Informal Learning in Online Knowledge Communities: Predicting Community Response to Visitor Inquiries

Nistor, N., Dascalu, M., Stavarache, L.L., Serafin, Y., & Trausan-Matu, S. (2015). Informal Learning in Online Knowledge Communities: Predicting Community Response to Visitor Inquiries. In G. Conole, T. Klobucar, C. Rensing, J. Konert & É. Lavoué (Eds.), 10th European Conf. on Technology Enhanced Learning (pp. 447–452). Toledo, Spain: Springer.

Feeding of anchovy Engraulis encrasicolus larvae in the northwestern Adriatic Sea in response to changing hydrobiological conditions

Results from depth integrated and vertically stratified plankton sampling in the northwestern Adriatic Sea were used for comparison of gut contents of larvae of European anchovy Engraulis encrasicolus with composition and concentration of potential prey in the plankton. Sampling was carried out over a grid of stations both before and after a period of increased wind mixing to investigate changes in food availability and larval feeding success. All larvae had empty guts soon after dusk, indicating daytime feeding and rapid gut clearance. With increasing larval length there was a greater percentage of specimens with empty guts, despite suitable food being available in the plankton for these larger larvae; this suggests differential gut evacuation during sampling-possibly related to the degree of gut development. Larval diet was principally the various developmental stages of copepods, especially calanoid and cyclopoid nauplii, which were preferentially selected by larvae, whereas selection was against harpacticoid nauplii. Lamellibranch larvae and Peridinium were generally abundant in the plankton, but were only present in the gut contents in any number when the preferred dietary organisms were present in the plankton at low concentrations. The number of food organisms in the gut contents increased with concentration of the preferred food organisms in the plankton up to a limit of similar to 50 organisms/l. Within the upper 18 m of the water column, there was a reduction in the proportion of larvae with food in their guts with increasing depth, irrespective of the vertical profile of food concentration. Following a period of wind mixing the composition of the plankton changed. This was reflected in the diet of anchovy larvae, which altered in parallel. There was also an overall 41% decrease in concentration of the preferred food particles of larvae in the plankton following the period of wind mixing, but larvae were still able to maintain their food intake. These results show that anchovy larvae can successfully adapt their diet to a changing prey field and suggest that in the conditions observed in the northern Adriatic, quite radical changes in the feeding environment were probably insufficient to affect overall larval mortality.

BRCA1 Functions as a Differential Modulator of Chemotherapy-induced Apoptosis

We have evaluated the role played by BRCA1 in mediating the phenotypic response to a range of chemotherapeutic agents commonly used in cancer treatment. Here we provide evidence that BRCA1 functions as a differential mediator of chemotherapy-induced apoptosis. Specifically, we demonstrate that BRCA1 mediates sensitivity to apoptosis induced by antimicrotubule agents but conversely induces resistance to DNA-damaging agents. These data are supported by a variety of experimental models including cells with inducible expression of BRCA1, siRNA-mediated inactivation of endogenous BRCA1, and reconstitution of BRCA1-deficient cells with wild-type BRCA1. Most notably we demonstrate that BRCA1 induces a 10–1000-fold increase in resistance to a range of DNA-damaging agents, in particular those that give rise to double-strand breaks such as etoposide or bleomycin. In contrast, BRCA1 induces a >1000-fold increase in sensitivity to the spindle poisons, paclitaxel and vinorelbine. Fluorescence-activated cell sorter analysis demonstrated that BRCA1 mediates G2/M arrest in response to both antimicrotubule and DNA-damaging agents. However, poly(ADP-ribose) polymerase and caspase-3 cleavage assays indicate that the differential effect mediated by BRCA1 in response to these agents occurs through the inhibition or induction of apoptosis. Therefore, our data suggest that BRCA1 acts as a differential modulator of apoptosis depending on the nature of the cellular insult.

Differential expression of components of the cardiomyocyte adrenomedullin/intermedin receptor system following blood pressure reduction in nitric oxide-deficient hypertension.

Adrenomedullin (AM) and intermedin (IMD; adrenomedulln-2) are vasodilator peptides related to calcitonin gene-related peptide (CGRP). The actions of these peptides are mediated by the calcitonin receptor-like receptor (CLR) in association with one of three receptor activity-modifying proteins. CGRP is selective for CLR/receptor activity modifying protein (RAMP)1, AM for CLR/RAMP2 and -3, and IMD acts at both CGRP and AM receptors. In a model of pressure overload induced by inhibition of nitric-oxide synthase, up-regulation of AM was observed previously in cardiomyocytes demonstrating a hypertrophic phenotype. The current objective was to examine the effects of blood pressure reduction on cardiomyocyte expression of AM and IMD and their receptor components. Nomega-nitro-L-arginine methyl ester (L-NAME) (35 mg/kg/day) was administered to rats for 8 weeks, with or without concurrent administration of hydralazine (50 mg/kg/day) and hydrochlorothiazide (7.5 mg/kg/day). In left ventricular cardiomyocytes from L-NAME-treated rats, increases (-fold) in mRNA expression were 1.6 (preproAM), 8.4 (preproIMD), 3.4 (CLR), 4.1 (RAMP1), 2.8 (RAMP2), and 4.4 (RAMP3). Hydralazine/hydrochlorothiazide normalized systolic blood pressure (BP) and abolished mRNA up-regulation of hypertrophic markers sk-alpha-actin and BNP and of preproAM, CLR, RAMP2, and RAMP3 but did not normalize cardiomyocyte width nor preproIMD or RAMP1 mRNA expression. The robust increase in IMD expression indicates an important role for this peptide in the cardiac pathology of this model but, unlike AM, IMD is not associated with pressure overload upon the myocardium. The concordance of IMD and RAMP1 up-regulation indicates a CGRP-type receptor action; considering also a lack of response to BP reduction, IMD may, like CGRP, have an anti-ischemic function.

Differential Pharmacokinetics of Digoxin in Elderly Patients

Digoxin remains one of the most commonly prescribed of all cardiac medications. The main indications for digoxin usage include atrial fibrillation and heart failure; both these conditions are more prevalent in older patients. Given the aging population and the increasing incidence of heart failure we would expect prescribing of digoxin to remain as frequent or to even increase in older patients. Older patients are also more likely to develop toxicity and diagnosis of digoxin toxicity can be difficult in this group. Numerous components contribute to the development of toxicity in older patients, ranging from aging-related changes in renal function or body mass to polypharmacy and possible interactions with digoxin. It is therefore important to understand how the pharmacokinetics of digoxin may be altered in the older population. Application of basic pharmacological principles may be helpful in anticipating these problems. This review describes the pharmacokinetics of digoxin, the changes in pharmacokinetics with increasing age and how concomitant disease states or drug interactions may affect the pharmacokinetics of digoxin. Greater knowledge about the causes and prevention of digoxin toxicity should further reduce the morbidity and mortality arising from digoxin toxicity, especially in the elderly population.
For over 200 years debate has raged regarding the use of digitalis glycosides in cardiac disease. At present digoxin is the most commonly prescribed digitalis compound. This review describes the pharmacokinetics of digoxin and in particular how they are altered with increasing age. When considering the elderly population it is important to recognise the heterogeneity of response in this group, therefore there are no rules, with regards to prescribing, that can apply to the entire elderly population.

Interactions between invasive and native crustaceans: differential functional responses of intraguild predators towards juvenile hetero-specifics

Intraguild predation (IGP) between invasive and native species can lead to species exclusions or co-existence, dependent on the direction and strength of the interaction. Recently, derivation of 'functional responses' has been identified as a means of comparing the community impacts of invasive and native species. Here, we employ a novel use of this functional response methodology to evaluate any IGP asymmetries between the invasive Ponto-Caspian amphipod Echinogammarus ischnus and the North American native Gammarus fasciatus. The direction and magnitude of intraguild predation of adult males on hetero-specific adult females has previously been shown to reverse across a water conductivity gradient. This partially explains field patterns, but does not predict the co-existence of the two species observed in many habitats and locations. Here, we compared intraguild predation by both species on each other's juveniles in high- and low- conductivity water. G. fasciatus has a higher type II functional response towards E. ischnus juveniles compared to the reciprocal interaction. Conductivity did not influence the predation rate on juveniles of either E. ischnus or G. fasciatus. Thus, the male/female IGP advantage to the native G. fasciatus in low conductivity water is compounded by a juvenile IGP asymmetry, which also counteracts the male/female IGP advantage to E. ischnus in high conductivity waters, helping to explain field patterns of exclusion and co-existence. Thus, complex asymmetries in mutual IGP associated with inherent species differences, environmental modulation, and life-history effects can help us understand and predict the population and community level outcomes of species invasions.

ATM acts downstream of ATR in the DNA damage response signaling of bystander cells.

This study identifies ataxia-telangiectasia mutated (ATM) as a further component of the complex signaling network of radiation-induced DNA damage in nontargeted bystander cells downstream of ataxia-telangiectasia and Rad3-related (ATR) and provides a rationale for molecular targeted modulation of these effects. In directly irradiated cells, ATR, ATM, and DNA-dependent protein kinase (DNA-PK) deficiency resulted in reduced cell survival as predicted by the known important role of these proteins in sensing DNA damage. A decrease in clonogenic survival was also observed in ATR/ATM/DNA-PK–proficient, nonirradiated bystander cells, but this effect was completely abrogated in ATR and ATM but not DNA-PK–deficient bystander cells. ATM activation in bystander cells was found to be dependent on ATR function. Furthermore, the induction and colocalization of ATR, 53BP1, ATM-S1981P, p21, and BRCA1 foci in nontargeted cells was shown, suggesting their involvement in bystander DNA damage signaling and providing additional potential targets for its modulation. 53BP1 bystander foci were induced in an ATR-dependent manner predominantly in S-phase cells, similar to ?H2AX foci induction. In conclusion, these results provide a rationale for the differential modulation of targeted and nontargeted effects of radiation.

Dynamical instability in surface permeability characteristics of building sandstones in response to salt accumulation over time

This paper explores how the surface permeability of sandstone blocks changes over time in response to repeated salt weathering cycles. Surface permeability controls the amount of moisture and dissolved salt that can penetrate in and facilitate decay. Connected pores permit the movement of moisture (and hence soluble salts) into the stone interior, and where areas are more or less permeable soluble salts may migrate along preferred pathways at differential rates. Previous research has shown that salts can accumulate in the near-surface zone and lead to partial pore blocking which influences subsequent moisture ingress and causes rapid salt accumulation in the near-surface zone.

Two parallel salt weathering simulations were carried out on blocks of Peakmoor Sandstone of different volumes. Blocks were removed from simulations after 2, 5, 10, 20 and 60 cycles. Permeability measurements were taken for these blocks at a resolution of 20 mm, providing a grid of 100 permeability values for each surface. The geostatistical technique of ordinary kriging was applied to the data to produce a smoothed interpolation of permeability for these surfaces, and hence improve understanding of the evolution of permeability over time in response to repeated salt weathering cycles.

Results illustrate the different responses of the sandstone blocks of different volumes to repeated salt weathering cycles. In both cases, after an initial subtle decline in the permeability (reflecting pore blocking), the permeability starts to increase — reflected in a rise in mean, maximum and minimum values. However, between 10 and 20 cycles, there is a jump in the mean and range permeability of the group A block surfaces coinciding with the onset of meaningful debris release. After 60 cycles, the range of permeability in the group A block surface had increased markedly, suggesting the development of a secondary permeability. The concept of dynamic instability and divergent behaviour is applied at the scale of a single block surface, with initial small-scale differences across a surface having larger scale consequences as weathering progresses.

After cycle 10, group B blocks show a much smaller increase in mean permeability, and the range stays relatively steady — this may be explained by the capillary conditions set up by the smaller volume of the stone, allowing salts to migrate to the ‘back’ of the blocks and effectively relieving stress at the ‘front’ face.

Modelling the mechanical response of the Reed-mouthpiece-lip system of a clarinet. Part I. A one-dimensional distributed model

The motion of a clarinet reed that is clamped to a mouthpiece and supported by a lip is simulated in the time-domain using finite difference methods. The reed is modelled as a bar with non-uniform cross section, and is described using a one-dimensional, fourth-order partial differential equation. The interactions with the mouthpiece Jay and the player's lip are taken into account by incorporating conditional contact forces in the bar equation. The model is completed by clamped-free boundary conditions for the reed. An implicit finite difference method is used for discretising the system, and values for the physical parameters are chosen both from laboratory measurements and by accurate tuning of the numerical simulations. The accuracy of the numerical system is assessed through analysis of frequency warping effects and of resonance estimation. Finally, the mechanical properties of the system are studied by analysing its response to external driving forces. In particular, the effects of reed curling are investigated.

Differential modulation of angiogenesis by erythropoiesis-stimulating agents in a mouse model of ischaemic retinopathy

Background: Erythropoiesis stimulating agents (ESAs) are widely used to treat anaemia but concerns exist about their potential to promote pathological angiogenesis in some clinical scenarios. In the current study we have assessed the angiogenic potential of three ESAs; epoetin delta, darbepoetin alfa and epoetin beta using in vitro and in vivo models.

Methodology/Principal Findings: The epoetins induced angiogenesis in human microvascular endothelial cells at high doses, although darbepoetin alfa was pro-angiogenic at low-doses (1-20 IU/ml). ESA-induced angiogenesis was VEGF-mediated. In a mouse model of ischaemia-induced retinopathy, all ESAs induced generation of reticulocytes but only epoetin beta exacerbated pathological (pre-retinal) neovascularisation in comparison to controls (p<0.05). Only epoetin delta induced a significant revascularisation response which enhanced normality of the vasculature (p<0.05). This was associated with mobilisation of haematopoietic stem cells and their localisation to the retinal vasculature. Darbepoetin alfa also increased the number of active microglia in the ischaemic retina relative to other ESAs (p<0.05). Darbepoetin alfa induced retinal TNF alpha and VEGF mRNA expression which were up to 4 fold higher than with epoetin delta (p<0.001).

Conclusions: This study has implications for treatment of patients as there are clear differences in the angiogenic potential of the different ESAs.

Differential expression of steroid 5 alpha-reductase isozymes and association with disease severity and angiogenic genes predict their biological role in prostate cancer

The biological role of steroid 5 alpha-reductase isozymes (encoded by the SRD5A1 and SRD5A2 genes) and angiogenic factors that play important roles in the pathogenesis and vascularization of prostate cancer (PC) is poorly understood. The sub-cellular expression of these isozymes and vascular endothelial growth factor (VEGF) in PC tissue microarrays (n=62) was examined using immunohistochemistry. The effect of SRD5A inhibition on the angiogenesis pathway genes in PC was also examined in prostate cell lines, LNCaP, PC3, and RWPE-1, by treating them with the SRD5A inhibitors finasteride and dutasteride, followed by western blot, quantitative PCR, and ELISA chip array techniques. In PC tissues, nuclear SRD5A1 expression was strongly associated with higher cancer Gleason scores (P=0.02), higher cancer stage (P=0.01), and higher serum prostate specific antigen (PSA) levels (P=0.01), whereas nuclear SRD5A2 expression was correlated with VEGF expression (P=0.01). Prostate tumor cell viability was significantly reduced in dutasteride-treated PC3 and RWPE-1 cells compared with finasteride-treated groups. Expression of the angiogenesis pathway genes transforming growth factor beta 1 (TGFB1), endothelin (EDN1), TGF alpha (TGFA), and VEGFR1 was upregulated in LNCaP cells, and at least 7 out of 21 genes were upregulated in PC3 cells treated with finasteride (25 mu M). Our findings suggest that SRD5A1 expression predominates in advanced PC, and that inhibition of SRD5A1 and SRD5A2 together was more effective in reducing cell numbers than inhibition of SRD5A2 alone. However, these inhibitors did not show any significant difference in prostate cell angiogenic response. Interestingly, some angiogenic genes remained activated after treatment, possibly due to the duration of treatment and tumor resistance to inhibitors. Endocrine-Related Cancer (2010) 17 757-770

Differential effects of reduced glycoprotein VI levels on activation of murine platelets by glycoprotein VI ligands

We have investigated the effects of decreased levels of the complex between glycoprotein VI (GPVI) and the Fc receptor gamma-chain (FcRgamma) on responses to collagen and GPVI-specific ligands in murine platelets. We show that levels of GPVI-FcRgamma of the order of 50 % and 20 % of wild-type levels caused 2- and 5-fold shifts to the right respectively in the dose-response curve for aggregation in response to collagen, the snake toxin convulxin and the monoclonal antibody JAQ1. In addition, there is a delay in the onset of aggregation in response to collagen. In contrast, the stimulation of protein tyrosine phosphorylation by collagen (as measured after 150 s) and adhesion to a collagen-coated surface under static conditions were unaffected in platelets with 50 % and 20 % of wild-type levels of GPVI. In contrast, responses to a collagen-related peptide (CRP), made up of repeat glycine-proline-hydroxyproline motifs, were markedly inhibited and abolished in platelets expressing 50 % and 20 % of wild-type levels of GPVI respectively. We suggest that the marked effect of a reduction in GPVI levels on the CRP-induced activation of platelets is due to the multivalent nature of CRP and the fact that GPVI is its sole receptor on platelets. Thus it appears that the interaction of CRP with GPVI is determined by a combination of affinity and avidity. The observation that collagen does not behave like CRP in platelets expressing reduced levels of GPVI, even in the combined presence of blocking antibodies against integrin alpha2beta1 and GPV, suggests that collagen has a greater affinity than CRP for GPVI, and/or that other receptors are involved in its binding to platelets. The clinical significance of these results is discussed.

Langerin(+) Dermal Dendritic Cells Are Critical for CD8(+) T Cell Activation and IgH gamma-1 Class Switching in Response to Gene Gun Vaccines

The C-type lectin langerin/CD207 was originally discovered as a specific marker for epidermal Langerhans cells (LC). Recently, additional and distinct subsets of langerin(+) dendritic cells (DC) have been identified in lymph nodes and peripheral tissues of mice. Although the role of LC for immune activation or modulation is now being discussed controversially, other langerin(+) DC appear crucial for protective immunity in a growing set of infection and vaccination models. In knock-in mice that express the human diphtheria toxin receptor under control of the langerin promoter, injection of diphtheria toxin ablates LC for several weeks whereas other langerin(+) DC subsets are replenished within just a few days. Thus, by careful timing of diphtheria toxin injections selective states of deficiency in either LC only or all langerin(+) cells can be established. Taking advantage of this system, we found that, unlike selective LC deficiency, ablation of all langerin(+) DC abrogated the activation of IFN-gamma producing and cytolytic CD8(+) T cells after gene gun vaccination. Moreover, we identified migratory langerin(+) dermal DC as the subset that directly activated CD8(+) T cells in lymph nodes. Langerin(+) DC were also critical for IgG1 but not IgG2a Ab induction, suggesting differential polarization of CD4(+) T helper cells by langerin(+) or langerin-negative DC, respectively. In contrast, protein vaccines administered with various adjuvants induced IgG1 independently of langerin(+) DC. Taken together, these findings reflect a highly specialized division of labor between different DC subsets both with respect to Ag encounter as well as downstream processes of immune activation. The Journal of Immunology, 2011, 186: 1377-1383.

Androgen deprivation results in time-dependent hypoxia in LNCaP prostate tumours; informed scheduling of the bioreductive drug AQ4N improves treatment response

Androgen withdrawal induces hypoxia in androgen-sensitive tissue; this is important as in the tumour microenvironment hypoxia is known to drive malignant progression. This study examined the time-dependent effect of androgen deprivation therapy (ADT) on tumour oxygenation and investigated the role of ADT-induced hypoxia on malignant progression in prostate tumours. LNCaP xenografted tumours were treated with anti-androgens and tumour oxygenation measured. Dorsal skin fold chambers (DSF) were used to image tumour vasculature in vivo. Quantitative PCR (QPCR) identified differential gene expression following treatment with bicalutamide. Bicalutamide and vehicle-only treated tumours were re-established in vitro and invasion and sensitivity to docetaxel were measured. Tumour growth delay was calculated following treatment with bicalutamide combined with the bioreductive drug AQ4N. Tumour oxygenation measurements showed a precipitate decrease following initiation of ADT. A clinically relevant dose of bicalutamide (2mg/kg/day) decreased tumour oxygenation by 45% within 24h, reaching a nadir of 0.09% oxygen (0.67±0.06 mmHg) by day 7; this persisted until day 14 when it increased up to day 28. Using DSF chambers, LNCaP tumours treated with bicalutamide showed loss of small vessels at days 7 and 14 with revascularization occurring by day 21. QPCR showed changes in gene expression consistent with the vascular changes and malignant progression. Cells from bicalutamide-treated tumours were more malignant than vehicle-treated controls. Combining bicalutamide with AQ4N (50mg/kg; single dose) caused greater tumour growth delay than bicalutamide alone. This study shows that bicalutamide-induced hypoxia selects for cells that show malignant progression; targeting hypoxic cells may provide greater clinical benefit.

The electrical characterization and response to hydrogen of Schottky diodes with a resistive metal electrode—rectifying an oversight in Schottky diode investigation

Schottky-barrier structures with a resistive metal electrode are examined using the 4-point probe method where the probes are connected to the metal electrode only. The observation of a significant decrease in resistance with increasing temperature (over a range of similar to 100 K) in the diode resistance-temperature (R(D)-T) characteristic is considered due to charge carrier confinement to the metal electrode at low temperature (high resistance), with the semiconductor progressively opening up as a parallel current carrying channel (low resistance) with increasing temperature due to increasing thermionic emission across the barrier. A simple model is constructed, based on thermionic emission at quasi-zero bias, that generates good fits to the experimental data. The negative differential resistance (NDR) region in the R(D)-T characteristic is a general effect and is demonstrated across a broad temperature range for a variety of Schottky structures grown on Si-, GaAs- and InP-substrates. In addition the NDR effect is harnessed in micro-scaled Pd/n-InP devices for the detection of low levels of hydrogen in an ambient atmosphere of nitrogen.