Parallel increase of heterochromatic increment threshold and postadaptation thresholds in Parkinson's disease and in neuroleptic treatment

Following reports on a predominant loss of blue/yellow contrast sensitivity in Parkinson's disease, we revisited the physiological phenomenon of transient tritanopia. Normative data were collected from 33 healthy individuals using different colour and time combinations. Stimuli of 440 nm wavelength (blue) proved optimal, if flashed for 50 msec within the early phase of a 2 sec pause in the 600 nm adaptation light. These conditions were then applied to 15 patients with Parkinson's disease. We found a parallel increase of increment threshold (P < 0.001) and postadaptation thresholds (P < 0.01), with little change in the extent of transient tritanopia. The same tendency at a lower significance level was found in 15 psychiatric patients under chronic treatment with depot neuroleptics

Can filesharers be triggered by economic incentives? Results of an experiment

Illegal filesharing on the internet leads to considerable financial losses for artists and copyright owners as well as producers and sellers of music. Thus far, measures to contain this phenomenon have been rather restrictive. However, there are still a considerable number of illegal systems, and users are able to decide quite freely between legal and illegal downloads because the latter are still difficult to sanction. Recent economic approaches account for the improved bargaining position of users. They are based on the idea of revenue-splitting between professional sellers and peers. In order to test such an innovative business model, the study reported in this article carried out an experiment with 100 undergraduate students, forming five small peer-to-peer networks.The networks were confronted with different economic conditions.The results indicate that even experienced filesharers hold favourable attitudes towards revenue-splitting.They seem to be willing to adjust their behaviour to different economic conditions

Non-canonical shedding of TNFα by SPPL2a is determined by the conformational flexibility of its transmembrane helix

Ectodomain (EC) shedding defines the proteolytic removal of a membrane protein EC and acts as an important molecular switch in signaling and other cellular processes. Using tumor necrosis factor (TNF)α as a model substrate, we identify a non-canonical shedding activity of SPPL2a, an intramembrane cleaving aspartyl protease of the GxGD type. Proline insertions in the TNFα transmembrane (TM) helix strongly increased SPPL2a non-canonical shedding, while leucine mutations decreased this cleavage. Using biophysical and structural analysis, as well as molecular dynamic simulations, we identified a flexible region in the center of the TNFα wildtype TM domain, which plays an important role in the processing of TNFα by SPPL2a. This study combines molecular biology, biochemistry, and biophysics to provide insights into the dynamic architecture of a substrate\u27s TM helix and its impact on non-canonical shedding. Thus, these data will provide the basis to identify further physiological substrates of non-canonical shedding in the future

Non-canonical Shedding of TNFα by SPPL2a Is Determined by the Conformational Flexibility of Its Transmembrane Helix

Ectodomain (EC) shedding defines the proteolytic removal of a membrane protein EC and acts as an important molecular switch in signaling and other cellular processes. Using tumor necrosis factor (TNF)α as a model substrate, we identify a non-canonical shedding activity of SPPL2a, an intramembrane cleaving aspartyl protease of the GxGD type. Proline insertions in the TNFα transmembrane (TM) helix strongly increased SPPL2a non-canonical shedding, while leucine mutations decreased this cleavage. Using biophysical and structural analysis, as well as molecular dynamic simulations, we identified a flexible region in the center of the TNFα wildtype TM domain, which plays an important role in the processing of TNFα by SPPL2a. This study combines molecular biology, biochemistry, and biophysics to provide insights into the dynamic architecture of a substrate\u27s TM helix and its impact on non-canonical shedding. Thus, these data will provide the basis to identify further physiological substrates of non-canonical shedding in the future

CANreduce 2.0 Adherence-Focused Guidance for Internet Self-Help Among Cannabis Users: Three-Arm Randomized Controlled Trial

Background: Despite increasing demand for treatment among cannabis users in many countries, most users are not in treatment. Internet-based self-help offers an alternative for those hesitant to seek face-to-face therapy, though low effectiveness and adherence issues often arise. Objective: Through adherence-focused guidance enhancement, we aimed to increase adherence to and the effectiveness of internet-based self-help among cannabis users. Methods: From July 2016 to May 2019, cannabis users (n=775; male: 406/575, 70.6%, female: 169/575, 29.4%; age: mean 28.3 years) not in treatment were recruited from the general population and were randomly assigned to (1) an adherence-focused guidance enhancement internet-based self-help intervention with social presence, (2) a similar intervention with an impersonal service team, and (3) access to internet as usual. Controls who were placed on a waiting list for the full intervention after 3 months underwent an assessment and had access to internet as usual. The primary outcome measurement was cannabis-use days over the preceding 30 days. Secondary outcomes included cannabis-dependence severity, changes in common mental disorder symptoms, and intervention adherence. Differences between the study arms in primary and secondary continuous outcome variables at baseline, posttreatment, and follow-up were tested using pooled linear models. Results: All groups exhibited reduced cannabis-use days after 3 months (social presence: -8.2 days; service team: -9.8 days; internet as usual: -4.2 days). The participants in the service team group (P=.01, d=.60) reported significantly fewer cannabis-use days than those in the internet as usual group; the reduction of cannabis use in the social presence group was not significant (P=.07, d=.40). There was no significant difference between the 2 intervention groups regarding cannabis-use reduction. The service team group also exhibited superior improvements in cannabis-use disorder, cannabis-dependence severity, and general anxiety symptoms after 3 months to those in the internet as usual group. Conclusions: The adherence-focused guidance enhancement internet-based self-help intervention with an impersonal service team significantly reduced cannabis use, cannabis-use disorder, dependence severity, and general anxiety symptoms. Trial registration: ISRCTN Registry ISRCTN11086185; http://www.isrctn.com/ISRCTN11086185. Keywords: adherence; cannabis; cognitive behavioral therapy; common mental disorders; drug abuse; guidance; internet; mental disorder; mental health; motivational interviewing; randomized controlled trial; self-help; social presence; therapy

Helical stability of the GnTV transmembrane domain impacts on SPPL3 dependent cleavage

Signal-Peptide Peptidase Like-3 (SPPL3) is an intramembrane cleaving aspartyl protease that causes secretion of extracellular domains from type-II transmembrane proteins. Numerous Golgi-localized glycosidases and glucosyltransferases have been identified as physiological SPPL3 substrates. By SPPL3 dependent processing, glycan-transferring enzymes are deactivated inside the cell, as their active site-containing domain is cleaved and secreted. Thus, SPPL3 impacts on glycan patterns of many cellular and secreted proteins and can regulate protein glycosylation. However, the characteristics that make a substrate a favourable candidate for SPPL3-dependent cleavage remain unknown. To gain insights into substrate requirements, we investigated the function of a GxxxG motif located in the transmembrane domain of N-acetylglucosaminyltransferase V (GnTV), a well-known SPPL3 substrate. SPPL3-dependent secretion of the substrate’s ectodomain was affected by mutations disrupting the GxxxG motif. Using deuterium/hydrogen exchange and NMR spectroscopy, we studied the effect of these mutations on the helix flexibility of the GnTV transmembrane domain and observed that increased flexibility facilitates SPPL3-dependent shedding and vice versa. This study provides first insights into the characteristics of SPPL3 substrates, combining molecular biology, biochemistry, and biophysical techniques and its results will provide the basis for better understanding the characteristics of SPPL3 substrates with implications for the substrates of other intramembrane proteases

Helical stability of the GnTV transmembrane domain impacts on SPPL3 dependent cleavage

Signal-Peptide Peptidase Like-3 (SPPL3) is an intramembrane cleaving aspartyl protease that causes secretion of extracellular domains from type-II transmembrane proteins. Numerous Golgi-localized glycosidases and glucosyltransferases have been identified as physiological SPPL3 substrates. By SPPL3 dependent processing, glycan-transferring enzymes are deactivated inside the cell, as their active site-containing domain is cleaved and secreted. Thus, SPPL3 impacts on glycan patterns of many cellular and secreted proteins and can regulate protein glycosylation. However, the characteristics that make a substrate a favourable candidate for SPPL3-dependent cleavage remain unknown. To gain insights into substrate requirements, we investigated the function of a GxxxG motif located in the transmembrane domain of N-acetylglucosaminyltransferase V (GnTV), a well-known SPPL3 substrate. SPPL3-dependent secretion of the substrate’s ectodomain was affected by mutations disrupting the GxxxG motif. Using deuterium/hydrogen exchange and NMR spectroscopy, we studied the effect of these mutations on the helix flexibility of the GnTV transmembrane domain and observed that increased flexibility facilitates SPPL3-dependent shedding and vice versa. This study provides first insights into the characteristics of SPPL3 substrates, combining molecular biology, biochemistry, and biophysical techniques and its results will provide the basis for better understanding the characteristics of SPPL3 substrates with implications for the substrates of other intramembrane proteases

Treatment with Octreotide in Patients with Well-Differentiated Neuroendocrine Tumors of the Ileum: Prognostic Stratification with Ga-68-DOTA-TATE Positron Emission Tomography

We investigated the use of Ga-68-DOTA-Tyr(3)-octreotate (Ga-68-DOTA-TATE) positron emission tomography (PET) and standardized uptake values (SUVs) to predict the effectiveness of treatment with the somatostatin analogue octreotide acetate (Sandostatin LAR) in patients with neuroendocrine tumors (NETs). Thirty patients with well-differentiated NETs of the ileum (grades G1 and G2) were studied with Ga-68-DOTA-TATE. The average SUV of a 50% isocontour volume of interest covering the lesion with maximum uptake (SUVmean) and the maximum SUV (SUVmax) were determined. Patients were followed up, and the time to progression was recorded. Twenty-one patients showed progressive disease at the end of the study;nine patients had stable disease. The median progression-free survival (PFS) was 51.0 weeks (95% confidence interval [CI] 26.4-75.6). A cutoff for the SUVmax of 29.4 and for the SUVmean of 20.3 could separate between patients with a long PFS (69.0 weeks; 95% CI 9.8-128.2) and a short PFS (26.0 weeks; 95% CI 8.7-43.3) response to octreotide acetate therapy. Patients with high radiotracer uptake had significantly higher PFS with a 2.9-fold higher chance for stable disease after 45 weeks;however, the prognostic performance of SUVmax on an individual basis was poor, with a sensitivity of 75% and a specificity of 64%. SUVmax and SUVmean of NET tumor lesions in Ga-68-DOTA-TATE PET are important prognostic indices for predicting the response to therapy with octreotide acetate

The Effects of Social Presence on Adherence-Focused Guidance in Problematic Cannabis Users: Protocol for the CANreduce 2.0 Randomized Controlled Trial

Background: In European countries, including Switzerland, cannabis is the most commonly used illicit drug. Offering a Web-based self-help tool could potentially reach users who otherwise would not seek traditional help. However, such Web-based self-help tools often suffer from low adherence. Objective: Through adherence-focused guidance enhancements, the aim of this study was to increase adherence in cannabis users entering a Web-based self-help tool to reduce their cannabis use and, in this way, augment its effectiveness. Methods: This paper presents the protocol for a three-arm randomized controlled trial (RCT) to compare the effectiveness of (1) an adherence-focused, guidance-enhanced, Web-based self-help intervention with social presence; (2) an adherence-focused, guidance-enhanced, Web-based self-help intervention without social presence; and (3) a treatment-as-usual at reducing cannabis use in problematic users. The two active interventions, each spanning 6 weeks, consist of modules designed to reduce cannabis use and attenuate common mental disorder (CMD) symptoms, including depression, anxiety, and stress-related disorder symptoms based on the approaches of motivational interviewing and cognitive behavioral therapy. With a target sample size of 528, data will be collected at baseline, 6 weeks, and 3 months after baseline. The primary outcome measurement will be the number of days of cannabis use on the preceding 7 days. Secondary outcomes will include the quantity of cannabis used in standardized cannabis joints, the severity of cannabis dependence, changes in CMD symptoms, and adherence to the program. Data analysis will follow the intention-to-treat principle and employ (generalized) linear mixed models. Results: The project commenced in August 2016; recruitment is anticipated to end by December 2018. First results are expected to be submitted for publication in summer 2019. Conclusions: This study will provide detailed insights on if and how the effectiveness of a Web-based self-help intervention aiming to reduce cannabis use in frequent cannabis users can be improved by theory-driven, adherence-focused guidance enhancement