hiroko , Munakata Kaori , Hasegawa Hideki , Watanabe Kenji
Published: June 2013

A Kampo medicine, Hochuekkito (TJ-41), with an influenza virus-preventing effect had life-extending effectiveness, and immunological responses other than interferon (IFN)-α release were examined. TJ-41 (1 g/kg) was given to C57BL/6 male mice orally once a day for 2 weeks. Mice were then intranasally infected with influenza virus. After infection, virus titers and various parameters, mRNA levels and protein expression, for immunoresponses in the bronchoalveolar lavage fluid or removed lung homogenate, were measured by plaque assay, quantitative RT-PCR and ELISA. IFN-α and -β levels of TJ-41-treated mice were higher than those of the control. Toll-like receptor TLR7 and TLR9 mRNAs were elevated after infection, but retinoic acid-inducible gene (RIG-1) family mRNA levels, RIG-1, melanoma differentiation-associated gene 5 and Leishmania G protein 2 showed no response in either TJ-41 or control groups. Interferon regulatory transcription factor (IRF)-3 mRNA levels to stimulate type I (α/β) IFN were increased, but IRF-7 did not change. Only granulocyte-macrophage colony-stimulating factor (GM-CSF) after Hochuekkito treatment was significantly elevated 2 and 3 days after infection. The mRNA levels of 7 defensins after infection increased compared to preinfection values. The key roles of TJ-41 were not only stimulation of type I IFN release but also GM-CSF-derived anti-inflammation activity. Furthermore, defensin (antimicrobial peptide) mRNA levels increased by infection and were further enhanced by TJ-41 treatment. Defensin might prevent influenza virus replication.
IGF2 Methylation Is Associated with Lipid Profile in Obese Children
Authors: Deodati Annalisa , Inzaghi Elena , Liguori Alice , Puglianiello Antonella , Germani Daniela , Brufani Claudia , Fintini Danilo , Cappa Marco , Barbetti Fabrizio , Cianfarani Stefano
Published: June 2013

Aim: Our aim was to investigate the relationships between the degree of IGF2 methylation and the metabolic status in obese children and adolescents. Subjects and Methods: Eighty-five obese subjects aged 11.6 ± 2.1 years were studied. Anthropometry, metabolic parameters, blood pressure and body composition were assessed. DNA methylation analysis was performed by restriction enzyme digestion assay. The study population was subdivided into two groups according to the percentage of IGF2 cytidine-guanosine (CpG) island methylation. Results: Twenty-two subjects showed intermediate methylation (a percentage of CpG site methylation comprised between 10 and 60%), 56 were hypomethylated (percentage of methylation lower than 10%), and only 1 showed a high rate of hypermethylation (percentage of methylation above 60%). Children with intermediate methylation showed significantly higher levels of triglycerides (107.6 ± 41.99 vs. 76.6 ± 30.18 mg/dl, p < 0.005) and a higher triglyceride/high-density lipoprotein-cholesterol ratio (2.23 ± 0.98 vs. 1.79 ± 0.98, p < 0.02) compared with hypomethylated children. Conclusions: These preliminary findings show for the first time a relationship between IGF2 methylation pattern and lipid profile in obese children. Although the correlation does not imply causation, if our findings are confirmed in further studies, IGF2 methylation might represent an epigenetic marker of metabolic risk.
Behandlung eines Oneiroids in Alpträumen mit einer standardisierten Alptraumtherapie
Authors: Thünker Johanna , Pietrowsky Reinhard
Published: June 2013

Hintergrund: Dargestellt wird die Anwendung einer standardisierten Alptraumtherapie bei einem Patienten mit posttraumatischer Belastungsstörung (PTBS). Falldarstellung: Inhalt der posttraumatischen Alpträume waren dabei Oneiroide, d.h. bizarre Illusionen und Halluzinationen mit ausgeprägtem Wirklichkeitscharakter, die im Rahmen einer mehrwöchigen intensivmedizinischen Behandlung auftraten. Die Alptraumtherapie wurde zusätzlich zu einer Behandlung der PTBS und einer depressiven Symptomatik durchgeführt und basierte auf dem Ansatz der «imagery rehearsal therapy». Schlussfolgerung: Durch die Behandlung gelang es, die Anzahl der Alpträume und ihre Intensität abzumildern. Dieser Effekt hielt auch über einen Katamnesezeitraum von 10 Wochen an.
The Mechanism and Physiological Function of Macroautophagy
Authors: Klionsky Daniel J. , Codogno Patrice
Published: June 2013

With regard to cell biology, one area of focus that has shifted back and forth over the years has been the relative emphasis on catabolic versus anabolic processes: the breakdown of glucose, the synthesis of DNA, the oxidation of pyruvate, the biogenesis of membranes, protein degradation, and protein synthesis. Historically, the majority of studies concerned with degradation dealt with the production of energy; however, the analysis of the ubiquitin-proteasome system revealed the importance of protein degradation for controlling various aspects of cell physiology. The ubiquitin-proteasome system is limited primarily to targeting individual proteins for destruction, but cells also have to deal with larger structures that are damaged, potentially toxic or superfluous, and these substrates, including entire organelles, are the purview of autophagy. As a general definition, autophagy encompasses a range of processes in which the cell degrades parts of itself within the lysosome (or the analogous organelle, the vacuole, in yeast and plants), followed by the release and reuse of the breakdown products. Thus, autophagy is in part a mechanism for cellular recycling, but such a definition belies the importance of the different autophagic processes in cell and organismal function and homeostasis. Indeed, defects in autophagy are associated with many human diseases and metabolic disorders. Here, we provide a brief overview of the mechanism of autophagy and some of the physiological roles in which this process is involved.