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We present the development and characterization of a nasal drug delivery system comprised of a thermosensitive mucoadhesive hydrogel based on a mixture of the polymers Poloxamer 407, Poloxamer 188 and Hydroxypropyl-methylcellulose, and the psychedelic drug 5-methoxy-N,-N-dimethyltryptamine. The development relied on a 3 × 3 Box-Behnken experimental design, focusing on optimizing gelification temperature, viscosity and mucoadhesion. The primary objective of this work was to tailor the formulation for efficient nasal drug delivery. This would increase contact time between the hydrogel and the mucosa while preserving normal ciliary functioning. Following optimization, the final formulation underwent characterization through an examination of the in vitro drug release profile via dialysis under sink conditions. Additionally, homogeneity of its composition was assessed using Raman Confocal Spectroscopy. The results demonstrate complete mixing of drug and polymers within the hydrogel matrix. Furthermore, the formulation exhibits sustained release profile, with 73.76% of the drug being delivered after 5 h in vitro. This will enable future studies to assess the possibility of using this formulation to treat certain mental disorders. We have successfully developed a promising thermosensitive and mucoadhesive hydrogel with a gelling temperature of around 32 °C, a viscosity close to 100 mPas and a mucoadhesion of nearly 4.20 N·m.

During the last decade, immunotherapy has radically changed perspectives on anti-tumor treatments. However, solid tumor treatment by immunotherapy has not met expectations. Indeed, poor clinical response to treatment has highlighted the need to understand and avoid immunotherapy resistance. Cholangiocarcinoma (CCA) is the second cause of hepatic cancer-related deaths because of drug inefficacy and chemo-resistance in a majority of patients. Thus, intense research is ongoing to better understand the mechanisms involved in the chemo-resistance processes. The tumor microenvironment (TME) may be involved in tumor therapy resistance by limiting drug access. Indeed, cells such as cancer-associated fibroblasts (CAFs) alter TME by producing in excess an aberrant extracellular matrix (ECM). Interestingly, CAFs are the dominant stromal component in CCA that secrete large amounts of stiff ECM. Stiff ECM could contribute to immune exclusion by limiting anti-tumor T-cells drop-in. Herein, we summarize features, functions, and interactions among CAFs, tumor-associated ECM, and immune cells in TME. Moreover, we discuss the strategies targeting CAFs and the remodeling of the ECM to improve immunotherapy and drug therapies.

Basic wood density (BWD) is a functional characteristic important to quantify carbon storage and is related to tree growth and its survival. We investigated BWD variability among tree species, populations, and forest types across the Atlantic Forest biome in Rio de Janeiro state, Brazil. We sampled and measured 576 trees of 83 species in 28 natural ecosystems in the Dense Ombrophilous Forest, Seasonal Semi-deciduous Forest, and the Restinga Forest. Stem wood from two different heights at each tree was acquired using a drill borer; discs were removed from branches in 20% of the height from 39 trees. BWD means increased from 0.42 for the most humid ecosystem to 0.675 g*[cm.sup.-3] from the driest ecosystem. We identified changes in the wood as a result of climatic variables particular to different typologies, such as increased wood density in areas with lower precipitation and higher temperatures, were also observed within species, but with little difference in means. We identified three groups of species according to their BWD, different in mean height and diameter. The branches can be used to estimate tree wood density. Key words: biodiversity, branches, functional trait, non-destructive sampling, stem wood La densite de base du bois (DBB) est une caracteristique fonctionnelle importante pour quantifier le stockage du carbone et est liee a la croissance et a la survie des arbres. Dans cette etude, nous avons examine la variabilite de la densite de base du bois parmi les especes d'arbres, les populations et les types de forets dans le biome de la foret atlantique de l'Etat de Rio de Janeiro, au Bresil. Nous avons echantillonne et mesure 576 arbres de 83 especes dans 28 ecosystemes naturels de la foret ombrophile dense, de la foret semi-decidue saisonniere et de la foret de Restinga. Le bois de la tige a deux hauteurs differentes de chaque arbre a ete acquis a l'aide d'une foreuse (methode non destructive), de plus, des disques ont ete preleves sur les branches a 20% de la hauteur de 39 arbres. Les moyennes de densite de base du bois ont augmente de 0,42 pour l'ecosysteme le plus humide a 0,675 g*[cm.sup.-3] de l'ecosysteme le plus sec. Nous avons identifie des changements dans le bois resultant de variables climatiques particulieres aux differentes typologies, comme l'augmentation de la densite du bois dans les regions ou les precipitations sont plus faibles et des temperatures plus elevees ont egalement ete observees au sein d'une meme espece, mais avec peu de difference entre les moyennes. Nous avons identifie trois groupes d'especes en fonction de leur DBB, differentes en hauteur et en diametre moyens. De plus, les branches representent la densite des tiges des especes de la foret atlantique et, par consequent, peuvent etre utilisees pour estimer la densite du bois des arbres. [Traduit par la Redaction] Mots-cles : biodiversite, branches, trait fonctionnel, echantillonnage non destructif, bois de tige, Introduction The Atlantic Forest is an important hotspot with high conservation priority (Myers et al. 2000; Rezende et al. 2018). Its biodiversity is influenced by geological, pedological, and climatic heterogeneity [...]

Introduction: The identification of chemical compounds that interfere with SARS-CoV-2 replication continues to be a priority in several academic and pharmaceutical laboratories. Computational tools and approaches have the power to integrate, process and analyze multiple data in a short time. However, these initiatives may yield unrealistic results if the applied models are not inferred from reliable data and the resulting predictions are not confirmed by experimental evidence.Methods: We undertook a drug discovery campaign against the essential major protease (MPro) from SARS-CoV-2, which relied on an in silico search strategy –performed in a large and diverse chemolibrary– complemented by experimental validation. The computational method comprises a recently reported ligand-based approach developed upon refinement/learning cycles, and structure-based approximations. Search models were applied to both retrospective (in silico) and prospective (experimentally confirmed) screening.Results: The first generation of ligand-based models were fed by data, which to a great extent, had not been published in peer-reviewed articles. The first screening campaign performed with 188 compounds (46 in silico hits and 100 analogues, and 40 unrelated compounds: flavonols and pyrazoles) yielded three hits against MPro (IC50 ≤ 25 μM): two analogues of in silico hits (one glycoside and one benzo-thiazol) and one flavonol. A second generation of ligand-based models was developed based on this negative information and newly published peer-reviewed data for MPro inhibitors. This led to 43 new hit candidates belonging to different chemical families. From 45 compounds (28 in silico hits and 17 related analogues) tested in the second screening campaign, eight inhibited MPro with IC50 = 0.12–20 μM and five of them also impaired the proliferation of SARS-CoV-2 in Vero cells (EC50 7–45 μM).Discussion: Our study provides an example of a virtuous loop between computational and experimental approaches applied to target-focused drug discovery against a major and global pathogen, reaffirming the well-known “garbage in, garbage out” machine learning principle.

Objective: To compare bioelectrical impedance analysis (BIA)-derived parameters in healthy volunteers and critically ill patients and to assess its prognostic value in an ICU patient cohort. Design: Retrospective, observational data analysis. Setting: Single centre, tertiary-level ICU (Ziekenhuis Netwerk Antwerpen, ZNA Stuivenberg Hospital). Patients: 101 patients and 101 healthy subjects, participants of International Fluid Academy Days. Measurements and main results: Compared to healthy volunteers, both male and female ICU patients had significantly higher values for total body water (TBW), extracellular water (ECW), extracellular fluid (ECF), plasma, and interstitial fluid volumes. The phase angle was significantly lower and the malnutrition index was significantly higher in ICU patients, regardless of gender. Non-survivors in the ICU had significantly higher extracellular water content (ECW, 50.7 ± 5.1 vs. 48.9 ± 4.3%, p = 0.047) and accordingly significantly lower intracellular water (ICW, 49.2 ± 5.1 vs. 51.1 ± 4.3%, p = 0.047). The malnutrition index was also significantly higher in non-survivors compared to survivors (0.94 ± 0.17 vs. 0.87 ± 0.16, p = 0.048), as was the capillary leak index (ECW/ICW). Conclusions: Compared to healthy volunteers, this study observed a higher malnutrition index and TBW in ICU patients with an accumulation of fluids in the extracellular compartment. ICU non-survivors showed similar results, indicating that ICU patients and a fortiori non-survivors are generally overhydrated, with increased TBW and ECW, and more undernourished, as indicated by a higher malnutrition index.

Abstract Background Dietary interventions have been previously explored in children with ADHD. Elimination diets and supplementation can produce beneficial behaviour changes, but little is known about the mechanisms mediating change. We propose that these interventions may work, in part, by causing changes in the gut microbiota. A microbiome-targeted dietary intervention was developed, and its feasibility assessed. Methods A non-randomised feasibility study was conducted on nine non-medicated children with ADHD, aged 8–13 years (mean 10.39 years), using a prospective one-group pre-test/post-test design. Participants were recruited from ADHD support groups in London and took part in the 6-week microbiome-targeted dietary intervention, which was specifically designed to impact the composition of gut bacteria. Children were assessed pre- and post-intervention on measures of ADHD symptomatology, cognition, sleep, gut function and stool-sample microbiome analysis. The primary aim was to assess the study completion rate, with secondary aims assessing adherence, adverse events (aiming for no severe and minimal), acceptability and suitability of outcome measures. Results Recruitment proved to be challenging and despite targeting 230 participants directly through support groups, and many more through social media, nine families (of the planned 10) signed up for the trial. The completion rate for the study was excellent at 100%. Exploration of secondary aims revealed that (1) adherence to each aspect of the dietary protocol was very good; (2) two mild adverse events were reported; (3) parents rated the treatment as having good acceptability; (4) data collection and outcome measures were broadly feasible for use in an RCT with a few suggestions recommended; (5) descriptive data for outcome measures is presented and suggests that further exploration of gut microbiota, ADHD symptoms and sleep would be helpful in future research. Conclusions This study provides preliminary evidence for the feasibility of a microbiome-targeted dietary intervention in children with ADHD. Recruitment was challenging, but the diet itself was well-tolerated and adherence was very good. Families wishing to trial this diet may find it an acceptable intervention. However, recruitment, even for this small pilot study, was challenging. Because of the difficulty experienced recruiting participants, future randomised controlled trials may wish to adopt a simpler dietary approach which requires less parental time and engagement, in order to recruit the number of participants required to make meaningful statistical interpretations of efficacy. Trial registration ClinicalTrials.gov Identifier: NCT03737877 . Registered 13 November 2018—retrospectively registered, within 2 days of the first participant being recruited.

The anatomical description of wood and charcoal for a wide variety of purposes is an essential tool for compiling databases to correctly identify species. This study describes and compares the anatomy of the wood and charcoal of Manilkara sp., collected in a protected area in the Pará state, Brazil. The qualitative anatomical characteristics of the wood, such as diffuse-porosity; vessels in radial multiples; alternate intervessel pits; axial parenchyma in lines or reticulate; rays uniseriate or biseriate, not storied, are corroborated in the literature. Moreover, this work reports the presence of helical thickenings in the vessel elements and possible helical thickenings in fibres in Manilkara. After the carbonization process, there were morphometric changes in the anatomical elements, as an increase in vessel frequency between 23 % and 141 %, and in ray frequency between 2.8 % and 12.9 %; while ray height decreased and ray width increased. Overall, some anatomical variations could be related to, or a result of the interaction between species plasticity, genetics, age and environmental factors. These characteristics enabled the identification of the samples at the genus level and the anatomical description of the wood and charcoal can be useful for forest inspections. [ABSTRACT FROM AUTHOR]

Female athletes' participation in the Olympic Games has increased over the years, however, they are still underrepresented or not covered in global media. Prior literature about gender studies and sport reveals that female athletes were often described through stereotypes, or other linguistic features minimizing their achievements, or focusing on their physical appearance rather than their sports abilities. The present study adopts textual analysis to examine how female athletes were represented during the Beijing 2022 Winter Olympic Games in two Italian leading newspapers. The findings show that there have been positive changes in the portrayal of women in sports, but this may be influenced by the increased nationalism during these mega events. The Italian media are more open to gender equality, and adopt different strategies to describe female athletes, nonetheless, some very limited negative cases are still found. The press tended to emphasize some main themes: female athletes as heroines of the nation, friendship, rivalries and conflicts, and athletes' private lives. This demonstrates that the Italian newspapers are now more focused on non-sports related stories, to make the articles more interesting in terms of entertainment and emotional stories, to attract more readership. [ABSTRACT FROM AUTHOR]

Objetivos: Evaluar el flujo salival en reposo y estimulado y la prevalencia de xerostomía y/ o hiposialia en mujeres posmenopáusicas, considerando la condición sistémica de cada participante. Objetivos específicos: a) estimar la correspondencia entre el relato de xerostomía y la condición de hiposialia; b) analizar la probable asociación entre xerostomía e hiposalivación con signos y/o síntomas deperiodontitis. Métodos: Es un estudio descriptivo y transversal realizado en la Clínica Integrada de la Facultad de Odontología de la Udelar. La muestra estará compuesta por 25 participantes en etapa postmenopáusica y similar tamaño en período fértil. La metodología consiste en anamnesis y sialometría de reposo y estimulada. Criterios de inclusión: sexo femenino, rango etario 45-55 años, en etapa posmenopáusica. Como grupo control se relevará población de sexo femenino en etapa fértil y rango etario 35 a 44 años. Criterios de exclusión: haber recibido profilaxis bucal profesional y/o tratamiento periodontal los últimos 6 meses. Se realiza anamnesis sobre xerostomía y de la historia clínica se obtienen los índices periodontales registrados antes del tratamiento. La obtención de saliva de reposo y estimulada sigue un protocolo. Resultados esperados: La sequedad bucal persistente es un importante problema de salud que ocasiona alteraciones funcionales y lesiones orales. Se espera que el grupo objeto de estudio presente mayor prevalencia de sequedad bucal y/o de enfermedad periodontal.

Rationale & Objective: Venglustat, a glucosylceramide synthase inhibitor, inhibits cyst growth and reduces kidney failure in mouse models of autosomal dominant polycystic kidney disease (ADPKD). STAGED-PKD aims to determine the safety and efficacy of venglustat and was designed using patient enrichment for progression to end-stage kidney disease and modeling from prior ADPKD trials. Study Design: STAGED-PKD is a 2-stage, international, double-blind, randomized, placebo-controlled trial in adults with ADPKD (Mayo Class 1C-1E) and estimated glomerular filtration rate (eGFR) 45-