Time-varying effective connectivity during visual object naming as a function of semantic demands

Accumulating evidence suggests that visual object understanding involves a rapid feedforward sweep, after which subsequent recurrent interactions are necessary. The extent to which recurrence plays a critical role in object processing remains to be determined. Recent studies have demonstrated that recurrent processing is modulated by increasing semantic demands. Differentially from previous studies, we used dynamic causal modeling to model neural activity recorded with magnetoencephalography while 14 healthy humans named two sets of visual objects that differed in the degree of semantic accessing demands, operationalized in terms of the values of basic psycholinguistic variables associated with the presented objects (age of acquisition, frequency, and familiarity). This approach allowed us to estimate the directionality of the causal interactions among brain regions and their associated connectivity strengths. Furthermore, to understand the dynamic nature of connectivity (i.e., the chronnectome; Calhoun et al., 2014) we explored the time-dependent changes of effective connectivity during a period (200–400 ms) where adding semantic-feature information improves modeling and classifying visual objects, at 50 ms increments. First, we observed a graded involvement of backward connections, that became active beyond 200 ms. Second, we found that semantic demands caused a suppressive effect in the backward connection from inferior frontal cortex (IFC) to occipitotemporal cortex over time. These results complement those from previous studies underscoring the role of IFC as a common source of top-down modulation, which drives recurrent interactions with more posterior regions during visual object recognition. Crucially, our study revealed the inhibitory modulation of this interaction in situations that place greater demands on the conceptual system

The Running of the Cosmological and the Newton Constant controlled by the Cosmological Event Horizon

We study the renormalisation group running of the cosmological and the Newton constant, where the renormalisation scale is given by the inverse of the radius of the cosmological event horizon. In this framework, we discuss the future evolution of the universe, where we find stable de Sitter solutions, but also "big crunch"-like and "big rip"-like events, depending on the choice of the parameters in the model.Comment: 14 pages, 7 figures, minor improvements, references adde

Disruption of Yarrowia lipolytica TPS1 Gene Encoding Trehalose-6-P Synthase Does Not Affect Growth in Glucose but Impairs Growth at High Temperature

We have cloned the Yarrowia lipolytica TPS1 gene encoding trehalose-6-P synthase by complementation of the lack of growth in glucose of a Saccharomyces cerevisiae tps1 mutant. Disruption of YlTPS1 could only be achieved with a cassette placed in the 3′half of its coding region due to the overlap of its sequence with the promoter of the essential gene YlTFC1. The Yltps1 mutant grew in glucose although the Y. lipolytica hexokinase is extremely sensitive to inhibition by trehalose-6-P. The presence of a glucokinase, insensitive to trehalose-6-P, that constitutes about 80% of the glucose phosphorylating capacity during growth in glucose may account for the growth phenotype. Trehalose content was below 1 nmol/mg dry weight in Y. lipolytica, but it increased in strains expressing YlTPS1 under the control of the YlTEF1promoter or with a disruption of YALI0D15598 encoding a putative trehalase. mRNA levels of YlTPS1 were low and did not respond to thermal stresses, but that of YlTPS2 (YALI0D14476) and YlTPS3 (YALI0E31086) increased 4 and 6 times, repectively, by heat treatment. Disruption of YlTPS1 drastically slowed growth at 35°C. Homozygous Yltps1 diploids showed a decreased sporulation frequency that was ascribed to the low level of YALI0D20966 mRNA an homolog of the S. cerevisiae MCK1 which encodes a protein kinase that activates early meiotic gene expression

Implementation of Recommendations for the Management of Psoriasis During Preconception, Pregnancy, Postpartum, Breastfeeding, and Perinatal Care

Objetivo Analizar el grado de implementación de las recomendaciones del Grupo de Psoriasis (GPS) sobre las actuaciones a seguir durante la edad fértil, el embarazo, el posparto, la lactancia y el cuidado perinatal en la psoriasis. Métodos Se diseñó y envió una encuesta cerrada, estructurada y anónima, en formato electrónico a miembros del GPS a través del correo electrónico. Se recogieron las variables sociodemográficas y profesionales de los participantes, y otras relacionadas con los objetivos propuestos. Se realizó un análisis descriptivo. Resultados Se analizaron 53 encuestas. El 96% de los participantes conocen las recomendaciones del GPS, pero su nivel de participación en unidades de atención multidisciplinar o la disposición de protocolos específicos en los servicios es muy baja. El 70% pregunta de forma regular sobre el deseo gestacional, aunque solo el 46% lo pregunta a varones y mujeres. Se ofrece consejo preconcepcional más a mujeres que a varones (54 vs. 19%). Gran variabilidad en cuanto a los consejos ofrecidos. El 90% suspende tratamientos tópicos durante el embarazo, y prácticamente el 100% los tratamientos sistémicos salvo la ciclosporina A. En el tercer trimestre se suspenden la mayoría de las terapias biológicas a excepción de certolizumab pegol. Los tratamientos tópicos, fototerapia y certolizumab pegol son usados casi por el 100% de los encuestados en la lactancia. La falta de tiempo, de apoyo de los gestores y de datos robustos son las principales limitaciones a la implementación de las recomendaciones. Conclusiones A pesar de que son ampliamente conocidas, las recomendaciones del GPS aún quedan áreas de mejora.Objective To analyze degree of implementation of recommendations on the management of psoriasis during preconception, pregnancy, postpartum, breastfeeding, and perinatal care published by the Psoriasis Working Group of the Spanish Academy of Dermatology and Venereology (AEDV). Methods We designed a structured online survey consisting of closed questions. A link was emailed to all the members of the Psoriasis Working Group to collect their anonymous responses. We also collected sociodemographic, professional, and practice-related data related to the goals of the study and then compiled descriptive statistics to analyze the survey findings. Results We received 53 responses for analysis. Overall, 96% of respondents were familiar with the recommendations, but very few of them worked in multidisciplinary maternity care units or had access to specific protocols on the management of psoriasis before, during, and after pregnancy in their departments. Seventy percent of dermatologists regularly ask their patients about pregnancy plans, but only 46% ask both men and women. Women also receive more preconception advice than men (54% vs. 19%). Significant variations were observed in the type of advice given. Ninety percent of the dermatologists interrupt topical treatments during pregnancy, and nearly all suspend conventional systemic drugs with the exception of cyclosporin A. Most biologics are also being discontinued in the third trimester, with the exception of certolizumab pegol. Almost all the respondents indicated that they use topical treatments, phototherapy, and certolizumab pegol in breastfeeding mothers. The main barriers to implementing the working group's recommendations are a lack of time, a lack of support, and a lack of robust data. Conclusions Although the AEDV psoriasis working group's recommendations are widely known, areas for improvement remain.PsoriasisFertilidadEmbarazoPospartoLactanciaRecomendacionesImplementació

Assessment of Safety and Efficacy of Combined Trabectedin and Low-Dose Radiotherapy for Patients with Metastatic Soft-Tissue Sarcomas: A Nonrandomized Phase 1/2 Clinical Trial

Importance: Active therapeutic combinations, such as trabectedin and radiotherapy, offer potentially higher dimensional response in second-line treatment of advanced soft-tissue sarcomas. Dimensional response can be relevant both for symptom relief and for survival. Objective: To assess the combined use of trabectedin and radiotherapy in treating patients with progressing metastatic soft-tissue sarcomas. Design, Setting, and Participants: Phase 1 of this nonrandomized clinical trial followed the classic 3 + 3 design, with planned radiotherapy at a fixed dose of 30 Gy (3 Gy/d for 10 days) and infusion of trabectedin at 1.3 mg/m2 as the starting dose, 1.5 mg/m2 as dose level +1, and 1.1 mg/m2 as dose level-1. Phase 2 followed the Simon optimal 2-stage design. Allowing for type I and II errors of 10%, treatment success was defined as an overall response rate of 35%. This study was conducted in 9 sarcoma referral centers in Spain, France, and Italy from April 13, 2015, to November 20, 2018. Adult patients with progressing metastatic soft-tissue sarcoma and having undergone at least 1 previous line of systemic therapy were enrolled. In phase 2, patients fitting inclusion criteria and receiving at least 1 cycle of trabectedin and the radiotherapy regimen constituted the per-protocol population; those receiving at least 1 cycle of trabectedin, the safety population. Interventions: Trabectedin was administered every 3 weeks in a 24-hour infusion. Radiotherapy was required to start within 1 hour after completion of the first trabectedin infusion (cycle 1, day 2). Main Outcomes and Measures: The dose-limiting toxic effects of trabectedin (phase 1) and the overall response rate (phase 2) with use of trabectedin plus irradiation in metastatic soft-tissue sarcomas. Results: Eighteen patients (11 of whom were male) were enrolled in phase 1, and 27 other patients (14 of whom were female) were enrolled in phase 2. The median ages of those enrolled in phases 1 and 2 were 42 (range, 23-74) years and 51 (range, 27-73) years, respectively. In phase 1, dose-limiting toxic effects included grade 4 neutropenia lasting more than 5 days in 1 patient at the starting dose level and a grade 4 alanine aminotransferase level increase in 1 of 6 patients at the +1 dose level. In phase 2, among 25 patients with evaluable data, the overall response rate was 72% (95% CI, 53%-91%) for local assessment and 60% (95% CI, 39%-81%) for central assessment. Conclusions and Relevance: The findings of this study suggest that the recommended dose of trabectedin for use in combination with this irradiation regimen is 1.5 mg/m2. The trial met its primary end point, with a high overall response rate that indicates the potential of this combination therapy for achieving substantial tumor shrinkage beyond first-line systemic therapy in patients with metastatic, progressing soft-tissue sarcomas. Trial Registration: ClinicalTrials.gov Identifier: NCT02275286

Moderate to Severe Psoriasis in Pediatric and Young Patients: The BIOBADADERM Registry Experience

Childhood-onset psoriasis generally follows an indolent course but patients with moderate or severe disease may require systemic treatment. The aim of this study was to determine the relative proportion of children and young people aged up to 21 years with moderate to severe psoriasis in the BIOBADADERM registry and to analyze the characteristics of these patients, treatments used, and adverse events. Of the 3946 patients in the registry, 24 were aged 21 years or younger. The mean age of this group when they started treatment upon registration on Biobadaderm was 16.1 years and the mean Psoriasis Area and Severity Index was 9.4. In 67% the first treatment recorded was with a conventional systemic drug. Treatment was discontinued in 14 patients (58%) due to adverse events or a loss or lack of effectiveness. In conclusion, the BIOBADADERM registry shows that young people account for a small proportion of psoriasis patients receiving systemic treatment, and they are more likely to be treated using conventional systemic drugs. (C) 2021 AEDV. Published by Elsevier Espana, S.L.U