Ventilatory Pattern Influences Tolerance to Normobaric Hypoxia in Healthy Adults.

INTRODUCTION: Tolerance to breathing in conditions with a decreased oxygen ratio is subject-specific. A normobaric hypoxia tolerance test (NHTT) is performed to assess the ability of each individual, as this may be influenced by genetic or personal factors such as age or gender. The aim of this study is to test the influence of deep breathing on hypoxia tolerance time. MATERIAL AND METHODS: A total of 45 subjects (21 parachutists and 24 students) performed two NHTTs at 5050 m altitude (iAltitude). Arterial (SatO2) and muscle (SmO2) oxygen saturation were monitored with the Humon Hex® device. The first NHTT was performed with free breathing, without any instructions; and the second NHTT was performed with wide, slow, diaphragmatic breathing. The NHTT was terminated at the end of 10 min or when a value of less than 83% was obtained. RESULTS: The first NHTT was completed by 38.1% of parachutist and 33.3% of students while the second NHTT was completed by 85.7% and 75%, respectively. In the second NHTT, both parachutists and students had a significantly (p = 0.001) longer duration compared to the first NHTT. SmO2 and SatO2 values also increased significantly (p < 0.001) in both groups (p < 0.05). CONCLUSION: Performing controlled diaphragmatic breathing is successful in increasing hypoxia tolerance time and/or SatO2 values.

Unusually High Affinity of the PLK Inhibitors RO3280 and GSK461364 to HSA and Its Possible Pharmacokinetic Implications.

The binding processes of two Polo-like kinase inhibitors, RO3280 and GSK461364, to the human serum albumin (HSA) protein as well as the protonation equilibria of both compounds have been studied combining absorbance and fluorescence spectroscopy experiments together with density functional theory calculations. We found that the charge states of RO3280 and GSK461364 are +2 and +1, respectively, at the physiological pH. Nevertheless, RO3280 binds to HSA in the charge state +1 prior to a deprotonation pre-equilibrium. Binding constants to site I of HSA of 2.23 × 106 and 8.80 × 104 M-1 were determined for RO3280 and GSK461364, respectively, at 310 K. The binding processes of RO3280 and GSK461364 to HSA are entropy- and enthalpy-driven, respectively. The positive enthalpy found for the RO3280-HSA complex formation could be related to a proton pre-equilibrium of RO3280.

Opinions of nurses regarding Euthanasia and Medically Assisted Suicide.

BACKGROUND: Safeguarding the right to die according to the principles of autonomy and freedom of each person has become more important in the last decade, therefore increasing regulation of Euthanasia and Medically Assisted Suicide (MAS). AIMS: To learn the opinions that the nurses of the autonomous region of Madrid have regarding Euthanasia and Medically Assisted Suicide. RESEARCH DESIGN: Cross-sectional descriptive study. PARTICIPANTS AND RESEARCH CONTEXT: All registered nurses in Madrid. The study was done by means of a self-completed anonymous questionnaire. The variables studied were social-demographic, giving opinions about Euthanasia and MAS. ETHICAL CONSIDERATIONS: Each participant was assured maximum confidentiality and anonymity, ensuring the ethical principles set out in the Declaration of Helsinki, as well as in the Organic Law 3/2018, on Personal Data Protection and guarantee of digital rights. FINDINGS: A total of 489 nurses answered the questionnaire. In total, 75.7% of the nurses confirmed that Euthanasia should be regulated in Spain. 66.3% indicated that information on Euthanasia should be provided jointly by doctors and nurses, and 42.3% considered that it could be applied by both medical and nursing professionals. A total of 87.2% advocated the participation of nurses in health policy, influencing the drafting of the law. In the face of possible regulation, 35% would request Conscientious Objection, being closely related to their religious beliefs. DISCUSSION: Different authors point out that nurses' perceptions and attitudes towards Euthanasia are conditioned by different factors, such as religion, gender, poor palliative care, legality and the patient's right to die. CONCLUSION: Nurses are positioned in favour of the regulation and practice of Euthanasia and MAS, depending on their age, years of experience, training, model of care and especially religious beliefs.

Kinetics of CF3CH2OCH3 (HFE-263fb2), CHF2CF2CH2OCH3 (HFE-374pcf), and CF3CF2CH2OCH3 (HFE-365mcf3) with OH radicals, IR absorption cross sections, and global warming potentials.

Hydrofluoroethers (HFEs), such as CF3CH2OCH3 (HFE-263fb2), CHF2CF2CH2OCH3 (HFE-374pcf), and CF3CF2CH2OCH3 (HFE-365mcf3), have been proposed in the last few decades as the third-generation replacements for perfluorocarbons (PFCs) and hydrofluorocarbons (HFCs) because of their zero stratospheric ozone depletion potentials and relatively low global warming potentials (GWPs). These GWPs depend on the radiative efficiency (RE) and the atmospheric lifetime (τOH) of HFEs due to the reaction with hydroxyl (OH) radicals. The temperature and pressure dependencies of the OH-rate coefficient (kOH(T)) for HFE-263fb2, HFE-374pcf, and HFE-365mcf3 are not known. Therefore, in this paper, we present the first study on the temperature (263-353 K) and pressure (50-500 torr of helium) dependence of kOH(T) for the titled HFEs. No pressure dependence of kOH(T) was observed in the investigated range. From kOH(298 K), estimated τOH are 17 days (for HFE-263fb2), 12 days (for HFE-374pcf), and 13 days (for HFE-365mcf3). The observed T-dependencies of kOH(T) (in cm3 molecule-1 s-1) are well described by (3.88 ± 0.89) × 10-12 exp[-(508 ± 69)/T] for HFE-263fb2, (2.81 ± 0.33) × 10-12 exp[-(312 ± 35)/T] for HFE-374pcf, and (2.60 ± 0.31) × 10-12 exp[-(319 ± 35)/T] for HFE-365mcf3. A correlation between log kOH(298 K) and the activation energy (Ea) of the process is presented, allowing the prediction of Ea for OH-reactions with other HFEs, exclusively investigated at room temperature. In addition to the kinetic measurements, the infrared absorption cross sections of HFE-263fb2, HFE-374pcf, and HFE-365mcf3 were determined between 520 and 3100 cm-1. Lifetime corrected REs and GWPs relative to CO2 at 100 years' time horizon were reexamined. The impact of the investigated HFEs on the radiative forcing of climate change would be negligible.

Shedding light on the binding mechanism of kinase inhibitors BI-2536, Volasetib and Ro-3280 with their pharmacological target PLK1.

In the present work, the interactions of the novel kinase inhibitors BI-2536, Volasetib (BI-6727) and Ro-3280 with the pharmacological target PLK1 have been studied by fluorescence spectroscopy and molecular dynamics calculations. High Stern-Volmer constants were found in fluorescence experiments suggesting the formation of stable protein-ligand complexes. In addition, it was observed that the binding constant between BI-2536 and PLK1 increases about 100-fold in presence of the phosphopeptide Cdc25C-p that docks to the polo box domain of the protein and releases the kinase domain. All the determined binding constants are higher for the kinase inhibitors than for their competitor for the active center (ATP) being BI-2536 and Volasertib the inhibitors that showed more affinity for PLK1. Calculated binding free energies confirmed the higher affinity of PLK1 for BI-2536 and Volasertib than for ATP. The higher affinity of the inhibitors to PLK1 compared to ATP was mainly attributed to stronger van der Waals interactions. Results may help with the challenge of designing and developing new kinase inhibitors more effective in clinical cancer therapy.

Novel Fluorescence Guanidine Molecules for Selective Sulfate Anion Detection in Water Complex Samples over a Wide pH Range.

Quantitative analysis of sulfate anions in water still remains an important challenge for the society. Among all the methodologies, the most successful one is based on optical supramolecular receptors because the presence of small concentrations of sulfate anion modifies the photophysical properties of the receptor. In this case, fluorescence anion sensors have been designed by the incorporation of guanidine motifs into fluorenyl cores. The photophysical behaviors of the new mono- (M) and bis-guanidine (B) derivatives were studied through pH dependence, solvent effects, and ion sensing on steady-state spectra and time-resolved fluorescence spectroscopy. In more detail, the results demonstrate that M is a highly selective and sensitive sulfate ion receptor in real water samples and, even more importantly, its function remains unchanged at different ranges of pH. The reason behind this resides on the fluorescence quenching produced by an internal charge-transfer process when the sulfate anion is complexed with M. It is worth noting that the global and partial affinity constants (1010 M-2 and 105 M-1, respectively) of complex formation are far above from the current sulfate sensors in water (104 M-1) which give an LOD of 0.10 µM in water with an analytical range of 2.5-10 µM. On the other hand, although it would seem, at first sight, that the B derivate will be the most promising one, the possibility of having two simultaneous protonation states reduces the complex formation and, therefore, its sensitivity to sulfate anions. The results presented here offer the possibility of using a new molecule in water environments, which opens the door to infinite applications such as the detection of trace amounts of sulfate ions in food or water.

Gas-Phase Reaction of trans-2-Methyl-2-butenal with Cl: Kinetics, Gaseous Products, and SOA Formation.

The gas-phase reaction between trans-2-methyl-2-butenal and chlorine (Cl) atoms has been studied in a simulation chamber at 298 ± 2 K and 760 ± 5 Torr of air under free-NOx conditions. The rate coefficient of this reaction was determined as k = (2.45 ± 0.32) × 10-10 cm3 molecule-1 s-1 by using a relative method and Fourier transform infrared spectroscopy. In addition to this technique, gas chromatography coupled to mass spectrometry and proton transfer time-of-flight mass spectrometry were used to detect and monitor the time evolution of the gas-phase reaction products. The major primary reaction product from the addition of Cl to the C-3 of trans-2-methyl-2-butenal was 3-chloro-2-butanone, with a molar yield (YProd) of (52.5 ± 7.3)%. Acetaldehyde (Y = (40.8 ± 0.6)%) and HCl were also identified, indicating that the H-abstraction by Cl from the aldehyde group is a reaction pathway as well. Secondary organic aerosol (SOA) formation was investigated by using a fast mobility particle sizer spectrometer. The SOA yield in the Cl + trans-2-methyl-2-butenal reaction is reported to be lower than 2.4%, thus its impact can be considered negligible. The atmospheric importance of the titled reaction is similar to the corresponding OH reaction in areas with high Cl concentration.

Gas-phase kinetics of CH3CHO with OH radicals between 11.7 and 177.5 K.

Gas-phase reactions in the interstellar medium (ISM) are a source of molecules in this environment. The knowledge of the rate coefficient for neutral-neutral reactions as a function of temperature, k(T), is essential to improve astrochemical models. In this work, we have experimentally measured k(T) for the reaction between the OH radical and acetaldehyde, both present in many sources of the ISM. Laser techniques coupled to a CRESU system were used to perform the kinetic measurements. The obtained modified Arrhenius equation is k(T = 11.7-177.5 K) = (1.2 ± 0.2) × 10-11 (T/300 K)-(1.8±0.1) exp-{(28.7 ± 2.5)/T} cm3 molecule-1 s-1. The k(T) value of the title reaction has been measured for the first time below 60 K. No pressure dependence of k(T) was observed at ca. 21, 50, 64 and 106 K. Finally, a pure gas-phase model indicates that the title reaction could become the main CH3CO formation pathway in dark molecular clouds, assuming that CH3CO is the main reaction product at 10 K.

Functionalized CdSe/ZnS Quantum Dots for Intracellular pH Measurements by Fluorescence Lifetime Imaging Microscopy.

pH is an important biomarker for many human diseases and great efforts are being made to develop new pH probes for bioimaging and biomedical applications. Here, the use of three different CdSe/ZnS QDs, functionalized with d-penicillamine and small peptides, as pH probes for fluorescence lifetime imaging microscopy (FLIM) is investigated. The fluorescence pH sensitivity of the nanoparticles is analyzed in different experimental media: aqueous solution, synthetic intracellular medium, and mesenchymal C3H10T1/2 and tumoral SK-MEL-2 cell lines. Different experiments along with theoretical calculations are conducted to unravel the mechanisms causing pH sensitivity of the nanoparticles and the effect of the length and composition of the peripheral branches on their photophysical properties. Absolute intracellular pH values measured in live cells with FLIM using a fluorescent probe based on a QD are reported here for the first time (intracellular pH values of 7.0 and 7.1 for C3H10T1/2 and SK-MEL-2 cells, respectively). These fluorescent nanoprobes can also be used to distinguish between different types of cells in cocultures on the basis of their different fluorescence lifetimes in dissimilar intracellular environments.

The role of water and influence of hydrogen bonding on the self-assembly aggregation induced emission of an anthracene-guanidine-derivative.

We report a luminescent anthracene-guanidine derivative that forms rare T-shape dimers, resulting in an excimer with a quantum yield approaching one. Water plays a fundamental role through H-bonding guiding the self-assembly. These results establish a new framework for environmentally friendly aggregation-induced emission luminogens.

Experimental and theoretical investigation on the OH + CH3C(O)CH3 reaction at interstellar temperatures (T=11.7-64.4 K).

The rate coefficient, k(T), for the gas-phase reaction between OH radicals and acetone CH3C(O)CH3, has been measured using the pulsed CRESU (French acronym for Reaction Kinetics in a Uniform Supersonic Flow) technique (T = 11.7-64.4 K). The temperature dependence of k(T = 10-300 K) has also been computed using a RRKM-Master equation analysis after partial revision of the potential energy surface. In agreement with previous studies we found that the reaction proceeds via initial formation of two pre-reactive complexes both leading to H2O + CH3C(O)CH2 by H-abstraction tunneling. The experimental k(T) was found to increase as temperature was lowered. The measured values have been found to be several orders of magnitude higher than k(300 K). This trend is reproduced by calculations, with a special good agreement with experiments below 25 K. The effect of total gas density on k(T) has been explored. Experimentally, no pressure dependence of k(20 K) and k(64 K) was observed, while k(50 K) at the largest gas density 4.47×1017 cm-3 is twice higher than the average values found at lower densities. The computed k(T) is also reported for 103 cm-3 of He (representative of the interstellar medium). The predicted rate coefficients at 10 K surround the experimental value which appears to be very close to the low pressure regime prevailing in the interstellar medium. For gas-phase model chemistry of interstellar molecular clouds, we suggest using the calculated value of 1.8×10-10 cm3 molecule-1 s-1 at 10 K and the reaction products are water and CH3C(O)CH2 radicals.

Gas-phase reactivity of CH3OH toward OH at interstellar temperatures (11.7-177.5 K): experimental and theoretical study.

The reactivity of methanol (CH3OH) toward the hydroxyl (OH) radical was investigated in the temperature range 11.7-177.5 K using the CRESU (French acronym for Reaction Kinetics in a Uniform Supersonic Flow) technique. In the present study, the temperature dependence of the rate coefficient for the OH + CH3OH reaction, k(T), has been revisited and additional experimental and computational data are reported. New kinetic measurements were performed to fill the existing gaps (<22 K, 22-42 K and 88-123 K), reporting k(T < 20 K) for the first time. The lowest temperature ever achieved by a pulsed CRESU has been obtained in this work (11.7 K). k(T) abruptly increases by almost 2 orders of magnitude from 177.5 K to around 100 K. At T < 100 K, this increase is less pronounced, reaching the capture limit at temperatures below 22 K. The pressure dependence of k(T) has been investigated for selected temperatures and gas densities (1.5 × 1016 to 4.3 × 1017 cm-3), combining our results with those previously reported. No dependence was observed within the experimental uncertainties below 110 K. The high- and low-pressure rate coefficients, kHPL(T) and kLPL(T), were also studied in detail using high-level quantum chemical and theoretical kinetic methodologies, closely reproducing the experimental data between 20 and 400 K. The results suggest that the experimental data are near the high pressure limit at the lowest temperatures, but that the reaction remains a fast and effective source of CH2OH and CH3O at the low pressures and temperatures prevalent in the interstellar medium.

Assessment of doxorubicin delivery devices based on tailored bare polycaprolactone against glioblastoma.

Bare polycaprolactones with controlled molar mass and dispersity were employed to manufacture biodegradable devices, which were applied for doxorubicin delivery in glioblastoma. Micro- and nanoscale devices were prepared by emulsion formation or by a combination of precipitation and hydrolysis. The carriers were characterized by scanning electron microscopy, dynamic light scattering techniques, thermogravimetric analysis and differential scanning calorimetry. The encapsulation parameters and drug-release profiles are discussed in order to evaluate the influence of different fundamental parameters, such as molar mass and dispersity value, pH, morphology or crystallinity, on the efficiency of the doxorubicin delivery systems. The ability of doxorubicin-loaded micro- and nanoscale devices to induce cellular toxicity in glioblastoma cells was also explored. A cell viability assay against C6 cells of doxorubicin-loaded nanocarriers showed higher cytotoxicity than doxorubicin-loaded microcarriers. In addition, doxorubicin-loaded nanocarriers also showed good antitumor profile in human tumoral cells and improved the security profile in relation to free doxorubicin in non-tumoral cells. Consistent with the assessment study described in this manuscript, the results provide a proof of concept for the suitability of the approach, based on bare polycaprolactone, to local controlled-sustained release of doxorubicin for the treatment of glioblastoma.

Atmospheric Chemistry of E- and Z-CF3CH═CHF (HFO-1234ze): OH Reaction Kinetics as a Function of Temperature and UV and IR Absorption Cross Sections.

We report here the rate coefficients for the OH reactions (kOH) with E-CF3CH═CHF and Z-CF3CH═CHF, potential substitutes of HFC-134a, as a function of temperature (263-358 K) and pressure (45-300 Torr) by pulsed laser photolysis coupled to laser-induced fluorescence techniques. For the E-isomer, the existing discrepancy among previous results on the T dependence of kOH needs to be elucidated. For the Z-isomer, this work constitutes the first absolute determination of kOH. No pressure dependence of kOH was observed, while kOH exhibits a non-Arrhenius behavior: kOH(E) = [Formula: see text] and kOH(Z) = [Formula: see text] cm3 molecule-1 s-1, where uncertainties are 2σ. UV absorption cross sections, σλ, are reported for the first time. From σλ and considering a photolysis quantum yield of 1, an upper limit for the photolysis rate coefficients and lifetimes due to this process in the troposphere are estimated: 3 × 10-8 s-1 and >1 year for the E-isomer and 2 × 10-7 s-1 and >2 months for Z-CF3CH═CHF, respectively. Under these conditions, the overall estimated tropospheric lifetimes are 15 days (for the E-isomer) and 8 days (for the Z-isomer), the major degradation pathway being the OH reaction, with a contribution of the photolytic pathway of less than 3% (for E) and 13% (for Z). IR absorption cross sections were determined both experimentally (500-4000 cm-1) and theoretically (0-2000 cm-1). From the theoretical IR measurements, it is concluded that the contribution of the 0-500 cm-1 region to the total integrated cross sections is appreciable for the E-isomer (9%) but almost negligible for the Z-isomer (0.5%). Nevertheless, the impact on their radiative efficiency and global warming potential is negligible.

Binding of the anticancer drug BI-2536 to human serum albumin. A spectroscopic and theoretical study.

BI-2536 is a potent Polo-like kinase inhibitor which induces apoptosis in diverse human cancer cell lines. The binding affinity of BI-2536 for human serum albumin (HSA) protein may define its pharmacokinetic and pharmacodynamic profile. We have studied the binding of BI-2536 to HSA by means of different spectroscopic techniques and docking calculations. We have experimentally observed that the affinity of BI-2536 for HSA is higher than that of other common HSA binding drugs. Therefore, it can be postulated that the drug dose should be increased to achieve a certain concentration of free drug in plasma, although BI-2536 could also reach tumour tissues by uptaking HSA/BI-2536 complex. Only a single binding site on HSA has been observed for BI-2536 which seems to correspond to the subdomain IIA pocket. The formation of the HSA/BI-2536 complex is a spontaneous and entropy-driven process that does not cause a significant change of the secondary structure of the protein. Its endothermic character could be related to proton release. Thermodynamic analysis showed that the main protein-drug interactions are of the van der Waals type although the presence of amide and ether groups in BI-2536 could also allow H-bonding with some residues in the subdomain IIA pocket.

Atmospheric fate of hydrofluoroolefins, CxF2x+1CHCH2 (x = 1,2,3,4 and 6): Kinetics with Cl atoms and products.

Rate coefficients for the gas-phase reactions of CxF2x+1CHCH2 (x = 1, 2, 3, 4 and 6) with Cl atoms were determined at (298 ± 2) K and (710 ± 5) Torr of air using a relative rate technique. Two experimental setups with simulation chambers were employed with Fourier Transform Infrared (FTIR) spectroscopy and Gas Chromatography coupled to Mass Spectrometry (GC-MS) as detection techniques. The Cl-rate coefficients obtained were (in 10-10 cm3 molecule-1 s-1): (0.85 ± 0.11) for CF3CHCH2, (1.11 ± 0.08) for C2F5CHCH2, (1.12 ± 0.18) for C3F7CHCH2, (0.97 ± 0.09) for C4F9CHCH2, and (0.99 ± 0.08) for C6F13CHCH2. Additionally, the gas-phase products were identified and quantified, when possible, by FTIR spectroscopy or GC-MS. The main reaction product was reported to be CxF2x+1C(O)CH2Cl. The fluorinated species, CxF2x+1CHO and CxF2x+1C(O)CH2Cl, were identified. CF3C(O)CH2Cl and CF3CHO were found to be formed with molar yield of (69 ± 5)% and (9 ± 1)%, respectively. The global lifetime of the investigated CxF2x+1CHCH2 due to their Cl-reaction is more than 100 days so this route does not compete with the removal by OH radicals. This lifetime is long enough for CxF2x+1CHCH2 to be transported to remote areas where they can be degraded. However, at a local scale, in marine regions at dawn the removal of CxF2x+1CHCH2 is expected to occur in ca. 1 day. The atmospheric degradation of these hydrofluoroolefins by Cl atoms is not expected to be a source of bioaccumulative perfluorinated carboxylic acids, CxF2x+1C(O)OH. Additionally, the UV absorption cross sections of CF3C(O)CH2Cl were determined together with the rate coefficient of the OH reaction by an absolute kinetic method at room temperature.

Synthesis, characterization, DNA interactions and antiproliferative activity on glioblastoma of iminopyridine platinum(II) chelate complexes.

A series of iminopyridine platinum chelate compounds has been prepared and characterized by NMR spectroscopy and single-crystal X-ray diffraction. The complexes were evaluated in C6 tumoral cells as an in vitro model for glioblastoma multiforme. The DNA-binding properties of these complexes were studied by UV-Vis absorption and fluorescence spectroscopy and Density Functional Theory calculations were performed in an effort to rationalize the observed properties at the molecular level. The most promising drug candidate displayed a similar potency in inducing cell death to the clinically used reference compound and showed significant inhibition of glioblastoma cell proliferation. Moreover, this compound had a safer profile than cisplatin on non-tumoral cells.

Tris(pentafluorophenyl)borane as an efficient catalyst in the guanylation reaction of amines.

Tris(pentafluorophenyl)borane, [B(C6F5)3], has been used as an efficient catalyst in the guanylation reaction of amines with carbodiimide under mild conditions. A combined approach involving NMR spectroscopy and DFT calculations was employed to gain a better insight into the mechanistic features of this process. The results allowed us to propose a new Lewis acid-assisted Brønsted acidic pathway for the guanylation reaction. The process starts with the interaction of tris(pentafluorphenyl)borane and the amine to form the corresponding adduct, [(C6F5)3B-NRH2] , followed by a straightforward proton transfer to one of the nitrogen atoms of the carbodiimide, (i)PrN[double bond, length as m-dash]C[double bond, length as m-dash]N(i)Pr, to produce, in two consequent steps, a guanidine-borane adduct, [(C6F5)3B-NRC(N(i)PrH)2] . The rupture of this adduct liberates the guanidine product RNC(N(i)PrH)2 and interaction with additional amine restarts the catalytic cycle. DFT studies have been carried out in order to study the thermodynamic characteristics of the proposed pathway. Significant borane adducts with amines and guanidines have been isolated and characterized by multinuclear NMR in order to study the N-B interaction and to propose the existence of possible Frustrated Lewis Pairs. Additionally, the molecular structures of significant components of the catalytic cycle, namely 4-tert-butylaniline-[B(C6F5)3] adduct and both free and [B(C6F5)3]-bonded 1-(phenyl)-2,3-diisopropylguanidine, and respectively, have been established by X-ray diffraction.