ECHO: A hierarchical combination of classical and multi-agent epistemic planning problems

The continuous interest in Artificial Intelligence (AI) has brought, among other things, the development of several scenarios where multiple artificial entities interact with each other. As for all the other autonomous settings, these multi-agent systems require orchestration. This is, generally, achieved through techniques derived from the vast field of Automated Planning. Notably, arbitration in multi-agent domains is not only tasked with regulating how the agents act, but must also consider the interactions between the agents' information flows and must, therefore, reason on an epistemic level. This brings a substantial overhead that often diminishes the reasoning process's usability in real-world situations. To address this problem, we present ECHO, a hierarchical framework that embeds classical and multi-agent epistemic (epistemic, for brevity) planners in a single architecture. The idea is to combine (i) classical; and(ii) epistemic solvers to model efficiently the agents' interactions with the (i) 'physical world'; and(ii) information flows, respectively. In particular, the presented architecture starts by planning on the 'epistemic level', with a high level of abstraction, focusing only on the information flows. Then it refines the planning process, due to the classical planner, to fully characterize the interactions with the 'physical' world. To further optimize the solving process, we introduced the concept of macros in epistemic planning and enriched the 'classical' part of the domain with goal-networks. Finally, we evaluated our approach in an actual robotic environment showing that our architecture indeed reduces the overall computational time

A Bio-Conjugated Fullerene as a Subcellular-Targeted and Multifaceted Phototheranostic Agent

Fullerenes are candidates for theranostic applications because of their high photodynamic activity and intrinsic multimodal imaging contrast. However, fullerenes suffer from low solubility in aqueous media, poor biocompatibility, cell toxicity, and a tendency to aggregate. C70@lysozyme is introduced herein as a novel bioconjugate that is harmless to a cellular environment, yet is also photoactive and has excellent optical and optoacoustic contrast for tracking cellular uptake and intracellular localization. The formation, water-solubility, photoactivity, and unperturbed structure of C70@lysozyme are confirmed using UV-visible and 2D 1H, 15N NMR spectroscopy. The excellent imaging contrast of C70@lysozyme in optoacoustic and third harmonic generation microscopy is exploited to monitor its uptake in HeLa cells and lysosomal trafficking. Last, the photoactivity of C70@lysozyme and its ability to initiate cell death by means of singlet oxygen (1O2) production upon exposure to low levels of white light irradiation is demonstrated. This study introduces C70@lysozyme and other fullerene-protein conjugates as potential candidates for theranostic applications

Obtenção de vinagre de laranja em processo semicontínuo, em escala de laboratório

Vinegar is the product obtained from wine acetic acid fermentation and is mainly produced by semicontinuous operation, which consists in developing successive discontinuous acetification cycles. Citric vinegars and wines are typical products with regional qualities. The aim of the present work was to establish the optimal values for the substrate loading proportion (wine/vinegar) at two levels (40 % and 60 %) in order to obtain orange vinegar in semicontinuous submerged culture. The results were evaluated in terms of acetification rate and fermentation yield. Experiments were carried out in duplicate. Stirring speed, air supply and temperature were maintained constant with values of 600 rpm, 0.4 vvm and 30°C respectively. It was demonstrated that the loading proportion did not affect significantly the responses (α=0.05) at both levels evaluated. It is feasible to develop a semicontinuous acetification process with a 60 % loading proportion and in this way, obtain greater orange vinegar volumes.El vinagre es el producto de la fermentación acética del vino. El sistema semicontinuo es el más común en la industria vinagrera; consiste en el desarrollo de ciclos discontinuos de acetificación. El vinagre y los vinos cítricos son productos típicos con características regionales. El objetivo del presente trabajo fue la obtención de vinagre de naranja en biorreactor de laboratorio en sistema semicontinuo, a dos niveles de la variable proporción de carga (vino/vinagre): 40 % y 60 % usando como respuestas velocidad de acetificación y rendimiento para elegir el mejor proceso. Cada tratamiento se realizó por duplicado. Las variables operativas fueron 600 rpm, 0,4 vvm y 30 ºC. Se demostró que la proporción carga/descarga, no afecta significativamente (α=0,05) las respuestas durante el segundo ciclo para ninguno de los dos niveles. Se puede establecer la proporción de carga para un proceso semicontinuo en 60% y obtener mayor volumen de vinagre de naranja.O vinagre é o produto da fermentação acética do vinho. O sistema semicontínuo é o mais comum na indústria vinagreira; consiste no desenvolmimento de ciclos discontínuos de acetificação. O vinagre e os vinhos cítricos são produtos típicos com características regionais. O objetivo deste trabalho foi obter vinagre de laranja em biorreator de laboratório em sistema semicontínuo, a dois níveis da variável proporção de carga (vinho/vinagre): 40 % e 60 % utilizando-se como respostas velocidade de acetificação e rendimento para escolher o melhor processo. Cada tratamento foi realizado em duplicado. As variáveis operacionais foram 600 rpm, 0,4 vvm e 30 ºC. Foi demonstrado que a proporção carga/descarga, não afeta significativamente (α=0,05) as respostas durante o segundo ciclo para nenhum dos dois níveis. É possível estabelecer a proporção de carga para um processo semicontínuo em 60% para obter maior volume de vinagre de laranja

Lenvatinib versus Sorafenib as first-line treatment in hepatocellular carcinoma: A multi-institutional matched case-control study

Background: Advanced Hepatocarcinoma (HCC) is an important health problem worldwide. Recently, the REFLECT trial demonstrated the non-inferiority of Lenvatinib compared to Sorafenib in I line setting, thus leading to the approval of new first-line standard of care, along with Sorafenib. Aims and methods: With aim to evaluate the optimal choice between Sorafenib and Lenvatinib as primary treatment in clinical practice, we performed a multicentric analysis with the propensity score matching on 184 HCC patients. Results: The median overall survival (OS) were 15.2 and 10.5 months for Lenvatinib and Sorafenib arm, respectively. The median progression-free survival (PFS) was 7.0 and 4.5 months for Lenvatinib and Sorafenib arm, respectively. Patients treated with Lenvatinib showed a 36% reduction of death risk (p = 0.0156), a 29% reduction of progression risk (p = 0.0446), a higher response rate (p < 0.00001) and a higher disease control rate (p = 0.002). Sorafenib showed to be correlated with more hand-foot skin reaction and Lenvatinib with more hypertension and fatigue. We highlighted the prognostic role of Barcelona Clinic Liver Cancer (BCLC) stage, Eastern Cooperative Oncology Group Performance Status (ECOG-PS), bilirubin, alkaline phosphatase and eosinophils for Sorafenib. Conversely, albumin, aspartate aminotransferase (AST), alkaline phosphatase and Neutrophil-Lymphocyte Ratio (NLR) resulted prognostic in Lenvatinib arm. Finally, we highlighted the positive predictive role of albumin > Normal Value (NV), ECOG > 0, NLR < 3, absence of Hepatitis C Virus positivity, and presence of portal vein thrombosis in favor of Lenvatinib arm. Eosinophil < 50 and ECOG > 0 negatively predicted the response to Sorafenib. Conclusion: SLenvatinib showed to better perform in a real-word setting compared to Sorafenib. More researches are needed to validate the predictor factors of response to Lenvatinib rather than Sorafenib

The impact of proton LET/RBE modeling and robustness analysis on base-of-skull and pediatric craniopharyngioma proton plans relative to VMAT

Purpose: Pediatric craniopharyngioma, adult base-of-skull sarcoma and chordoma cases are all regarded as priority candidates for proton therapy. In this study, a dosimetric comparison between volumetric modulated arc therapy (VMAT) and intensity modulated proton therapy (IMPT) was first performed. We then investigated the impact of physical and biological uncertainties. We assessed whether IMPT plans remained dosimetrically superior when such uncertainty estimates were considered, especially with regards to sparing organs at risk (OARs). Methodology: We studied 10 cases: four chondrosarcoma, two chordoma and four pediatric craniopharyngioma. VMAT and IMPT plans were created according to modality-specific protocols. For IMPT, we considered (i) variable RBE modeling using the McNamara model for different values of (a/b)x, and (ii) robustness analysis with ±3 mm set-up and 3.5% range uncertainties. Results: When comparing the VMAT and IMPT plans, the dosimetric advantages of IMPT were clear: IMPT led to reduced integral dose and, typically, improved CTV coverage given our OAR constraints. When physical robustness analysis was performed for IMPT, some uncertainty scenarios worsened the CTV coverage but not usually beyond that achieved by VMAT. Certain scenarios caused OAR constraints to be exceeded, particularly for the brainstem and optical chiasm. However, variable RBE modeling predicted even more substantial hotspots, especially for low values of (a/b)x. Variable RBE modeling often prompted dose constraints to be exceeded for critical structures. Conclusion: For base-of-skull and pediatric craniopharyngioma cases, both physical and biological robustness analyses should be considered for IMPT: these analyses can substantially affect the sparing of OARs and comparisons against VMAT. All proton RBE modeling is subject to high levels of uncertainty, but the clinical community should remain cognizant possible RBE effects. Careful clinical and imaging follow-up, plus further research on end-of-range RBE mitigation strategies such as LET optimization, should be prioritized for these cohorts of proton patients

Functional Relationship between Protein Disulfide Isomerase Family Members during the Oxidative Folding of Human Secretory Proteins

We systematically depleted PDI family members and show that whereas ERp72 and P5 contributed minimally to oxidative protein folding, PDI and ERp57 were the predominant catalysts. Depletion of PDI or ERp57 alone modestly delayed folding, but depletion of both led to generalized protein misfolding and degradation

Minimal in vivo efficacy of iminosugars in a lethal Ebola virus guinea pig model

The antiviral properties of iminosugars have been reported previously in vitro and in small animal models against Ebola virus (EBOV); however, their effects have not been tested in larger animal models such as guinea pigs. We tested the iminosugars N-butyl-deoxynojirimycin (NB-DNJ) and N-(9-methoxynonyl)-1deoxynojirimycin (MON-DNJ) for safety in uninfected animals, and for antiviral efficacy in animals infected with a lethal dose of guinea pig adapted EBOV. 1850 mg/kg/day NB-DNJ and 120 mg/kg/day MON-DNJ administered intravenously, three times daily, caused no adverse effects and were well tolerated. A pilot study treating infected animals three times within an 8 hour period was promising with 1 of 4 infected NB-DNJ treated animals surviving and the remaining three showing improved clinical signs. MON-DNJ showed no protective effects when EBOV-infected guinea pigs were treated. On histopathological examination, animals treated with NB-DNJ had reduced lesion severity in liver and spleen. However, a second study, in which NB-DNJ was administered at equally-spaced 8 hour intervals, could not confirm drug-associated benefits. Neither was any antiviral effect of iminosugars detected in an EBOV glycoprotein pseudotyped virus assay. Overall, this study provides evidence that NB-DNJ and MON-DNJ do not protect guinea pigs from a lethal EBOV-infection at the dose levels and regimens tested. However, the one surviving animal and signs of improvements in three animals of the NB-DNJ treated cohort could indicate that NB-DNJ at these levels may have a marginal beneficial effect. Future work could be focused on the development of more potent iminosugars

Profiles of Small Non-Coding RNAs in Schistosoma japonicum during Development

Schistosomiasis, a debilitating disease, caused by agents of the genus Schistosoma afflicts more than 200 million people worldwide. Schistosomes could serve as an interesting model to explore gene regulation due to its evolutional position, complex life cycle and sexual dimorphism. We previously indicated that sncRNA profile in the parasite S. japonicum was developmentally regulated in hepatic and adult stages. In this study, we systematically investigated mircoRNA (miRNA) and endogenous siRNA (endo-siRNA) profile in this parasite in more detailed developmental stages (cercariae, lung-stage schistosomula, separated adult worms, and liver tissue-trapped eggs) using high-throughput RNA sequencing technology. We observed that the ratio of miRNAs to endo-siRNAs was dynamically changed throughout different developmental stages of the parasite. MiRNAs were expressed dominantly in cercariae, while endo-siRNAs accumulated in adult female worms and hepatic eggs. We demonstrated that miRNAs were mostly derived from intergenic regions whereas siRNAs were mostly derived from transposable elements. We also annotated miRNAs and siRNAs with stage- and gender- biased expression. Our findings would facilitate to understand the gene regulation mechanism of this parasite and discover novel targets for anti-parasite drugs