Effect of emotional valence on true and false recognition controlling arousal.

The aim of our experiment was to analyse the effect of the emotional valence (positive, negative, or neutral) on true and false recognition, matching the arousal, frequency, concreteness, and associative strength of the study and recognition words. Fifty younger adults and 46 healthy older adults performed three study tasks (with words of different valence: positive, negative, neutral) and their corresponding recognition tests. Two weeks later, they performed the three recognition tests again. The results show that words with a negative valence produced less true recognition and less false recognition than words with a positive or neutral valence, in both younger and older adults, on the immediate recognition test. This pattern of results was also found in the younger adults on the delayed recognition test, whereas in the older participants, these differences disappeared. Thus, when arousal is controlled, both younger and older adults tend to recognise negative information worse than positive or neutral information, but they also commit fewer errors. Results would suggest that the greater arousal commonly associated with negative stimuli, rather than their own valence, could explain some of the contradictory results found in the literature.

Synthesis and Evaluation of Antimicrobial Activity of the Rearranged Abietane Prattinin A and Its Synthetic Derivatives.

Synthesis of the natural product prattinin A and some new derivatives has been achieved using abietic acid. The final products and a selection of intermediates were evaluated for their antibacterial activity against three human pathogenic bacteria: E. coli, P. aeruginosa, and S. aureus. The results showed that the antibacterial activity varies depending on the chemical structure of the compounds. Notably, compound 27 exhibited the most potent activity against E. coli and P. aeruginosa, with a minimal inhibitory concentration (MIC) of 11.7 µg/mL, comparable to that of the standard antibiotic ciprofloxacin, and strong activity against S. aureus, with an MIC of 23.4 µg/mL. Furthermore, we assessed the stability of these derivative compounds as potential antimicrobial agents and determined their interactions with the crystal structure of the protein receptor mutant TEM-12 from E. coli (pdb:1ESU) using molecular docking via UCSF Chimera software 1.17.3. The results suggest that 27 has potential as a natural antibiotic agent.

Evaluation of Anticancer and Anti-Inflammatory Activities of Some Synthetic Rearranged Abietanes.

Synthesis of the rearranged abietane diterpenes pygmaeocins C and D, viridoquinone, saprorthoquinone, and 1-deoxyviroxocine has been successfully achieved. The anticancer and anti-inflammatory activities of selected orthoquinonic compounds 5, 7, 13, and 19, as well as pygmaeocin C (17), were evaluated for the first time. The antitumor properties were assessed using three cancer cell lines: HT29 colon cancer cells, Hep G2 hepatocellular carcinoma cells, and B16-F10 murine melanoma cells. Compounds 5 and 13 showed the highest cytotoxicity in HT29 cells (IC50 = 6.69 ± 1.2 µg/mL and IC50 = 2.7 ± 0.8 µg/mL, respectively). Cytometric studies showed that this growth inhibition involved phase S cell cycle arrest and apoptosis induction, possibly through the activation of the intrinsic apoptotic pathway. Morphological apoptotic changes, including nuclear fragmentation and chromatin condensation, were also observed. Furthermore, the anti-inflammatory activity of these compounds was evaluated on the basis of their ability to inhibit nitric oxide production on the lipopolysaccharide activated RAW 264.7 macrophage cell line. Although all compounds showed high anti-inflammatory activity, with percentages between 40 and 100%, the highest anti-inflammatory potential was obtained by pygmaeocin B (5) (IC50NO = 33.0 ± 0.8 ng/mL). Our results suggest that due to their dual roles, this type of compound could represent a new strategy, contributing to the development of novel anticancer agents.

Unprecedented Elimination Reactions of Cyclic Aldols: A New Biosynthetic Pathway toward the Taiwaniaquinoid Skeleton.

The acid treatment of 6,7-seco-abietane dialdehydes gives, in high yield, the corresponding derivatives with the 4a-methyltetrahydrofluorene skeleton of taiwaniaquinoids. A mechanism involving the elimination of formic acid from the cyclic aldol intermediate is proposed here. This process can be postulated as a new biogenetic pathway from abietane diterpenes to taiwaniaquinoids. Using this novel reaction, the first enantiospecific synthesis of bioactive natural cupresol and taxodal has been obtained.

Synthesis of Tricyclic Pterolobirin H Analogue: Evaluation of Anticancer and Anti-Inflammatory Activities and Molecular Docking Investigations.

Pterolobirin H (3), a cassane diterpene isolated from the roots of Pterolobium macropterum, exhibits important anti-inflammatory and anticancer properties. However, its relatively complex tetracyclic structure makes it difficult to obtain by chemical synthesis, thus limiting the studies of its biological activities. Therefore, we present here a short route to obtain a rational simplification of pterolobirin H (3) and some intermediates. The anti-inflammatory activity of these compounds was assayed in LPS-stimulated RAW 264.7 macrophages. All compounds showed potent inhibition of NO production, with percentages between 54 to 100% at sub-cytotoxic concentrations. The highest anti-inflammatory effect was shown for compounds 15 and 16. The simplified analog 16 revealed potential NO inhibition properties, being 2.34 higher than that of natural cassane pterolobirin H (3). On the other hand, hydroxyphenol 15 was also demonstrated to be the strongest NO inhibitor in RAW 264.7 macrophages (IC50 NO = 0.62 ± 0.21 µg/mL), with an IC50NO value 28.3 times lower than that of pterolobirin H (3). Moreover, the anticancer potential of these compounds was evaluated in three cancer cell lines: HT29 colon cancer cells, Hep-G2 hepatoma cells, and B16-F10 murine melanoma cells. Intermediate 15 was the most active against all the selected tumor cell lines. Compound 15 revealed the highest cytotoxic effect with the lowest IC50 value (IC50 = 2.45 ± 0.29 µg/mL in HT29 cells) and displayed an important apoptotic effect through an extrinsic pathway, as evidenced in the flow cytometry analysis. Furthermore, the Hoechst staining assay showed that analog 15 triggered morphological changes, including nuclear fragmentation and chromatin condensation, in treated HT29 cells. Finally, the in silico studies demonstrated that cassane analogs exhibit promising binding affinities and docking performance with iNOS and caspase 8, which confirms the obtained experimental results.

Impact of house dust mite-driven asthma on children's school performance and activity.

Evidence regarding asthma's impact on children's daily lives is limited. This prospective and cross-sectional, observational, multicenter study assessed school/work and activity impairment in children and adolescents with allergic asthma and their caregivers and allergen immunotherapy (AIT) effects. Included patients were schooled children and adolescents (5 to 17 years) with allergic asthma due to house dust mites (HDM). Impairment of school/work (i.e., absenteeism and presenteeism) and activity was measured in patients and their caregivers using the Work Productivity Impairment Questionnaire plus Classroom Impairment Questions: Allergy Specific (WPAI + CIQ:AS). HDM allergic patients with school impairment received subcutaneous AIT with a MicroCrystalline Tyrosine-associated allergoid. WPAI + CIQ:AS and effectiveness variables were compared between baseline and 1-year post-AIT. Of the 113 patients included, 59 (52.2%) and 51 (45.1%) showed school and activity impairment, respectively, missing a mean (SD) of 37.6 (24.4) % and 42.6 (25.6) % of school and activity time, respectively. Twenty-six (23%) caregivers reported activity impairment and, of the 79 (69.9%) employed, 30 (38%) reported work impairment. Of the 65 patients with school/activities impairment, 41 (63.1%) received AIT, of which 21 (51.2%) completed 1 year of treatment. Effectiveness variables and WPAI + CIQ:AS significantly improved: Mean (SD) school impairment decreased from 39.7 (26.7) to 2.1 (7.1) % (p < 0.001) and activity impairment from 46.2 (34.6) to 1.4 (3.6) % (p < 0.001). CONCLUSION: Allergic asthma due to HDMs results in school/work and activity impairment in children and adolescents and their caregivers. One year of AIT provided clinical benefits and reduced school and activity impairment. WHAT IS KNOWN: • Allergic asthma impairs children's school performance and daily activities. • Allergen immunotherapy modifies allergic disease course and ameliorates its symptoms. WHAT IS NEW: • Asthma symptoms due to allergy to house dust mites impair children's school attendance and productivity and daily activity and their caregivers' work performance and daily lives. • Allergen immunotherapy with a house dust mite MicroCrystalline Tyrosine (MCT)-associated allergoid seems to provide clinical benefits, associated with decreased school and activity impairment, supporting it as an effective treatment option.

Exploring Short and Efficient Synthetic Routes Using Titanocene(III)-Catalyzed Reactions: Total Synthesis of Natural Meroterpenes with Trisubstituted Unsaturations.

The stereo- and regioselective total syntheses of OMe derivatives of the scarce bioactive meroterpenoids makassaric acid (1) and fascioquinol B (2) have been accomplished. The synthetic sequences are based on the following three efficient and selective catalytic reactions: Cu-catalyzed addition of Grignard compounds to an epoxide; a regioselective Barbier-type reaction, catalyzed by Cp2TiCl; and regio- and stereoselective bioinspired cyclization, also catalyzed by Cp2TiCl. These three key processes allow us to obtain the main skeletons of 1 and 2 in a few steps. The valuable synthetic proposal shown in this work provides fast access to scarce, structurally complex meroterpenes with promising biological activities, which are a sustainable source for later studies and applications in medicine.

Synthesis and Biological Evaluation of Cassane Diterpene (5α)-Vuacapane-8(14), 9(11)-Diene and of Some Related Compounds.

A set of thirteen cassane-type diterpenes was synthesized and an expedient synthetic route was used to evaluate 14-desmethyl analogs of the most active tested cassane. The anti-inflammatory activities of these 13 compounds were evaluated on a lipopolysaccharide (LPS)-activated RAW 264.7 cell line by inhibition of nitric oxide (NO) production, some of them reaching 100% NO inhibition after 72 h of treatment. The greatest anti-inflammatory effect was observed for compounds 16 and 20 with an IC50 NO of 2.98 ± 0.04 µg/mL and 5.71 ± 0.14 µg/mL, respectively. Flow-cytometry analysis was used to determine the cell cycle distribution and showed that the inhibition in NO release was accompanied by a reversion of the differentiation processes. Moreover, the anti-cancer potential of these 13 compounds were evaluated in three tumor cell lines (B16-F10, HT29, and Hep G2). The strongest cytotoxic effect was achieved by salicylaldehyde 20, and pterolobirin G (6), with IC50 values around 3 µg/mL in HT29 cells, with total apoptosis rates 80% at IC80 concentrations, producing a significant cell-cycle arrest in the G0/G1 phase, and a possible activation of the extrinsic apoptotic pathway. Additionally, initial SAR data analysis showed that the methyl group at the C-14 positions of cassane diterpenoids is not always important for their cytotoxic and anti-inflammatory activities.

Pyrene-Containing ortho-Oligo(phenylene)ethynylene Foldamer as a Ratiometric Probe Based on Circularly Polarized Luminescence.

In this manuscript, we report the first synthesis of an organic monomolecular emitter, which behaves as a circularly polarized luminescence (CPL)-based ratiometric probe. The enantiopure helical ortho-oligo(phenylene)ethynylene ( o-OPE) core has been prepared by a new and efficient macrocyclization reaction. The combination of such o-OPE helical skeleton and a pyrene couple leads to two different CPL emission features in a single structure whose ratio linearly responds to silver(I) concentration.

Exploring potentialities and limitations of stapled o-oligo(phenyleneethynylene)s (o-OPEs) as efficient circularly polarized luminescence emitters.

In this paper, we have studied the chiroptical properties of a family of o-oligo(phenyleneethynylene) (o-OPE) derivatives with different steric hindrance. Experimental results show high dissymmetry factors (gabs and glum up to 1.1 × 10-2 ) and very similar electronic circular dichroism (ECD) and circularly polarized luminescence (CPL) for all the derivatives that make this basic o-OPE scaffold a robust pure organic emitter. Vibrational circular dichroism spectra are used to characterize conformational properties in solution. Density functional theory and time-dependent density functional theory calculations support experimental results also proving that ECD and CPL are almost exclusively linked to helical moiety and not to size or conformation of substituents. As chiroptical properties of these emitters are independent of substituents, this OPE scaffold can be used as basic skeleton for the design of sensing probes with high CPL efficiencies.

Quantification of oleacein and oleuropein aglycone in olive oil using deuterated surrogates by normal-phase ultra high performance liquid chromatography with quadrupole time-of-flight mass spectrometry.

An analytical method for the analysis of relevant secoiridoid-based components in olive oil, oleacein and oleuropein aglycone, is described using for the first time deuterated surrogates. 0.2 g of sample was necessary to perform the analysis using liquid-liquid extraction and ultrasound-assisted extraction with a mixture of methanol/water (4:1, v/v). To avoid the formation of by-products, normal-phase ultra high performance liquid chromatography was chosen for the chromatographic separation. The selected mobile phase was a gradient mixture of tetrahydrofurane and hexane, and an ACE Excel 3 CN-ES column as stationary phase. The detection and quantification was performed with a SYNAPT G2-Si mass spectrometer. The calibration curves for oleacein and oleuropein aglycone were linear and quadratic, respectively. The validation was done at three levels of concentration. Relative errors from 0.1 to 10.5% and relative standard deviations lower than 9% were obtained. The method was applied to study different samples of olive oil.

Ti(III)-catalyzed cyclizations of ketoepoxypolyprenes: control over the number of rings and unexpected stereoselectivities.

We describe a new strategy to control the number of cyclization steps in bioinspired radical (poly)cyclizations involving epoxypolyenes containing keto units positioned along the polyene chain. This approach provides an unprecedentedly straightforward access to natural terpenoids with pendant unsaturated side chains. Additionally, in the case of bi- and tricyclizations, decalins with cis stereochemistry have been obtained as a consequence of the presence of the ketone. The preferential formation of cis-fused adducts was rationalized using DFT calculations. This result is completely unprecedented in biomimetic cyclizations and permits the access to natural terpenoids with this stereochemistry, as well as to non-natural analogues.

Synthesis and photophysics of a new family of fluorescent 9-alkyl-substituted xanthenones.

9-Alkyl xanthenones with different aliphatic pendant groups have been easily prepared by means of nucleophilic addition of the corresponding Grignard derivative to a tert-butyldimethylsilyl ether (TBDMS)-protected 3,6-dihydroxy-xanthenone. The photophysical behavior of the new dyes has been explored by using absorption, steady-state-, and time-resolved fluorescence measurements. We determined the equilibrium constants, visible spectral characteristics, fluorescence quantum yield, and decay times. Remarkably, they retain similar fluorescent properties of fluorescein including the characteristic phosphate-mediated excited-state proton-transfer (ESPT) reaction. 6-Hydroxy-9-isopropyl-3H-xanthen-3-one (5) was investigated in living cells; it presented a good permeability and efficient accumulation inside the cytosol. For the first time, we reported that the requirement of an aryl group at C-9 is no longer needed and new fluorescent sensors can be therefore easily developed.

Role of C-reactive protein as a biomarker for prediction of the severity of pulmonary exacerbations in patients with cystic fibrosis.

BACKGROUND: Pulmonary exacerbation is one of the main risk factors for death in patients with cystic fibrosis. Several biomarkers have proven useful in the diagnosis and treatment of pulmonary exacerbations, although none has been associated with severity. The objective of the present study was to investigate whether C-reactive protein (CRP) level was associated with the severity of pulmonary exacerbation requiring admission to hospital in patients with cystic fibrosis. METHODS: We designed a severity index for exacerbations based on 4 clinical parameters and determined whether there was an association between CRP levels and severity of the exacerbation. We also investigated the association between CRP and baseline functional and clinical variables. RESULTS: Twenty-seven patients with cystic fibrosis required 62 admissions to hospital. CRP levels were not significantly associated with the severity index, although they were associated with specific patient characteristics: colonization by Pseudomonas aeruginosa, allergic bronchopulmonary aspergillosis, treatment with oral corticosteroids, and number of severe exacerbations treated with intravenous antibiotics during the previous year. CONCLUSIONS: CRP level is not associated with the severity of pulmonary exacerbations, but it is associated with specific clinical characteristics. This simple scoring system (severity index) could prove very useful for evaluating the severity of exacerbations.

Validation of the first treatment-specific questionnaire for the assessment of patient satisfaction with allergen-specific immunotherapy in allergic patients: the ESPIA questionnaire.

BACKGROUND: Satisfaction with treatment is a patient-reported outcome shown to be associated with the patient's health-related decisions and treatment-related behavior, thereby influencing the chances of successful treatment, and is especially relevant in long-term treatment, such as allergen-specific immunotherapy (AIT). OBJECTIVE: We sought to assess the psychometric properties of the Satisfaction Scale for Patients Receiving Allergen Immunotherapy (ESPIA) questionnaire so as to determine the satisfaction of patients receiving AIT treatment. METHODS: An observational, longitudinal, multicenter study was performed on patients with allergic rhinitis (AR) undergoing AIT treatment. Sociodemographic, clinical, and patient-centered health outcomes data were gathered at the study visits. Feasibility, reliability, validity, and sensitivity to change of the prevalidated version of the ESPIA questionnaire were assessed. RESULTS: Four hundred twenty-nine patients were included (52.2% women, 33.6 years of age, 54.5% of the cases with intermittent AR and 62.5% with moderate AR). Low levels of missing items and ceiling/floor effects were found for the overall score of the ESPIA questionnaire. The overall Cronbach α value and intraclass correlation coefficient were 0.90 and 0.92, respectively. The overall score for the ESPIA questionnaire was strongly associated with months receiving AIT, AR type and intensity, presence of conjunctivitis, self-perceived health status, effect of AR on daily life, and expectations about the AIT treatment. The pattern of correlations obtained with other patient-centered health outcomes was consistent with expectations. The ESPIA questionnaire also showed good sensitivity to change for improved health status. CONCLUSION: The ESPIA questionnaire to assess patient satisfaction with respect to AIT treatment presented satisfactory psychometric properties for its use in clinical practice.

Mild and Selective Hydrogenation of Unsaturated Compounds Using Mn/Water as a Hydrogen Gas Source.

A mild and highly selective reduction of alkenes and alkynes using Mn/water is described. The highly controlled generation of H2 allows the selective reduction of these compounds in the presence of labile functional groups under mild and environmentally acceptable conditions.

Epidemiology, Treatment Patterns, and Cost Analysis of Immune Thrombocytopenia in Spain between 2014 and 2020: A Population-based Study.

Background Immune thrombocytopenia (ITP) is characterised by low platelet counts and often leads to bleeding, fatigue, and reduced health-related quality of life. Methods This observational, retrospective, population-based study using BIG-PAC® database included Spanish paediatric and adult patients with primary ITP diagnosed in primary care and hospitals between 2014 and 2020 (median follow-up: 4 years). Epidemiology, baseline/clinical characteristics, treatment trends, healthcare resources and costs were analysed. Results The BIG-PAC® database contains records of 1,818,588 patients; 170 adults and 27 children with ITP were included in our analysis. ITP prevalence and annual incidence per 100,000 were estimated in 10.8 (2.8 in chronic ITP [cITP] patients) and 1.5 (0.3 in cITP patients), respectively. Epistaxis was the most common bleeding event, followed by genitourinary and gastrointestinal bleeding; >50%/> 75% of ITP/cITP patients reported fatigue. Chronic patients had lower platelet counts at baseline and required more transfusions. Corticosteroids, immunosuppressants, and thrombopoietin receptor agonists were the most used agents in first-, second- and third-line treatment, respectively. Thirty-five patients, all of them in chronic phase, underwent splenectomy. Patients had on average 13.9, 6.6, and 1.2 visits/year to primary care, haematology/internal medicine, and emergency departments, respectively. More than one-fourth of adult patients took on average 16.3 days of sick leave annually. Mean annual total health care costs were €10,741 (ITP patients) and €19,809 (cITP patients). Conclusion This is the first study to provide an overall perspective on the situation of the Spanish ITP population in terms of epidemiology, treatment trends, health care resources and costs, highlighting unmet patient needs, and direct and indirect costs/resource use between 2014 and 2020.

Titanocene(III)-catalyzed 6-exo versus 7-endo cyclizations of epoxypolyprenes: efficient control and synthesis of versatile terpenic building blocks.

In this article, a complete study on the selectivity of titanocene(III) cyclization of epoxypolyprenes is presented. The requirements for the formation of six- or seven-membered rings during these cyclizations are determined, taking into account the different substitution pattern in the epoxypolyprene precursor. Thus, a complete selectivity to 6-exo or 7-endo cyclization process has been achieved, yielding mono-, bi-, and even tricyclic compounds, constituting a new and efficient access to this type of derivative. Additionally, this procedure opens the possibility to prepare excellent building blocks for the synthesis of polycyclic compounds with a trisubstituted oxygenated function, which is present in several natural terpenes.

Combining the power of Ti(III)-mediated processes for easy access to hydroxylated polycyclic terpenoids: synthesis of sesterstatin 1 and C-D rings of aspergilloxide.

A straightforward access to polyhydroxylated terpenoids based on two key titanocene(III)-mediated reactions is presented: the "head-to-tail" Barbier-type addition of prenyl chlorides to α,ß-unsaturated aldehydes, which allows the introduction of hydroxy groups at desirable positions of the acyclic precursor, and the subsequent bioinspired radical cyclisation. This methodology has been also used in the first total synthesis of pentacyclic sesterstatin 1 and a model compound of the C-D rings of aspergilloxide.

Clarifying the structure of granadaene: total synthesis of related analogue [2]-granadaene and confirmation of its absolute stereochemistry.

Streptococcus agalactiae is an important agent in the infection of neonates in the first world. One of the most extended methods for its identification is based on the detection of a characteristic red pigment in the patient samples, named [12]-granadaene (1). In this article, we present a modular and flexible approach to simple analogues of this ornithine rhamno-polyene 1 and the elucidation of the most important features of its structure: the absolute configuration at C-27, the stereochemistry of the anomeric center and the link of the amino acid ornithine to the rest of the structure.