In Vivo; In Vitro Interaction of Silver Nanoparticles with Leucine Aminopeptidase from Human and Plasmodium falciparum.

There is increasing requirement for the development of new drug protocols against malaria, a fatal disease caused by the lethal parasite Plasmodium falciparum. Leucine aminopeptidase (Pf LAP) of Plasmodium falciparum, is being pursued as a promising target for the discovery of novel antimalarials. The effects of silver nanoparticles (AgNPs) against P. falciparum leucine amino-peptidase (Pf LAP) and the human homolog (HsLAP) were compared. Pf LAP and HsLAP were expressed in Escherichia coli, and AgNPs (3-10 nm) characterized by ultra-violet spectroscopy and transmission electron microscopy. Pf LAP indicated a Km of 694 µM towards leucine-p-nitroanilide and a Vmax of 57.9 µmol.ml-1 · min-1 while HsLAP had a Km of 1.6 mM and Vmax of 119.6 µmol · ml-1 · min-1. On interaction with AgNPs (670 nM) Pf LAP was selectively inhibited (57.1%; Ki = 610 nM) relative to HsLAP (10.8%; Ki = 5.22 µM). Structural differences between the enzyme variants, particularly the orientation and distance of surface Met349 in Pf LAP and Met306 in HsLAP to the zinc binding sites were significant and may allow for selective targeting of Pf LAP by AgNPs. The viability of P. falciparum parasites was decreased when exposed to silver nanoparticles, with an IC50 value of 6.96 µM, compared to an IC50 value of 647.7 µM for human HeLa cells.

Thermally stable and efficient polymer solar cells based on a novel donor-acceptor copolymer.

We report high photovoltaic performance of a novel donor-acceptor (D-A) conjugated polymer poly[2,6[4,8-bis(2-ethyl-hexyl)benzo[1,2-b;4,5-b']dithiophene-co-2,5-thiophene-co-4,7[5,6-bis-octyloxy-benzo[1,2,5]thiadiazole]-co-2,5-thiophene] (PBDTTBTZT) in bulk heterojunctions with [6,6]-phenyl-C71-butyric acid methyl ester (PC70BM). A power conversion efficiency (PCE) of more than 7% is obtained for optimized charge-extracting electrodes. Upon application of thermal stress via annealing, a superior thermal stability is demonstrated as compared to poly[N-9″-hepta-decanyl-2,7-carbazole-alt-5,5-(4',7'-di-2-thienyl-2',1',3'-benzothiadiazole)] (PCDTBT).

Venous Leak Embolization in Patients with Venogenic Erectile Dysfunction via Deep Dorsal Penile Vein Access: Safety and Early Efficacy.

PURPOSE: This all-comers registry aimed to assess safety and early efficacy of venous embolization in patients with venogenic erectile dysfunction due to venous leak in an unselected cohort. METHODS: Between October 2019 and September 2022, patients with venogenic erectile dysfunction resistant to phosphodiesterase-5-inhibitors were treated with venous embolization using ultrasound-guided anterograde access via a deep dorsal penile vein in a single center. A mix of ethiodized oil and modified cyanoacrylate-based glue n-butyl 2 cyanoacrylate (NBCA) monomer plus methacryloxy-sulpholane monomer (Glubran-2, GEM, Italy) was used as liquid embolic agent. Prior to embolization, venous leak had been verified based on penile duplex sonography and computed tomography cavernosography. Procedural success was defined as technically successful and complete target vein embolization. The primary safety outcome measure was any major adverse event 6 weeks after the procedure. The primary feasibility outcome measure was IIEF-15 (International Index of Erectile Function-15) score improvement ≥ 4 points in ≥ 50% of subjects on 6 weeks follow-up post intervention. RESULTS: Fifty consecutive patients (mean age 61.8 ± 10.0 years) with severe erectile dysfunction due to venous leak underwent venous embolization. Procedural success was achieved in 49/50 (98%) of patients with no major adverse events on follow-up. The primary feasibility outcome measure at 6 weeks was reached by 34/50 (68%) of patients. CONCLUSION: Venous leak embolization via deep dorsal penile vein access using a liquid embolic agent was safe for all and efficacious in the majority of patients with severe venogenic erectile dysfunction on 6 weeks follow-up.

Developing a framework for investigating citizen science through a combination of web analytics and social science methods-The CS Track perspective.

Over the past decade, Citizen Science (CS) has shown great potential to transform the power of the crowd into knowledge of societal value. Many projects and initiatives have produced high quality scientific results by mobilizing peoples' interest in science to volunteer for the public good. Few studies have attempted to map citizen science as a field, and assess its impact on science, society and ways to sustain its future practice. To better understand CS activities and characteristics, CS Track employs an analytics and analysis framework for monitoring the citizen science landscape. Within this framework, CS Track collates and processes information from project websites, platforms and social media and generates insights on key issues of concern to the CS community, such as participation patterns or impact on science learning. In this paper, we present the operationalization of the CS Track framework and its three-level analysis approach (micro-meso-macro) for applying analytics techniques to external data sources. We present three case studies investigating the CS landscape using these analytical levels and discuss the strengths and limitations of combining web-analytics with quantitative and qualitative research methods. This framework aims to complement existing methods for evaluating CS, address gaps in current observations of the citizen science landscape and integrate findings from multiple studies and methodologies. Through this work, CS Track intends to contribute to the creation of a measurement and evaluation scheme for CS and improve our understanding about the potential of analytics for the evaluation of CS.

Targeting to rhoptry organelles of Toxoplasma gondii involves evolutionarily conserved mechanisms.

Intracellular parasites of the phylum Apicomplexa contain specialized rhoptry secretory organelles that have a crucial function in host-cell invasion and establishment of the parasitophorous vacuole. Here we show that localization of the Toxoplasma gondii rhoptry protein ROP2 is dependent on a YEQL sequence in the cytoplasmic tail that binds to micro-chain subunits of T. gondii and mammalian adaptors, and conforms to the YXXstraight phi mammalian sorting motif. Chimaeric reporters, containing the transmembrane domains and cytoplasmic tails of the low-density lipoprotein receptor and of Lamp-1, are sorted to the Golgi or the trans-Golgi network (TGN), and partially to apical microneme organelles of the parasite, respectively. Targeting of these reporters is mediated by YXXstraight phi- and NPXY-type signals. This is the first demonstration of tyrosine-dependent sorting in protozoan parasites, indicating that T. gondii proteins may be targeted to, and involved in biogenesis of, morphologically unique organelles through the use of evolutionarily conserved signals and machinery.

A real-time control strategy for separation of highly polluted storm water based on UV-Vis online measurements--from theory to operation.

'Classical' real-time control (RTC) strategies in sewer systems are based on water level and flow measurements with the goal of activation of retention volume. The control system rule of 'clean (storm water) runoff into the receiving water - polluted runoff into the treatment plant' has been thwarted by rough operating conditions and lack of measurements. Due to the specific boundary conditions in the city of Wuppertal's separate sewer system (clean stream water is mixed with polluted storm water runoff) a more sophisticated--pollution-based--approach was needed. In addition the requirements to be met by the treatment of storm water runoff have become more stringent in recent years. To separate the highly-polluted storm water runoff during rain events from the cleaner stream flow a pollution-based real-time control (P-RTC) system was developed and installed. This paper describes the measurement and P-RTC equipment, the definition of total suspended solids as the pollution-indicating parameter, the serviceability of the system, and also gives a cost assessment. A sensitivity analysis and pollution load calculations have been carried out in order to improve the P-RTC algorithm. An examination of actual measurements clearly shows the ecological and economic advantages of the P-RTC strategy.

Cost effectiveness of centralised and decentralised storm water treatment.

As part of a research & development project commissioned by the Land of North Rhine-Westphalia's Ministry for the Environment and Nature Conservation, Agriculture and Consumer Protection (MUNLV) an examination is being carried out of the general possibilities for centralised and decentralised treatment storm water runoff to be discharged into (canalised) receiving waters and the costs ensuing from this. The examination of the different options is being carried out under real conditions, with the Briller Creek (Wuppertal/Germany) and Müggen Creek (Remscheid/Germany) catchment areas being used as models. The range of investigations deals with a comparison between 'decentralised, semicentralised, centralised' storm water treatment, centralised storm water treatment involving a separate sewer and parameter-specific pollution based storm water runoff control. In the framework of the research project each of the variants is to be elaborated and the costs are to be calculated so as to permit a comparison between the different system designs. In particular, the investigations are to take into account the actual requirements to be met by storm water drainage systems involving separate sewage systems.

A Virtual Sandbox Approach to Studying the Effect of Augmented Communication on Human-Robot Collaboration.

Human-Robot Collaboration (HRC) has the potential for a paradigm shift in industrial production by complementing the strengths of industrial robots with human staff. However, exploring these scenarios in physical experimental settings is costly and difficult, e.g., due to safety considerations. We present a virtual reality application that allows the exploration of HRC work arrangements with autonomous robots and their effect on human behavior. Prior experimental studies conducted using this application demonstrated the benefits of augmenting an autonomous robot arm with communication channels on subjective aspects such as perceived stress. Motivated by current safety regulations that hinder HRC to expand its full potential, we explored the effects of the augmented communication on objective measures (collision rate and produced goods) within a virtual sandbox application. Explored through a safe and replicable setup, the goal was to determine whether communication channels that provide guidance and explanation on the robot can help mitigate safety hazards without interfering with the production effectiveness of both parties. This is based on the theoretical foundation that communication channels enable the robot to explain its action, helps the human collaboration partner to comprehend the current state of the shared task better, and react accordingly. Focused on the optimization of production output, reduced collision rate, and increased perception of safety, a between-subjects experimental study with two conditions (augmented communication vs non-augmented) was conducted. The results revealed a statistically significant difference in terms of production quantity output and collisions with the robot, favoring the augmented conditions. Additional statistically significant differences regarding self-reported perceived safety were found. The results of this study provide an entry point for future research regarding the augmentation of industrial robots with communication channels for safety purposes.

Management of blunt injuries to the spleen.

BACKGROUND: Non-operative management (NOM) of blunt splenic injuries is nowadays considered the standard treatment. The present study identified selection criteria for primary operative management (OM) and planned NOM. METHODS: All adult patients with blunt splenic injuries treated at Berne University Hospital, Switzerland, between 2000 and 2008 were reviewed. RESULTS: There were 206 patients (146 men) with a mean(s.d.) age of 38.2(19.1) years and an Injury Severity Score of 30.9(11.6). The American Association for the Surgery of Trauma classification of the splenic injury was grade 1 in 43 patients (20.9 per cent), grade 2 in 52 (25.2 per cent), grade 3 in 60 (29.1 per cent), grade 4 in 42 (20.4 per cent) and grade 5 in nine (4.4 per cent). Forty-seven patients (22.8 per cent) required immediate surgery. Transfusion of at least 5 units of red cells (odds ratio (OR) 13.72, 95 per cent confidence interval 5.08 to 37.01), Glasgow Coma Scale score below 11 (OR 9.88, 1.77 to 55.16) and age 55 years or more (OR 3.29, 1.07 to 10.08) were associated with primary OM. The rate of primary OM decreased from 33.3 to 11.9 per cent after the introduction of transcatheter arterial embolization in 2005. Overall, 159 patients (77.2 per cent) qualified for NOM, which was successful in 143 (89.9 per cent). The splenic salvage rate was 69.4 per cent. In multivariable analysis age at least 40 years was the only factor independently related to failure of NOM (OR 13.58, 2.76 to 66.71). CONCLUSION: NOM of blunt splenic injuries has a low failure rate. Advanced age is independently associated with an increased failure rate.

Endovascular treatment for chronic atherosclerotic occlusive mesenteric disease: is stenting superior to balloon angioplasty?

BACKGROUND: Endovascular treatment is an increasingly used therapeutic option in patients with chronic atherosclerotic occlusive mesenteric disease. Purpose of this study was evaluation of patency and mortality in patients treated with visceral artery percutaneous transluminal angioplasty (PTA) or stenting including follow-up. PATIENTS AND METHODS: A retrospective review of 17 consecutive patients (4 women, 13 men) with endovascular treatment for symptomatic chronic mesenteric ischemia from 1998 to 2004 was performed. Mean follow-up period was 42 months. Patient demographics, interventional details, primary and/or secondary patency and mortality were recorded. Cumulative mortality and patency rates were determined using Kaplan-Meier life table analysis. RESULTS: Twenty-six interventions (PTA alone n=13, PTA and stenting n=13) were performed in 17 patients. Interventions were performed in the superior mesenteric artery (n=13) and celiac artery (n=13). The re-intervention rate was 30% (6/26). Re-interventions were performed for the superior mesenteric artery (n=4) and celiac artery (n=2). Cumulative overall 1-year results were primary patency rate 81%, secondary patency rate 94%, and survival rate 82%. Cumulative 10-year results were primary patency rate 73%, secondary patency rate 94%, and survival rate 65%. The 10-year secondary patency rate was 100% in patients post initial stenting and 86% in patients post initial PTA. CONCLUSIONS: Long-term follow-up post endovascular treatment for chronic mesenteric ischemia demonstrated a considerable overall secondary patency rate of 94%. However, the long-term secondary patency rate was higher in patients post initial stenting compared to PTA alone.

Differential sorting and post-secretory targeting of proteins in parasitic invasion.

Toxoplasma gondii uses a highly coordinated arsenal of three structurally and biochemically distinct secretory granules to invade and develop in a wide range of host cells. Proteins of these secretory granules are sorted to strategic subcellular locations using distinctive sorting signals and are then triggered differentially for exocytosis. These secreted proteins are subsequently targeted and inserted into membrane domains.

Options and limits of quantitative and qualitative online-monitoring of industrial discharges into municipal sewage systems.

In some cities, industrial enterprises' discharges into municipal sewage systems have a major impact on the quantity and quality of inflows to the municipal treatment plants. In many cases, industrial discharges stand out on account of the great fluctuations in their volumetric rates of flow, pollution loads and temperatures. As a result, these discharges put a great strain on the sewage system, the treatment plant, and ultimately the receiving waters. The enterprises concerned have to pay the treatment plant operators fees based on the load and/or volume discharged. In most cases, qualitative monitoring operations merely consist of spot checks. This means that continuously surveillance is not possible and infringements of the permissible limit values are only discovered by accident. If impermissible discharges are carried out that may be susceptible to causing a treatment plant failure, the rapid initiation of countermeasures is not possible. Hence, spectrometer probes and mobile flowmeters were used in order to determine volumetric rates of flow, COD concentrations, and ultimately the loads discharged. The possibilities for, and limits to, online monitoring as well as shortcomings of spot-checks are discussed in the course of this paper, which also includes an uncertainty analysis.

CFA-15 - a perfluorinated metal-organic framework with linear 1-D CuII-chains containing accessible unsaturated, reactive metal centres.

The synthesis and crystal structure of the perfluorinated metal-organic framework CFA-15 (Coordination Framework Augsburg University-15), CuII3(tfpc)2(OH)2·DMF, as well as the crystal structure of its ligand (H2-tfpc = 3,5-bis(trifluoromethyl)-1H-pyrazole-4-carboxylic acid) are described. The MOF crystallizes in the monoclinic crystal system within the chiral space group C2 (no. 5). It features a 3-D microporous framework with rhombic channels along the c-axis. The MOF is formed by 1-D chains of Cu(ii) ions expanding in the c-direction, bridged by OH- groups, DMF molecules and tfpc2- ligands. Two different Cu(ii) species are located within the structure, bridged in a {Cu1-Cu1-Cu2-Cu1-Cu1-Cu2} mode. By thermal treatment, it was possible to remove coordinated solvent molecules and generate free accessible, unsaturated and reactive metal centres. The structure of activated CFA-15 was refined via Rietveld method. DRIFT measurements, which were used to study adsorption of CO2 and NO in the MOF, showed a formation of a stable NO-CFA-15 complex. CFA-15 was further characterized by thermogravimetric analysis, variable temperature powder X-ray diffraction measurements, IR spectroscopy, as well as photoluminescence and gas sorption measurements. The isosteric heats of adsorption for CO, CO2, H2 and O2 were determined, and compared to DFT calculated sorption energies as well as to data reported in literature for similar materials.

Factors favouring palliative treatment multidisciplinary decisions for newly diagnosed visceral and soft tissue sarcomas.

AIMS: The multidisciplinary medical decision-making process is a key element of the clinical management of cancers, especially rare cancers such as visceral and soft tissue sarcomas. One of the most important decisions stated is to discriminate patients considered for palliative-intent treatment. The aim of this retrospective study was to establish the rationale parameters that justify this decision for newly diagnosed sarcomas. PATIENTS AND METHODS: From a retrospective cohort of 341 patients we investigated the parameters justifying a palliative-intent strategy decision in univariate and multivariate analyses, based on the logistic regression model. We also measured the effect of this decision on overall survival using the Cox model. RESULTS: Seventy-one of 341 patients (20%) were considered for a palliative-intent strategy. In multivariate analysis, five variables justified this decision: contraindication for general anaesthesia (adjusted odds ratio 10.5), head and neck location (odds ratio 3.7), visceral sarcoma (odds ratio 2.8), tumour size over 8 cm (odds ratio 3.5) and presence of metastasis (odds ratio 39.5). In the Cox model we found that two independent factors were associated with poor outcome: grade 3 (hazard ratio 2.7) and palliative-intent strategy (hazard ratio 3.3). CONCLUSIONS: About 20% of newly diagnosed sarcomas were considered for palliative strategy by multidisciplinary committee. This decision was based on rationale parameters and had an intrinsic prognostic value.

Using attractiveness model for actors ranking in social media networks.

BACKGROUND: Influential actors detection in social media such as Twitter or Facebook can play a major role in gathering opinions on particular topics, improving the marketing efficiency, predicting the trends, etc. PROPOSED METHODS: This work aims to extend our formally defined T measure to present a new measure aiming to recognize the actor's influence by the strength of attracting new important actors into a networked community. Therefore, we propose a model of the actor's influence based on the attractiveness of the actor in relation to the number of other attractors with whom he/she has established connections over time. RESULTS AND CONCLUSIONS: Using an empirically collected social network for the underlying graph, we have applied the above-mentioned measure of influence in order to determine optimal seeds in a simulation of influence maximization. We study our extended measure in the context of information diffusion because this measure is based on a model of actors who attract others to be active members in a community. This corresponds to the idea of the IC simulation model which is used to identify the most important spreaders in a set of actors.

Differential inhibition of adenylylated and deadenylylated forms of M. tuberculosis glutamine synthetase as a drug discovery platform.

Glutamine synthetase is a ubiquitous central enzyme in nitrogen metabolism that is controlled by up to four regulatory mechanisms, including adenylylation of some or all of the twelve subunits by adenylyl transferase. It is considered a potential therapeutic target for the treatment of tuberculosis, being essential for the growth of Mycobacterium tuberculosis, and is found extracellularly only in the pathogenic Mycobacterium strains. Human glutamine synthetase is not regulated by the adenylylation mechanism, so the adenylylated form of bacterial glutamine synthetase is of particular interest. Previously published reports show that, when M. tuberculosis glutamine synthetase is expressed in Escherichia coli, the E. coli adenylyl transferase does not optimally adenylylate the M. tuberculosis glutamine synthetase. Here, we demonstrate the production of soluble adenylylated M. tuberulosis glutamine synthetase in E. coli by the co-expression of M. tuberculosis glutamine synthetase and M. tuberculosis adenylyl transferase. The differential inhibition of adenylylated M. tuberulosis glutamine synthetase and deadenylylated M. tuberulosis glutamine synthetase by ATP based scaffold inhibitors are reported. Compounds selected on the basis of their enzyme inhibition were also shown to inhibit M. tuberculosis in the BACTEC 460TB™ assay as well as the intracellular inhibition of M. tuberculosis in a mouse bone-marrow derived macrophage assay.

Trimeric C-type lectin domains in host defence.

Recent crystal structures, established for fragments of human and rat mannose-binding proteins, indicate that the triple-stranded alpha-helical coiled coil present in these collectins is responsible for the trimeric orientation of C-type lectin domains.

Crystal structure of the trimeric alpha-helical coiled-coil and the three lectin domains of human lung surfactant protein D.

BACKGROUND: Human lung surfactant protein D (hSP-D) belongs to the collectin family of C-type lectins and participates in the innate immune surveillance against microorganisms in the lung through recognition of carbohydrate ligands present on the surface of pathogens. The involvement of this protein in innate immunity and the allergic response make it the subject of much interest. RESULTS: We have determined the crystal structure of a trimeric fragment of hSP-D at 2.3 A resolution. The structure comprises an alpha-helical coiled-coil and three carbohydrate-recognition domains (CRDs). An interesting deviation from symmetry was found in the projection of a single tyrosine sidechain into the centre of the coiled-coil; the asymmetry of this residue influences the orientation of one of the adjacent CRDs. The cleft between the three CRDs presents a large positively charged surface. CONCLUSIONS: The fold of the CRD of hSP-D is similar to that of the mannan-binding protein (MBP), but its orientation relative to the alpha-helical coiled-coil region differs somewhat to that seen in the MBP structure. The novel central packing of the tyrosine sidechain within the coiled-coil and the resulting asymmetric orientation of the CRDs has unexpected functional implications. The positively charged surface might facilitate binding to negatively charged structures, such as lipopolysaccharides.

Concentration-dependent mutation by alkylating agents in human lymphoblasts and Salmonella typhimurium: N-methyl-N-nitrosourethane and beta-propiolactone.

The toxic and mutagenic effects of the alkylating agents N-methyl-N-nitrosourethane (MNUT) and beta-propiolactone (BPL) were quantitatively measured in human lymphoblasts and Salmonella typhimurium. Forward mutation to 6-thioguanine resistance was measured in the human lymphoblasts, and forward mutation to 8-azaguanine resistance was measured in the bacterial cells after equigenerational (1.5 doubling times) exposures. In both systems, the induced mutant fraction rose linearly as a function of concentration for BPL and was biphasic for MNUT. The responses of the two assay systems to eight alkylating agents were compared. The exposure of the cells to each alkylating agent was calculated as exposure concentration multiplied by the time of exposure, and allowance was made for the decomposition of the alkylating agents during exposure (integral exposure). Human cells were 2.5--13 times more sensitive than was S. typhimurium to the alkylating agents methyl methanesulfonate, ethyl methanesulfonate, propyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, methylnitrosourea, and MNUT. S. typhimurium cells were three times more sensitive to butyl methanesulfonate and 25 times more sensitive to BPL than were human cells.

Alkyl methane sulfonate mutation of diploid human lymphoblasts and Salmonella typhimurium.

Concentration dependence of mutation in equigenerational exposures to methyl, ethyl, propyl, and butyl methanesulfonates has been determined in diploid human lymphoblasts and Salmonella typhimurium. Forward mutation was measured at the hypoxanthine guanine phosphoribosyltransferase locus in human lymphoblasts and at the putative guanine phosphoribosyltransferase locus in S. typhimurium. Reverse mutation at the his G46 locus was also measured in S. typhimurium. This analysis and previous reports support the conclusion that S. typhimurium and mammalian cells are essentially equisensitive to the mutagenic effects of ethyl methanesulfonate when concentration and exposure time are taken into account. Comparison of forward and reverse mutation assays in S. typhimurium reveals no important differences in sensitivities for the four compounds studied.