STRING and STITCH: known and predicted interactions between proteins and chemicals

Information on protein-protein and protein-chemical interactions is essential for understanding cellular functions. The STRING and STITCH web resources integrate interaction evidence derived from pathways, automatic literature mining, primary experimental data, and genomic context. The resulting interaction networks cover 1.5 million proteins from 373 organisms and 68,000 chemicals

Variability in synovial inflammation in rheumatoid arthritis investigated by microarray technology

In recent years microarray technology has been used increasingly to acquire knowledge about the pathogenic processes involved in rheumatoid arthritis. The present study investigated variations in gene expression in synovial tissues within and between patients with rheumatoid arthritis. This was done by applying microarray technology on multiple synovial biopsies obtained from the same knee joints. In this way the relative levels of intra-patient and inter-patient variation could be assessed. The biopsies were obtained from 13 different patients: 7 by orthopedic surgery and 6 by rheumatic arthroscopy. The data show that levels of heterogeneity varied substantially between the biopsies, because the number of genes found to be differentially expressed between pairs of biopsies from the same knee ranged from 6 to 2,133. Both arthroscopic and orthopedic biopsies were examined, allowing us to compare the two sampling methods. We found that the average number of differentially expressed genes between biopsies from the same patient was about three times larger in orthopedic than in arthroscopic biopsies. Using a parallel analysis of the tissues by immunohistochemistry, we also identified orthopedic biopsies that were unsuitable for gene expression analysis of synovial inflammation due to sampling of non-inflamed parts of the tissue. Removing these biopsies reduced the average number of differentially expressed genes between the orthopedic biopsies from 455 to 171, in comparison with 143 for the arthroscopic biopsies. Hierarchical clustering analysis showed that the remaining orthopedic and arthroscopic biopsies had gene expression signatures that were unique for each patient, apparently reflecting patient variation rather than tissue heterogeneity. Subsets of genes found to vary between biopsies were investigated for overrepresentation of biological processes by using gene ontology. This revealed representative 'themes' likely to vary between synovial biopsies affected by inflammatory disease

Probing Reionization with the 21 cm-Galaxy Cross Power Spectrum

The cross-correlation between high redshift galaxies and 21 cm emission from the high redshift intergalactic medium (IGM) promises to be an excellent probe of the Epoch of Reionization (EoR). On large scales, the 21 cm and galaxy fields are anti-correlated during most of the reionization epoch. However, on scales smaller than the size of the H II regions around detectable galaxies, the two fields become roughly uncorrelated. Consequently, the 21 cm-galaxy cross power spectrum provides a tracer of bubble growth during reionization, with the signal turning over on progressively larger scales as reionization proceeds. The precise turnover scale depends on the minimum host mass of the detectable galaxies, and the galaxy selection technique. Measuring the turnover scale as a function of galaxy luminosity constrains the characteristic bubble size around galaxies of different luminosities. The cross spectrum becomes positive on small scales if ionizing photons fail to escape from low mass galaxies, and these galaxies are detectable longward of the hydrogen ionization edge, because in this case some identifiable galaxies lie outside of ionized regions. LOFAR can potentially measure the 21 cm-galaxy cross spectrum in conjunction with mild extensions to the existing Subaru survey for $z=6.6$ Lyman-alpha emitters, while the MWA is slightly less sensitive for detecting the cross spectrum. A futuristic galaxy survey covering a sizable fraction of the MWA field of view ($\sim 800$ deg$^2$) can probe the scale dependence of the cross spectrum, constraining the filling factor of H II regions at different redshifts during reionization, and providing other valuable constraints on reionization models.Comment: 17 pages, 12 figures, submitted to Ap

Cannabis Use in Adults Who Screen Positive for Attention Deficit/Hyperactivity Disorder: CANreduce 2.0 Randomized Controlled Trial Subgroup Analysis

Background: Prevalence rates for lifetime cannabis use and cannabis use disorder are much higher in people with attention deficit/hyperactivity disorder than in those without. CANreduce 2.0 is an intervention that is generally effective at reducing cannabis use in cannabis misusers. This self-guided web-based intervention (6-week duration) consists of modules grounded in motivational interviewing and cognitive behavioral therapy. Objective: We aimed to evaluate whether the CANreduce 2.0 intervention affects cannabis use patterns and symptom severity in adults who screen positive for attention deficit/hyperactivity disorder more than in those who do not. Methods: We performed a secondary analysis of data from a previous study with the inclusion criterion of cannabis use at least once weekly over the last 30 days. Adults with and without attention deficit/hyperactivity disorder (based on the Adult Attention deficit/hyperactivity disorder Self-Report screener) who were enrolled to the active intervention arms of CANreduce 2.0 were compared regarding the number of days cannabis was used in the preceding 30 days, the cannabis use disorder identification test score (CUDIT) and the severity of dependence scale score (SDS) at baseline and the 3-month follow-up. Secondary outcomes were Generalized Anxiety Disorder score, Center for Epidemiological Studies Depression scale score, retention, intervention adherence, and safety. Results: Both adults with (n=94) and without (n=273) positive attention-deficit/hyperactivity disorder screening reported significantly reduced frequency (reduction in consumption days: with: mean 11.53, SD 9.28, P<.001; without: mean 8.53, SD 9.4, P<.001) and severity of cannabis use (SDS: with: mean 3.57, SD 3.65, P<.001; without: mean 2.47, SD 3.39, P<.001; CUDIT: with: mean 6.38, SD 5.96, P<.001; without: mean 5.33, SD 6.05, P<.001), as well as anxiety (with: mean 4.31, SD 4.71, P<.001; without: mean 1.84, SD 4.22, P<.001) and depression (with: mean 10.25, SD 10.54; without: mean 4.39, SD 10.22, P<.001). Those who screened positive for attention deficit/hyperactivity disorder also reported significantly decreased attention deficit/hyperactivity disorder scores (mean 4.65, SD 4.44, P<.001). There were no significant differences in change in use (P=.08), dependence (P=.95), use disorder (P=.85), attention deficit/hyperactivity disorder status (P=.84), depression (P=.84), or anxiety (P=.26) between baseline and final follow-up, dependent on positive attention-deficit/hyperactivity disorder screening. Attention deficit/hyperactivity disorder symptom severity at baseline was not associated with reduced cannabis use frequency or severity but was linked to greater reductions in depression (Spearman ρ=.33) and anxiety (Spearman ρ=.28). Individuals with positive attention deficit/hyperactivity disorder screening were significantly less likely to fill out the consumption diary (P=.02), but the association between continuous attention deficit/hyperactivity disorder symptom severity and retention (Spearman ρ=-0.10, P=.13) was nonsignificant. There also was no significant intergroup difference in the number of completed modules (with: mean 2.10, SD 2.33; without: mean 2.36, SD 2.36, P=.34), and there was no association with attention deficit/hyperactivity disorder symptom severity (Spearman ρ=-0.09; P=.43). The same was true for the rate of adverse effects (P=.33). Conclusions: Cannabis users screening positive for attention deficit/hyperactivity disorder may benefit from CANreduce 2.0 to decrease the frequency and severity of cannabis dependence and attenuate symptoms of depression and attention deficit/hyperactivity disorder-related symptoms. This web-based program's advantages include its accessibility for remote users and a personalized counselling option that may contribute to increased adherence and motivation to change among program users. Trial registration: International Standard Randomized Controlled Trial Number (ISRCTN) 11086185; http://www.isrctn.com/ISRCTN11086185. Keywords: ADHD; CANreduce; anxiety; attention deficit/hyperactivity disorder; cannabis; cannabis use disorder; depression; digital health; mental health; online health; online tool; web-based self-help tool

Cannabis Use in Adults Who Screen Positive for Attention Deficit/Hyperactivity Disorder: CANreduce 2.0 Randomized Controlled Trial Subgroup Analysis.

BACKGROUND Prevalence rates for lifetime cannabis use and cannabis use disorder are much higher in people with attention deficit/hyperactivity disorder than in those without. CANreduce 2.0 is an intervention that is generally effective at reducing cannabis use in cannabis misusers. This self-guided web-based intervention (6-week duration) consists of modules grounded in motivational interviewing and cognitive behavioral therapy. OBJECTIVE We aimed to evaluate whether the CANreduce 2.0 intervention affects cannabis use patterns and symptom severity in adults who screen positive for attention deficit/hyperactivity disorder more than in those who do not. METHODS We performed a secondary analysis of data from a previous study with the inclusion criterion of cannabis use at least once weekly over the last 30 days. Adults with and without attention deficit/hyperactivity disorder (based on the Adult Attention deficit/hyperactivity disorder Self-Report screener) who were enrolled to the active intervention arms of CANreduce 2.0 were compared regarding the number of days cannabis was used in the preceding 30 days, the cannabis use disorder identification test score (CUDIT) and the severity of dependence scale score (SDS) at baseline and the 3-month follow-up. Secondary outcomes were Generalized Anxiety Disorder score, Center for Epidemiological Studies Depression scale score, retention, intervention adherence, and safety. RESULTS Both adults with (n=94) and without (n=273) positive attention-deficit/hyperactivity disorder screening reported significantly reduced frequency (reduction in consumption days: with: mean 11.53, SD 9.28, P<.001; without: mean 8.53, SD 9.4, P<.001) and severity of cannabis use (SDS: with: mean 3.57, SD 3.65, P<.001; without: mean 2.47, SD 3.39, P<.001; CUDIT: with: mean 6.38, SD 5.96, P<.001; without: mean 5.33, SD 6.05, P<.001), as well as anxiety (with: mean 4.31, SD 4.71, P<.001; without: mean 1.84, SD 4.22, P<.001) and depression (with: mean 10.25, SD 10.54; without: mean 4.39, SD 10.22, P<.001). Those who screened positive for attention deficit/hyperactivity disorder also reported significantly decreased attention deficit/hyperactivity disorder scores (mean 4.65, SD 4.44, P<.001). There were no significant differences in change in use (P=.08), dependence (P=.95), use disorder (P=.85), attention deficit/hyperactivity disorder status (P=.84), depression (P=.84), or anxiety (P=.26) between baseline and final follow-up, dependent on positive attention-deficit/hyperactivity disorder screening. Attention deficit/hyperactivity disorder symptom severity at baseline was not associated with reduced cannabis use frequency or severity but was linked to greater reductions in depression (Spearman ρ=.33) and anxiety (Spearman ρ=.28). Individuals with positive attention deficit/hyperactivity disorder screening were significantly less likely to fill out the consumption diary (P=.02), but the association between continuous attention deficit/hyperactivity disorder symptom severity and retention (Spearman ρ=-0.10, P=.13) was nonsignificant. There also was no significant intergroup difference in the number of completed modules (with: mean 2.10, SD 2.33; without: mean 2.36, SD 2.36, P=.34), and there was no association with attention deficit/hyperactivity disorder symptom severity (Spearman ρ=-0.09; P=.43). The same was true for the rate of adverse effects (P=.33). CONCLUSIONS Cannabis users screening positive for attention deficit/hyperactivity disorder may benefit from CANreduce 2.0 to decrease the frequency and severity of cannabis dependence and attenuate symptoms of depression and attention deficit/hyperactivity disorder-related symptoms. This web-based program's advantages include its accessibility for remote users and a personalized counselling option that may contribute to increased adherence and motivation to change among program users. TRIAL REGISTRATION International Standard Randomized Controlled Trial Number (ISRCTN) 11086185; http://www.isrctn.com/ISRCTN11086185

STRING 8—a global view on proteins and their functional interactions in 630 organisms

Functional partnerships between proteins are at the core of complex cellular phenotypes, and the networks formed by interacting proteins provide researchers with crucial scaffolds for modeling, data reduction and annotation. STRING is a database and web resource dedicated to protein-protein interactions, including both physical and functional interactions. It weights and integrates information from numerous sources, including experimental repositories, computational prediction methods and public text collections, thus acting as a meta-database that maps all interaction evidence onto a common set of genomes and proteins. The most important new developments in STRING 8 over previous releases include a URL-based programming interface, which can be used to query STRING from other resources, improved interaction prediction via genomic neighborhood in prokaryotes, and the inclusion of protein structures. Version 8.0 of STRING covers about 2.5 million proteins from 630 organisms, providing the most comprehensive view on protein-protein interactions currently available. STRING can be reached at http://string-db.or

Studying Reionization with Ly-alpha Emitters

We show that observations of high-redshift Ly-alpha emitters (LAEs) have the potential to provide definitive evidence for reionization in the near future. Using 200 Mpc radiative transfer simulations, we calculate the effect that patchy reionization has on the line profile, on the luminosity function, and, most interestingly, on the clustering of emitters for several realistic models of reionization. Reionization increases the measured clustering of emitters, and we show that this enhancement would be essentially impossible to attribute to anything other than reionization. Our results motivate looking for the signature of reionization in existing LAE data. We find that for stellar reionization scenarios the angular correlation function of the 58 LAEs in the Subaru Deep Field z = 6.6 photometric sample is more consistent with a fully ionized universe (mean volume ionized fraction x_i = 1) than a universe with x_i 2-sigma confidence level. Measurements in the next year on Subaru will increase their z = 6.6 LAE sample by a factor of five and tighten these limits. If the clustering signature of reionization is detected in a LAE survey, a comparison with a Lyman-break or a H-alpha survey in the same field would confirm the reionization hypothesis. We discuss the optimal LAE survey specifications for detecting reionization, with reference to upcoming programs.Comment: 24 pages, 17 figures, accepted by MNRA

The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored

An essential prerequisite for any systems-level understanding of cellular functions is to correctly uncover and annotate all functional interactions among proteins in the cell. Toward this goal, remarkable progress has been made in recent years, both in terms of experimental measurements and computational prediction techniques. However, public efforts to collect and present protein interaction information have struggled to keep up with the pace of interaction discovery, partly because protein-protein interaction information can be error-prone and require considerable effort to annotate. Here, we present an update on the online database resource Search Tool for the Retrieval of Interacting Genes (STRING); it provides uniquely comprehensive coverage and ease of access to both experimental as well as predicted interaction information. Interactions in STRING are provided with a confidence score, and accessory information such as protein domains and 3D structures is made available, all within a stable and consistent identifier space. New features in STRING include an interactive network viewer that can cluster networks on demand, updated on-screen previews of structural information including homology models, extensive data updates and strongly improved connectivity and integration with third-party resources. Version 9.0 of STRING covers more than 1100 completely sequenced organisms; the resource can be reached at http://string-db.or

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

The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored

An essential prerequisite for any systems-level understanding of cellular functions is to correctly uncover and annotate all functional interactions among proteins in the cell. Toward this goal, remarkable progress has been made in recent years, both in terms of experimental measurements and computational prediction techniques. However, public efforts to collect and present protein interaction information have struggled to keep up with the pace of interaction discovery, partly because protein–protein interaction information can be error-prone and require considerable effort to annotate. Here, we present an update on the online database resource Search Tool for the Retrieval of Interacting Genes (STRING); it provides uniquely comprehensive coverage and ease of access to both experimental as well as predicted interaction information. Interactions in STRING are provided with a confidence score, and accessory information such as protein domains and 3D structures is made available, all within a stable and consistent identifier space. New features in STRING include an interactive network viewer that can cluster networks on demand, updated on-screen previews of structural information including homology models, extensive data updates and strongly improved connectivity and integration with third-party resources. Version 9.0 of STRING covers more than 1100 completely sequenced organisms; the resource can be reached at http://string-db.org