Repeated intravenous doses of human umbilical cord-derived mesenchymal stromal cells for bronchopulmonary dysplasia: results of a phase 1 clinical trial with 2-year follow-up.

BACKGROUND: Currently, there is a lack of effective treatments or preventive strategies for bronchopulmonary dysplasia (BPD). Pre-clinical studies with mesenchymal stromal cells (MSCs) have yielded encouraging results. The safety of administering repeated intravenous doses of umbilical cord tissue-derived mesenchymal stromal cells (UC-MSCs) has not yet been tested in extremely-low-gestational-age newborns (ELGANs). AIMS: to test the safety and feasibility of administering three sequential intravenous doses of UC-MSCs every 7 days to ELGANs at risk of developing BPD. METHODS: In this phase 1 clinical trial, we recruited ELGANs (birth weight ≤1250 g and ≤28 weeks in gestational age [GA]) who were on invasive mechanical ventilation (IMV) with FiO2 ≥ 0.3 at postnatal days 7-14. Three doses of 5 × 106/kg of UC-MSCs were intravenously administered at weekly intervals. Adverse effects and prematurity-related morbidities were recorded. RESULTS: From April 2019 to July 2020, 10 patients were recruited with a mean GA of 25.2 ± 0.8 weeks and a mean birth weight of 659.8 ± 153.8 g. All patients received three intravenous UC-MSC doses. The first dose was administered at a mean of 16.6 ± 2.9 postnatal days. All patients were diagnosed with BPD. All patients were discharged from the hospital. No deaths or any serious adverse events related to the infusion of UC-MSCs were observed during administration, hospital stays or at 2-year follow-up. CONCLUSIONS: The administration of repeated intravenous infusion of UC-MSCs in ELGANs at a high risk of developing BPD was feasible and safe in the short- and mid-term follow-up.

Modifying dental composites to formulate novel methacrylate-based bone cements with improved polymerisation kinetics, and mechanical properties.

OBJECTIVES: The aim was to develop bone composites with similar working times, faster polymerisation and higher final conversion in comparison to Cortoss™. Additionally, low shrinkage/heat generation and improved short and longer-term mechanical properties are desirable. METHODS: Four urethane dimethacrylate based composites were prepared using tri-ethylene-glycol dimethacrylate (TEGDMA) or polypropylene dimethacrylate (PPGDMA) diluent and 0 or 20 wt% fibres in the glass filler particles. FTIR was used to determine reaction kinetics, final degrees of conversions, and polymerisation shrinkage/heat generation at 37 °C. Biaxial flexural strength, Young's modulus and compressive strength were evaluated after 1 or 30 days in water. RESULTS: Experimental materials all had similar inhibition times to Cortoss™ (140 s) but subsequent maximum polymerisation rate was more than doubled. Average experimental composite final conversion (76%) was higher than that of Cortoss™ (58%) but with less heat generation and shrinkage. Replacement of TEGDMA by PPGDMA gave higher polymerisation rates and conversions while reducing shrinkage. Early and aged flexural strengths of Cortoss™ were 93 and 45 MPa respectively. Corresponding compressive strengths were 164 and 99 MPa. Early and lagged experimental composite flexural strengths were 164-186 and 240-274 MPa whilst compressive strengths were 240-274 MPa and 226-261 MPa. Young's modulus for Cortoss™ was 3.3 and 2.2 GPa at 1 day and 1 month. Experimental material values were 3.4-4.8 and 3.0-4.1 GPa, respectively. PPGDMA and fibres marginally reduced strength but caused greater reduction in modulus. Fibres also made the composites quasi-ductile instead of brittle. SIGNIFICANCE: The improved setting and higher strengths of the experimental materials compared to Cortoss™, could reduce monomer leakage from the injection site and material fracture, respectively. Lowering modulus may reduce stress shielding whilst quasi-ductile properties may improve fracture tolerance. The modified dental composites could therefore be a promising approach for future bone cements.

The Montecristo mining district, northern Chile: the relationship between vein-like magnetite-(apatite) and iron oxide-copper-gold deposits.

The Montecristo district, northern Chile, is one of the few places worldwide where there is a direct relationship between magnetite-(apatite) (MtAp) mineralization and iron oxide-copper-gold (IOCG) mineralization. The MtAp mineralization includes Ti-poor magnetite, fluorapatite, and actinolite and is crosscut and partially replaced by a younger IOCG mineralization that includes a second generation of actinolite and magnetite with quartz, chalcopyrite, pyrite, and molybdenite. The MtAp stage at Montecristo is interpreted as the crystallized iron-rich melts that used the pre-existing structures of the Atacama Fault System as conduits. These rocks later acted as a trap for hydrothermal IOCG mineralization. Geochronology data at Montecristo indicate that the host diorite (U-Pb zircon 153.3 ± 1.8 Ma, 2-sigma), MtAp mineralization (40Ar-39Ar in actinolite, 154 ± 2 Ma and 153 ± 4 Ma, 2-sigma), and the IOCG event (Re-Os on molybdenite, 151.8 ± 0.6 Ma, 2-sigma) are coeval within error and took place in a time span of less than 3.4 Ma. The εHfi and εNdi values of the host diorite are + 8.0 to + 9.8 and + 4.3 to + 5.4, respectively. The whole-rock 87Sr/86Sri values of the IOCG mineralization (0.70425 to 0.70442) are in the lower end of those of the MtAp mineralization (0.70426-0.70629). In contrast, εNdi values for the IOCG mineralization (+ 5.4 and + 5.7) fall between those of the MtAp rocks (+ 6.6 to + 7.2) and the host diorite, which suggests that the IOCG event was related to fluids having a more crustal Nd (εNdi < + 5.7) composition than the MtAp mineralization. This likely reflects the mixing of Nd from the MtAp protolith and a deep magmatic-hydrothermal source, very likely an unexposed intrusion equivalent to the host diorite. Sulfur isotope compositions (δ34S, + 0.3 to + 3.4‰) are consistent with a magmatic source. Supplementary Information: The online version contains supplementary material available at 10.1007/s00126-023-01172-0.

Application of CO2 Gas Hydrates as Leavening Agents in Black-and-White Cookies.

In this unprecedented study, the application of CO2 gas hydrates (GH) as a leavening agent to produce black-and-white cookies by replacing ammonium bicarbonate is investigated. Ammonium bicarbonate, the principal leavening ingredient in black-and-white cookies, has been linked to the creation of a carcinogenic substance known as acrylamide. Three distinct GH concentrations, 20%, 40%, and 50%, were utilized to determine the necessary amount to obtain a good leavening effect. However, the abrupt reduction in temperature brought on by the addition of GH had an inadmissible effect on the cookie dough. Consequently, an innovative kneading method carried out in a closed mixing unit at a high temperature was developed. The specific volume of the cookies when employing 50% GH as a baking agent was more than half that produced when using ammonium bicarbonate. In the cookies with GH, the springiness and hardness, which are the quality-determining textural characteristics of the pastry, remained within an acceptable range. The amount of acrylamide was reduced from 24.8 µg/Kg to around 18 µg/Kg by this research. Therefore, the presented study demonstrates the possibility of using CO2 GH as a leavening agent in black-and-white cookies and in other products for a healthier future.

Improving the Leavening Effect of Ice like CO2 Gas Hydrates by Addition of Gelling Agents in Wheat Bread.

This article brings together the application of ice-like CO2 gas hydrates (GH) as a leavening agent in wheat bread along with the incorporation of some natural gelling agents or flour improvers into the bread to enhance the textural properties of the wheat bread. The gelling agents used for the study were ascorbic acid (AC), egg white (EW), and rice flour (RF). These gelling agents were added to the GH bread containing different amounts of GH (40, 60, and 70% GH). Moreover, a combination of these gelling agents in a wheat GH bread recipe was studied for each respective percentage of GH. The combinations of gelling agents used in the GH bread were as follows: (1) AC, (2) RF + EW, and (3) RF + EW + AC. The best combination of GH wheat bread was 70% GH + AC + EW + RF combination. The primary goal of this research is to gain a better understanding of the complex bread dough created by CO2 GH and its influence on product quality when certain gelling agents are added to the dough. Moreover, the prospect of managing and modifying wheat bread attributes by the use of CO2 GH with the addition of natural gelling agents has not yet been researched and is a fresh idea in the food industry.

High-throughput discovery of novel small-molecule inhibitors of acid Ceramidase.

Ceramide has a key role in the regulation of cellular senescence and apoptosis. As Ceramide levels are lowered by the action of acid ceramidase (AC), abnormally expressed in various cancers, the identification of AC inhibitors has attracted increasing interest. However, this finding has been mainly hampered by the lack of formats suitable for the screening of large libraries. We have overcome this drawback by adapting a fluorogenic assay to a 384-well plate format. The performance of this optimised platform has been proven by the screening a library of 4100 compounds. Our results show that the miniaturised platform is well suited for screening purposes and it led to the identification of several hits, that belong to different chemical classes and display potency ranges of 2-25 µM. The inhibitors also show selectivity over neutral ceramidase and retain activity in cells and can therefore serve as a basis for further chemical optimisation.

An Innovative Approach in the Baking of Bread with CO2 Gas Hydrates as Leavening Agents.

Gas (guest) molecules are trapped in hydrogen-bonded water molecules to form gas hydrates (GH), non-stoichiometric solids that resemble ice. High pressure and low temperature are typical conditions for their development, with van der Waals forces joining the host and guest molecules. This article study investigates the application of CO2 gas hydrates (CO2 GH) as a leavening agent in baking, with particular reference to the production of wheat bread. The main intention of this study is to better understand the complex bread dough formed by CO2 GH and its impact on product quality. This may enable the adaptation of CO2 GH in baking applications, such as those that can specifically influence wheat bread properties, and so the final bread quality. The present research further examines the comparative evaluation of yeast bread with the GH bread's impact on bread quality parameters. The amount of GH was varied from 10 to 60%/amount of flour for the GH breads. The GH breads were compared with the standard yeast bread for different quality parameters such as volume, texture, and pore analysis. The results show that the bread with 20% and 40% GH obtained the best results in terms of volume and pore size. Moreover, this article also sheds some light on the future applications of the use of CO2 GH as leavening agents in foods. This knowledge could help to create new procedures and criteria for improved GH selection for applications in bread making and other bakery or food products.

Effect of rapid maxillary expansion on the apnoea-hypopnoea index during sleep in children. Systematic review.

Background: Rapid maxillary expansion (RME) treatment is prescribed in patients with maxillary compression, achieving increases in transverse palate and nasal cavity dimensions together with an increase in the distance between the pterygoid processes. Sleep apnoea-hypopnoea syndrome (SAHS) in children is often associated with anatomical risk factors and treatment may involve surgery, drugs, dentofacial orthopaedics, myofunctional and positional approaches. Material and Methods: The aim of this systematic review it to obtain scientific evidence of the effect of RME on the apnoea-hypopnoea index (AHI) in growing patients. PubMed, Cochrane Library and EMBASE were the online databases used for the search. The scientific publications selected met the following inclusion criteria: articles published from 2011 to May 2021; growing patients undergoing rapid maxillary expansion surgery; and studies with records of AHI before and after rapid maxillary expansion using polysomnography or respiratory polygraphy. Results: Seven articles that provided the necessary quality of scientific evidence were finally selected. The review followed the Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0, and the GRADE approach for rating the certainty of evidence. Data analysis was performed using Numbers 4.3 and ReviewManager (RevMan) 5.4.1 software and GRADEpro and Mendeley online platforms. Conclusions: The results show a reduction in AHI following RME therapy in growing patients. More research is needed with larger sample sizes, more specific inclusion criteria and standardised data sharing. Key words:Rapid maxillary expansion, maxillary distraction, sleep apnoea, children.

Methuosis Contributes to Jaspine-B-Induced Cell Death.

Methuosis is a type of programmed cell death in which the cytoplasm is occupied by fluid-filled vacuoles that originate from macropinosomes (cytoplasmic vacuolation). A few molecules have been reported to behave as methuosis inducers in cancer cell lines. Jaspine B (JB) is a natural anhydrous sphingolipid (SL) derivative reported to induce cytoplasmic vacuolation and cytotoxicity in several cancer cell lines. Here, we have investigated the mechanism and signalling pathways involved in the cytotoxicity induced by the natural sphingolipid Jaspine B (JB) in lung adenocarcinoma A549 cells, which harbor the G12S K-Ras mutant. The effect of JB on inducing cytoplasmic vacuolation and modifying cell viability was determined in A549 cells, as well as in mouse embryonic fibroblasts (MEF) lacking either the autophagy-related gene ATG5 or BAX/BAK genes. Apoptosis was analyzed by flow cytometry after annexin V/propidium iodide staining, in the presence and absence of z-VAD. Autophagy was monitored by LC3-II/GFP-LC3-II analysis, and autophagic flux experiments using protease inhibitors. Phase contrast, confocal, and transmission electron microscopy were used to monitor cytoplasmic vacuolation and the uptake of Lucifer yellow to assess macropinocyosis. We present evidence that cytoplasmic vacuolation and methuosis are involved in Jaspine B cytotoxicity over A549 cells and that activation of 5' AMP-activated protein kinase (AMPK) could be involved in Jaspine-B-induced vacuolation, independently of the phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin complex 1 (PI3K/Akt/mTORC1) axis.

Experimental investigation of CO2 uptake in CO2 hydrates formation with amino acids as kinetic promoters and its dissociation at high temperature.

The dissociation of CO2 gas hydrates (GH) with amino acid kinetic promoters and without promoters was studied at a high temperature of 90 °C for a period of 20 min to understand the percentage of CO2 gas and to select the best promoter that aids CO2 gas entrapment along with stability at a high temperature. The possibility of using four hydrophobic food grade amino acids, namely cysteine, valine, leucine, and methionine, and one surfactant, lecithin, as kinetic promoters for CO2 GH has been studied. The amino acids were added 0.5 g (wt%), and lecithin was added 5 g for the GH production. Furthermore, the amino acids leucine and methionine gave some positive results, therefore, these amino acids were carried further for the experimentation purpose in the production of CO2 GH. Also, a combinational use of these amino acids was studied to investigate the effect on % CO2 retention in comparison to the normal GH. From the results, it was observed that the stability of GH decreases with an increase in temperature, but the addition of promoters, especially leucine + methionine + lecithin increased the CO2 uptake during GH formation.

Caracterización de niños diagnosticados con COVID-19 en una provincia de la sierra norte del Perú / Characterization of children diagnosed with COVID-19 in a province in the northern sierra of Peru

Introducción: La población infantil presenta una escasa morbilidad y mortalidad por COVID-19; sin embargo, los niños infectados por el SARS-CoV-2 están en aumento y cabe la necesidad de caracterizarlos según sus diversas variables de presentación. Objetivo: Examinar las características sociales, clínicas, condiciones epidemiológicas y cuadro clínico de los niños diagnosticados con COVID-19. Métodos: Estudio descriptivo retrospectivo, con muestra de 88 niños menores de 12 años. Se revisó la base de datos de la oficina de epidemiología del hospital autorizado para el registro de casos confirmados de COVID-19 en la provincia de Chota, Perú. Se obtuvo la autorización de la dirección de la institución para utilizar la data exclusivamente con fines investigativos. El periodo de análisis: 14 de abril (caso cero en la provincia) de 2020-28 de enero de 2021. Resultados: En la muestra 51,1 por ciento fueron mujeres, el promedio de edad 5,6 años; 10,2 por ciento estuvo hospitalizado, 83 por ciento fue puesto en aislamiento, y 98,9 por ciento presentó una recuperación satisfactoria. Las manifestaciones fundamentales en los niños fueron: tos 26,1 por ciento; fiebre 23,9 por ciento y cefalea 19,3 por ciento. Las condiciones epidemiológicas detectadas fueron: 1,4 por ciento viajó en las últimas dos semanas; 47,7 por ciento tuvo contagio intradomiciliario y 67 por ciento asintomático. No se informaron niños fallecidos, intubados, ventilados o con neumonía. Conclusiones: Los niños son igual de susceptibles a la COVID-19 que otras personas; presentan cuadros clínicos menos graves que cursan principalmente con tos, fiebre, cefalea y malestar general; muestran una evolución más favorable y altas prevalencias de asintomáticos y contagios intradomiciliarios(AU)

Introduction: Children population has low morbidity and mortality by COVID-19; however, children infected with SARS-CoV-2 are on the rise and may need to be characterized according to their various presentation variables. Objective: Examine the social, clinical characteristics, epidemiological conditions and clinical picture of children diagnosed with COVID-19. Methods: Retrospective descriptive study, with a sample of 88 children under 12 years old. The database of the hospital´s epidemiology office authorized for the registration of confirmed cases of COVID-19 in Chota province, Peru, was reviewed. Authorization was obtained from the institution's management to use the data exclusively for research purposes. The analysis period was from April 14, 2020 (zero case in the province) to January 28, 2021. Results: In the sample 51.1 percent were women, the average age was 5.6 years; 10.2 percent were hospitalized, 83 percent were put in isolation, and 98.9 percent had a satisfactory recovery. The main manifestations in children were: cough, 26.1 percent; fever, 23.9 percent and headache, 19.3 percent. Epidemiological conditions detected were: 1.4 percent traveled in the last two weeks; 47.7 percent had intradomyciliary contagion, and 67 percent were asymptomatic. No children were reported deceased, intubated, ventilated or with pneumonia. Conclusions: Children are just as susceptible to COVID-19 as other people; they have less severe clinical pictures that occur mainly with cough, fever, headache and general discomfort; they show a more favorable evolution and high prevalence of asymptomatic and intradomyciliary contagions(AU)

Discovery of deoxyceramide analogs as highly selective ACER3 inhibitors in live cells.

Acid (AC), neutral (NC) and alkaline ceramidase 3 (ACER3) are the most ubiquitous ceramidases and their therapeutic interest as targets in cancer diseases has been well sustained. This supports the importance of discovering potent and specific inhibitors for further use in combination therapies. Although several ceramidase inhibitors have been reported, most of them target AC and a few focus on NC. In contrast, well characterized ACER3 inhibitors are lacking. Here we report on the synthesis and screening of two series of 1-deoxy(dihydro)ceramide analogs on the three enzymes. Activity was determined using fluorogenic substrates in recombinant human NC (rhNC) and both lysates and intact cells enriched in each enzyme. None of the molecules elicited a remarkable AC inhibitory activity in either experimental setup, while using rhNC, several compounds of both series were active as non-competitive inhibitors with Ki values between 1 and 5 µM. However, a dramatic loss of potency occurred in NC-enriched cell lysates and no activity was elicited in intact cells. Interestingly, several compounds of Series 2 inhibited ACER3 dose-dependently in both cell lysates and intact cells with IC50's around 20 µM. In agreement with their activity in live cells, they provoked a significant increase in the amounts of ceramides. Overall, this study identifies highly selective ACER3 activity blockers in intact cells, opening the door to further medicinal chemistry efforts aimed at developing more potent and specific compounds.

TGF-ß1-mediated transition of resident fibroblasts to cancer-associated fibroblasts promotes cancer metastasis in gastrointestinal stromal tumor.

Cancer-associated fibroblasts (CAFs) are the most abundant cells in the tumor microenvironment. Crosstalk between tumor cells and CAFs contributes to tumor survival in most epithelial cancers. Recently, utilizing gastrointestinal stromal tumor (GIST) as a model for sarcomas, we identified paracrine networks by which CAFs promote tumor progression and metastasis. However, the mechanisms by which CAFs arise in sarcomas remain unclear. Here, RNA sequencing analysis revealed that transforming growth factor-ß1 (TGF-ß1) is highly expressed in both tumor cells and CAFs. To determine the functional role of TGF-ß1, we treated normal gastric fibroblasts (GFs) with recombinant TGF-ß1, which caused the GFs to adopt a more stellate morphology, as well as increased the mRNA expression of CAF-mediated genes (CCL2, RAB3B, and TNC) and genes encoding fibroblast growth factors (FGFs). Moreover, while either GIST or CAF conditioned media enhanced the transition from GFs to CAFs, a TGF-ß1-blocking antibody attenuated this effect. Transwell migration assays revealed that the TGF-ß1-mediated transition from GFs to CAFs enhanced tumor cell migration. This migratory effect was abrogated by an anti-TGF-ß1 antibody, suggesting that TGF-ß1 secreted from GIST cells or CAFs is associated with GIST migration via GF-to-CAF transition. In addition, the murine spleen-to-liver metastasis model showed that GF pre-treated with TGF-ß1 promoted GIST metastasis. Collectively, these findings reveal unappreciated crosstalk among tumor cells, CAFs, and normal resident fibroblasts in the stroma of sarcomas, which enhances a GF-to-CAF transition associated with tumor migration and metastasis.

Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis.

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

Presbyvestibulopathy, Comorbidities, and Perception of Disability: A Cross-Sectional Study.

Objective: To assess the perception of disability in patients with presbyvestibulopathy and to determine the factors (demographic, balance test scores, and comorbidities) that determine higher levels of disability. Material and Methods: This was a cross-sectional study conducted in a tertiary university hospital. There were 103 patients who fulfilled the diagnostic criteria for presbyvestibulopathy and were included. Dizziness Handicap Inventory (DHI) score was the main variable used to quantify disability. Influence on DHI score, sex, age, time of evolution, equilibriometric parameters (posturographic scores and timed up and go test), history of falls, comorbidities (high blood pressure, diabetes, and dyslipidemia), psychotropic drug use, tobacco or alcohol use, living environment (urban or rural), and active lifestyle were analyzed. Results: Most of the DHI scores showed a moderate (46 patients, 44.7%) or severe (39 participants, 37.9%) handicap. DHI scores were higher in women (59.8 vs. 36.1, p < 0.001), patients with obesity (58.92 vs. 48.68; p = 0.019), benzodiazepine (59.9 vs. 49.1, p = 0.008) or other psychotropic drug (60.7 vs. 49.2, p = 0.017) users, and fallers (57.1 vs. 47.3, p = 0.048). There was also a significant positive correlation between DHI score, time (Rho coefficient: 0.371, p < 0.001), and steps (Rho coefficient: 0.284, p = 0.004) used in the TUG and with the short FES-I questionnaire (a shortened version of the Falls Efficacy Scale-International) score (Rho coefficient: 0.695, p < 0.001). DHI scores were lower in alcohol consumers than in non-drinkers (46.6 vs. 56, p = 0.048). No significant correlation was found between DHI scores and age, time of evolution, posturographic scores, comorbidities, environment (rural or urban), or active lifestyle. Conclusion: Most patients with presbyvestibulopathy show an important subjective perception of disability in relation to their symptoms. This perception is substantially higher in women than in men. The most influential factors are difficulties in walking, fear of falling, and obesity. Unique Identifier: NCT03034655, www.clinicaltrials.gov.

Activity-Based Imaging of Acid Ceramidase in Living Cells.

Acid ceramidase (AC) hydrolyzes ceramides into sphingoid bases and fatty acids. The enzyme is overexpressed in several types of cancer and Alzheimer's disease, and its genetic defect causes different incurable disorders. The availability of a method for the specific visualization of catalytically active AC in intracellular compartments is crucial for diagnosis and follow-up of therapeutic strategies in diseases linked to altered AC activity. This work was undertaken to develop activity-based probes for the detection of AC. Several analogues of the AC inhibitor SABRAC were synthesized and found to act as very potent (two-digit nM range) irreversible AC inhibitors by reaction with the active site Cys143. Detection of active AC in cell-free systems was achieved either by using fluorescent SABRAC analogues or by click chemistry with an azide-substituted analogue. The compound affording the best features allowed the unprecedented labeling of active AC in living cells.

SCOTfluors: Small, Conjugatable, Orthogonal, and Tunable Fluorophores for In†Vivo Imaging of Cell Metabolism.

The transport and trafficking of metabolites are critical for the correct functioning of live cells. However, in situ metabolic imaging studies are hampered by the lack of fluorescent chemical structures that allow direct monitoring of small metabolites under physiological conditions with high spatial and temporal resolution. Herein, we describe SCOTfluors as novel small-sized multi-colored fluorophores for real-time tracking of essential metabolites in live cells and in vivo and for the acquisition of metabolic profiles from human cancer cells of variable origin.

Evolução da Política de Educação Médica em Cabo Verde / Evolution of the Medical Education Policy in Cabo Verde

Resumo Cabo Verde é um dos Pequenos Estados Insulares em Desenvolvimento do mundo, com especificidades e desafios próprios. Independente há 43 anos, com meio milhão de habitantes, a formação dos seus médicos tem sido feita no exterior, incrementando a força de trabalho do país, mas não o suficiente, em número e diferenciação, para sustentar os desafios da saúde, nomeadamente a extensão da cobertura universal. Em 2015 as autoridades decidiram implantar a educação médica local, tornando necessário reformular a Política de Educação Médica enquanto política de educação e de saúde, envolvendo os vários atores, organizações e instituições. O objetivo deste artigo é analisar a percepção de vários informantes-chave sobre a implantação da educação médica em Cabo Verde e propor subsídios à reformulação da sua Política de Educação Médica. Um estudo qualitativo que resulta da análise de conteúdo de entrevistas e discussões em grupo, bem como de notícias na media cabo-verdiana, identificou elementos-chave da reformulação de políticas em termos de conteúdo, contexto, processos e principais atores envolvidos na reconsideração do curso de medicina. Os entrevistados consideraram essencial ter uma política de educação médica envolvente que oriente o desenvolvimento do curso e identifique os principais impulsionadores de sua implementação.

Abstract Cabo Verde is one of the world's Small Island Developing States, with its own specificities and challenges. Independent 43 years ago, with half a million inhabitants, the education of its physicians has been done abroad, increasing the country's workforce but not enough in number and differentiation to support the challenges of health care, namely the extension of universal coverage. In 2015 the authorities decided to implement local medical education, making it necessary to reformulate the Medical Education Policy as an education and health policy involving the many actors, organizations, and institutions. The objective of this article is to analyze the perception of several key informants of the Cabo Verdean society about the medical education in the country and to propose means to reformulate its Policy of Medical Education. A qualitative study that results from the content analysis of interviews and group discussions, as well as news in the Cabo Verdean media, identified key elements of policy reformulation in terms of content, context, processes and main actors involved in the reconsideration of the medical course. Respondents considered essential to have an engaging medical education policy to guide the development of the course and identifies the key drivers for its implementation.

In situ Multispecies Colonization of An Acrylic Resin: Comparison to Oral Microbiome and Potential for Inflammatory Response.

BACKGROUND: Conventional acrylic resin is prone to microbial colonization and may cause inflammatory and allergic response. AIMS: This study aims to research the initial microbial adhesion in situ and tissue response to an acrylic resin used in prosthodontics. MATERIALS AND METHODS: Disks of a commercial acrylic resin were prepared and included on the surface of individual intraoral splints fabricated for 50 participants. The splints were used for 4 h, under clinical conditions. Beforehand, each participant was swabbed to provide a control for microbiological comparison. A cytological control sample was also taken from the palate. After the time elapsed, each splint was removed and growth of anaerobes, aerobes, Pseudomonas, oral streptococci, staphylococci, yeasts, and Streptococcus mutans was determined by plate counts and compared to the oral microbiome. A cytological sample was taken from the contact zone, stained using the Papanicolaou technique, analyzed in light microscopy, and classified accordingly. Means and standard deviations were calculated, and a nonparametric Wilcoxon test was employed to compare experimental groups. The significance level was set at 0.05 (95% confidence interval, and statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) version 20.0. RESULTS: Nuclear-cytoplasm ratio increase was found in 84% of the smears retrieved from the contact zone. Over 60% showed nuclear alterations. With exception to yeasts and Pseudomonas, all microbial groups colonized the resin. No statistically significant differences were found between the oral microbiome and the acrylic resin's colonization except regarding yeasts (P > 0.05). CONCLUSIONS: Cellular alterations were found but a diagnosis of inflammation is inconclusive. Microbial adhesion to the acrylic resin was substantial, with multiple species adhering.

Stereoselective preparation of quaternary 2-vinyl sphingosines and ceramides and their effect on basal sphingolipid metabolism.

The dicyclohexylborane-mediated addition of allene 1 to (E)-2-tridecenal affords a quaternary protected 2-amino-2-vinyl-1,3-diol in good yield as a single diastereomer. This compound is readily transformed into the four stereoisomers of the quaternary (E)-2-vinyl analogs of sphingosine. The metabolic fate and the effect of these compounds on the basal sphingolipid metabolism in human A549 lung adenocarcinoma cells has been studied, together with the ceramide analog of the most relevant vinylsphingosine derivative.