Machine-learning-assisted material discovery of oxygen-rich highly porous carbon active materials for aqueous supercapacitors.

Porous carbons are the active materials of choice for supercapacitor applications because of their power capability, long-term cycle stability, and wide operating temperatures. However, the development of carbon active materials with improved physicochemical and electrochemical properties is generally carried out via time-consuming and cost-ineffective experimental processes. In this regard, machine-learning technology provides a data-driven approach to examine previously reported research works to find the critical features for developing ideal carbon materials for supercapacitors. Here, we report the design of a machine-learning-derived activation strategy that uses sodium amide and cross-linked polymer precursors to synthesize highly porous carbons (i.e., with specific surface areas > 4000 m2/g). Tuning the pore size and oxygen content of the carbonaceous materials, we report a highly porous carbon-base electrode with 0.7 mg/cm2 of electrode mass loading that exhibits a high specific capacitance of 610 F/g in 1 M H2SO4. This result approaches the specific capacitance of a porous carbon electrode predicted by the machine learning approach. We also investigate the charge storage mechanism and electrolyte transport properties via step potential electrochemical spectroscopy and quasielastic neutron scattering measurements.

Structure-Dynamics Interrelation Governing Charge Transport in Cosolvated Acetonitrile/LiTFSI Solutions.

Concentrated ionic solutions present a potential improvement for liquid electrolytes. However, their conductivity is limited by high viscosities, which can be attenuated via cosolvation. This study employs a series of experiments and molecular dynamics simulations to investigate how different cosolvents influence the local structure and charge transport in concentrated lithium bis(trifluoromethane-sulfonyl)imide (LiTFSI)/acetonitrile solutions. Regardless of whether the cosolvent's dielectric constant is low (for toluene and dichloromethane), moderate (acetone), or high (methanol and water), they preserve the structural and dynamical features of the cosolvent-free precursor. However, the dissimilar effects of each case must be individually interpreted. Toluene and dichloromethane reduce the conductivity by narrowing the distribution of Li+-TFSI- interactions and increasing the activation energies for ionic motions. Methanol and water broaden the distributions of Li+-TFSI- interactions, replace acetonitrile in the Li+ solvation, and favor short-range Li+-Li+ interactions. Still, these cosolvents strongly interact with TFSI-, leading to conductivities lower than that predicted by the Nernst-Einstein relation. Finally, acetone preserves the ion-ion interactions from the cosolvent-free solution but forms large solvation complexes by joining acetonitrile in the Li+ solvation. We demonstrate that cosolvation affects conductivity beyond simply changing viscosity and provide fairly unexplored molecular-scale perspectives regarding structure/transport phenomena relation in concentrated ionic solutions.

Water Dynamics in Cancer Cells: Lessons from Quasielastic Neutron Scattering.

The severity of the cancer statistics around the globe and the complexity involving the behavior of cancer cells inevitably calls for contributions from multidisciplinary areas of research. As such, materials science became a powerful asset to support biological research in comprehending the macro and microscopic behavior of cancer cells and untangling factors that may contribute to their progression or remission. The contributions of cellular water dynamics in this process have always been debated and, in recent years, experimental works performed with Quasielastic neutron scattering (QENS) brought new perspectives to these discussions. In this review, we address these works and highlight the value of QENS in comprehending the role played by water molecules in tumor cells and their response to external agents, particularly chemotherapy drugs. In addition, this paper provides an overview of QENS intended for scientists with different backgrounds and comments on the possibilities to be explored with the next-generation spectrometers under construction.

Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial-PEARL.

BACKGROUND: Palbociclib plus endocrine therapy (ET) is the standard treatment of hormone receptor-positive and human epidermal growth factor receptor 2-negative, metastatic breast cancer (MBC). However, its efficacy has not been compared with that of chemotherapy in a phase III trial. PATIENTS AND METHODS: PEARL is a multicentre, phase III randomised study in which patients with aromatase inhibitor (AI)-resistant MBC were included in two consecutive cohorts. In cohort 1, patients were randomised 1 : 1 to palbociclib plus exemestane or capecitabine. On discovering new evidence about estrogen receptor-1 (ESR1) mutations inducing resistance to AIs, the trial was amended to include cohort 2, in which patients were randomised 1 : 1 between palbociclib plus fulvestrant and capecitabine. The stratification criteria were disease site, prior sensitivity to ET, prior chemotherapy for MBC, and country of origin. Co-primary endpoints were progression-free survival (PFS) in cohort 2 and in wild-type ESR1 patients (cohort 1 + cohort 2). ESR1 hotspot mutations were analysed in baseline circulating tumour DNA. RESULTS: From March 2014 to July 2018, 296 and 305 patients were included in cohort 1 and cohort 2, respectively. Palbociclib plus ET was not superior to capecitabine in both cohort 2 [median PFS: 7.5 versus 10.0 months; adjusted hazard ratio (aHR): 1.13; 95% confidence interval (CI): 0.85-1.50] and wild-type ESR1 patients (median PFS: 8.0 versus 10.6 months; aHR: 1.11; 95% CI: 0.87-1.41). The most frequent grade 3-4 toxicities with palbociclib plus exemestane, palbociclib plus fulvestrant and capecitabine, respectively, were neutropenia (57.4%, 55.7% and 5.5%), hand/foot syndrome (0%, 0% and 23.5%), and diarrhoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET offered better quality of life (aHR for time to deterioration of global health status: 0.67; 95% CI: 0.53-0.85). CONCLUSIONS: There was no statistical superiority of palbociclib plus ET over capecitabine with respect to PFS in MBC patients resistant to AIs. Palbociclib plus ET showed a better safety profile and improved quality of life.

The variegated scallop, Mimachlamys varia, undergoes alterations in several of its metabolic pathways under short-term zinc exposure.

The variegated scallop (Mimachlamys varia) is a filter feeder bivalve encountered in marine regions of the Atlantic coast. In particular, it is present in the La Rochelle marina (France), where it is used for the biomonitoring of marine pollution, due to its ability to strongly bioaccumulate pollutants. In this semi-closed environment, contamination generated by port activities leads to an accumulation of both organic and metal pollutants. Zinc is one of these pollutants, present at a dose of up to 150 µg.L-1. This study investigated the effects of 48 h zinc exposure upon the metabolic profiles of Mimachlamys varia using UHPLC/QToF (ultra-high performance liquid chromatography-quadrupole time-of-flight) tandem mass spectrometry metabolomics. After acclimation in mesocosms recreating in situ conditions, both controls and exposed with Zn2+ (150 µg.L-1) bivalves were dissected to recover the gills after 48 h and stored at -80 °C before metabolites extraction. UHPLC/QToF tandem mass spectrometry was performed to study metabolite composition of samples. Statistical analysis of results using multivariate techniques showed a good classification between control and exposed groups. Eleven identified metabolites were found to be down-modulated in exposed scallops. These variations could reflect potential zinc effects on several of the biological processes, such as energy metabolism, osmoregulation and defense against oxidative stress. Among the eleven metabolites highlighted, four were reported for the first time in an aquatic organism exposed to Zn. This study demonstrates once again the diversity of interactions between bivalves and metals and the complexity of the physiological response of marine bivalves to pollutants.

Effect of Paclitaxel in the Water Dynamics of MCF-7 Breast Cancer Cells Revealed by Dielectric Spectroscopy.

Using dielectric spectroscopy experiments performed at multiple temperatures and frequency ranges, we demonstrate how the chemotherapy drug paclitaxel changes the dynamic properties of water in a breast cancer cell line (MCF-7). From the measured data, we present evidence that treatment with paclitaxel leads to a slight increase in activation energy in a relaxation related to bulk-like water. More importantly, we also observe that paclitaxel changes the constraining imposed by the biological interfaces on hydration water, whose single-particle dynamics becomes slower and with higher activation energy. These variations are only observable after freezing the dynamics from other cellular components, such as proteins and DNAs, regardless of the state of the cells, that is, treated or not treated or even if the cells are no longer viable. Therefore, changes in water dynamics could be detected prior to those related to the global dynamics within the cellular environment.

Immobilization of Paclitaxel on Hydroxyapatite for Breast Cancer Investigations.

A simple method for immobilization of the chemotherapy drug paclitaxel (PTX) on hydroxyapatite nanoparticles (n-HAP) using the biopolymer chitosan as a trapping agent is described focusing on applications involving breast cancer cells. n-HAP with two distinct crystallinity profiles were used: with predominant crystallization along the long axis and with a more homogeneous crystallization in all directions. In the first scenario, the interactions between chitosan and both the OH and PO43- groups on the surface of the nanoparticles are favored and lead to a more efficient attachment of the drug. In this case, PTX is found to remain mostly attached to the n-HAP for at least 24 h, while being dispersed in aqueous solution. During this time, the activity of the drug is inhibited as corroborated by in vitro assays with breast cancer cells. With that, the in vitro experiments revealed distinct effects from the drug-loaded nanoparticles on the cells depending on the experimental conditions. In a short term, that is, in 24 h, the cells exhibit higher viability than those challenged with nonloaded materials. Nevertheless, after 72 h, even a small content of PTX in the presence of n-HAP can reduce the cells' viability via stimulation of the apoptotic phenotype and suppression of survival stimuli.

Water dynamics in MCF-7 breast cancer cells: a neutron scattering descriptive study.

Water mobility in cancer cells could be a powerful parameter to predict the progression or remission of tumors. In the present descriptive work, new insight into this concept was achieved by combining neutron scattering and thermal analyses. The results provide the first step to untangle the role played by water dynamics in breast cancer cells (MCF-7) after treatment with a chemotherapy drug. By thermal analyses, the cells were probed as micrometric reservoirs of bulk-like and confined water populations. Under this perspective we showed that the drug clearly alters the properties of the confined water. We have independently validated this idea by accessing the cellular water dynamics using inelastic neutron scattering. Finally, analysis of the quasi-elastic neutron scattering data allows us to hypothesize that, in this particular cell line, diffusion increases in the intracellular water in response to the action of the drug on the nanosecond timescale.

Size-Strain Analysis of Iron-Excess Mn-Zn Ferrite Nanoparticles Using Synchrotron Diffraction and Its Correlation with Magnetic Saturation and Isoelectric pH.

Iron-excess Mn-Zn ferrite nanoparticles were prepared by coprecipitation with sodium hydroxide (NaOH) at different concentrations (0.1, 0.2, 0.5 and 1.0 mol/L). The results of X-ray diffraction (XRD) analysis using Whole Powder Pattern Modeling (WPPM) showed that higher concentrations of NaOH promote crystallite growth and broader dispersion in crystallite sizes. Energy dispersive X-ray spectroscopy indicates that zinc loss is noticeable when [NaOH] ≥ 0.2 mol/L. XRD revealed also a significant less-crystalline phase contribution alongside the main peaks of the nanocrystalline cubic spinel ferrite phase. The less-crystalline fraction is lower for the ferrite obtained with 0.2 mol/L of NaOH, being about 50% and more than 70% for the other samples. Despite of the less-crystalline fraction and the excess of iron, no secondary phases were detected. The Warren curves showed that the concentration of NaOH significantly influences the microstrain in the crystallites, being smaller for the sample obtained with NaOH at 0.2 mol/L. The sample prepared with this condition presented the better properties to be used as magnetic tracer in clinical diagnoses combining small mean crystallite size, low microstrain, which resulted in materials with higher magnetic saturation and high surface charge under blood pH.

Safety of everolimus plus exemestane in patients with hormone-receptor-positive, HER2-negative locally advanced or metastatic breast cancer: results of phase IIIb BALLET trial in Spain.

BACKGROUND: Everolimus with exemestane has shown promising activity in patients with hormone-receptor (HR)-positive HER2-negative endocrine-resistant advanced breast cancer. It is necessary, therefore, to characterize the safety profile of this new combination in the real-world clinical setting and in the broadest possible population. PATIENTS AND METHODS: Post-menopausal women with HR-positive HER2-negative advanced breast cancer progressing after prior non-steroidal aromatase inhibitors (NSAIs) were included. The objectives of this analysis were to evaluate the safety profile of this combination in a subset of Spanish patients in the BALLET trial and to characterize grade 3 and 4 adverse events (AEs) in routine clinical practice in Spain. RESULTS: Between September 2012 and July 2013, 429 patients (20% of the overall study population) were included in the BALLET study in 52 hospitals in Spain, of whom 100 (23%) were ≥ 70 years. The median treatment duration was 3.14 and 3.03 months for exemestane and everolimus, respectively. The most common reasons for discontinuation of treatment were local reimbursement of everolimus (43%), followed by disease progression (31%) and the incidence of AEs (15%). The most frequent AEs causing permanent discontinuation were pneumonitis (4%), asthenia (2%) and stomatitis (2%). Overall, 87% of patients experienced at least one AE of any grade, 30% of patients at least one grade 3 AE and 2% of patients a grade 4 AE. CONCLUSION: The safety profile in Spanish patients of the BALLET trial is consistent with the results obtained in the overall population of the trial, as well as in previous clinical trials.

Raman and Infrared spectroscopies and X-ray diffraction data on bupivacaine and ropivacaine complexed with 2-hydroxypropyl-ß-cyclodextrin.

The data presented in this article are related to the research article entitled "Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations (http://dx.doi.org/10.1016/j.ijpharm.2017.03.051)" (Martins et al., 2017) [1]. This work shows the molecular and structural behavior of the local anesthetics (LAs) bupivacaine (BVC, C18H28N2O) and ropivacaine (RVC, C17H26N2O) before and after complexation with the water-soluble oligosaccharide 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD).

Probing the dynamics of complexed local anesthetics via neutron scattering spectroscopy and DFT calculations.

Since potential changes in the dynamics and mobility of drugs upon complexation for delivery may affect their ultimate efficacy, we have investigated the dynamics of two local anesthetic molecules, bupivacaine (BVC, C18H28N2O) and ropivacaine (RVC, C17H26N2O), in both their crystalline forms and complexed with water-soluble oligosaccharide 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD). The study was carried out by neutron scattering spectroscopy, along with thermal analysis, and density functional theory computation. Mean square displacements suggest that RVC may be less flexible in crystalline form than BVC, but both molecules exhibit very similar dynamics when confined in HP-ß-CD. The use of vibrational analysis by density functional theory (DFT) made possible the identification of molecular modes that are most affected in both molecules by insertion into HP-ß-CD, namely those of the piperidine rings and methyl groups. Nonetheless, the somewhat greater structure in the vibrational spectrum at room temperature of complexed RVC than that of BVC, suggests that the effects of complexation are more severe for the latter. This unique approach to the molecular level study of encapsulated drugs should lead to deeper understanding of their mobility and the respective release dynamics.

Common variants associated with changes in levels of circulating free fatty acids after administration of glucose-insulin-potassium (GIK) therapy in the IMMEDIATE trial.

Glucose-insulin-potassium (GIK) therapy may promote a shift from oxygen-wasteful free fatty acid (FFA) metabolism to glycolysis, potentially reducing myocardial damage during ischemia. Genetic variation associated with FFA response to GIK was investigated in an IMMEDIATE (Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency care) sub-study (n=117). In patients with confirmed acute coronary syndromes, associations between 132 634 variants and 12-h circulating FFA response were assessed. Between initial and 6-h measurements, three LINGO2 variants were associated with increased levels of total FFA (P-value for 2 degree of freedom test, P2df ⩽5.51 × 10-7). Lead LINGO2 single-nucleotide polymorphism, rs12003487, was nominally associated with reduced 30-day ejection fraction (P2df=0.03). Several LINGO2 signals were linked to alterations in epigenetic profile and gene expression levels. Between 6 and 12 h, rs7017336 nearest to IMPA1/FABP12 showed an association with decreased saturated FFAs (P2df=5.47 × 10-7). Nearest to DUSP26, rs7464104 was associated with a decrease in unsaturated FFAs (P2df=5.51 × 10-7). Genetic variation may modify FFA response to GIK, potentially conferring less beneficial outcomes.

[Value of plasma C-reactive protein and lactate dehydrogenase levels in the diagnosis of intestinal obstruction in an emergency department]. / Proteína C reactiva y lactato deshidrogenasa en el diagnóstico de la obstrucción intestinal en un servicio de urgencias.

BACKGROUND: Intestinal obstruction is one of the most frequent surgical emergencies. Its diagnosis is essentially based on clinical history, physical exploration and image tests. The aim of this study was to analyze the diagnostic value of acute phase reactants in patients with benign versus malign intestinal obstruction. METHOD: Historical cohort study of 53 patients who underwent surgery because of intestinal obstruction and/or non-obstructive colorectal cancer. The patients were placed in three groups: group 1 (colorectal cancer with intestinal obstruction) (n=23), group 2 (benign intestinal obstruction)(n=10) and group 3 (non-obstructive cancer of the colon)(n=20). We determined the initial plasma values of the C-reactive protein (CRP) and the lactate dehydrogenase (LDH)enzyme. RESULTS: CRP was quantitatively higher in patients with benign intestinal obstruction (group 2) (p=0.001), while LDH was quantitatively higher in group 1 (patients with obstructive cancer). The plasma levels of LDH were significantly greater in the groups with intestinal obstruction (groups 1 and 2) than in patients without obstruction (p<0.001). Plasma levels of CRP above 11 mg/l and of LDH above 317 U/L showed an acceptable diagnostic value for differentiating patients with intestinal obstruction, with areas under the ROC curve of 80% (CI 95% = 68-92%) and 86% (CI 95%= 75-96%)respectively. Their diagnostic value for differentiating benign or malign origin is lower, with areas under the ROC curve of 56% for levels of CRP > 24 ng/l (CI 95% = 30-82%) and 52% (CI 95% = 29-74%) for levels of LDH > 359 U/L. CONCLUSION: Determination of plasma concentrations of CRP can help in the diagnosis of intestinal obstruction and indicate its benign or malign origin in emergency services.

Restricted mobility of specific functional groups reduces anti-cancer drug activity in healthy cells.

The most common cancer treatments currently available are radio- and chemo-therapy. These therapies have, however, drawbacks, such as, the reduction in quality of life and the low efficiency of radiotherapy in cases of multiple metastases. To lessen these effects, we have encapsulated an anti-cancer drug into a biocompatible matrix. In-vitro assays indicate that this bio-nanocomposite is able to interact and cause morphological changes in cancer cells. Meanwhile, no alterations were observed in monocytes and fibroblasts, indicating that this system might carry the drug in living organisms with reduced clearance rate and toxicity. X-rays and neutrons were used to investigate the carrier structure, as well as to assess the drug mobility within the bio-nanocomposite. From these unique data we show that partial mobility restriction of active groups of the drug molecule suggests why this carrier design is potentially safer to healthy cells.

Decoy receptors block TRAIL sensitivity at a supracellular level: the role of stromal cells in controlling tumour TRAIL sensitivity.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a death ligand cytokine known for its cytotoxic activity against malignantly transformed cells. TRAIL induces cell death through binding to death receptors DR4 and DR5. The inhibitory decoy receptors (DcR1 and DcR2) co-expressed with death receptor 4 (DR4)/DR5 on the same cell can block the transmission of the apoptotic signal. Here, we show that DcRs also regulate TRAIL sensitivity at a supracellular level and thus represent a mechanism by which the microenvironment can diminish tumour TRAIL sensitivity. Mathematical modelling and layered or spheroid stroma-extracellular matrix-tumour cultures were used to model the tumour microenvironment. By engineering TRAIL to escape binding by DcRs, we found that DcRs do not only act in a cell-autonomous or cis-regulatory manner, but also exert trans-cellular regulation originating from stromal cells and affect tumour cells, highlighting the potent inhibitory effect of DcRs in the tumour tissue and the necessity of selective targeting of the two death-inducing TRAIL receptors to maximise efficacy.

Effect of biotic and abiotic factors on diversity patterns of anthophyllous insect communities in a tropical mountain forest.

The determinants of diversity are a central issue in ecology, particularly in Andean forests that are known to be a major diversity hotspot for several taxa. We examined the effect of abiotic (elevation and precipitation) and biotic (flowering plant diversity) factors considered to be decisive causal factors of diversity patterns on anthophyllous insect communities on mountain forest. Sampling was carried out in 100-m transects at eight elevational levels and during a period of 8 months. All flowering plants in the understory and their flowering visitors were recorded. Species richness and diversity were estimated for each elevation and month. Diversity of flowering plants, elevation, and precipitation were used as independent variables in multiple regressions against insect diversity. The evaluated abiotic and biotic factors had contrasting effects on insect diversity: a significant decrease on insect diversity occurred at high elevation and dry months (i.e., threshold effect), while it showed a positive relationship with flowering plant diversity through time (i.e., linear effect), but not along elevation. Rapid turnover of species of both interacting guilds was observed every 100-m altitude and month. Local insect communities were also divided functionally depending on the plant family they visit. These results indicate that each insect community is distinctive among elevations and months and that diversity of flowering plants, precipitation, and elevation influence their structure and composition. Thus, conservation strategies should involve protection of forest cover at the whole elevation gradient, in order to preserve common and exclusive components of diversity and consequently, the mosaic of plant-pollinator interactions.

Enhancing the versatility of alternate current biosusceptometry (ACB) through the synthesis of a dextrose-modified tracer and a magnetic muco-adhesive cellulose gel.

Alternate Current Biosusceptometry (ACB) is a promising bio-magnetic method, radiation free and easily performed used for gastric emptying exams. Due to development on its sensitivity level, interesting nature, noninvasiveness and low cost it has attracted a lot of attention. In this work, magnetic nanoparticles of Mn-Zn ferrite as well as dextrose-modified nanoparticles were synthesized to be used as possible tracers in ACB gastric emptying exams. In addition, a magnetic muco-adhesive gel was obtained by modifying the ferrite nanoparticles with cellulose. Based on in-vivo tests in rats, we show that the pure ferrite nanoparticles, whose isoelectric point was found to be at pH=3.2, present a great sensitivity to pH variations along the gastrointestinal tract, while the reduction of the isoelectric point by the dextrose modification leads to suitable nanoparticles for rapid gastric emptying examinations. On the other hand, the in-vivo tests show that the muco-adhesive cellulose gel presents substantial stomach adhesion and is a potential drug delivery system easily traceable by the ACB system.

Comparative study of the bioconversion process using R-(+)- and S-(-)-limonene as substrates for Fusarium oxysporum 152B.

This study compared the bioconversion process of S-(-)-limonene into limonene-1,2-diol with the already established biotransformation of R-(+)-limonene into α-terpineol using the same biocatalyst in both processes, Fusarium oxysporum 152B. The bioconversion of the S-(-)-isomer was tested on cell permeabilisation under anaerobic conditions and using a biphasic system. When submitted to permeabilisation trials, this biocatalyst has shown a relatively high resistance; still, no production of limonene-1,2-diol and a loss of activity of the biocatalyst were observed after intense cell treatment, indicating a complete loss of cell viability. Furthermore, the results showed that this process can be characterised as an aerobic system that was catalysed by limonene-1,2-epoxide hydrolase, had an intracellular nature and was cofactor-dependent because the final product was not detected by an anaerobic process. Finally, this is the first report to characterise the bioconversion of R-(+)- and S-(-)-limonene by cellular detoxification using ultra-structural analysis.

Genetic and metabolic engineering of microorganisms for the development of new flavor compounds from terpenic substrates.

Throughout human history, natural products have been the basis for the discovery and development of therapeutics, cosmetic and food compounds used in industry. Many compounds found in natural organisms are rather difficult to chemically synthesize and to extract in large amounts, and in this respect, genetic and metabolic engineering are playing an increasingly important role in the production of these compounds, such as new terpenes and terpenoids, which may potentially be used to create aromas in industry. Terpenes belong to the largest class of natural compounds, are produced by all living organisms and play a fundamental role in human nutrition, cosmetics and medicine. Recent advances in systems biology and synthetic biology are allowing us to perform metabolic engineering at the whole-cell level, thus enabling the optimal design of microorganisms for the efficient production of drugs, cosmetic and food additives. This review describes the recent advances made in the genetic and metabolic engineering of the terpenes pathway with a particular focus on systems biotechnology.