Targeting dihydroceramide desaturase 1 (Des1): Syntheses of ceramide analogues with a rigid scaffold, inhibitory assays, and AlphaFold2-assisted structural insights reveal cyclopropenone PR280 as a potent inhibitor.

Dihydroceramide desaturase 1 (Des1) catalyzes the formation of a CC double bond in dihydroceramide to furnish ceramide. Inhibition of Des1 is related to cell cycle arrest and programmed cell death. The lack of the Des1 crystalline structure, as well as that of a close homologue, hampers the detailed understanding of its inhibition mechanism and difficults the design of new inhibitors, thus making Des1 a strategic target. Based on previous structure-activity studies, different ceramides containing rigid scaffolds were designed. The synthesis and evaluation of these compounds as Des1 inhibitors allowed the identification of PR280 as a better Des 1 inhibitor in vitro (IC50 = 700 nM) than GT11 and XM462, the current reference inhibitors. This cyclopropenone ceramide was obtained in a 6-step synthesis with a 24 % overall yield. The highly confident 3D structure of Des1, recently predicted by AlphaFold2, served as the basis for conducting docking studies of known Des1 inhibitors and the ceramide derivatives synthesized by us in this study. For this purpose, a complete holoprotein structure was previously constructed. This study has allowed a better knowledge of key ligand-enzyme interactions for Des1 inhibitory activity. Furthermore, it sheds some light on the inhibition mechanism of GT11.

Revealing 2-dimethylhydrazino-2-alkyl alkynyl sphingosine derivatives as sphingosine kinase 2 inhibitors: Some hints on the structural basis for selective inhibition.

Sphingosine kinase (SphK), which catalyzes the transfer of phosphate from ATP to sphingosine (Sph) generating sphingosine-1-phosphate (S1P) has emerged as therapeutic target since the discovery of connections of S1P with cancer progress. So far, most effort has focused on the development of inhibitors of SphK1, and selective inhibitors of SphK2 have been much less explored. Here, we describe the syntheses of new sphingosine derivatives bearing a tetrasubstituted carbon atom at C-2, dimethylhydrazino or azo moieties in the polar head, and alkane, alkene or alkyne moieties as linkers between the polar ahead and the fatty tail. In vitro inhibitory assays based on a time resolved fluorescence energy transfer (TR-FRET) have revealed the hydrazino and alkynyl moieties as the best combination for the design of selective SphK2 inhibitors (19a and 19b). Docking studies showed that compounds 19a-b have the optimal binding to SphK2 through the exploitation of polar but also hydrophobic interactions of their head group with the head of the enzyme binding pocket, while also producing full contact of the fatty tail with the hydrophobic pocket of the enzyme. By contrast, this elongation causes loss of contact surface with the shorter hydrophobic toe of the SphK1 isoform, thus accounting for the SphK2-biased selectivity of these compounds. Cell viability assays of the most promising candidates 19a-b have shown that 19a is not cytotoxic to human endothelial cells at 30 µM.

Impact of adrenomedullin levels on clinical risk stratification and outcome in subarachnoid haemorrhage.

PURPOSE: To use classification tree analysis to identify risk factors for nonsurvival in a neurological patients with subarachnoid haemorrhage (SAH) and to propose a clinical model for predicting of mortality. METHODS: Prospective study of SAH admitted to a Critical Care Department and Stroke Unit over a 2-year period. Middle region of pro-ADM plasma levels (MR-proADM) was measured in EDTA plasma within the first 24 hours of hospital admission using the automatic immunofluorescence test. A regression tree was made to identify prognostic models for the development of mortality at 90 days. RESULTS: Ninety patients were included. The mean MR-proADM plasma value in the samples analysed was 0.78 ± 0.41 nmol/L. MR-proADM plasma levels were significantly associated with mortality at 90 days (1.05 ± 0.51 nmol/L vs 0.64 ± 0.25 nmol/L; P < .001). Regression tree analysis provided an algorithm based on the combined use of clinical variables and one biomarker allowing accurate mortality discrimination of three distinct subgroups with high risk of 90-day mortality ranged from 75% to 100% (AUC 0.9; 95% CI 0.83-0.98). CONCLUSIONS: The study established a model (APACHE II, MR-proADM and Hunt&Hess) to predict fatal outcomes in patients with SAH. The proposed decision-making algorithm may help identify patients with a high risk of mortality.

[PAPPS Cancer Expert Group. Cancer Prevention Recommendations. 2020 PAPPS update]. / Grupos de Expertos de Cáncer del PAPPS. Recomendaciones de Prevención del Cáncer. Actualización PAPPS 2020.

Cancer is a major cause of morbidity and mortality. Tobacco use, unhealthy diet, and physical inactivity are some of the lifestyle risk factors that have led to an increase in cancer. This article updates the evidence, and includes recommendations for prevention strategies for each of the cancers with the highest incidence. These are based on the reduction of risk factors (primary prevention) and early diagnosis of cancer through screening and early detection of signs and symptoms, in medium-risk and high-risk populations.

Enantioselective Synthesis of 3-Heterosubstituted-2-amino-1-ols by Sequential Metal-Free Diene Aziridination/Kinetic Resolution.

A general protocol for the enantioselective synthesis of 3-heterosubstituted-2-amino-1-ols was developed based on metal- free intramolecular regio- and stereoselective diene aziridination and regioselective opening. Kinetic resolution of the resulting (1'-NR1 R2 and 1'-SR)-4-oxazolidinones was performed using ABCs organocatalysts, expanding the application of this methodology.

Enantioselective Synthesis of Aminodiols by Sequential Rhodium-Catalysed Oxyamination/Kinetic Resolution: Expanding the Substrate Scope of Amidine-Based Catalysis.

Regio- and stereoselective oxyamination of dienes through a tandem rhodium-catalysed aziridination-nucleophilic opening affords racemic oxazolidinone derivatives, which undergo a kinetic resolution acylation process with amidine-based catalysts (ABCs) to achieve s values of up to 117. This protocol was applied to the enantioselective synthesis of sphingosine.

Fluorinated triazole-containing sphingosine analogues. Syntheses and in vitro evaluation as SPHK inhibitors.

Sphingosine analogues with a rigid triazole moiety in the aliphatic chain and systematic modifications in the polar head and different degrees of fluorination at the terminus of the alkylic chain were synthesized from a common alkynyl aziridine key synthon. This key synthon was obtained by enantioselective organocatalyzed aziridination and it was subsequently ring opened in a regioselective manner in acidic medium. Up to 16 sphingosine analogues were prepared in a straightforward manner. The in vitro activity of the obtained products as SPHK1 and SPHK2 inhibitors was evaluated, displaying comparable activity to that of DMS.

Chemical Access to d-Sarmentose Units Enables the Total Synthesis of Cardenolide Monoglycoside N-1 from Nerium oleander.

Herein we present a chemical approach for the ready preparation of d-sarmentosyl donors enabling the first total synthesis and structure validation of cardenolide N-1, a challenging 2,6-dideoxy-3-O-methyl-ß-d-xylo-hexopyranoside extracted from Nerium oleander twigs that displays anti-inflammatory properties and cell growth inhibitory activity against tumor cells. The strategy highlights the synthetic value of the sequential methodology developed in our group for the synthesis of 2-deoxyglycosides. Key steps include Wittig-Horner olefination of a d-xylofuranose precursor, [I+]-induced 6-endo cyclization, and 1,2-trans stereoselective glycosylation.

Palladium-catalyzed allylic amination: a powerful tool for the enantioselective synthesis of acyclic nucleoside phosphonates.

Acyclic nucleoside phosphonates have been prepared in a straightforward manner and in high yields by an enantioselective palladium-catalyzed allylic substitution involving nucleic bases as nucleophiles followed by cross-metathesis reaction with diethyl allylphosphonate.

Enantioselective Formal Synthesis of Nectrisine Using a Palladium-Catalyzed Asymmetric Allylic Amination and Cross-Metathesis as Key Steps.

A formal enantioselective synthesis of nectrisine, a potent α-glucosidase inhibitor, was carried out starting from butadiene monoepoxide through a synthetic sequence involving enantioselective allylic substitution, cross-metathesis, dihydroxylation, and cyclization.

Tuning the stereoelectronic properties of 1-sulfanylhex-1-enitols for the sequential stereoselective synthesis of 2-deoxy-2-iodo-ß-D-allopyranosides.

The preparation of challenging 2-deoxy-2-iodo-ß-D-allo precursors of 2-deoxy-ß-D-ribo-hexopyranosyl units and other analogues is reported using a robust olefination-cyclization-glycosylation sequence. Here, we particularly focus on tuning the stereoelectronic properties of the alkenyl sulfides intermediates in order to improve the diastereoselectivity of the cyclization step and, hence, the efficiency of the overall transformation. Phosphine oxides with the general formula Ph2P(O)CH2SR (R = t-Bu, Cy, p-MeOPh, 2,6-di-ClPh, and 2,6-di-MePh) were easily synthesized and subsequently used in the olefination reaction with 2,3,5-tri-O-benzyl-D-ribose and -D-arabinose. The corresponding sugar-derived alkenyl sulfides were submitted to a 6-endo [I(+)]-induced cyclization, and the resulting 2-deoxy-2-iodohexopyranosyl-1-thioglycosides were used as glycosyl donors for the stereoselective synthesis of 2-deoxy-2-iodohexopyranosyl glycosides. Among the different S-groups studied, t-Bu derivative was the best performer for the synthesis of cholesteryl 2-deoxy-2-iodomannopyranosides, whereas for the synthesis of 2-deoxy-2-iodoallopyranosides none of the derivatives here studied proved superior to the phenyl analogue previously described. Glycosylation of cholesterol with different d-allo and d-manno derivatives produced 2-deoxy-2-iodoglycosides with stereoselectivities in the same order in each case, reinforcing the involvement of an oxocarbenium ion as the common intermediate of this crucial glycosylation step.

Syntheses of a novel fluorinated trisphosphinoborate ligand and its copper and silver complexes. Catalytic activity toward nitrene transfer reactions.

A novel fluorinated ligand, the anionic PhB(CH2P(p-CF3C6H4)2)3 (PhBP3 (p-CF3Ph)), has been synthesized and characterized, as well as its corresponding thallium, copper, and silver derivatives. The presence of fluorine atoms in the ligand structure induced the desired effect of enhancing electrophilic character at the metal center, without promoting substantial changes in the ligand skeleton compared with the parent ligand PhB(CH2PPh2)3(-) (PhBP3). Olefin aziridination and C-H amidation reactions have been induced with those complexes as catalyst precursors. The copper derivative catalyzed the olefin aziridination of an array of olefins bearing either electron-donating or electron-withdrawing groups. The silver analogue was found to promote the C-H amidation of a series of substrates in moderate to high yields.

Advances in the enantioselective synthesis of carbocyclic nucleosides.

Carbocyclic nucleosides are nucleoside analogues in which the furanosidic moiety has been replaced by a carbocycle. Several members of this family have been isolated from natural sources and include a 5-membered ring carbocycle. The aim of this review is to examine critically the different methodologies for the enantioselective construction of 3- to 6-membered rings, with a particular focus on 5-membered rings and their modifications. The procedures for bonding the heterocyclic moiety and the carbohydrate are treated separately. The methods for synthesising the carbocyclic moiety mainly focus on the construction of the cycle, although precise details about the functionalisation are provided in some cases. The selected methods aim to provide an overview of the synthesis of carbocycles related to the synthesis of carbocyclic nucleosides. The methods of synthesis of 5-membered rings are classified into two types: methods in which the cyclopentane ring is formed by ring closing reactions (C=C and C-C formation) and methods that start from preformed 5-membered rings, based mainly on cycloaddition reactions. With respect to the methods of synthesis of 3-, 4- and 6-membered ring carbocyclic nucleosides, a selection of the more relevant enantioselective procedures is presented in a systematic manner.

[Influence of leadership style on knowledge management and hospital efficiency]. / Influencia del liderazgo en gestión del conocimiento y eficiencia hospitalaria.

OBJECTIVE: To analyse the effect of leadership style on knowledge management in hospitals and hospital efficiency based on the opinion of experts in hospital management, applying fuzzy cognitive maps (FCM). METHOD: FCM are relational models that can be used to graphically represent expert opinion and knowledge to infer cause-effect relationships between different concepts. The use of FCM as a simulation tool allows the evaluation of possible scenarios based on different leadership styles in hospitals. RESULTS: In the resulting augmented matrix, standardized effects range from 0.02 to 0.84, with the highest value representing the strongest relationship between knowledge exploitation and hospital efficiency. From the viewpoint of experts, knowledge creation within the hospital also influences hospital efficiency. Regarding variables reflecting leadership characteristics, positive effects have been identified, though with varying intensities, between authority, benevolence, and charisma, both in terms of knowledge creation and exploitation, as well as hospital efficiency. The transformational leadership style is associated with coefficients having higher values for knowledge management and hospital efficiency. CONCLUSIONS: Experts suggest that hospitals with authoritarian leadership styles would exhibit lower levels of knowledge creation and management, as well as lower hospital efficiency. On the other hand, they associate hospitals managed with a paternalistic leadership style with better values in both knowledge creation and exploitation, as well as hospital efficiency, compared to the authoritarian leadership style. Finally, they attribute the highest levels in aspects related to knowledge management and hospital efficiency to the transformational leadership style.

Association between histological diaphragm atrophy and ultrasound diaphragm expiratory thickness in ventilated patients.

BACKGROUND: Diaphragm fiber atrophy has been evidenced after short periods of mechanical ventilation (MV) and related to critical illness-associated diaphragm weakness. Atrophy is described as a decrease in diaphragm fiber cross-sectional area (CSA) in human diaphragm biopsy, but human samples are still difficult to obtain in clinics. In recent years, ultrasound has become a useful tool in intensive care to evaluate diaphragm anatomy. The present study aimed to evaluate the ability of diaphragm expiratory thickness (Tdi) measured by ultrasound to predict diaphragm atrophy, defined by a decrease in diaphragm fiber CSA obtained through diaphragm biopsy (the gold standard technique) in ventilated patients. METHODS: Diaphragm biopsies and diaphragm ultrasound were performed in ventilated donors and in control subjects. Demographic variables, comorbidities, severity on admission, treatment, laboratory test results and evolution variables were evaluated. Immunohistochemical analysis to determine CSA and ultrasound measurements of Tdi at end-expiration were performed, and median values of the control group were used as thresholds to determine agreement between them in further analysis. Sensitivity, specificity, and positive and negative predictive values of an ultrasound Tdi cutoff for detecting histologic atrophy were calculated. Agreement between two ultrasound observers was also assessed. RESULTS: Thirty-five ventilated organ donors and 5 ventilated controls were included, without differences in basic characteristics. CSA and Tdi were lower in donors than in controls. All donors presented lower CSA, but only 74% lower Tdi regarding control group thresholds. The cut-off value for lower diaphragm expiratory thickness (Tdi < 1.7 mm) presented a sensitivity of 73%, a specificity of 67%, a positive predictive value of 96% and a negative predictive value of 17% for determining the presence of diaphragm atrophy (CSA < 2851 µm2). CONCLUSIONS: Diaphragm atrophy and thickness reduction is associated to MV. While a lower Tdi in diaphragm ultrasound is a good tool for diagnosing atrophy, normal or increased Tdi cannot rule atrophy out showing that both parameters should not be considered as synonymous.

Sequential directed epoxydation-acidolysis from glycals with MCPBA. A flexible approach to protected glycosyl donors.

4,6-Di-O-protected glucal and allal derivatives react with MCPBA to afford manno- and allo-1-O-m-chlorobenzoate derivatives, respectively, as a result of a syn epoxidation directed by the allylic hydroxyl group, and consecutive ring-opening by m-ClBzOH. When glucal and allal derivatives are fully protected, initial epoxidation proceeds mainly anti to the allylic group to give, after ring-opening, the corresponding pyranosyl chlorobenzoates. Stereoselectivity in the reaction of fully protected galactal derivatives was complete, although only a moderate increase in the syn epoxidation product was observed in 4,6- and 3,4-di-O-protected derivatives. 1-O-m-Chlorobenzoate 18 was selectively protected and activated as donor in the synthesis of disaccharide 21.

Patient preferences and treatment safety for uncomplicated vulvovaginal candidiasis in primary health care.

BACKGROUND: Vaginitis is a common complaint in primary care. In uncomplicated candidal vaginitis, there are no differences in effectiveness between oral or vaginal treatment. Some studies describe that the preferred treatment is the oral one, but a Cochrane's review points out inconsistencies associated with the report of the preferred way that limit the use of such data. Risk factors associated with recurrent vulvovaginal candidiasis still remain controversial. METHODS/DESIGN: This work describes a protocol of a multicentric prospective observational study with one year follow up, to describe the women's reasons and preferences to choose the way of administration (oral vs topical) in the treatment of not complicated candidal vaginitis. The number of women required is 765, they are chosen by consecutive sampling. All of whom are aged 16 and over with vaginal discharge and/or vaginal pruritus, diagnosed with not complicated vulvovaginitis in Primary Care in Madrid.The main outcome variable is the preferences of the patients in treatment choice; secondary outcome variables are time to symptoms relief and adverse reactions and the frequency of recurrent vulvovaginitis and the risk factors. In the statistical analysis, for the main objective will be descriptive for each of the variables, bivariant analysis and multivariate analysis (logistic regression).. The dependent variable being the type of treatment chosen (oral or topical) and the independent, the variables that after bivariant analysis, have been associated to the treatment preference. DISCUSSION: Clinical decisions, recommendations, and practice guidelines must not only attend to the best available evidence, but also to the values and preferences of the informed patient.

Short and general procedure for synthesizing cis-1,2-fused 1,3-oxathiolan-, 1,3-oxaselenolan-, and 1,3-oxazolidin-2-imine carbohydrate derivatives.

Novel cis-1,2-fused 1,3-oxathiolan-, 1,3-oxaselenolan-, and 1,3-oxazolidin-2-imine carbohydrate derivatives have been prepared by treatment of the corresponding 1,2-anhydrosugars with potassium thiocyanate, potassium selenocyanate, and sodium cyanamide, respectively. The procedure is compatible with several protecting groups such as acyl, benzyl, and silyl and also with sugars of different configurations.

A pilot study of a new test to predict extubation failure.

INTRODUCTION: To determine whether subjecting patients to 100 ml of additional dead space after a 120-minute weaning trial could predict readiness for extubation. METHODS: This was a prospective, non-randomised pilot study in an intensive care unit at a university hospital with 14 beds. It included all non-tracheostomised patients with improvement of the underlying cause of acute respiratory failure, and those with no need for vasoactive or sedative drugs were eligible. Patients fulfilling the Consensus Conference on Weaning extubation criteria after 120 minutes spontaneous breathing (n = 152) were included. To the endotracheal tube, 100 cc dead space was added for 30 minutes. Patients tolerating the test were extubated; those not tolerating it received six hours of supplementary ventilation before extubation. The measurements taken and main results were: arterial pressure, heart rate, respiratory rate, oxygen saturation, end-tidal carbon dioxide and signs of respiratory insufficiency were recorded every five minutes; and arterial blood gases were measured at the beginning and end of the test. Extubation failure was defined as the need for mechanical and non-invasive ventilation within 48 hours of extubation. RESULTS: Twenty-two patients (14.5%) experienced extubation failure. Only intercostal retraction was independently associated with extubation failure. The sensitivity (40.9%) and specificity (97.7%) yield a probability of extubation failure of 75.1% for patients not tolerating the test versus 9.3% for those tolerating it. CONCLUSIONS: Observing intercostal retraction after adding dead space may help detect susceptibility to extubation failure. The ideal amount of dead space remains to be determined. TRIAL REGISTRATION: Current Controlled Trials ISRCTN76206152.

Asymmetric sulfur ylide based enantioselective synthesis of D-erythro-sphingosine.

An asymmetric sulfur ylide reaction was employed to prepare an epoxide intermediate in a convergent manner. This epoxide was efficiently transformed into D-erythro-sphingosine.