S100A4 downregulates filopodia formation through increased dynamic instability

Cell migration requires the initial formation of cell protrusions, lamellipodia and/or filopodia, the attachment of the leading lamella to extracellular cues and the formation and efficient recycling of focal contacts at the leading edge. The small calcium binding EF-hand protein S100A4 has been shown to promote cell motility but the direct molecular mechanisms responsible remain to be elucidated. In this work, we provide new evidences indicating that elevated levels of S100A4 affect the stability of filopodia and prevent the maturation of focal complexes. Increasing the levels of S100A4 in a rat mammary benign tumor derived cell line results in acquired cellular migration on the wound healing scratch assay. At the cellular levels, we found that high levels of S100A4 induce the formation of many nascent filopodia, but that only a very small and limited number of those can stably adhere and mature, as opposed to control cells, which generate fewer protrusions but are able to maintain these into more mature projections. This observation was paralleled by the fact that S100A4 overexpressing cells were unable to establish stable focal adhesions. Using different truncated forms of the S100A4 proteins that are unable to bind to myosin IIA, our data suggests that this newly identified functions of S100A4 is myosin-dependent, providing new understanding on the regulatory functions of S100A4 on cellular migration.

An initial evaluation of gellan gum as a material for tissue engineering applications

Alpha-modified minimum essential medium (αMEM) has been found to cross-link a 1% gellan gum solution, resulting in the formation of a self-supporting hydrogel in 1:1 and 5:1 ratios of polysaccharide: αMEM. Rheological data from temperature sweeps confirm that in addition to orders of magnitude differences in G' between 1% gellan and 1% gellan with αMEM, there is also a 20°C increase in the temperature at which the onset of gelation takes place when αMEM is present. Frequency sweeps confirm the formation of a true gel; mechanical spectra for mixtures of gellan and αMEM clearly demonstrate G' to be independent of frequency. It is possible to immobilize cells within a three-dimensional (3D) gellan matrix that remain viable for up to 21 days in culture by adding a suspension of rat bone marrow cells (rBMC) in αMEM to 1% gellan solution. This extremely simple approach to cell immobilization within 3D constructs, made possible by the fact that gellan solutions cross-link in the presence of millimolar concentrations of cations, poses a very low risk to a cell population immobilized within a gellan matrix and thus indicates the potential of gellan for use as a tissue engineering scaffold. © 2007 Sage Publications.

A cross-national investigation into the marketing department's influence within the firm:toward initial empirical generalizations

An ongoing strong debate within the marketing discipline concerns the role of marketing within the firm. It has been frequently reported that the marketing function is in a deep decline. Marketing executives and academics alike are interested in the antecedents of this decline and potential performance consequences of this decline. Recent academic research have started investigations on this important topic. Using studies in single countries innovativeness and accountability of the marketing department has been reported as major antecedents of the influence of the marketing department within the organization. Academic research, however, does not provide convincing evidence for a direct link between this influence and business performance. Instead it shows that market orientation is a crucial intervening variable, as marketing department influence is positively related market orientation, which subsequently positively related to business performance. As noted prior research, however, studies firms in single countries. In this article we execute a cross-national study on the antecedents and performance consequences of marketing department influence in order to derive initial empirical generalizations. This study is executed in seven Western-oriented countries, including USA, UK, The Netherlands, Germany, Sweden, Israel and Australia. The study heavily builds on the framework developed in the 2009 Journal of Marketing article of Verhoef and Leeflang. This framework is tested per country and subsequently meta-analytic tests are used to derive initial empirical generalizations. An important empirical generalization is that innovativeness, the customer-connecting capabilities, and accountability of the marketing department are positively related to marketing department influence. Interestingly, a second initial generalization is that creativity of the marketing negative induces less influence. Our results also show a third empirical generalization in that firms having a CEO with a marketing background tend to have more influential marketing departments. Confirming prior research a fourth initial empirical generalization is that MD influence measures and market orientation are positively related. Market orientation is subsequently positively related to business performance. Our most important generalization is, however, that MD influence is positively related to business performance. Hence, beyond striving to become market oriented, firms should also aim to have strong marketing departments. These departments can create a stronger focus on the customer and can also coordinate marketing efforts. In order to become more influential marketing departments should: (1) acquire innovative capabilities, (2) be more connected to customers, (3) invest in accountability, and (4) be careful with be careful being too creative.

A procedure for determining a spacewise dependent heat source and the initial temperature

The inverse problem of determining a spacewise dependent heat source, together with the initial temperature for the parabolic heat equation, using the usual conditions of the direct problem and information from two supplementary temperature measurements at different instants of time is studied. These spacewise dependent temperature measurements ensure that this inverse problem has a unique solution, despite the solution being unstable, hence the problem is ill-posed. We propose an iterative algorithm for the stable reconstruction of both the initial data and the source based on a sequence of well-posed direct problems for the parabolic heat equation, which are solved at each iteration step using the boundary element method. The instability is overcome by stopping the iterations at the first iteration for which the discrepancy principle is satisfied. Numerical results are presented for a typical benchmark test example, which has the input measured data perturbed by increasing amounts of random noise. The numerical results show that the proposed procedure gives accurate numerical approximations in relatively few iterations.

An integral equation method for a mixed initial boundary value problem for unsteady Stokes system in a doubly-connected domain

We present a novel numerical method for a mixed initial boundary value problem for the unsteady Stokes system in a planar doubly-connected domain. Using a Laguerre transformation the unsteady problem is reduced to a system of boundary value problems for the Stokes resolvent equations. Employing a modied potential approach we obtain a system of boundary integral equations with various singularities and we use a trigonometric quadrature method for their numerical solution. Numerical examples are presented showing that accurate approximations can be obtained with low computational cost.

Cross ontology query answering on the semantic web:an initial evaluation

PowerAqua is a Question Answering system, which takes as input a natural language query and is able to return answers drawn from relevant semantic resources found anywhere on the Semantic Web. In this paper we provide two novel contributions: First, we detail a new component of the system, the Triple Similarity Service, which is able to match queries effectively to triples found in different ontologies on the Semantic Web. Second, we provide a first evaluation of the system, which in addition to providing data about PowerAqua's competence, also gives us important insights into the issues related to using the Semantic Web as the target answer set in Question Answering. In particular, we show that, despite the problems related to the noisy and incomplete conceptualizations, which can be found on the Semantic Web, good results can already be obtained.

Initial nucleation study and new technique for sublimation growth of AlN on SiC substrate

Single crystal platelets of AlN were successfully grown on 6H-SiC(0001) by a novel technique designed to suppress SiC decomposition, promote two-dimensional growth, and eliminate cracking in the AlN. X-ray diffractometry and synchrotron white beam X-ray topography demonstrate that the final AlN single crystal is of high structural quality.

Effect of initial retinal thickness on outcome of intravitreal bevacizumab therapy for diabetic macular edema

Purpose: To investigate whether eyes with diabetic macular edema (DME) and central retinal thickness (CRT) >400 μm had better visual and anatomical outcomes compared to eyes with a CRT <400 μm when treated with intravitreal bevacizumab in a real-world setting. Patients and methods: Patients undergoing intravitreal bevacizumab therapy for DME were identified from the departmental database of a tertiary referral unit. Following the initial injection, a retreatment was performed for any persistent macular edema, unless there had been no previous response to repeated doses. Recorded parameters included visual acuity, CRT on optical coherence tomography (spectral domain optical coherence tomography [SD-OCT]), and SD-OCT characteristics. Comparisons were made between data at baseline and 12 months after the first injection, and differences were tested for statistical significance using the Student's t-test. Results: In all, 175 eyes of 142 patients were analyzed. Patients in group 2 (CRT >400 μm) had significantly more injections than group 1 (CRT <400 μm) (4.0 versus 3.3; P=0.003). Both groups had similar numbers of eyes with preexisting epiretinal membrane and/or vitreomacular traction at baseline. The reduction in CRT was significantly greater in group 2 when compared to group 1 (P<0.0001). In terms of visual gain between baseline and month 12, each gained significantly by a mean of 0.12 logarithm of the minimum angle of resolution units (P=0.0001), but there was no difference between groups 1 and 2 (P=0.99). Conclusion: These results do not support a 400 μm baseline CRT cut-off for treating DME with bevacizumab, in contrast to published data on ranibizumab. Our results also indicate that patients with a thicker CRT require more bevacizumab injections, making treatment less cost-effective for these patients. Our results could be used by practitioners to support the use of bevacizumab in DME without applying a CRT cut-off. © 2014 Mushtaq et al.

Ranibizumab 0.5 mg for diabetic macular edema with bimonthly monitoring after a phase of initial treatment:18-month, multicenter, phase IIIB RELIGHT study

Abstract PURPOSE: To evaluate ranibizumab 0.5 mg using bimonthly monitoring and individualized re-treatment after monthly follow-up for 6 months in patients with visual impairment due to diabetic macular edema (DME). DESIGN: A phase IIIb, 18-month, prospective, open-label, multicenter, single-arm study in the United Kingdom. PARTICIPANTS: Participants (N = 109) with visual impairment due to DME. METHODS: Participants received 3 initial monthly ranibizumab 0.5 mg injections (day 0 to month 2), followed by individualized best-corrected visual acuity (BCVA) and optical coherence tomography-guided re-treatment with monthly (months 3-5) and subsequent bimonthly follow-up (months 6-18). Laser was allowed after month 6. MAIN OUTCOME MEASURES: Mean change in BCVA from baseline to month 12 (primary end point), mean change in BCVA and central retinal thickness (CRT) from baseline to month 18, gain of ≥10 and ≥15 letters, treatment exposure, and incidence of adverse events over 18 months. RESULTS: Of 109 participants, 100 (91.7%) and 99 (90.8%) completed the 12 and 18 months of the study, respectively. The mean age was 63.7 years, the mean duration of DME was 40 months, and 77.1% of the participants had received prior laser treatment (study eye). At baseline, mean BCVA was 62.9 letters, 20% of patients had a baseline BCVA of >73 letters, and mean baseline CRT was 418.1 μm, with 32% of patients having a baseline CRT <300 μm. The mean change in BCVA from baseline to month 6 was +6.6 letters (95% confidence interval [CI], 4.9-8.3), and after institution of bimonthly treatment the mean change in BCVA at month 12 was +4.8 letters (95% CI, 2.9-6.7; P < 0.001) and +6.5 letters (95% CI, 4.2-8.8) at month 18. The proportion of participants gaining ≥10 and ≥15 letters was 24.8% and 13.8% at month 12 and 34.9% and 19.3% at month 18, respectively. Participants received a mean of 6.8 and 8.5 injections over 12 and 18 months, respectively. No new ocular or nonocular safety findings were observed during the study. CONCLUSIONS: The BCVA gain achieved in the initial 6-month treatment period was maintained with an additional 12 months of bimonthly ranibizumab PRN treatment.

How should initial fit inform soft contact lens prescribing

Purpose: To investigate how initial HEMA and silicone-hydrogel (SiHy) contact lens fit on insertion, which informs prescribing decisions, reflect end of day fit. Methods: Thirty participants (aged 22.9. ±. 4.9 years) were fitted contralaterally with HEMA and SiHy contact lenses. Corneal topography and tear break-up time were assessed pre-lens wear. Centration, lag, post-blink movement during up-gaze and push-up recovery speed were recorded after 5,10,20. min and 8. h of contact lens wear by a digital slit-lamp biomicroscope camera, along with reported comfort. Lens fit metrics were analysed using bespoke software. Results: Comfort and centration were similar with the HEMA and SiHy lenses (p > 0.05), but comfort decreased with time (p <. 0.01) whereas centration remained stable (F = 0.036, p = 0.991). Movement-on-blink and lag were greater with the HEMA than the SiHy lens (p <. 0.01), but movement-on-blink decreased with time after insertion (F = 22.423, p <. 0.001) whereas lag remained stable (F = 1.967, p = 0.129). Push-up recovery speed was similar with the HEMA and the SiHy lens 5-20. min after insertion (p > 0.05), but was slower with SiHy after 8. h wear (p = 0.016). Lens movement on blink and push-up recovery speed was predictive of the movement after 8. h of wear after 10-20. min SiHy wear, but after 5 to 20. min of HEMA lens wear. Conclusions: A HEMA or SiHy contact lens with poor movement on blink/push-up after at least 10. min after insertion should be rejected.

The tuberous sclerosis 2000 study:presentation initial assessments and implications for diagnosis and management

Aims: The Tuberous Sclerosis 2000 Study is the first comprehensive longitudinal study of tuberous sclerosis (TS) and aims to identify factors that determine prognosis. Mode of presentation and findings at initial assessments are reported here. Methods: Children aged 0-16 years newly diagnosed with TS in the UK were evaluated. Results: 125 children with TS were studied. 114 (91%) met clinical criteria for a definite diagnosis and the remaining 11 (9%) had pathogenic TSC1 or TSC2 mutations. In families with a definite clinical diagnosis, the detection rate for pathogenic mutations was 89%. 21 cases (17%) were identified prenatally, usually with abnormalities found at routine antenatal ultrasound examination. 30 cases (24%) presented before developing seizures and in 10 of these without a definite diagnosis at onset of seizures, genetic testing could have confirmed TS. 77 cases (62%) presented with seizures. Median age at recruitment assessment was 2.7 years (range:4 weeks-18 years). Dermatological features of TS were present in 81%. The detection rate of TS abnormalities was 20/107 (19%) for renal ultrasound including three cases with polycystic kidney disease, 51/88 (58%) for echocardiography, 29/35 (83%) for cranial CT and 95/104 (91%) for cranial MRI. 91% of cases had epilepsy and 65% had intellectual disability (IQ<70). Conclusions: Genetic testing can be valuable in confirming the diagnosis. Increasing numbers of cases present prenatally or in early infancy, before onset of seizures, raising important questions about whether these children should have EEG monitoring and concerning the criteria for starting anticonvulsant therapy.

Numerical solution of the Dirichlet initial boundary value problem for the heat equation in exterior 3-dimensional domains using integral equations

A numerical method for the Dirichlet initial boundary value problem for the heat equation in the exterior and unbounded region of a smooth closed simply connected 3-dimensional domain is proposed and investigated. This method is based on a combination of a Laguerre transformation with respect to the time variable and an integral equation approach in the spatial variables. Using the Laguerre transformation in time reduces the parabolic problem to a sequence of stationary elliptic problems which are solved by a boundary layer approach giving a sequence of boundary integral equations of the first kind to solve. Under the assumption that the boundary surface of the solution domain has a one-to-one mapping onto the unit sphere, these integral equations are transformed and rewritten over this sphere. The numerical discretisation and solution are obtained by a discrete projection method involving spherical harmonic functions. Numerical results are included.