Chaotic Transport of Solutes in Unsaturated Porous Media.

Unsaturated porous media, characterized by the combined presence of several immiscible fluid phases in the pore space, are highly relevant systems in nature, because they control the fate of contaminants and the availability of nutrients in the subsoil. However, a full understanding of the mechanisms controlling solute mixing in such systems is still missing. In particular, the role of saturation in the development of chaotic solute mixing has remained unexplored. Using three-dimensional numerical simulations of flow and transport at the pore scale, built upon X-ray tomograms of a porous medium at different degrees of liquid (wetting)-phase saturation, we show the occurrence of chaotic dynamics in both the deformation of the solute plume, as characterized by computed chaos metrics (Lyapunov exponents), and the mixing of the injected solute. Our results show an enhancement of these chaotic dynamics at lower saturation and their occurrence even under diffusion-relevant conditions over the medium's length, also being strengthened by larger flow velocities. These findings highlight the dominant role of the pore-scale spatial heterogeneity of the system, enhanced by the presence of an immiscible phase (e.g., air), on the mixing efficiency. This represents a stepping stone for the assessment of mixing and reactions in unsaturated porous media.

Synthesis, Optical Properties, and Antiproliferative Evaluation of NBD-Triterpene Fluorescent Probes.

A fluorescent labeling protocol for hydroxylated natural compounds with promising antitumor properties has been used to synthesize, in yields of 72-86%, 12 derivatives having fluorescent properties and biological activity. The reagent used for the synthesis of these fluorescent derivatives was 7-nitrobenzo-2-oxa-1,3-diazole chloride (NBD-Cl). The linkers employed to bind the NBD-Cl reagent to the natural compounds were ω-amino acids (Aa) of different chain lengths. The natural triterpene compounds chosen were oleanolic and maslinic acid, as their corresponding 28-benzylated derivatives. Thus, 12 NBD-Aa-triterpene conjugates have been studied for their optical fluorescence properties and their biological activities against cell proliferation in three cancer cell lines (B16-F10, HT-29, and HepG2), compared with three nontumor cell lines (HPF, IEC-18, and WRL68) from different tissues. The results of the fluorescence study have shown that the best fluorescent labels are those in which the ω-amino acid chain is shorter, and the carboxylic group is not benzylated. Analysis by confocal microscopy showed that these compounds were rapidly incorporated into cells in all three cancer cell lines, with these same derivatives showing the highest toxicity against the cancer cell lines tested. Then, the fluorescent labeling of these NBD-Aa-triterpene conjugates enabled their uptake and subcellular distribution to be followed in order to probe in detail their biological properties at the cellular and molecular level.

Synthesis and Biological Activity of Triterpene-Coumarin Conjugates.

A set of 12 maslinic acid-coumarin conjugates was synthesized, with 9 being maslinic acid-diamine-coumarin conjugates at the C-28 carboxylic acid group of triterpene acid and the other three being maslinic acid-coumarin conjugates at C-2/C-3 and/or C-28 of the triterpene skeleton. The cytotoxic effects of these 12 triterpene conjugates were evaluated in three cancer cell lines (B16-F10, HT29, and Hep G2) and compared, respectively, with three nontumor cell lines from the same or similar tissue (HPF, IEC-18, and WRL68). The most potent cytotoxic results were achieved by a conjugate with two molecules of coumarin-3-carboxylic acid coupled through the C-2 and C-3 hydroxy groups of maslinic acid. This conjugate showed submicromolar IC50 values in two of the three cancer cell lines tested (0.6, 1.1, and 0.9 µM), being between 110- and 30-fold more effective than its corresponding precursor. Furthermore, this conjugate (10) showed percentages of cell viability for the three nontumor lines of 90%. Four maslinic acid-coumarin conjugates displayed apoptotic effects in the treated cells, with total apoptosis rates of between 40 and 85%, relative to the control. Almost all the compounds assayed caused cell-cycle arrest in all cancer cell lines, increasing the number of these cells in the G0/G1 phase.

Efficient In Vitro and In Vivo Anti-Inflammatory Activity of a Diamine-PEGylated Oleanolic Acid Derivative.

Recent evidence has shown that inflammation can contribute to all tumorigenic states. We have investigated the anti-inflammatory effects of a diamine-PEGylated derivative of oleanolic acid (OADP), in vitro and in vivo with inflammation models. In addition, we have determined the sub-cytotoxic concentrations for anti-inflammatory assays of OADP in RAW 264.7 cells. The inflammatory process began with incubation with lipopolysaccharide (LPS). Nitric oxide production levels were also determined, exceeding 75% inhibition of NO for a concentration of 1 µg/mL of OADP. Cell-cycle analysis showed a reversal of the arrest in the G0/G1 phase in LPS-stimulated RAW 264.7 cells. Furthermore, through Western blot analysis, we have determined the probable molecular mechanism activated by OADP; the inhibition of the expression of cytokines such as TNF-α, IL-1ß, iNOS, and COX-2; and the blocking of p-IκBα production in LPS-stimulated RAW 264.7 cells. Finally, we have analyzed the anti-inflammatory action of OADP in a mouse acute ear edema, in male BL/6J mice treated with OADP and tetradecanoyl phorbol acetate (TPA). Treatment with OADP induced greater suppression of edema and decreased the ear thickness 14% more than diclofenac. The development of new derivatives such as OADP with powerful anti-inflammatory effects could represent an effective therapeutic strategy against inflammation and tumorigenic processes.

Peroral endoscopic myotomy as treatment for Zenker's diverticulum (Z-POEM): a multi-center international study.

BACKGROUND: Peroral endoscopic myotomy for the treatment of Zenker's diverticulum (Z-POEM) is a novel technique that has been described in several recent reports. This method utilizes the third space (submucosal layer) to create a tunnel to facilitate complete visualization of the septum and hence cutting it entirely. Conventional endoscopic septotomy carries the risk of recurrence due to incomplete visualization of the septum. While surgical correction is a risky and lengthy procedure in old comorbid patients with Zenker's diverticulum. The aim of this study is to assess the efficacy and safety of Z-POEM. METHODS: The study enrolled 24 patients diagnosed with Zenker's diverticulum (ZD) who underwent Z-POEM at seven independent endoscopy centers in five different countries. RESULTS: Mean patient age ± standard deviation (SD) was 74.3 ± 11 years. Most of the patients were males (n = 20, 83.3%); four (16.7%) were females. More than 50% of the patients (n = 14, 58.3%) had associated comorbidities. The mean size of the diverticula was 4 cm (range 2-7 cm). The Kothari-Haber Score was used to assess clinical symptoms; values ranged from 6 to 14 (median = 9). We achieved 100% technical success with a median procedure time of 61 min and no adverse events. Median hospital stay was 1 day (range 1-5 days). There is a significant reduction in the Kothari-Haber Score after Z-POEM (P < 0.0001). Technical success was achieved in 100% of the patients. Clinical success was achieved in 23/24 (95.8%) of the patients with a median follow-up of 10 months (range 6-24 months). CONCLUSION: Z-POEM is a safe and effective modality for managing ZD.

Impact of COVID-19 on endoscopy trainees: an international survey.

BACKGROUND AND AIMS: Although coronavirus disease 2019 (COVID-19) has affected endoscopy services globally, the impact on trainees has not been evaluated. We aimed to assess the impact of COVID-19 on procedural volumes and on the emotional well-being of endoscopy trainees worldwide. METHODS: An international survey was disseminated over a 3-week period in April 2020. The primary outcome was the percentage reduction in monthly procedure volume before and during COVID-19. Secondary outcomes included potential variation of COVID-19 impact between different continents and rates and predictors of anxiety and burnout among trainees. RESULTS: Across 770 trainees from 63 countries, 93.8% reported a reduction in endoscopy case volume. The median percentage reduction in total procedures was 99% (interquartile range, 85%-100%), which varied internationally (P < .001) and was greatest for colonoscopy procedures. Restrictions in case volume and trainee activity were common barriers. A total of 71.9% were concerned that the COVID-19 pandemic could prolonged training. Anxiety was reported in 52.4% of respondents and burnout in 18.8%. Anxiety was independently associated with female gender (odds ratio [OR], 2.15; P < .001), adequacy of personal protective equipment (OR, 1.75; P = .005), lack of institutional support for emotional health (OR, 1.67; P = .008), and concerns regarding prolongation of training (OR, 1.60; P = .013). Modifying existing national guidelines to support adequate endoscopy training during the pandemic was supported by 68.9%. CONCLUSIONS: The COVID-19 pandemic has led to restrictions in endoscopic volumes and endoscopy training, with high rates of anxiety and burnout among endoscopy trainees worldwide. Targeted measures by training programs to address these key issues are warranted to improve trainee well-being and support trainee education.

Regional Specialization of Pyramidal Neuron Morphology and Physiology in the Tree Shrew Neocortex.

The mammalian cerebral cortex is divided into different areas according to their function and pattern of connections. Studies comparing primary visual (V1) and prefrontal cortex (PFC) of primates have demonstrated striking pyramidal neuron (PN) specialization not present in comparable areas of the mouse neocortex. To better understand PFC evolution and regional PN specialization, we studied the tree shrew, a species with a close phylogenetic relationship to primates. We defined the tree shrew PFC based on cytoarchitectonic borders, thalamic connectivity and characterized the morphology and electrophysiology of layer II/III PNs in V1 and PFC. Similar to primates, the PFC PNs in the tree shrew fire with a regular spiking pattern and have larger dendritic tree and spines than those in V1. However, V1 PNs showed strikingly large basal dendritic arbors with high spine density, firing at higher rates and in a more varied pattern than PFC PNs. Yet, unlike in the mouse and unreported in the primate, medial prefrontal PN are more easily recruited than either the dorsolateral or V1 neurons. This specialization of PN morphology and physiology is likely to be a significant factor in the evolution of cortex, contributing to differences in the computational capacities of individual cortical areas.

Oleanolic Acid Derivatives as Potential Inhibitors of HIV-1 Protease.

Pentacyclic triterpenes, such as oleanolic acid (I), are promising scaffolds for diversification through the use of combinatorial methods to obtain derivatives that improve their biological properties, increasing their bioavailability and enhancing their therapeutic efficacy. The purpose of this study was to evaluate the influence that derivatives of oleanolic acid, conjugated with one or two amino acids and an acyl group, might exert on HIV-1 protease inhibition. The in vitro studies conducted suggested that the presence of a carboxyacyl group generally improves the inhibition of HIV-1 protease, especially when a phthaloyl group is present, with IC50 concentration values below 5 µM. The gain in activity of three 3-phthaloyl derivatives, with sub-micromolar IC50 values, was between 60- and 100-fold more active than oleanolic acid. A molecular docking study has also been performed to elucidate the mode of binding to the protease by these oleanolic acid derivatives. In general, the derivatives that exhibited the highest inhibitory activity of HIV-1 protease also showed the highest binding energies in docking simulations. The overall results suggest that the coupling of one or two amino acids and a phthaloyl group to oleanolic acid improves HIV-1 protease inhibition, implying that these triterpene derivatives may be promising antiviral agents against HIV.

Quantitative NMR analysis of L-Dopa in seeds from two varieties of Mucuna pruriens.

INTRODUCTION: L-Dopa, a key neurotransmitter used to treat neural disorders such as Parkinson's disease, is found in the seeds of the genus Mucuna at a sufficient concentration for possible commercial use. OBJECTIVE: To develop a simple and reliable method to extract L-Dopa from M. pruriens seeds in an aqueous medium and then quantitate this compound using a 1 H qNMR method (internal standard); and also to evaluate the accuracy and reproducibility of this method with an NMR calibration curve. METHODOLOGY: The extraction method of L-Dopa from M. pruriens was optimized. The quantitation with single point quantitative NMR (qNMR) and NMR calibration curve was based on the resonance properties of the main functional groups of the L-Dopa molecule, in particular the signals of the three aromatic protons, which were compared with the signal of an internal standard such as syringic acid. The accuracy (precision and trueness) and reproducibility of both NMR techniques were evaluated. RESULTS: The methods of single point qNMR and NMR calibration curve, applied to the seeds of two M. pruriens varieties, gave very similar L-Dopa contents: 3.0-3.2% and 3.0-3.1%, respectively. CONCLUSION: The statistical analysis confirmed the accuracy and reproducibility of this single point qNMR method (internal standard) for determining L-Dopa, as well as other commercial preparations of this species, without performing an NMR calibration curve.

Microstructure Design for Fast Lifetime Measurements of Magnetic Tunneling Junctions.

The estimation of the reliability of magnetic field sensors against failure is a critical point concerning their application for industrial purposes. Due to the physical stochastic nature of the failure events, this can only be done by means of a statistical approach which is extremely time consuming and prevents a continuous observation of the production. Here, we present a novel microstructure design for a parallel measurement of the lifetime characteristics of a sensor population. By making use of two alternative designs and the Weibull statistical distribution function, we are able to measure the lifetime characteristics of a CoFeB/MgO/CoFeB tunneling junction population. The main parameters governing the time evolution of the failure rate are estimated and discussed and the suitability of the microstructure for highly reliable sensor application is proven.

Semisynthesis of ω-Hydroxyalkylcarbonate Derivatives of Hydroxytyrosol as Antitrypanosome Agents.

Several lipophilic ω-hydroxyalkylcarbonate hydroxytyrosol derivatives and also their corresponding dimeric derivatives have been synthesized, coupling the primary hydroxy group of this phenolic compound with several terminal diols of different chain lengths, by the use of a carbonate linker. The trypanocidal activity and cytotoxicity of these ω-hydroxyalkylcarbonate derivatives of hydroxytyrosol and known alkylcarbonate derivatives of hydroxytyrosol were assessed. Three of the hydroxytyrosol alkylcarbonate derivatives were active against Trypanosoma brucei: two with an alkyl chain of average size (0.2 and 0.5 µM) and another with a double bond in the alkyl chain (0.4 µM). These values suggest an increase in activity with respect to hydroxytyrosol (264-, 90-, and 116-fold, respectively). Furthermore, these compounds showed high selectivity indices against MRC-5, a nontumor human cell line (62, 71, and 39, respectively). Some other ω-hydroxyalkylcarbonate and alkylcarbonate derivatives of hydroxytyrosol were also active against T. brucei within a low micromolar range (about 1 µM).

Robotic-assisted Roux-en-Y hepaticojejunostomy after bile duct injury.

BACKGROUND: The Da Vinci Robotic Surgical System has positioned itself as a tool that improves the ergonomics of the surgeon, facilitating dissection in confined spaces and enhancing the surgeon's skills. The technical aspects for successful bile duct repair are well-vascularized ducts, tension-free anastomosis, and complete drainage of hepatic segments, and all are achievable with robotic-assisted approach. METHODS: This was a retrospective study of our prospectively collected database of patients with iatrogenic bile duct injury who underwent robotic-assisted Roux-en-Y hepaticojejunostomy. Pre-, intra-, and short-term postoperative data were analyzed. RESULTS: A total of 30 consecutive patients were included. The median age was 46.5 years and 76.7% were female. Neo-confluences with section of hepatic segment IV were performed in 7 patients (those classified as Strasberg E4). In the remaining 23, a Hepp-Couinaud anastomosis was built. There were no intraoperative complications, the median estimated blood loss was 100 mL, and the median operative time was 245 min. No conversion was needed. The median length of stay was 6 days and the median length of follow-up was 8 months. The overall morbidity rate was 23.3%. Two patients presented hepaticojejunostomy leak. No mortality was registered. CONCLUSION: Robotic surgery is feasible and can be safely performed, with acceptable short-term results, in bile duct injury repair providing the advantages of minimally invasive surgery. Further studies with larger number of cases and longer follow-up are needed to establish the role of robotic assisted approaches in the reconstruction of BDI.

Microwave-assisted extraction versus Soxhlet extraction to determine triterpene acids in olive skins.

Microwave-assisted extraction is compared with a more classical technique, Soxhlet extraction, to determine the content of triterpene acids in olive skins. The samples used in their original unmilled state and milled were extracted with ethyl acetate or methanol as solvents. The optimized operating conditions (e.g., amount and type of solvent, and time and temperature of extractions) to attain the better extraction yields have been established. For the identification and quantitation of the target compounds, an ultra high performance liquid chromatography with tandem mass spectrometry method was employed. The best results were achieved using the microwave-assisted extraction technique, which was much faster than the Soxhlet extraction method, and showed higher efficiency in the extraction of the triterpenic acids (oleanolic and maslinic).

Biotransformation of Salpichrolides A, C, and G by Three Filamentous Fungi.

Incubation of salpichrolide A (1) with Rhizomucor miehei produced hydroxylation in rings B and C (C-7 and C-12) and led to C-5-C-6 epoxide opening, while incubation of salpichrolides C (2) and G (3) with R. miehei led to epoxide opening at the C-24-C-25 and C-5-C-6 positions, respectively. Biotransformation of salpichrolide A (1) with Cunninghamella elegans produced stereoselective hydroxylated, oxidized, and reduced derivatives in different positions of the A, B, and C rings and C-5-C-6 epoxide opening. In addition, selective epoxide opening at the C-5-C-6 or C-24-C-25 positions was obtained from the incubation of salpichrolide A (1) with Curvularia lunata.

Synthesis and Antioxidant Activity of Hydroxytyrosol Alkyl-Carbonate Derivatives.

Three procedures have been investigated for the isolation of tyrosol (1) and hydroxytyrosol (2) from a phenolic extract obtained from the solid residue of olive milling. These three methods, which facilitated the recovery of these phenols, were chemical or enzymatic acetylation, benzylation, and carbomethoxylation, and subsequent carbonylation or acetonation reactions. Several new lipophilic alkyl-carbonate derivatives of hydroxytyrosol have been synthesized, coupling the primary hydroxy group of this phenol, through a carbonate linker, using alcohols with different chain lengths. The antioxidant properties of these lipophilic derivatives have been evaluated by different methods and compared with free hydroxytyrosol (2) and also with the well-known antioxidants BHT and α-tocopherol. Three methods were used for the determination of this antioxidant activity: FRAP and ABTS assays, to test the antioxidant power in hydrophilic media, and the Rancimat test, to evaluate the antioxidant capacity in a lipophilic matrix. These new alkyl-carbonate derivatives of hydroxytyrosol enhanced the antioxidant activity of this natural phenol, with their antioxidant properties also being higher than those of the commercial antioxidants BHT and α-tocopherol. There was no clear influence of the side-chain length on the antioxidant properties of the alkyl-carbonate derivatives of 2, although the best results were achieved mainly by the compounds with a longer chain on the primary hydroxy group of this natural phenolic substance.

Amplified cold transduction in native nociceptors by M-channel inhibition.

Topically applied camphor elicits a sensation of cool, but nothing is known about how it affects cold temperature sensing. We found that camphor sensitizes a subpopulation of menthol-sensitive native cutaneous nociceptors in the mouse to cold, but desensitizes and partially blocks heterologously expressed TRPM8 (transient receptor potential cation channel subfamily M member 8). In contrast, camphor reduces potassium outward currents in cultured sensory neurons and, in cold nociceptors, the cold-sensitizing effects of camphor and menthol are additive. Using a membrane potential dye-based screening assay and heterologously expressed potassium channels, we found that the effects of camphor are mediated by inhibition of Kv7.2/3 channels subtypes that generate the M-current in neurons. In line with this finding, the specific M-current blocker XE991 reproduced the cold-sensitizing effect of camphor in nociceptors. However, the M-channel blocking effects of XE991 and camphor are not sufficient to initiate cold transduction but require a cold-activated inward current generated by TRPM8. The cold-sensitizing effects of XE991 and camphor are largest in high-threshold cold nociceptors. Low-threshold corneal cold thermoreceptors that express high levels of TRPM8 and lack potassium channels are not affected by camphor. We also found that menthol--like camphor--potently inhibits Kv7.2/3 channels. The apparent functional synergism arising from TRPM8 activation and M-current block can improve the effectiveness of topical coolants and cooling lotions, and may also enhance TRPM8-mediated analgesia.

Physiological and psychological effects of a high dose of alcohol in young men and women.

The objective of this study was to evaluate the effects of a high dose of alcohol on physiological and psychological parameters in young men and women with a previous history of alcohol consumption. Systolic and diastolic blood pressure, heart rate, state anxiety, attention, time estimation and manual dexterity were registered before (phase 1) and after (phase 2) intake of alcohol (38.4 g) or a non-alcoholic beverage. Trait anxiety was registered in phase 2 only. The results showed that acute consumption of a high dose of alcohol: i) improves attention in men (although the performance of alcohol consumers was not better than that of non-consumers); ii) blocks the systolic blood pressure habituation phenomenon (observed in controls) in women; and iii) blocks the improvement in manual dexterity (associated with experience in non-consumers) in both sexes. On the other hand, male consumers had a lower heart rate than non-consumers, independently of the phase, while female consumers had a higher state anxiety and performed worse in attention than controls, also independently of the phase. These results help to understand the extent of performance impairment of different tasks produced by risk alcohol consumption in young men and women.

Antiallodynic and analgesic effects of maslinic acid, a pentacyclic triterpenoid from Olea europaea.

The effects of maslinic acid (1), a pentacyclic triterpenoid obtained from Olea europaea, were studied in several tests for nociception in mice. Systemic administration of 1 reduced acetic acid-induced writhing, the inflammatory phase of formalin-induced pain, and capsaicin-induced mechanical allodynia. However, it did not induce motor incoordination in the rotarod test. The topical administration of 1 also reduced the inflammatory phase of the formalin test, indicating that at least some of its effects are mediated peripherally. The present results demonstrate for the first time that maslinic acid induces antinociceptive and antiallodynic effects.

Mixing Controlled Adsorption at the Liquid-Solid Interfaces in Unsaturated Porous Media.

The unsaturated zone, located between the soil surface and the phreatic level, plays an important role in defining the fate of any substance entering the subsoil. In addition to the processes of flow and transport taking place in the liquid phase, surface reactions such as adsorption to the solid phase may occur and increase the residence time of the substance entering the system. In this study, we aim to understand the pore-scale mechanisms that control adsorption in unsaturated systems. We combine 2D pore-scale experimental images with numerical simulations to analyze flow, transport, and adsorption under different liquid saturation degrees. We demonstrate the role of mixing on adsorption at the liquid-solid interfaces by analyzing the deformation in time of a pulse-injected surfactant. We also analyze the impact of the isotherm functional shape and the inclusion of the liquid-gas interfaces as adsorption sites on this surface reaction. The enhancement of mixing as saturation decreases is accompanied by a reduction in the amount of adsorbed mass, located mainly along preferential flow paths, where the solute is primarily transported. For the same isotherm, a nonlinear behavior of adsorption as a function of liquid saturation has been observed. This is explained by the nonlinear variation of the volume fraction of liquid behaving as preferential path or stagnation zone as liquid saturation decreases, despite the linear decrease in the surface area of solids accessible for adsorption. Supplementary Information: The online version contains supplementary material available at 10.1007/s11242-022-01747-x.

Maslinic acid solid lipid nanoparticles as hydrophobic anticancer drug carriers: Formulation, in vitro activity and in vivo biodistribution.

Maslinic acid (MA) is a natural pentacyclic triterpenoid with inherent antitumor activity which has a very low solubility in water. MA solid lipid nanoparticles (SLNs) were prepared using Poloxamer 407 and Dicarboxylic acid-Poloxamer 407 as surfactants. Both MA SLNs are monodisperse, with sizes around 130 nm, and stable. Curcumin has been encapsulated in both types of nanoparticles without altering their colloidal properties. Moreover, SLNs greatly improve the solubility of MA and Curcumin. The cytotoxicity of MA and SLNs has been evaluated in BxPC3 human pancreatic cancer cells, MCF7 human breast cancer cells, and in a human fibroblast primary cell line. MA shows higher cytotoxic effect in BxPC3 and MCF7 cancer cells than in human primary fibroblasts. Nile Red loaded MA SLNs are quickly uptaken by BxPC3 and MCF7 cells, and show different cytoplasmic distributions depending on the cellular line. The oral or intravenous administration of MA SLNs in mice does not report any toxic effect, and the intravenous administration of fluorescent MA SLNs shows a homogeneous distribution in mice, without site-specific accumulation. Results suggest the great potential of MA SLNs as nanocarriers of anticancer drugs and as promising targeted theranostic nanodevices.