Intestinal serotonergic system is modulated by Toll-like receptor 9

Intestinal serotonergic system is a key modulator of intestinal homeostasis; however, its regulation is still unclear. Toll-like receptor 9 (TLR9), an innate immune receptor, detects different external agents in the intestine, preserving intestinal integrity. Since little is known about TLR9 role in the intestine, our aim was to address the potential regulation between TLR9 and intestinal serotonergic system. Caco-2/TC7 cell line and intestinal tract of Tlr9−/− mice were used in this study. Serotonin uptake studies were performed, and molecular expression of different serotonergic components was analyzed by western blot and real-time PCR. Our results show that TLR9 activation inhibits serotonin transporter activity and expression, involving p38/MAPK and ERK/MAPK intracellular pathways, and reciprocally, serotonin increases TLR9 expression. Supporting this interaction, serotonin transporter, serotonin receptors and serotonin producer enzymes were found altered in intestinal tract of Tlr9−/− mice. We conclude that TLR9 could contribute to intestinal homeostasis by modulation of intestinal serotonergic system

Mobile Phone and Wearable Sensor-Based mHealth Approach for Psychiatric Disorders and Symptoms : Systematic Review and Link to the m-RESIST Project

Background: Mobile Therapeutic Attention for Patients with Treatment-Resistant Schizophrenia (m-RESIST) is an EU Horizon 2020-funded project aimed at designing and validating an innovative therapeutic program for treatment-resistant schizophrenia. The program exploits information from mobile phones and wearable sensors for behavioral tracking to support intervention administration. Objective: To systematically review original studies on sensor-based mHealth apps aimed at uncovering associations between sensor data and symptoms of psychiatric disorders in order to support the m-RESIST approach to assess effectiveness of behavioral monitoring in therapy. Methods: A systematic review of the English-language literature, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, was performed through Scopus, PubMed, Web of Science, and the Cochrane Central Register of Controlled Trials databases. Studies published between September 1, 2009, and September 30, 2018, were selected. Boolean search operators with an iterative combination of search terms were applied. Results: Studies reporting quantitative information on data collected from mobile use and/or wearable sensors, and where that information was associated with clinical outcomes, were included. A total of 35 studies were identified; most of them investigated bipolar disorders, depression, depression symptoms, stress, and symptoms of stress, while only a few studies addressed persons with schizophrenia. The data from sensors were associated with symptoms of schizophrenia, bipolar disorders, and depression. Conclusions: Although the data from sensors demonstrated an association with the symptoms of schizophrenia, bipolar disorders, and depression, their usability in clinical settings to support therapeutic intervention is not yet fully assessed and needs to be scrutinized more thoroughly.Peer reviewe

Persons with first episode psychosis have distinct profiles of social cognition and metacognition

Altres ajuts: Obra Social La Caixa (RecerCaixa call 2013), by the Agencia Estatal de Investigación (AEI, Spain). Junta de Andalucía: PI-0634/2011; PI-0193/2014.Subjects with first-episode psychosis experience substantial deficits in social cognition and metacognition. Although previous studies have investigated the role of profiles of individuals in social cognition and metacognition in chronic schizophrenia, profiling subjects with first-episode psychosis in both domains remains to be investigated. We used latent profile analysis to derive profiles of the abilities in 174 persons with first-episode psychosis using the Beck's Cognitive Insight Scale, the Faces Test, the Hinting Task, the Internal, Personal and Situational Attributions Questionnaire, and the Beads Task. Participants received a clinical assessment and a neuropsychological assessment. The best-fitting model was selected according to the Bayesian information criterion (BIC). We assessed the importance of the variables via a classification tree (CART). We derived three clusters with distinct profiles. The first profile (33.3%) comprised individuals with low social cognition. The second profile (60.9%) comprised individuals that had more proneness to present jumping to conclusions. The third profile (5.7%) presented a heterogeneous profile of metacognitive deficits. Persons with lower social cognition presented worse clinical and neuropsychological features than cluster 2 and cluster 3. Cluster 3 presented significantly worst functioning. Our results suggest that individuals with FEP present distinct profiles that concur with specific clinical, neuropsychological, and functional challenges. Each subgroup may benefit from different interventions

Be Careful Where You Live When You Die: Termination of Copyright Transfers and Marriage Inequality

Copyright law gives a deceased author’s surviving spouse the right to terminate a transfer of copyright rights that the author made decades earlier. The spouse who recovers the author’s rights can, in many instances, negotiate a new transfer on more favorable terms. Because the statute grants this termination right to a deceased author’s widow or widower, copyright law must determine who qualifies as the author’s spouse, a question more familiar to family law than copyright law.Copyright’s termination provisions, from their enactment in 1978, have treated gay and lesbian authors with same-sex partners less favorably than authors with different-sex partners. The statute’s facially neutral language has, in practice, always treated authors with same-sex partners unequally because its marriage recognition rule has incorporated by reference unequal treatment of those couples by state and federal law. This unequal treatment has evolved over time, as some states allowed same-sex couples to marry, as Congress enacted the so-called Defense of Marriage Act (DOMA), and as the Supreme Court struck down DOMA’s federal marriage recognition provisions in Windsor v. United States. But even after Windsor, copyright law still treats gay and lesbian couples unequally, so that an author with a same-sex spouse must be careful where she lives when she dies - if she is domiciled in a state that does not recognize her marriage, then copyright law will not recognize her surviving spouse.The Supreme Court’s decision later this year in Obergefell v. Hodges, challenging state prohibitions on marrying same-sex couples, could perpetuate, reduce, or largely eliminate copyright law’s remaining inequality. But even the most favorable Court decision for marriage equality would leave copyright law’s unequal treatment in place for authors - American and foreign - who live in most other countries in the world, as long as copyright’s statutory marriage recognition rule remains unchanged

Effect of Pam3CSK4 (TLR2/1 ligand) and Pam2CSK4 (TLR2/6 ligand) on 5-HT uptake.

<p>Uptake was measured after 6 min incubation of 0.2 μM 5-HT. (A) Pam3CSK4 concentrations assayed were 1, 5, 10, 15, and 20 μg/ml. (B) Pam2CSK4 concentrations were 1, 10, 50, 100 and 1000 ng/ml. The treatment periods were 30 min (short-term) or 1 day (long-term). The results are expressed as the percentage of the uptake control (100%) and are the mean ± SEM of 5 independent experiments. Absolute control values were 11.05±0.50 and 10.90±0.63 pmol 5-HT/mg protein at 30 min or 1 day, respectively. ***P<0.001, **P<0.01, and *P<0.05 compared with the control value (untreated cells).</p

SERT mRNA and protein levels in the intestine from <i>Tlr2</i>^<i>-/-</i> mice.

<p>(A) Real-time PCR analysis of SERT mRNA expression level in ileum and colon. Relative quantification was performed using comparative Ct method (2^–ΔΔCt). Results are expressed as arbitrary units (WT = 1) and are the mean ± SEM of 10 animals. ***P<0.001 compared with the control value. (B) Immunodetection of SERT by western blot in lysate from ileum and colon. (C) Quantitation of SERT protein in lysate from ileum and colon using β-actin as an internal control of the protein load (SERT/β-actin ratio). The results are expressed as a percentage of the control value (100%) and are the mean ± SEM of 10 animals. ***P<0.001 and **P<0.01 compared with WT.</p

Involvement of p38 MAPK on TLR2 effect on SERT mRNA expression.

<p>(A) Real-time PCR analysis of SERT mRNA expression in cells treated with 5 μg/ml Pam3CSK4, 50 ng/ml Pam2CSK4, and/or 1 μM SB 220025. Relative quantification was performed using comparative Ct method (2^–ΔΔCt). Results are expressed as arbitrary units (control = 1) and are the mean ± SEM of 5 independent experiments. ***P<0.001 compared with the control value; ^###P<0.001 compared with corresponding values without SB 220025. (B) Immunodetection of p38 MAPK and p-p38 MAPK protein levels by western blot in cell homogenate of Caco-2/TC7 cells treated with 5 μg/ml Pam3CSK4 or 50 ng/ml Pam2CSK4. (C) Quantification of p-p38 MAPK and p38 MAPK relative expression in Caco-2/TC7 cells treated with Pam3CSK4 or Pam2CSK4. Results are expressed as p-p38 MAPK/p38 MAPK ratio and are the mean ± SEM of 4 independent experiments. ***P<0.001 and **P<0.01 compared with the control value.</p

TLR2 mRNA and protein expression in 5-HT treated cells.

<p>(A) Real-time PCR analysis of TLR2 mRNA expression level. Relative quantification was performed using comparative Ct method (2^–ΔΔCt). Results are expressed as arbitrary units (control = 1) and are the mean ± SEM of 4 independent experiments. ***P<0.001 compared with the control value; ^###P<0.001 compared with 5-HT 10⁻⁴ M condition. (B) Immunodetection of TLR2 by western blot in cell lysate of Caco-2/TC7 cells treated with 10⁻⁸, 10⁻⁶, and 10⁻⁴ M 5-HT for 1 day. C: Quantification of TLR2 protein expression in cell lysate using β-actin as an internal control of the protein load (TLR2/β-actin ratio). The results are expressed as a percentage of the control value (100%) and are the mean ± SEM of 8 independent experiments. **P<0.01 and *P<0.05 compared with the control value. ^#P<0.05 compared with 10⁻⁴ M 5-HT condition.</p

Effect of Pam3CSK4 (TLR2/1 ligand) and Pam2CSK4 (TLR2/6 ligand) on 5-HT transepithelial flux and resistance.

<p>(A) 5 μg/ml Pam3CSK4 or 50 ng/ml Pam2CSK4 were added to the apical or basal side for 30 min or 1 day and 5-HT apical-to-basal (A–B) flux was measured. The control condition corresponds to untreated cells. 5-HT concentration was 0.1 μM, and samples were taken every 10 min. The results are expressed as the percentage of the control value (100%) and are the mean ± SEM of 3 independent experiments. Absolute control values in pmol 5 HT/10 min were 0.53±0.06 and 0.63±0.06 (apical, 30 min, and 1-day treatment, respectively); 0.42±0.04 and 0.48±0.03 (basal, 30 min, and 1-day treatment, respectively). ***P<0.001, **P<0.01, and *P<0.05 compared with the control value. (B) Transepithelial resistance (TER) values under the same experimental conditions as in flux measurement are represented. Results are expressed as the percentage of control value (100%) and are the mean ± SEM of 3 independent experiments. Absolute control values in Ω/cm² were 323.22±25.30 and 275.33±18.50 (apical, 30 min, and 1-day treatment, respectively), 301.56±31.07 and 280.50±30.10 (basal, 30 min, and 1-day treatment, respectively). No differences were observed.</p