The anthropogenic increase of carbon dioxide (CO2 ) alters the seawater carbonate chemistry, with a decline of pH and an increase in the partial pressure of CO2 (pCO2 ). Although bacteria play a ...major role in carbon cycling, little is known about the impact of rising pCO2 on bacterial carbon metabolism, especially for natural bacterial communities. In this study, we investigated the effect of rising pCO2 on bacterial production (BP), bacterial respiration (BR) and bacterial carbon metabolism during a mesocosm experiment performed in Kongsfjorden (Svalbard) in 2010. Nine mesocosms with pCO2 levels ranging from ca. 180 to 1400 μatm were deployed in the fjord and monitored for 30 days. Generally BP gradually decreased in all mesocosms in an initial phase, showed a large (3.6-fold average) but temporary increase on day 10, and increased slightly after inorganic nutrient addition. Over the wide range of pCO2 investigated, the patterns in BP and growth rate of bulk and free-living communities were generally similar over time. However, BP of the bulk community significantly decreased with increasing pCO2 after nutrient addition (day 14). In addition, increasing pCO2 enhanced the leucine to thymidine (Leu : TdR) ratio at the end of experiment, suggesting that pCO2 may alter the growth balance of bacteria. Stepwise multiple regression analysis suggests that multiple factors, including pCO2 , explained the changes of BP, growth rate and Leu : TdR ratio at the end of the experiment. In contrast to BP, no clear trend and effect of changes of pCO2 was observed for BR, bacterial carbon demand and bacterial growth efficiency. Overall, the results suggest that changes in pCO2 potentially influence bacterial production, growth rate and growth balance rather than the conversion of dissolved organic matter into CO2 .
Bacterial toxins are known to be effective for cancer therapy. Clostridium perfringens enterotoxin (CPE) is produced by the bacterial Clostridium type A strain. The transmembrane proteins claudin-3 ...and -4, often overexpressed in numerous human epithelial tumors (for example, colon, breast, pancreas, prostate and ovarian), are the targeted receptors for CPE. CPE binding to them triggers formation of membrane pore complexes leading to rapid cell death. In this study, we aimed at selective tumor cell killing by CPE gene transfer. We generated expression vectors bearing the bacterial wild-type CPE cDNA (wtCPE) or translation-optimized CPE (optCPE) cDNA for in vitro and in vivo gene therapy of claudin-3- and -4-overexpressing tumors. The CPE expression analysis at messenger RNA and protein level revealed more efficient expression of optCPE compared with wtCPE. Expression of optCPE showed rapid cytotoxic activity, hightened by CPE release as bystander effect. Cytotoxicity of up to 100% was observed 72 h after gene transfer and is restricted to claudin-3-and -4-expressing tumor lines. MCF-7 and HCT116 cells with high claudin-4 expression showed dramatic sensitivity toward CPE toxicity. The claudin-negative melanoma line SKMel-5, however, was insensitive toward CPE gene transfer. The non-viral intratumoral in vivo gene transfer of optCPE led to reduced tumor growth in MCF-7 and HCT116 tumor-bearing mice compared with the vector-transfected control groups. This novel approach demonstrates that CPE gene transfer can be employed for a targeted suicide gene therapy of claudin-3- and -4-overexpressing tumors, leading to the rapid and efficient tumor cell killing in vitro and in vivo.
Abstract
Background
The aging of baby boomers is expected to confront addiction care with new challenges. This study aims to investigate if German addiction care is confronted with a sustained change ...in its clientele that was initiated by the baby boomers.
Methods
Using data from Berlin outpatient addiction care facilities, we contrasted type of primary substance use disorder and number of comorbid substance use disorders in baby boomers with an older (n = 6524) as well as a younger cohort (n = 15677). To isolate cohort effects, two-level random-intercept regression models were applied in the overlapping age groups of the baby boomer cohort with each other cohort.
Results
Compared to the older cohort, alcohol use disorder lost importance while illicit substances use disorder gained importance in the baby boomers. Baby boomers presented a higher number of comorbid substance use disorders than the older cohort. Comparing baby boomers with the younger cohort, these relationships pointed in the opposite direction.
Conclusions
Outpatient addiction care faces a sustained change to more illicit and comorbid substance use disorders. The addiction care system ought to adapt its services to address the changing needs of its clientele.
Key messages
Baby boomers differed in comparison to the older cohort regarding type of substance use disorder and comorbid substance use disorders. The changes set off by the baby boomers continued in the younger cohort.
The excitation function and momentum distribution of η′ mesons have been measured in photon induced reactions on 12C in the energy range of 1250–2600 MeV. The experiment was performed with tagged ...photon beams from the ELSA electron accelerator using the Crystal Barrel and TAPS detectors. The data are compared to model calculations to extract information on the sign and magnitude of the real part of the η′-nucleus potential. Within the model, the comparison indicates an attractive potential of −(37±10(stat)±10(syst)) MeV depth at normal nuclear matter density. Since the modulus of this depth is larger than the modulus of the imaginary part of the η′-nucleus potential of −(10±2.5) MeV, determined by transparency ratio measurements, a search for resolved η′-bound states appears promising.
Today, various Science Gateways created in close collaboration with scientific communities provide access to remote and distributed HPC, Grid and Cloud computing resources and large-scale storage ...facilities. However, as we have observed there are still many entry barriers for new users and various limitations for active scientists. In this paper we present our latest achievements and software solutions that significantly simplify the use of large scale and distributed computing. We describe several Science Gateways that have been successfully created with the help of our application tools and the QCG (Quality in Cloud and Grid) middleware, in particular Vine Toolkit, QCG-Portal and QCG-Now, and make the use of HPC, Grid and Cloud more straightforward and transparent. Additionally, we share the best practices and lessons learned after creating jointly with user communities many domain-specific Science Gateways, e.g. dedicated for physicists, medical scientists, chemists, engineers and external communities performing multi-scale simulations. As our deployed software solutions have reached recently a critical mass of active users in the PLGrid e-infrastructure in Poland, we also discuss in this paper how changing technologies, visual design and user experience could impact the way we should re-design Science Getaways or even develop new attractive tools, e.g. desktop or mobile-based applications in the future. Finally, we present information and statistics regarding the behaviour of users to help readers understand how new capabilities and functionalities may influence the growth of user interest in Science Gateways and HPC technologies.
Despite significant progress in climate impact research, the narratives that science can presently piece together of a 2, 3, 4, or 5 °C warmer world remain fragmentary. Here we briefly review past ...undertakings to characterise comprehensively and quantify climate impacts based on multi-model approaches. We then report on the Inter-Sectoral Impact Model Intercomparison Project (ISI-MIP), a community-driven effort to compare impact models across sectors and scales systematically, and to quantify the uncertainties along the chain from greenhouse gas emissions and climate input data to the modelling of climate impacts themselves. We show how ISI-MIP and similar efforts can substantially advance the science relevant to impacts, adaptation and vulnerability, and we outline the steps that need to be taken in order to make the most of the available modelling tools. We discuss pertinent limitations of these methods and how they could be tackled. We argue that it is time to consolidate the current patchwork of impact knowledge through integrated cross-sectoral assessments, and that the climate impact community is now in a favourable position to do so.
Placement matching guidelines are promising means to optimize patient-centered care and to match patients' treatment needs. Despite considerable research regarding placement matching approaches to ...optimize alcohol abuse treatment, findings are inconclusive.
To investigate whether the use of patient-centered placement matching (PCPM) guidelines is more effective in reducing heavy drinking and costs 6 months after discharge from an inpatient alcohol withdrawal treatment compared to usual referral to aftercare. Secondary aims were to investigate whether age, gender, trial site or level of care (LOC) are moderators of efficacy and whether patients who were actually referred to the recommended LOC had better treatment outcomes compared to patients who were treated under- or overmatched.
Design. Exploratory randomized controlled trial with measurements during withdrawal treatment and 6 months after initial assessment.
Four German psychiatric clinics offering a 7-21 day inpatient qualified withdrawal program for patients suffering from alcohol dependence.
From 1,927 patients who had a primary diagnosis of alcohol dependence and did not have organized aftercare when entering withdrawal treatment, 299 were invited to participate. Of those, 250 were randomized to the intervention group (IG, n = 123) or the control group (CG, n = 127).
The PCPM were applied to patients of the IG by feeding back a recommendation to a LOC for aftercare that was calculated from the Measurements in the Addictions for Triage and Evaluation (MATE) and discussed with the staff of the treatment unit. Patients of the CG received a general feedback regarding their MATE interview on request.
The MATE, the Client Socio-Demographic and Service Receipt Inventory--European Version and the MATE-Outcomes were administered. Data were analyzed using generalized linear models.
In the intention-to-treat analysis, there were no significant differences between IG and CG regarding days of heavy drinking (incident risk ratio IRR 1.09; p = 0.640), direct (IRR 1.06; p = 0.779), indirect (IRR 0.77; p = 0.392) and total costs (IRR 0.89; p = 0.496). Furthermore, none of the investigated moderator variables affected statistically significant drinking or cost-related primary outcomes. Regardless of group allocation, patients who received matched aftercare reported significantly fewer days of heavy drinking than undermatched patients (IRR 2.09; p = 0.004). For patients who were overmatched, direct costs were significantly higher (IRR 1.79; p = 0.024), but with no additional effects on alcohol consumption compared to matched patients.
While the use of PCPM failed to affect the actual referral to aftercare, our findings suggest that treating patients on the recommended LOC may have the potential to reduce days of heavy drinking compared to undertreatment and costs compared to overtreatment.
Autosomal-dominant polycystic kidney disease (ADPKD) and von Hippel-Lindau (VHL) disease lead to large kidney cysts that share pathogenetic features. The polycystin-1 (PC1) and pVHL proteins may ...therefore participate in the same key signaling pathways. Jade-1 is a pro-apoptotic and growth suppressive ubiquitin ligase for beta-catenin and transcriptional coactivator associated with histone acetyltransferase activity that is stabilized by pVHL in a manner that correlates with risk of VHL renal disease. Thus, a relationship between Jade-1 and PC1 was sought. Full-length PC1 bound, stabilized and colocalized with Jade-1 and inhibited Jade-1 ubiquitination. In contrast, the cytoplasmic tail or the naturally occurring C-terminal fragment of PC1 (PC1-CTF) promoted Jade-1 ubiquitination and degradation, suggesting a dominant-negative mechanism. ADPKD-associated PC1 mutants failed to regulate Jade-1, indicating a potential disease link. Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1. By controlling Jade-1 abundance, PC1 and the PC1-CTF differentially regulate Jade-1-mediated transcriptional activity. A key target of PC1, the cyclin-dependent kinase inhibitor p21, is also up-regulated by Jade-1. Through Jade-1, PC1 and PC1 cleaved forms may exert fine control of beta-catenin and canonical Wnt signaling, a critical pathway in cystic renal disease. Thus, Jade-1 is a transcription factor and ubiquitin ligase whose activity is regulated by PC1 in a manner that is physiologic and may correlate with disease. Jade-1 may be an important therapeutic target in renal cystogenesis.
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