Miracle-dz/UniFAR-FTUs huggingface dataset:
Physiological calcium concentrations regulate calmodulin binding and catalysis of adenylyl cyclase exotoxins

Edema factor (EF) and CyaA are calmodulin (CaM)‐activated adenylyl cyclase exotoxins involved in the pathogenesis of anthrax and whooping cough, respectively. Using spectroscopic, enzyme kinetic and surface plasmon resonance spectroscopy analyses, we show that low Ca2+ concentrations increase the affinity of CaM for EF and CyaA causing their activation, but higher Ca2+ concentrations directly inhibit catalysis. Both events occur in a physiologically relevant range of Ca2+ concentrations. Despite the similarity in Ca2+ sensitivity, EF and CyaA have substantial differences in CaM binding and activation. CyaA has 100‐fold higher affinity for CaM than EF. CaM has N‐ and C‐terminal globular domains, each binding two Ca2+ ions. CyaA can be fully activated by CaM mutants with one defective C‐terminal Ca2+‐binding site or by either terminal domain of CaM while EF cannot. EF consists of a catalytic core and a helical domain, and both are required for CaM activation of EF. Mutations that decrease the interaction of the helical domain with the catalytic core create an enzyme with higher sensitivity to Ca2+–CaM activation. However, CyaA is fully activated by CaM without the domain corresponding to the helical domain of EF.
Comparing Classical Community Models: Theoretical Consequences for Patterns of Diversity

Mechanisms proposed to explain the maintenance of species diversity within ecological communities of sessile organisms include niche differentiation mediated by competitive trade‐offs, frequency dependence resulting from species‐specific pests, recruitment limitation due to local dispersal, and a speciation‐extinction dynamic equilibrium mediated by stochasticity (drift). While each of these processes, and more, have been shown to act in particular communities, much remains to be learned about their relative importance in shaping community‐level patterns. We used a spatially‐explicit, individual‐based model to assess the effects of each of these processes on species richness, relative abundance, and spatial patterns such as the species‐area curve. Our model communities had an order‐of‐magnitude more individuals than any previous such study, and we also developed a finite‐size scaling analysis to infer the large‐scale properties of these systems in order to establish the generality of our conclusions across system sizes. As expected, each mechanism can promote diversity. We found some qualitative differences in community patterns across communities in which different combinations of these mechanisms operate. Species‐area curves follow a power law with short‐range dispersal and a logarithmic law with global dispersal. Relative‐abundance distributions are more even for systems with competitive differences and trade‐offs than for those in which all species are competitively equivalent, and they are most even when frequency dependence (even if weak) is present. Overall, however, communities in which different processes operated showed surprisingly similar patterns, which suggests that the form of community‐level patterns cannot in general be used to distinguish among mechanisms maintaining diversity there. Nevertheless, parameterization of models such as these from field data on the strengths of the different mechanisms could yield insight into their relative roles in diversity maintenance in any given community.
Understanding ICT adoption in the small firm sector in Southern Africa

Purpose – This paper aims to examine information and communications technology (ICT) adoption among small hotel businesses in South Africa, Botswana and Zimbabwe.Design/methodology/approach – This qualitative research is based on seven case studies that fall within the South African and European Union small and medium enterprises (SMEs) definitions. The case studies are constructed on the basis of 60 semi‐structured interviews and supporting secondary data. The authors adopt the Gibbs et al. model which identifies and brings together ICT adoption factors that include government role, environmental attributes, owner/manager attributes, organisational attributes and social networks. Archer's epistemological bootstrapping technique is applied for analysing the data. In addition, Zappala and Gray's stage model is used to gauge the level of ICT uptake reached by each case study. In this way, the authors incorporate an important additional element for examining ICT adoption.Findings – Apart from providing rich .
Knockdown of VEGFR2 Inhibits Proliferation and Induces Apoptosis in Hemangioma-Derived Endothelial Cells

Angiogenesis is a process of development and growth of new capillary blood vessels from pre-existing vessels. Angiogenic growth factors play important roles in the development and maintenance of some malignancies, of which vascular endothelial growth factor (VEGF)/VEGFR2 interactions are involved in proliferation, migration, and survival of many cancer cells. The aim of this study was to investigate the function of VEGFR2 in human hemangiomas (HAs). Using immunohistochemistry assay, we examined the expression levels of VEGF, VEGFR2, Ki-67, glucose transporter-1 (Glut-1), phosphorylated protein kinase B (p-AKT) and p-ERK in different phases of human HAs. Positive expression of VEGF, VEGFR2, Ki-67, Glut-1, p-AKT and p-ERK was significantly increased in proliferating phase HAs, while decreased in involuting phase HAs (P=0.001; P=0.003). In contrast, cell apoptotic indexes were decreased in proliferating phase HAs, but increased in involuting phase HAs (P<0.01). Furthermore, we used small hairpin RNA (shRNA)-mediated VEGFR2 knockdown in primary HA-derived endothelial cells (HemECs) to understand the role of VEGF/VEGFR2 signaling. Knockdown of VEGFR2 by Lv-shVEGFR2 inhibited cell viability and induced apoptosis in primary HemECs companied with decreased expression of p-AKT, p-ERK, p-p38MAPK and Ki-67 and increased expression of caspase-3 (CAS-3); Overexpression of VEGFR2 promoted cell viability and blocked apoptosis in Lv-VEGFR2-transfected HemECs. Taken together, our findings demonstrate that, increased expression of VEGFR2 is involved in the development of primary HemECs possibly through regulation of the AKT and ERK pathways, suggesting that VEGFR2 may be a potential therapeutic target for HAs.
Genome‐wide screening of loci associated with drug resistance to 5‐fluorouracil‐based drugs

Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome‐wide correlation analysis between DNA copy number and antitumor activity against 5‐fluorouracil (5‐FU)‐based drugs (S‐1, tegafur + uracil [UFT], 5′‐DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nuceotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5‐FU‐based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5‐FU‐based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response. (Cancer Sci 2007; 98: 577–583)
Comparison of human eosinophils from normals and patients with eosinophilia.

Previous studies of the biochemistry and physiology of eosinophils have relied upon cells obtained from patients with eosinophilia (EE). It is unknown whether such cells might have been activated or partially exhausted by the pathological state causing eosinophilia. We examined cell surface charge, membrane transport of deoxyglucose, activation of lyso-somal acid phosphatase, and oxidative metabolism to provide a profile to compare EE with purified normal eosinophils (NE) and normal neutrophils. Eosinophils or neutrophils were obtained in >95% purity from normal individuals and patients with eosinophilia of diverse etiologies. Cell surface charge was determined by electrophoretic mobility in micromoles per second per volt per centimeter. Normal eosinophils demonstrated a surface charge of 2.46+/-0.03. Stimulation of the cells by zymosan-activated serum (ZAS) reduced the surface charge to 1.82+/-0.02. In contrast, the charge of "resting" EE was already reduced (1.89+/-0.05) and was not altered by ZAS. Resting and stimulated neutrophils had a charge of 1.98+/-0.01 and 1.69+/-0.02, respectively. Uptake of [(3)H]2-deoxyglucose has been shown to reflect carrier-facilitated hexose transport in granulocytes. Deoxyglucose uptake by resting NE and NE stimulated by ZAS was 2.40+/-0.40 and 5.44+/-0.39 (cpm x 10(-3)/2 x 10(5) eosinophils), respectively. Resting and stimulated EE demonstrated deoxyglucose uptake of 7.55+/-0.58 and 15.3+/-0.6, respectively.Lysosomal acid phosphatase was determined by an electron microscopic cytochemical technique. In normal eosinophils and neutrophils, lysosomal acid phosphatase in mature cells is held in a latent form. Normal eosinophils demonstrated weakly positive acid phosphatase activity in 7.8+/-1.2% of the specific granules. Normal eosinophils, stimulated by opsonized staphylococci or the calcium ionophore A23187, develop rapid activation of acid phosphatase in approximately 80% of the granules throughout the cells. Resting EE were usually already activated and demonstrated acid phosphatase in 48.6+/-8.6% of the granules (range, 2-95% granules positive; significant activation was observed in preparations in EE from 11 of 15 patients). Oxidative metabolism was monitored by measurement of the hexose monophosphate shunt (HMPS) (metabolism of 1-[(14)C]glucose to (14)CO(2)). Previous studies demonstrated that resting EE have an HMPS activity which is nearly that of stimulated neutrophils, yet EE remain capable of further 7-10-fold increase when stimulated by opsonized zymosan. In contrast, the HMPS of NE (resting and stimulated) was not significantly different from that of neutrophils. Thus eosinophils obtained from patients with eosinophilia appear significantly activated when compared with normal eosinophils by the criteria of surface charge, activation of lysosomal acid phosphatase, membrane hexose transport, and hexose monophosphate shunt activities.
Differential Molecular Responses of Rapeseed Cotyledons to Light and Dark Reveal Metabolic Adaptations toward Autotrophy Establishment

Photosynthesis competent autotrophy is established during the postgerminative stage of plant growth. Among the multiple factors, light plays a decisive role in the switch from heterotrophic to autotrophic growth. Under dark conditions, the rapeseed hypocotyl extends quickly with an apical hook, and the cotyledon is yellow and folded, and maintains high levels of the isocitrate lyase (ICL). By contrast, in the light, the hypocotyl extends slowly, the cotyledon unfolds and turns green, the ICL content changes in parallel with cotyledon greening. To reveal metabolic adaptations during the establishment of postgerminative autotrophy in rapeseed, we conducted comparative proteomic and metabolomic analyses of the cotyledons of seedlings grown under light versus dark conditions. Under both conditions, the increase in proteases, fatty acid β-oxidation and glyoxylate-cycle related proteins was accompanied by rapid degradation of the stored proteins and lipids with an accumulation of the amino acids. While light condition partially retarded these conversions. Light significantly induced the expression of chlorophyll-binding and photorespiration related proteins, resulting in an increase in reducing-sugars. However, the levels of some chlorophyllide conversion, Calvin-cycle and photorespiration related proteins also accumulated in dark grown cotyledons, implying that the transition from heterotrophy to autotrophy is programmed in the seed rather than induced by light. Various anti-stress systems, e.g., redox related proteins, salicylic acid, proline and chaperones, were employed to decrease oxidative stress, which was mainly derived from lipid oxidation or photorespiration, under both conditions. This study provides a comprehensive understanding of the differential molecular responses of rapeseed cotyledons to light and dark conditions, which will facilitate further study on the complex mechanism underlying the transition from heterotrophy to autotrophy.
RAD51C facilitates checkpoint signaling by promoting CHK2 phosphorylation

The RAD51 paralogues act in the homologous recombination (HR) pathway of DNA repair. Human RAD51C (hRAD51C) participates in branch migration and Holliday junction resolution and thus is important for processing HR intermediates late in the DNA repair process. Evidence for early involvement of RAD51 during DNA repair also exists, but its function in this context is not understood. In this study, we demonstrate that RAD51C accumulates at DNA damage sites concomitantly with the RAD51 recombinase and is retained after RAD51 disassembly, which is consistent with both an early and a late function for RAD51C. RAD51C recruitment depends on ataxia telangiectasia mutated, NBS1, and replication protein A, indicating it functions after DNA end resection but before RAD51 assembly. Furthermore, we find that RAD51C is required for activation of the checkpoint kinase CHK2 and cell cycle arrest in response to DNA damage. This suggests that hRAD51C contributes to the protection of genome integrity by transducing DNA damage signals in addition to engaging the HR machinery.
Collaborative access control in on-line social networks

Topology-based access control is today a de-facto standard for protecting resources in On-line Social Networks (OSNs) both within the research community and commercial OSNs. According to this paradigm, authorization constraints specify the relationships (and possibly their depth and trust level) that should occur between the requestor and the resource owner to make the first able to access the required resource. In this paper, we show how topology-based access control can be enhanced by exploiting the collaboration among OSN users, which is the essence of any OSN. The need of user collaboration during access control enforcement arises by the fact that, different from traditional settings, in most OSN services users can reference other users in resources (e.g., a user can be tagged to a photo), and therefore it is generally not possible for a user to control the resources published by another user. For this reason, we introduce collaborative security policies, that is, access control policies identifying a set of collaborative users that must be involved during access control enforcement. Moreover, we discuss how user collaboration can also be exploited for policy administration and we present an architecture on support of collaborative policy enforcement.
Algorithms for analysis of signals with time-warped cyclostationarity

Two philosophically different approaches to the analysis of signals with imperfect cyclostationarity or polycy-clostationarity of the autocorrelation function due to warping are presented. The first approach consists of directly estimating the time-warping function (or its inverse) in a manner that transforms data having an empirical autocorrelation with irregular cyclicity into data having regular cyclicity. The second approach consists of modeling the signal as a time-warped poly-cyclostationarity stochastic process, thereby providing a wide-sense probabilistic characterization-a time-varying probabilistic autocorrelation function-which is used to specify an estimator of the time-warping function that is intended to remove the impact of time-warping. From this estimate, an estimate of the autocorrelation function of the unwarped process is also obtained.
MULTI-LAYER HYDROSTATIC EQUILIBRIUM OF PLANETS AND SYNCHRONOUS MOONS: THEORY AND APPLICATION TO CERES AND TO SOLAR SYSTEM MOONS

The hydrostatic equilibrium of multi-layer bodies lacks a satisfactory theoretical treatment despite its wide range of applicability. Here we show that by using the exact analytical potential of homogeneous ellipsoids we can obtain recursive analytical solutions and an exact numerical method for the hydrostatic equilibrium shape problem of multi-layer planets and synchronous moons. The recursive solutions rely on the series expansion of the potential in terms of the polar and equatorial shape eccentricities, while the numerical method uses the exact potential expression. These solutions can be used to infer the interior structure of planets and synchronous moons from their observed shape, rotation, and gravity. When applied to the dwarf planet Ceres, we show that it is most likely a differentiated body with an icy crust of equatorial thickness 30–90 km and a rocky core of density 2.4–3.1 g cm−3. For synchronous moons, we show that the J2/C22 ≃ 10/3 and the (b − c)/(a − c) ≃ 1/4 ratios have significant corrections of order Ω2/(πGρ), with important implications for how their gravitational coefficients are determined from fly-by radio science data and for how we assess their hydrostatic equilibrium state.
The significance of context in information systems and organizational change

This paper argues that it is of crucial importance that information systems (IS) research and practice associates technology innovation with the context within which it is embedded. It identifies three principles to be followed in order to address the contextual processes involved in IS implementation: first, technology innovation should be considered in relation to socio‐organizational change; second, analysis should consider not only the local organizational, but also the national and international context; and third, analysis should consider both the technical/rational decisions and actions involved in the innovation process and the cultural, social and cognitive forces of such a process. These principles are demonstrated with the analysis of a case study of organizational reform in Cyprus.
A negative feedback loop attenuates EGF-induced morphological changes

Activation of the EGF receptor tyrosine kinase by ligand indirectly activates a series of other cellular enzymes, including protein kinase C. To test the hypothesis that phosphorylation of the EGF receptor by protein kinase C provides an intracellular negative feedback loop to attenuate EGF receptor signaling, we used scanning EM to follow the characteristic EGF-induced retraction of lamellipodia and concomitant cell shape changes. Wild type and mutant EGF receptors were expressed in receptor-deficient NR6 cells. The mutant receptors were prepared by truncation at C' terminal residue 973 (c'973) to provide resistance to ligand-induced down regulation that strongly attenuates receptor signaling and by replacement of threonine 654 (T654) with alanine (A654) to remove the site of phosphorylation by protein kinase C. Cells expressing WT and c'973 EGF receptors demonstrated characteristic lamellipodial retraction after exposure to EGF, with the non-down regulating c'973 EGF receptors responding more rapidly. Exposure of cells to TPA blocked this response. Replacement of T654 by alanine resulted in EGF receptors that were resistant to TPA. Cells expressing the A654 mutation underwent more rapid and more extensive morphologic changes than cells with the corresponding T654 EGF receptor. In cells expressing T654 EGF receptors, down regulation of protein kinase C resulted in more rapid and extensive EGF-induced changes similar to those seen in cells expressing A654 EGF receptors. These data indicate that activation of protein kinase C and subsequent phosphorylation of the EGF receptor at T654 lead to rapid physiological attenuation of EGF receptor signaling.
Measurement of fraction unbound paclitaxel in human plasma.

The clinical pharmacokinetic behavior of paclitaxel (Taxol) is distinctly nonlinear, with disproportional increases in systemic exposure with an increase in dose. We have recently shown that Cremophor EL, the formulation vehicle used for i.v. administration of paclitaxel, alters drug distribution as a result of micellar entrapment of paclitaxel, and we speculated that the free drug fraction (fu) is dependent on dose and time-varying concentrations of Cremophor EL in the central plasma compartment. To test this hypothesis, a reproducible equilibrium dialysis method has been developed for the measurement of paclitaxel fu in plasma. Equilibrium dialysis was performed at 37 degrees C in a humidified atmosphere of 5% CO(2) using 2.0-ml polypropylene test tubes. Experiments were carried out with 260-microliter aliquots of plasma containing a tracer amount of [G-(3)H]paclitaxel with high-specific activity against an equal volume of 0.01 M phosphate buffer (pH 7.4). Drug concentrations were measured by both reversed-phase HPLC and liquid scintillation counting. Using this method, fu has been measured in three patients receiving three consecutive 3-weekly courses of paclitaxel at dose levels of 135, 175, and 225 mg/m(2) and found to range between 0.036 and 0.079. The method was also used to define concentration-time profiles of unbound drug, estimated from the product of the total plasma concentration and fu.
Lattice Boltzmann simulations of apparent slip in hydrophobic microchannels

Various experiments have found a boundary slip in hydrophobic microchannel flows, but a consistent understanding of the results is still lacking. While Molecular Dynamics (MD) simulations cannot reach the low shear rates and large system sizes of the experiments, it is often impossible to resolve the needed details with macroscopic approaches. We model the interaction between hydrophobic channel walls and a fluid by means of a multi-phase lattice Boltzmann model. Our mesoscopic approach overcomes the limitations of MD simulations and can reach the small flow velocities of known experiments. We reproduce results from experiments at small Knudsen numbers and other simulations, namely an increase of slip with increasing liquid-solid interactions, the slip being independent of the flow velocity, and a decreasing slip with increasing bulk pressure. Within our model we develop a semi-analytic approximation of the dependence of the slip on the pressure.