Antimicrobial effects of murine mesenchymal stromal cells directed against Toxoplasma gondii and Neospora caninum: role of immunity-related GTPases (IRGs) and guanylate-binding proteins (GBPs).

Mesenchymal stromal cells (MSCs) have a multilineage differentiation potential and provide immunosuppressive and antimicrobial functions. Murine as well as human MSCs restrict the proliferation of T cells. However, species-specific differences in the underlying molecular mechanisms have been described. Here, we analyzed the antiparasitic effector mechanisms active in murine MSCs. Murine MSCs, in contrast to human MSCs, could not restrict the growth of a highly virulent strain of Toxoplasma gondii (BK) after stimulation with IFN-γ. However, the growth of a type II strain of T. gondii (ME49) was strongly inhibited by IFN-γ-activated murine MSCs. Immunity-related GTPases (IRGs) as well as guanylate-binding proteins (GBPs) contributed to this antiparasitic effect. Further analysis showed that IFN-γ-activated mMSCs also inhibit the growth of Neospora caninum, a parasite belonging to the apicomplexan group as well. Detailed studies with murine IFN-γ-activated MSC indicated an involvement in IRGs like Irga6, Irgb6 and Irgd in the inhibition of N. caninum. Additional data showed that, furthermore, GBPs like mGBP1 and mGBP2 could have played a role in the anti-N. caninum effect of murine MSCs. These data underline that MSCs, in addition to their regenerative and immunosuppressive activity, function as antiparasitic effector cells as well. However, IRGs are not present in the human genome, indicating a species-specific difference in anti-T. gondii and anti-N. caninum effect between human and murine MSCs.

Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells

Human pluripotent stem cells are a powerful tool for modeling brain development and disease. The human cortex is composed of two major neuronal populations: projection neurons and local interneurons. Cortical interneurons comprise a diverse class of cell types expressing the neurotransmitter GABA. Dysfunction of cortical interneurons has been implicated in neuropsychiatric diseases, including schizophrenia, autism, and epilepsy. Here, we demonstrate the highly efficient derivation of human cortical interneurons in an NKX2.1::GFP human embryonic stem cell reporter line. Manipulating the timing of SHH activation yields three distinct GFP+ populations with specific transcriptional profiles, neurotransmitter phenotypes, and migratory behaviors. Further differentiation in a murine cortical environment yields parvalbumin- and somatostatin-expressing neurons that exhibit synaptic inputs and electrophysiological properties of cortical interneurons. Our study defines the signals sufficient for modeling human ventral forebrain development in vitro and lays the foundation for studying cortical interneuron involvement in human disease pathology.

Directed Metalation Cascade To Access Highly Functionalized Thieno2,3-fbenzofuran and Exploration as Building Blocks for Organic Electronics

A tandem directed metalation has been successfully applied to the preparation of thieno2,3-fbenzofuran-4,8-dione, providing an efficient and facile approach to symmetrically and unsymmetrically functionalize the thieno2,3-fbenzofuran core at the 2,6 positions as well as to introduce the electron-withdrawing or -donating groups (EWG or EDG) at its 4,8 positions. The presence of various functional groups makes late-stage derivatization attainable.

UNSUPERVISED INDEXING OF MEDLINE ARTICLES THROUGH GRAPH-BASED RANKING

The biomedical literature is extensively catalogued and indexed in MEDLINE. MEDLINE indexing is done by trained human indexers, who identify the most important concepts in each article, and is expensive and inconsistent. Automating the indexing task is difficult: the National Library of Medicine produces the Medical Text Indexer (MTI), which suggests potential indexing terms to the indexers. MTI’s output is not good enough to work unattended. In my thesis, I propose a different way to approach the indexing task called MEDRank. MEDRank creates graphs representing the concepts in biomedical articles and their relationships within the text, and applies graph-based ranking algorithms to identify the most important concepts in each article. I evaluate the performance of several automated indexing solutions, including my own, by comparing their output to the indexing terms selected by the human indexers. MEDRank outperformed all other evaluated indexing solutions, including MTI, in general indexing performance and precision. MEDRank can be used to cluster documents, index any kind of biomedical text with standard vocabularies, or could become part of MTI itself.

Dirichlet-Neumann inverse spectral problem for a star graph of Stieltjes strings

We solve two inverse spectral problems for star graphs of Stieltjes strings with Dirichlet and Neumann boundary conditions, respectively, at a selected vertex called root. The root is either the central vertex or, in the more challenging problem, a pendant vertex of the star graph. At all other pendant vertices Dirichlet conditions are imposed; at the central vertex, at which a mass may be placed, continuity and Kirchhoff conditions are assumed. We derive conditions on two sets of real numbers to be the spectra of the above Dirichlet and Neumann problems. Our solution for the inverse problems is constructive: we establish algorithms to recover the mass distribution on the star graph (i.e. the point masses and lengths of subintervals between them) from these two spectra and from the lengths of the separate strings. If the root is a pendant vertex, the two spectra uniquely determine the parameters on the main string (i.e. the string incident to the root) if the length of the main string is known. The mass distribution on the other edges need not be unique; the reason for this is the non-uniqueness caused by the non-strict interlacing of the given data in the case when the root is the central vertex. Finally, we relate of our results to tree-patterned matrix inverse problems.

Fixed low-dose ultrasound-assisted catheter-directed thrombolysis for intermediate- and high-risk pulmonary embolism

AIMS No standardized local thrombolysis regimen exists for the treatment of pulmonary embolism (PE). We retrospectively investigated efficacy and safety of fixed low-dose ultrasound-assisted catheter-directed thrombolysis (USAT) for intermediate- and high-risk PE. METHODS AND RESULTS Fifty-two patients (65 ± 14 years) of whom 14 had high-risk PE (troponin positive in all) and 38 intermediate-risk PE (troponin positive in 91%) were treated with intravenous unfractionated heparin and USAT using 10 mg of recombinant tissue plasminogen activator per device over the course of 15 h. Bilateral USAT was performed in 83% of patients. During 3-month follow-up, two [3.8%; 95% confidence interval (CI) 0.5-13%] patients died (one from cardiogenic shock and one from recurrent PE). Major non-fatal bleeding occurred in two (3.8%; 95% CI, 0.5-13%) patients: one intrathoracic bleeding after cardiopulmonary resuscitation requiring transfusion, one intrapulmonary bleeding requiring lobectomy. Mean pulmonary artery pressure decreased from 37 ± 9 mmHg at baseline to 25 ± 8 mmHg at 15 h (P < 0.001) and cardiac index increased from 2.0 ± 0.7 to 2.7 ± 0.9 L/min/m(2) (P < 0.001). Echocardiographic right-to-left ventricular end-diastolic dimension ratio decreased from 1.42 ± 0.21 at baseline to 1.06 ± 0.23 at 24 h (n = 21; P < 0.001). The greatest haemodynamic benefit from USAT was found in patients with high-risk PE and in those with symptom duration < 14 days. CONCLUSION A standardized catheter intervention approach using fixed low-dose USAT for the treatment of intermediate- and high-risk PE was associated with rapid improvement in haemodynamic parameters and low rates of bleeding complications and mortality.

All eyes on me?! Social anxiety and self-directed perception of eye gaze

To date, only little is known about the self-directed perception and processing of subtle gaze cues in social anxiety that might however contribute to excessive feelings of being looked at by others. Using a web-based approach, participants (n=174) were asked whether or not briefly (300 ms) presented facial expressions modulated in gaze direction (0°, 2°, 4°, 6°, 8°) and valence (angry, fearful, happy, neutral) were directed at them. The results demonstrate a positive, linear relationship between self-reported social anxiety and stronger self-directed perception of others' gaze directions, particularly for negative (angry, fearful) and neutral expressions. Furthermore, faster responding was found for gaze more clearly directed at socially anxious individuals (0°, 2°, and 4°) suggesting a tendency to avoid direct gaze. In sum, the results illustrate an altered self-directed perception of subtle gaze cues. The possibly amplifying effects of social stress on biased self-directed perception of eye gaze are discussed.

Immunochemical interactions of peptides with site-directed polyclonal immunoglobulin G

The objective of this study was to investigate the immunochemical nature of the polyclonal immune response to the 14mer peptide TINKEDDESPGLYG and to identify interactions among antibodies to more than one epitope. Two groups of rabbits were immunized with the 14mer peptide and a Keyhole Limpet hemocyanin (KLH) carrier, but with KLH attached either to the 14mer's N- or C-terminus. Two approximate epitopes were mapped by an antibody-capture enzyme-linked immunosorbent assay method using antiserum obtained when KLH was oriented on the C-terminus of the 14mer. A precise mapping of the epitopes performed with inhibition enzyme immunoassays (iEIAs) resulted in an N-terminal 6mer epitope TINKED and a C-terminal 10mer epitope EDDESPGLYG. The epitopes overlapped by two amino acids. IEIAs and iEIAs incorporating antibody-blocking peptides indicated that the two anti-epitope antibody fractions did not interfere with one anothers' epitope binding. It was postulated that the anti-TINKED and anti-EDDESPGLYG antibody fractions individually bind their respective hydrophobic epitope "core" region at the N- or C-terminal of peptide TINKEDDESPGLYG, while sharing the two hydrophilic overlap amino acids. This antibody "lap joint" binding interaction can be accomplished by each of the anti-epitope antibodies binding an opposite side of the epitope overlap region in the shallow periphery of its binding site. ^

Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism.

BACKGROUND In patients with acute pulmonary embolism, systemic thrombolysis improves right ventricular (RV) dilatation, is associated with major bleeding, and is withheld in many patients at risk. This multicenter randomized, controlled trial investigated whether ultrasound-assisted catheter-directed thrombolysis (USAT) is superior to anticoagulation alone in the reversal of RV dilatation in intermediate-risk patients. METHODS AND RESULTS Fifty-nine patients (63±14 years) with acute main or lower lobe pulmonary embolism and echocardiographic RV to left ventricular dimension (RV/LV) ratio ≥1.0 were randomized to receive unfractionated heparin and an USAT regimen of 10 to 20 mg recombinant tissue plasminogen activator over 15 hours (n=30; USAT group) or unfractionated heparin alone (n=29; heparin group). Primary outcome was the difference in the RV/LV ratio from baseline to 24 hours. Safety outcomes included death, major and minor bleeding, and recurrent venous thromboembolism at 90 days. In the USAT group, the mean RV/LV ratio was reduced from 1.28±0.19 at baseline to 0.99±0.17 at 24 hours (P<0.001); in the heparin group, mean RV/LV ratios were 1.20±0.14 and 1.17±0.20, respectively (P=0.31). The mean decrease in RV/LV ratio from baseline to 24 hours was 0.30±0.20 versus 0.03±0.16 (P<0.001), respectively. At 90 days, there was 1 death (in the heparin group), no major bleeding, 4 minor bleeding episodes (3 in the USAT group and 1 in the heparin group; P=0.61), and no recurrent venous thromboembolism. CONCLUSIONS In patients with pulmonary embolism at intermediate risk, a standardized USAT regimen was superior to anticoagulation with heparin alone in reversing RV dilatation at 24 hours, without an increase in bleeding complications. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov. Unique identifier: NCT01166997.

Fixed low-dose ultrasound-assisted catheter-directed thrombolysis followed by routine stenting of residual stenosis for acute ilio-femoral deep-vein thrombosis.

Patients with ilio-femoral deep-vein thrombosis (DVT) are at high risk of developing the post-thrombotic syndrome (PTS). In comparison to anticoagulation therapy alone, extended venography-guided catheter-directed thrombolysis without routine stenting of venous stenosis in patients with ilio-femoral DVT is associated with an increased risk of bleeding and a moderate reduction of PTS. We performed a prospective single-centre study to investigate safety, patency and incidence of PTS in patients with acute ilio-femoral DVT treated with fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT; 20 mg rt-PA during 15 hours) followed by routing stenting of venous stenosis, defined as residual luminal narrowing >50%, absent antegrade flow, or presence of collateral flow at the site of suspected stenosis. A total of 87 patients (age 46 ± 21 years, 60% women) were included. At 15 hours, thrombolysis success ≥50% was achieved in 67 (77%) patients. Venous stenting (mean 1.9 ± 1.3 stents) was performed in 70 (80%) patients, with the common iliac vein as the most frequent stenting site (83%). One major (1%; 95% CI, 0-6%) and 6 minor bleedings (7%; 95%CI, 3-14%) occurred. Primary and secondary patency rates at 1 year were 87% (95% CI, 74-94%) and 96% (95% CI, 88-99%), respectively. At three months, 88% (95% CI, 78-94%) of patients were free from PTS according to the Villalta scale, with a similar rate at one year (94%, 95% CI, 81-99%). In conclusion, a fixed-dose USAT regimen followed by routine stenting of underlying venous stenosis in patients with ilio-femoral DVT was associated with a low bleeding rate, high patency rates, and a low incidence of PTS.

The Web KnowARR Framework: Orchestrating Computational Intelligence with Graph Databases

This chapter presents fuzzy cognitive maps (FCM) as a vehicle for Web knowledge aggregation, representation, and reasoning. The corresponding Web KnowARR framework incorporates findings from fuzzy logic. To this end, a first emphasis is particularly on the Web KnowARR framework along with a stakeholder management use case to illustrate the framework’s usefulness as a second focal point. This management form is to help projects to acceptance and assertiveness where claims for company decisions are actively involved in the management process. Stakeholder maps visually (re-) present these claims. On one hand, they resort to non-public content and on the other they resort to content that is available to the public (mostly on the Web). The Semantic Web offers opportunities not only to present public content descriptively but also to show relationships. The proposed framework can serve as the basis for the public content of stakeholder maps.

Hope as a resource for self-directed career management: Investigatiing mediating effects on proactive career behaviors, life and job satisfaction

ABSTRACT Hope is increasingly recognized as an important psychological resource for career development, yet the empirical research on its functioning in this domain is sparse. This paper describes an investigation of how dispositional hope is related to career decidedness, career planning, and career self-efficacy beliefs and whether these more proximal career attitudes mediate the effects of hope on proactive career behaviors, life satisfaction, and job satisfaction. This investigation was conducted using two independent samples of university students (N = 1,334) and working professionals (N = 233). The results showed that in both samples, hope was significantly related but empirically distinct from career variables. In both samples, hope had a direct effect on proactive career behaviors, partially mediated by more career planning. Hope had significant direct and indirect effects on life satisfaction among students, mediated by the three career development attitudes. Although hope was significantly correlated with job satisfaction among employees, no direct effect of hope was found in the mediation model, but an indirect effect through career decidedness was found. The results suggest that hope is an important resource for proactive career development at different career stages and that the positive relation of hope to life and job satisfaction can partially be attributed to the positive relation between hope and favorable career development attitudes.