The sequence selectivity of KSRP explains its flexibility in the recognition of the RNA targets

K-homology (KH) splicing regulator protein (KSRP) is a multi-domain RNA-binding protein that regulates different steps of mRNA metabolism, from mRNA splicing to mRNA decay, interacting with a broad range of RNA sequences. To understand how KSRP recognizes its different RNA targets it is necessary to define the general rules of KSRP–RNA interaction. We describe here a complete scaffold-independent analysis of the RNA-binding potential of the four KH domains of KSRP. The analysis shows that KH3 binds to the RNA with a significantly higher affinity than the other domains and recognizes specifically a G-rich target. It also demonstrates that the other KH domains of KSRP display different sequence preferences explaining the broad range of targets recognized by the protein. Further, KSRP shows a strong negative selectivity for sequences containing several adjacent Cytosines limiting the target choice of KSRP within single-stranded RNA regions. The in-depth analysis of the RNA-binding potential of the KH domains of KSRP provides us with an understanding of the role of low sequence specificity domains in RNA recognition by multi-domain RNA-binding proteins

Exploring the Relationship Between the Acceptability of an Internet-Based Intervention for Depression in Primary Care and Clinical Outcomes: Secondary Analysis of a Randomized Controlled Trial

Background: Depression is one of the most prevalent psychological disorders worldwide. Although psychotherapy for depression is effective, there are barriers to its implementation in primary care in Spain. The use of the Internet has been shown to be a feasible solution. However, the acceptability of Internet-based interventions has not been studied sufficiently. Objective: To assess the acceptability of an Internet-based intervention (IBI) for depression in primary care, and explore the relationship between expectations and satisfaction and the improvement in the clinical variables in primary care patients receiving this intervention. Furthermore, it offers data about the effects of some sociodemographic characteristics on these acceptability variables and analyzes whether the expectations are related to finalizing the intervention. Methods: Data were based on depressive patients who were participants in a randomized controlled trial. In the present study, we present the data from all the participants in the Internet intervention groups (N = 198). All the participants filled out the expectation and satisfaction scales (six-item scales regarding treatment logic, satisfaction, recommending, usefulness for other disorders, usefulness for the patient, and unpleasantness), the Beck Depression Inventory-II, and the secondary outcome measures: depression and anxiety impairment, and positive and negative affect. Results: Results showed that participants'' expectations and satisfaction with the program were both high and differences in expectations and satisfaction depended on some sociodemographic variables (age: older people have higher expectations; sex: women have greater satisfaction). A positive relationship between these variables and intervention efficacy was found: expectations related to "usefulness for the patient" were a statistically related predictor to the results on the BDI-11 (Beta = 0.364), and the perception of how logical the treatment is (Beta = 0.528) was associated with change in the clinical variable. Furthermore, the higher the expectations, the higher the improvements exhibited by the patients in all measures evaluated during the ten intervention modules. High expectations were also directly related to finalizing the intervention. Conclusions: This is the first study in Spain to address this issue in the field of IBIs for depression in primary care. The IBI showed high acceptance related to the intervention''s efficacy and completion. Research on IBI acceptability could help to implement the treatment offered

Exploring the Relationship Between the Acceptability of an Internet-Based Intervention for Depression in Primary Care and Clinical Outcomes: Secondary Analysis of a Randomized Controlled Trial

Background: Depression is one of the most prevalent psychological disorders worldwide. Although psychotherapy for depression is effective, there are barriers to its implementation in primary care in Spain. The use of the Internet has been shown to be a feasible solution. However, the acceptability of Internet-based interventions has not been studied sufficiently. Objective: To assess the acceptability of an Internet-based intervention (IBI) for depression in primary care, and explore the relationship between expectations and satisfaction and the improvement in the clinical variables in primary care patients receiving this intervention. Furthermore, it offers data about the effects of some sociodemographic characteristics on these acceptability variables and analyzes whether the expectations are related to finalizing the intervention. Methods: Data were based on depressive patients who were participants in a randomized controlled trial. In the present study, we present the data from all the participants in the Internet intervention groups (N = 198). All the participants filled out the expectation and satisfaction scales (six-item scales regarding treatment logic, satisfaction, recommending, usefulness for other disorders, usefulness for the patient, and unpleasantness), the Beck Depression Inventory-II, and the secondary outcome measures: depression and anxiety impairment, and positive and negative affect. Results: Results showed that participants'' expectations and satisfaction with the program were both high and differences in expectations and satisfaction depended on some sociodemographic variables (age: older people have higher expectations; sex: women have greater satisfaction). A positive relationship between these variables and intervention efficacy was found: expectations related to "usefulness for the patient" were a statistically related predictor to the results on the BDI-11 (Beta = 0.364), and the perception of how logical the treatment is (Beta = 0.528) was associated with change in the clinical variable. Furthermore, the higher the expectations, the higher the improvements exhibited by the patients in all measures evaluated during the ten intervention modules. High expectations were also directly related to finalizing the intervention. Conclusions: This is the first study in Spain to address this issue in the field of IBIs for depression in primary care. The IBI showed high acceptance related to the intervention''s efficacy and completion. Research on IBI acceptability could help to implement the treatment offered

Efficacy of Three Low-Intensity, Internet-Based Psychological Interventions for the Treatment of Depression in Primary Care: Randomized Controlled Trial

BACKGROUND: Primary care is a major access point for the initial treatment of depression, but the management of these patients is far from optimal. The lack of time in primary care is one of the major difficulties for the delivery of evidence-based psychotherapy. During the last decade, research has focused on the development of brief psychotherapy and cost-effective internet-based interventions mostly based on cognitive behavioral therapy (CBT). Very little research has focused on alternative methods of treatment for depression using CBT. Thus, there is a need for research into other therapeutic approaches. OBJECTIVE: This study aimed to assess the effectiveness of 3 low-intensity, internet-based psychological interventions (healthy lifestyle psychoeducational program [HLP], focused program on positive affect promotion [PAPP], and brief intervention based on mindfulness [MP]) compared with a control condition (improved treatment as usual [iTAU]). METHODS: A multicenter, 4-arm, parallel randomized controlled trial was conducted between March 2015 and March 2016, with a follow-up of 12 months. In total, 221 adults with mild or moderate major depression were recruited in primary care settings from 3 Spanish regions. Patients were randomly distributed to iTAU (n=57), HLP (n=54), PAPP (n=56), and MP (n=54). All patients received iTAU from their general practitioners. The main outcome was the Spanish version of the Patient Health Questionnaire-9 (PHQ-9) from pretreatment (time 1) to posttreatment (time 2) and up to 6 (time 3) and 12 (time 4) months'' follow-up. Secondary outcomes included the visual analog scale of the EuroQol, the Short-Form Health Survey (SF-12), the Positive and Negative Affect Schedule (PANAS), and the Pemberton Happiness Index (PHI). We conducted regression models to estimate outcome differences along study stages. RESULTS: A moderate decrease was detected in PHQ-9 scores from HLP (ß=-3.05; P=.01) and MP (ß=-3.00; P=.01) compared with iTAU at posttreatment. There were significant differences between all intervention groups and iTAU in physical SF-12 scores at 6 months after treatment. Regarding well-being, MP and PAPP reported better PHI results than iTAU at 6 months post treatment. PAPP intervention significantly decreased PANAS negative affect scores compared with iTAU 12 months after treatment. CONCLUSIONS: The low-intensity, internet-based psychological interventions (HLP and MP) for the treatment of depression in primary care are more effective than iTAU at posttreatment. Moreover, all low-intensity psychological interventions are also effective in improving medium- and long-term quality of life. PAPP is effective for improving health-related quality of life, negative affect, and well-being in patients with depression. Nevertheless, it is important to examine possible reasons that could be implicated for PAPP not being effective in reducing depressive symptomatology; in addition, more research is still needed to assess the cost-effectiveness analysis of these interventions

Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//muL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location

Hepatitis C virus to hepatocellular carcinoma

Hepatitis C virus causes acute and chronic hepatitis and can lead to permanent liver damage and hepatocellular carcinoma (HCC) in a significant number of patients via oxidative stress, insulin resistance (IR), fibrosis, liver cirrhosis and HCV induced steatosis. HCV induced steatosis and oxidative stress causes steato-hepatitis and these pathways lead to liver injury or HCC in chronic HCV infection. Steatosis and oxidative stress crosstalk play an important role in liver damage in HCV infection. This Review illustrates viral and host factors which induce Oxidative stress, steatosis and leads toward HCC. It also expresses Molecular cascade which leads oxidative stress and steatosis to HCC

Overview of the TCV tokamak experimental programme

The tokamak a configuration variable (TCV) continues to leverage its unique shaping capabilities, flexible heating systems and modern control system to address critical issues in preparation for ITER and a fusion power plant. For the 2019-20 campaign its configurational flexibility has been enhanced with the installation of removable divertor gas baffles, its diagnostic capabilities with an extensive set of upgrades and its heating systems with new dual frequency gyrotrons. The gas baffles reduce coupling between the divertor and the main chamber and allow for detailed investigations on the role of fuelling in general and, together with upgraded boundary diagnostics, test divertor and edge models in particular. The increased heating capabilities broaden the operational regime to include T (e)/T (i) similar to 1 and have stimulated refocussing studies from L-mode to H-mode across a range of research topics. ITER baseline parameters were reached in type-I ELMy H-modes and alternative regimes with \u27small\u27 (or no) ELMs explored. Most prominently, negative triangularity was investigated in detail and confirmed as an attractive scenario with H-mode level core confinement but an L-mode edge. Emphasis was also placed on control, where an increased number of observers, actuators and control solutions became available and are now integrated into a generic control framework as will be needed in future devices. The quantity and quality of results of the 2019-20 TCV campaign are a testament to its successful integration within the European research effort alongside a vibrant domestic programme and international collaborations

Structure and non-structure of centrosomal proteins

Here we perform a large-scale study of the structural properties and the expression of proteins that constitute the human Centrosome. Centrosomal proteins tend to be larger than generic human proteins (control set), since their genes contain in average more exons (20.3 versus 14.6). They are rich in predicted disordered regions, which cover 57% of their length, compared to 39% in the general human proteome. They also contain several regions that are dually predicted to be disordered and coiled-coil at the same time: 55 proteins (15%) contain disordered and coiled-coil fragments that cover more than 20% of their length. Helices prevail over strands in regions homologous to known structures (47% predicted helical residues against 17% predicted as strands), and even more in the whole centrosomal proteome (52% against 7%), while for control human proteins 34.5% of the residues are predicted as helical and 12.8% are predicted as strands. This difference is mainly due to residues predicted as disordered and helical (30% in centrosomal and 9.4% in control proteins), which may correspond to alpha-helix forming molecular recognition features (α-MoRFs). We performed expression assays for 120 full-length centrosomal proteins and 72 domain constructs that we have predicted to be globular. These full-length proteins are often insoluble: Only 39 out of 120 expressed proteins (32%) and 19 out of 72 domains (26%) were soluble. We built or retrieved structural models for 277 out of 361 human proteins whose centrosomal localization has been experimentally verified. We could not find any suitable structural template with more than 20% sequence identity for 84 centrosomal proteins (23%), for which around 74% of the residues are predicted to be disordered or coiled-coils. The three-dimensional models that we built are available at http://ub.cbm.uam.es/centrosome/models/index.php

Overview of progress in European medium sized tokamaks towards an integrated plasma-edge/wall solution

Integrating the plasma core performance with an edge and scrape-off layer (SOL) that leads to tolerable heat and particle loads on the wall is a major challenge. The new European medium size tokamak task force (EU-MST) coordinates research on ASDEX Upgrade (AUG), MAST and TCV. This multi-machine approach within EU-MST, covering a wide parameter range, is instrumental to progress in the field, as ITER and DEMO core/pedestal and SOL parameters are not achievable simultaneously in present day devices. A two prong approach is adopted. On the one hand, scenarios with tolerable transient heat and particle loads, including active edge localised mode (ELM) control are developed. On the other hand, divertor solutions including advanced magnetic configurations are studied. Considerable progress has been made on both approaches, in particular in the fields of: ELM control with resonant magnetic perturbations (RMP), small ELM regimes, detachment onset and control, as well as filamentary scrape-off-layer transport. For example full ELM suppression has now been achieved on AUG at low collisionality with n  =  2 RMP maintaining good confinement ${{H}_{\text{H}\left(98,\text{y}2\right)}}\approx 0.95$ . Advances have been made with respect to detachment onset and control. Studies in advanced divertor configurations (Snowflake, Super-X and X-point target divertor) shed new light on SOL physics. Cross field filamentary transport has been characterised in a wide parameter regime on AUG, MAST and TCV progressing the theoretical and experimental understanding crucial for predicting first wall loads in ITER and DEMO. Conditions in the SOL also play a crucial role for ELM stability and access to small ELM regimes