Cyclic peroxides and analogs: Antibacterial, antimalarial, and cytotoxic marine products from Xisha sponge Diacarnus sp.

A chemical investigation of the dichloromethane extract from the Xisha sponge Diacarnus sp. revealed seven undescribed norterpene cyclic peroxides, named diacarperoxides T-Z, and five unreported related norterpenes, named diacarnoids E-I, and eleven previously reported compounds. The structures of these isolated compounds, including their absolute configurations, were elucidated based on extensive spectroscopic analyses, electronic circular dichroism (ECD) calculations, Snatzke's method, [Rh2(OCOCF3)4]-induced ECD spectra, and modified Mosher's method. Bioassays were performed to assess the antibacterial activity against six pathogenic bacteria, cytotoxicities toward three cancer cell lines, and antimalarial activity against Plasmodium parasites. Most of the cyclic peroxides exhibited substantial antibacterial activity (MIC 1-8 µg/mL). Diacarperoxide W and nuapapuin A showed substantial antimalarial activity with IC50 values of 0.98 and 2.83 µM. Moreover, many compounds exhibited <50% cell survival rates, and IC50 values of 0.22-6.33 µM. The apoptosis assay showed that nuapapuin A induced cancer cell apoptosis in a dose-dependent manner.

Decay of HCoV-OC43 infectivity is lower in cell debris-containing media than in fresh culture media.

In the quantitative description of viral dynamics within cell cultures and, more broadly, in modeling within-host viral infections, a question that commonly arises is whether the degradation of a fraction of the virus could be disregarded in comparison with the massive synthesis of new viral particles. Surprisingly, quantitative data on the synthesis and degradation rates of RNA viruses in cell cultures are scarce. In this study, we investigated the decay of the human betacoronavirus OC43 (HCoV-OC43) infectivity in cell culture lysates and in fresh media. Our findings revealed a significantly slower viral decay rate in the medium containing lysate cells compared to the fresh medium. This observation suggests that the presence of cellular debris from lysed cells may offer protection or stabilize virions, slowing down their degradation. Moreover, the growth rate of HCoV-OC43 infectivity is significantly higher than degradation as long as there are productive cells in the medium, suggesting that, as a first approximation, degradation can be neglected during early infection.

Nanopore sequencing technology for clinical diagnosis of infectious diseases where laboratory capacity is meager: A case report.

In resource-limited settings, patients are often first presented to clinical settings when seriously ill and access to proper clinical microbial diagnostics is often very limited or non-existing. On February 16th, 2022 we were on a field trip to test a completely field-deployable metagenomics sequencing set-up, that includes DNA purification, sequencing, and bioinformatics analyses using bioinformatics tools installed on a laptop for water samples, just outside Moshi, Tanzania. On our way to the test site, we were contacted by the nearby Machame hospital regarding a child seriously ill with diarrhea and not responding to treatment. Within the same day, we conducted an onsite metagenomics examination of a fecal sample from the child, and Campylobacter jejuni was identified as the causative agent. The treatment was subsequently changed, with almost immediate improvement, and the child was discharged on February 21st.

Upscaling Mixing-Controlled Reactions in Unsaturated Porous Media.

We study mixing-controlled chemical reactions in unsaturated porous media from a pore-scale perspective. The spatial heterogeneity induced by the presence of two immiscible phases, here water and air, in the pore space generates complex flow patterns that dominate reactive mixing across scales. To assess the impact of different macroscopic saturation states (the fraction of pore volume occupied by water) on mixing-controlled chemical reactions, we consider a fast irreversible reaction between two initially segregated dissolved species that mix as one solution displaces the other in the heterogeneous flow field of the water phase. We use the pore-scale geometry and water distributions from the laboratory experiments reported by Jiménez-Martínez et al. (Geophys. Res. Lett. 42: 5316-5324, 2015). We analyze reactive mixing in three complementary ways. Firstly, we post-process experimentally observed spatially distributed concentration data; secondly, we perform numerical simulations of flow and reactive transport in the heterogeneous water phase, and thirdly, we use an upscaled mixing model. The first approach relies on an exact algebraic map between conservative and reactive species for an instantaneous irreversible bimolecular reaction that allows to estimate reactive mixing based on experimental conservative transport data. The second approach is based on reactive random walk particle tracking simulations in the numerically determined flow field in the water phase. The third approach uses a dispersive lamella approach that accounts for the impact of flow heterogeneity on mixing in terms of effective dispersion coefficients, which are estimated from both experimental data and numerical random walk particle tracking simulations. We observe a significant increase in reactive mixing for decreasing saturation, which is caused by the stronger heterogeneity of the water phase and thus of the flow field. This is consistently observed in the experimental data and the direct numerical simulations. The dispersive lamella model, parameterized by the effective interface width, provides robust estimates of the evolution of the product mass obtained from the experimental and numerical data.

Effect of positive pressure ventilation and bariatric surgery on extracellular vesicle microRNAs in patients with severe obesity and obstructive sleep apnea.

INTRODUCTION: Obstructive sleep apnea (OSA) and severe obesity share a common pathophysiological phenomenon, systemic and tissue hypoxia. Hypoxaemia modifies microRNA expression, particularly, extracellular vesicles microRNAs which are involved in the progression of cardiovascular diseases, metabolic syndrome and cancer. We aim to evaluate extracellular vesicle miRNAs among patients with severe obesity with and without OSA and the effect of OSA and severe obesity treatment: continuous positive airway pressure (CPAP) and bariatric surgery. METHODS: Patients were selected from the Epigenetics Modification in Morbid Obesity and Obstructive Sleep Apnea (EPIMOOSA) study (NCT03995836), a prospective observational study of patients undergoing bariatric surgery. Patients were divided into OSA (Apnea-hyponea index (AHI) > 10) and non-OSA (AHI < 10). Patients with OSA were treated with CPAP for 6 months. Then, all patients had bariatric surgery and re-evaluated 12 months later. At each visit, blood samples were obtained for biobanking. Subsequently, extracellular vesicles were extracted, and then, miRNA expression was analysed. RESULTS: 15 patients with OSA and 9 without OSA completed the protocol. At baseline, patients with OSA showed higher miR16, miR126 and miR320 (p < 0.05) and lower miR223 expression (p < 0.05) than those without OSA. In patients with severe obesity and OSA, after 6 months with CPAP, we observed a significant decrease in miR21 (p < 0.01), miR126 (p < 0.001) and miR320 (p < 0.001), with no changes in any miRNA in patients without OSA. No changes were detected in any miRNA after 6 months of bariatric surgery in patients with or without OSA. CONCLUSION: Co-existance of OSA and severe obesity alters the profile of extracellular vesicle miRNAs. Bariatric surgery and weight loss did not reverse this effect meanwhile the treatment with CPAP in patients with severe obesity and OSA showed a recovery outcome in those extracellular vesicle miRNAs. Those facts remark the need for OSA screening in patients with severe obesity. CLINICAL TRIAL REGISTRATION: The study has also been registered at ClinicalTrials.gov identifier: NCT03995836.

How to Take a Good Clinical History in Cases of Allergic Reactions to Medications.

The clinical history is the cornerstone of the doctor´s work. When assessing patients consulting for a suspected hypersensitivity reaction to a drug, the details collected in the patient´s clinical history are essential when deciding which tests to perform and for making recommendations about which drugs the patient should avoid and which can be taken. This area is especially important today, since many patients are labeled as allergic to drugs, especially penicillins, without this being the case. This article reviews the importance of the clinical history in a patient with a hypersensitivity reaction to a drug and considers which data should be collected. Likewise, a record-based model is proposed to help standardize the clinical history.

Prone position in covid-19: Can we tackle rising dead space?

Little is known about the impact of proning on oxygenation and ventilatory efficiency on patients with severe Covid-19. In this retrospective observational study we calculated Pa/FiO2 ratio (P/F) as a marker of oxygenation and dead space fraction (Vd/Vt) to assess ventilation. 12 patients who were proned twice or more were included. There was a significant improvement in P/F ratio when prone (110.18 ± 28.11) compared to supine (88.95 ± 19.34) (p < 0.01). There was no improvement in Vd/Vt on proning (p > 0.05). Vd/Vt as a function of time displayed a positive linear correlation in those who did not survive (n = 9) (Rs = 0.48, p < 0.01) but no observed correlation in those who survived (n = 3) (Rs = 0.002, p = 0.97). Our findings indicate that prone position in patients with Covid-19 has little effect on dead space fraction but does improve oxygenation. Rise in dead space with time appears to be a prognostic factor for death in patients with severe Covid- 19.

How we approach the treatment of patients with high-risk neuroblastoma with naxitamab: experience from the Hospital Sant Joan de Déu in Barcelona, Spain.

Naxitamab [humanized 3f8 (hu3F8)] is a humanized monoclonal antibody (mAb) targeting the disialoganglioside GD2. It was approved in 2020 by the United States Food and Drug Administration (FDA) in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF) for treatment of pediatric and adult patients with relapsed/refractory high-risk neuroblastoma, limited to the bone or bone marrow (BM). The team at Sant Joan de Déu Children's Hospital in Barcelona, Spain, have been using naxitamab to treat neuroblastoma under clinical trial protocols [e.g. Trial 201, and hu3F8, irinotecan, temozolomide, and sargramostim (GM-CSF) (HITS) study] and compassionate use since 2017. The team has experience with two primary regimens: naxitamab with GM-CSF only, or naxitamab in combination with irinotecan, temozolomide, and GM-CSF (chemoimmunotherapy). This article aims to provide a practical overview of the team's experience with naxitamab to date, including preparing the treatment room and selecting the team. Adverse event management, including the use of ketamine to manage pain during anti-GD2 mAb infusions, is also discussed. We hope this will provide practical information for other health care providers considering offering this treatment.

How to Take a Good Clinical History in Cases of Allergic Reactions to Medications

The clinical history is the cornerstone of the doctor's work. When assessing patients consulting for a suspected hypersensitivity reactionto a drug, the details collected in the patient's clinical history are essential when deciding which tests to perform and for makingrecommendations about which drugs the patient should avoid and which can be taken. This area is especially important today, since manypatients are labeled as allergic to drugs, especially penicillins, without this being the case. This article reviews the importance of the clinicalhistory in a patient with a hypersensitivity reaction to a drug and considers which data should be collected. Likewise, a record-based modelis proposed to help standardize the clinical history (AU)

La historia clínica es la piedra angular del trabajo del médico. En el estudio de los pacientes que consultan por una supuesta reacción dehipersensibilidad a un fármaco, los detalles recogidos en la historia clínica del paciente son fundamentales para decidir el estudio quehay que realizar y para, al final, dar recomendaciones al paciente sobre los fármacos que debe evitar o que puede tomar. Actualmentecobra especial importancia este tema, dado que hay un elevado porcentaje de la población que, sin serlo, está etiquetada de alergiaa fármacos, sobre todo a las penicilinas. En este artículo se revisa la importancia que tiene la historia clínica ante un paciente con unareacción de hipersensibilidad a un fármaco y qué datos deben ser recogidos. Asimismo, se propone un modelo de ficha que puede ayudara la estandarización de la historia clínica (AU)

Contributions of biofilm-induced flow heterogeneities to solute retention and anomalous transport features in porous media.

Microbial biofilms are ubiquitous within porous media and the dynamics of their growth influence surface and subsurface flow patterns which impacts the physical properties of porous media and large-scale transport of solutes. A two-dimensional pore-scale numerical model was used to evaluate the impact of biofilm-induced flow heterogeneities on conservative transport. Our study integrates experimental biofilm images of Paenibacillus 300A strain in a microfluidic device packed with cylindrical grains in a hexagonal distribution, with mathematical modeling. Biofilm is represented as a synthetic porous structure with locally varying physical properties that honors the impact of biofilm on the porous medium. We find that biofilm plays a major role in shaping the observed conservative transport dynamics by enhancing anomalous characteristics. More specifically, when biofilm is present, the pore structure in our geometry becomes more spatially correlated. We observe intermittent behavior in the Lagrangian velocities that switches between fast transport periods and long trapping events. Our results suggest that intermittency enhances solute spreading in breakthrough curves which exhibit extreme anomalous slope at intermediate times and very marked late solute arrival due to solute retention. The efficiency of solute retention by the biofilm is controlled by a transport regime which can extend the tailing in the concentration breakthrough curves. These results indicate that solute retention by the biofilm exerts a strong control on conservative solute transport at pore-scale, a role that to date has not received enough attention.

Targeted Isolation of a Cytotoxic Cyclic Hexadepsipeptide from the Mesophotic Zone Sponge-Associated Fungus Cymostachys sp. NBUF082.

LC-MS/MS-based molecular networking facilitated the targeted isolation of a new cyclic hexadepsipeptide, cymodepsipeptide (1), and two known analogues, RF-2691A (2) and RF-2691B (3), from the fungus Cymostachys sp. NBUF082 that was derived from a mesophotic zone Aaptos sponge collected near Apo Island. The constitution and configuration of 1 was elucidated through 1D and 2D NMR-spectroscopy, high resolution mass-spectrometry, and chemical degradations including Marfey's analysis and chiral HPLC. It was observed that 1 was moderately cytotoxic against CCRF-CEM human acute lymphocytic leukemia cells in vitro with the IC50 value of 9.2 ± 1.1 µM.

Cytotoxic Polyketide Metabolites from a Marine Mesophotic Zone Chalinidae Sponge-Associated Fungus Pleosporales sp. NBUF144.

Two new polyketide natural products, globosuxanthone F (1), and 2'-hydroxy bisdechlorogeodin (2), were isolated from the fungus Pleosporales sp. NBUF144, which was derived from a 62 m deep Chalinidae family sponge together with four known metabolites, 3,4-dihydroglobosuxanthone A (3), 8-hydroxy-3-methylxanthone-1-carboxylate (4), crosphaeropsone C (5), and 4-megastigmen-3,9-dione (6). The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis, including 1D and 2D NMR and high-resolution electrospray ionization mass spectra (HRESIMS) data. The absolute configuration of 1 was further established by single-crystal X-ray diffraction studies. Compounds 1-5 were evaluated for cytotoxicity towards CCRF-CEM human acute lymphatic leukemia cells, and it was found that 1 had an IC50 value of 0.46 µM.

Discovery of Cymopolyphenols A-F From a Marine Mesophotic Zone Aaptos Sponge-Associated Fungus Cymostachys sp. NBUF082.

Mesophotic coral ecosystems (MCEs) have complex but understudied biodiversity, especially for natural products discovery. Untargeted metabolomics research on 80 extracts prepared from marine sponge-associated fungi, half from shallow reefs (<30 m) and half from MCEs (30-150 m), facilitated prioritization for further study a Cymostachys fungus from a 103 m deep Aaptos sponge. LC-MS target-directed isolation yielded a series of new compounds, cymopolyphenols A-F (1-6), and two known phenylspirodrimanes, F1839-I (7) and stachybotrylactone (8). This is the first report of natural products from the recently described genus, Cymostachys. Compounds 1-6 and 8 contain a dihydroisobenzofuran moiety, and 4-6 are low-order polymers of 1 with novel scaffolds. The structures of the compounds were established by spectroscopic and spectrometric data interpretation, with further support from X-ray crystallography studies of 3 and 4. Compound 3 undergoes facile racemization in solution and was found to crystalize as a racemic mixture. Compound 5 was also obtained in racemic form, and after chiral chromatography, both separated enantiomers racemized in solution by a presumed keto-enol tautomerization. Compounds 1 and 3-6 were found to be weakly antimicrobial (MIC 16-64 µg/ml) in vitro against several Gram-positive and Gram-negative human or aquatic pathogens, compound 5 was shown to chelate iron in vitro at 10 µM, and 8 activated plant disease resistance in vivo in a transgenic model organism.

Impact of confined geometries on hopping and trapping of motile bacteria in porous media.

We use a random walk particle-tracking (RWPT) approach to elucidate the impact of porous media confinement and cell-cell interactions on bacterial transport. The model employs stochastic alternating motility states consisting of hopping movement and trapping reorientation. The stochastic motility patterns are defined based on direct visualization of individual trajectory data. We validate our model against experimental data, at single-cell resolution, of bacterial E. coli motion in three-dimensional confined porous media. Results show that the model is able to efficiently simulate the spreading dynamics of motile bacteria as it captures the impact of cell-cell interaction and pore confinement, which marks the transition to a late-time subdiffusive regime. Furthermore, the model is able to qualitatively reproduce the observed directional persistence. Our RWPT model constitutes a meshless simple method which is easy to implement and does not invoke ad hoc assumptions but represents the basis for a multiscale approach to the study of bacterial dispersal in porous systems.

Galactose-alfa-1, 3-galactose (alpha-gal) allergy: first pediatric case in a series of patients in Spain

INTRODUCTION AND OBJECTIVES: Allergy to galactose-α-1,3-galactose (alpha-gal) is a peculiar form of food allergy generally manifesting as an anaphylactic reaction hours after mammalian meat consumption, due to the presence of specific IgE against this oligosaccharide. In addition, immediate anaphylaxis may develop after exposure to other sources of alpha-gal, such as monoclonal antibody cetuximab, vaccines, plasma expanders or anti-snake venoms. Sensitization to alpha-gal has also been implicated in the rapid degeneration of biological valve implants, and recognized as a cause of occupational disease in cattle raisers. The implication of tick bites in this type of sensitization has been accepted by all the research groups dedicated to this disease. PATIENTS AND METHOD: The present study describes the clinical and sensitization characteristics of 39 patients diagnosed with alpha-gal allergy in the hospitals of our province (Lugo, Monforte de Lemos and Burela, Spain). RESULTS: Most patients were middle-age males. Of note, is the fact that the series includes the first pediatric patient reported in Spain to date. The predominant clinical manifestations were urticaria or delayed anaphylaxis after consumption of mammalian meat. Seventy-four percent of the patients reported having suffered a previous tick bite, and the clinical presentation of anaphylaxis was significantly more prevalent in those with a persistent local reaction following the bite than in those with no such reaction (p = 0.032). CONCLUSIONS: A review is also made of the disorder which, due to its variable clinical expression, is referred to as alpha-gal syndrome. The study concludes that a diagnosis of alpha-gal allergy should be considered in patients with urticaria-anaphylaxis of uncertain origin or manifesting after the administration of vaccines or products of bovine/porcine origin

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Three New Diketopiperazines from the Previously Uncultivable Marine Bacterium Gallaecimonas mangrovi HK-28 Cultivated by iChip.

The in situ application of iChip cultivation in mangrove sediment from Hainan province, China, led to the isolation of a novel bacterial species Gallaecimonas mangrovi HK-28. The extract of G. mangrovi HK-28 exhibited antibiotic activity against the aquatic pathogen Vibrio harveyi, and its chemical constituents were further investigated by bioactivity-guided isolation. Three new diketopiperazines, gallaecimonamides A-C, were accordingly isolated from the AcOEt extract of the fermentation broth of G. mangrovi HK-28. The planar structures of gallaecimonamides A-C were determined using HR-ESI-MS together with 1D- and 2D-NMR. The absolute configurations of gallaecimonamides A-C were assigned by optical rotation, NOESY experiment and TDDFT ECD calculations. The in vitro antibacterial and antimalarial activities of gallaecimonamides A-C were assessed. Gallaecimonamide A was found to display antibacterial activity against V. harveyi with a MIC value of 50 µm. However, gallaecimonamides B and C showed no antibacterial activity against V. harveyi (MIC >300 µm). In addition, all the isolates did not exhibit any inhibitory activities against V. parahaemolyticus (MIC>300 µm) and Plasmodium falciparum W2 (EC50 >100 µg/mL).