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Carbon nanostructures-silica aerogel composites were synthesized and characterized to assess the effect of carbon nanotubes (CNTs) or graphene oxide (GO) on the silica aerogel properties. The sol-gel chemistry was based on methyltrimethoxysilane (MTMS) and 3-aminopropyltrimethoxysilane (APTMS) as silica precursor system, with varying amounts of APTMS (0–20% mol of Si). APTMS significantly impacted the materials' physical properties. The chemistry and microstructure were investigated by FTIR, NMR, TEM, SEM, SAXS and BET. The addition of CNTs induced the growth of the silica matrix around them; thus, an elongated shape was observed in the silica structural units. APTMS and CNTs have a synergistic effect on the mechanical properties, increasing the Young's modulus up to 14 MPa. Small amounts of carbon materials (∼1 wt%) in the MTMS-matrix improved its thermal insulation property, particularly for temperatures above 50 °C. In terms of electrochemical properties, the carbon nanostructures lead to higher specific capacitances and a reduction in resistance. The characterizations here performed allowed a better understanding of the interactions between the silica and carbon phases. The possibility to obtain materials with tailored properties demonstrates their application potential in several areas, such as thermal insulation and energy storage.

Background and Purpose— The TST trial (Treat Stroke to Target) evaluated the benefit of targeting a LDL (low-density lipoprotein) cholesterol of 4 mm, in a French and Korean population. The follow-up lasted a median of 5.3 years in French patients (similar to the median follow-up time in the SPARCL trial [Stroke Prevention by Aggressive Reduction in Cholesterol Level]) and 2.0 years in Korean patients. Exposure duration to statin is a well-known driver for cardiovascular risk reduction. We report here the TST results in the French cohort. Methods— One thousand seventy-three French patients were assigned to Results— After a median follow-up of 5.3 years, the achieved LDL cholesterol was 66 (1.69 mmol/L) and 96 mg/dL (2.46 mmol/L) on average, respectively. The primary end point occurred in 9.6% and 12.9% of patients, respectively (HR, 0.74 [95% CI, 0.57–0.94]; P =0.019). Cerebral infarction or urgent carotid revascularization following transient ischemic attack was reduced by 27% ( P =0.046). Cerebral infarction or intracranial hemorrhage was reduced by 28% ( P =0.023). The primary outcome or intracranial hemorrhage was reduced by 25% ( P =0.021). Intracranial hemorrhages occurred in 13 and 11 patients, respectively (HR, 1.17 [95% CI, 0.53–2.62]; P =0.70). Conclusions— After an ischemic stroke of documented atherosclerotic origin, targeting a LDL cholesterol of Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875.

Rituximab plus polychemotherapy is the standard of care in diffuse large B-cell lymphoma (DLBCL). GAINED, a randomized phase 3 trial, compared obinutuzumab to rituximab. Transplant-eligible patients (18-60 years) with an untreated age-adjusted International Prognostic Index (aaIPI) score ≥1 DLBCL were randomized (1:1) between obinutuzumab or rituximab and stratified by aaIPI (1; 2-3) and chemotherapy regimen (doxorubicin, cyclophosphamide, prednisone plus vindesine, bleomycin [ACVBP] or vincristine [CHOP]). Consolidation treatment was determined according to response to interim positron emission tomography (PET). Responders after cycle 2 and 4 (PET2−/PET4−) received immunochemotherapy. Responders after only cycle 4 (PET2+/4−) received transplantation. The primary objective was an 8% improvement (hazard ratio [HR] = 0.73; 80% power; α risk, 2.5%; 1-sided) in 2-year event-free survival (EFS) in the obinutuzumab arm. From September 2012, 670 patients were enrolled (obinutuzumab, n = 336; rituximab, n = 334). A total of 383 (57.2%) were aaIPI 2-3, 339 (50.6%) received CHOP. Median follow-up was 38.7 months. The 2-year EFS was similar in both groups (59.8% vs 56.6%; P = .123; HR = 0.88). The 2-year PFS in the whole cohort was 83.1% (95% confidence interval, 80% to 85.8%). PET2−/4− and PET2+/4− had similar 2-year progression-free survival (PFS) and overall survival (OS): 89.9% vs 83.9% and 94.8% vs 92.8%. The 2-year PFS and OS for PET4+ patients were 62% and 83.1%. Grade 3-5 infections were more frequent in the obinutuzumab arm (21% vs 12%). Obinutuzumab is not superior to rituximab in aaIPI ≥1 DLBCL transplant-eligible patients. This trial was registered at www.clinicaltrials.gov as #NCT01659099.

APOBEC3A (A3A) and APOBEC3B (A3B) enzymes drive APOBEC-mediated mutagenesis. Identification of factors affecting the activity of these enzymes could help modulate mutagenesis and associated clinical outcomes. Here, we show that canonical and alternatively spliced A3A and A3B isoforms produce corresponding mutagenic and non-mutagenic enzymes. Increased expression of the mutagenic A3B isoform predicted shorter progression-free survival in bladder cancer. We demonstrate that the production of mutagenic vs. non-mutagenic A3B protein isoforms was considerably affected by inclusion/skipping of exon 5 in A3B. Furthermore, exon 5 skipping, resulting in lower levels of mutagenic A3B enzyme, could be increased in vitro. Specifically, we showed the effects of treatment with an SF3B1 inhibitor affecting spliceosome interaction with a branch point site in intron 4, or with splice-switching oligonucleotides targeting exon 5 of A3B. Our results underscore the clinical role of A3B and implicate alternative splicing of A3B as a mechanism that could be targeted to restrict APOBEC-mediated mutagenesis., A. Rouf Banday et al. report targeting alternative splicing of APOBEC3B as a strategy to modulate APOBEC-mediated mutagenesis in cancers. Higher expression of the mutagenic APOBEC3B isoform predicted shorter progression-free survival in bladder cancer patients. Expression of this mutagenic isoform could be decreased by inducing skipping of APOBEC3B exon 5 in cells treated with SF3B1 inhibitor or splice-switching oligos.

International audience; The microbial communities inhabiting the Atlantic-East Pacific (AEP) mangroves have been poorly studied, and mostly comprise chronically polluted mangroves. In this study, we characterized changes in the structure and diversity of microbial communities of mangroves along the urban-to-rural gradient of the Cayenne estuary (French Guiana, South America) that experience low human impact. The microbial communities were assigned into 50 phyla. Proteobacteria, Chloroflexi, Acidobacteria, Bacteroidetes, and Planctomycetes were the most abundant taxa. The environmental determinants found to significantly correlated to the microbial communities at these mangroves were granulometry, dieldrin concentration, pH, and total carbon (TC) content. Furthermore, a precise analysis of the sediment highlights the existence of three types of anthropogenic pressure among the stations: (i) organic matter (OM) enrichment due to the proximity to the city and its wastewater treatment plant, (ii) dieldrin contamination, and (iii) naphthalene contamination. These forms of weak anthropogenic pressure seemed to impact the bacterial population size and microbial assemblages. A decrease in Bathyarchaeota, “Candidatus Nitrosopumilus”, and Nitrospira genera was observed in mangroves subjected to OM enrichment. Mangroves polluted with organic contaminants were enriched in Desulfobacteraceae, Desulfarculaceae, and Acanthopleuribacteraceae (with dieldrin or polychlorobiphenyl contamination), and Chitinophagaceae and Geobacteraceae (with naphthalene contamination). These findings provide insights into the main environmental factors shaping microbial communities of mangroves in the AEP that experience low human impact and allow for the identification of several potential microbial bioindicators of weak anthropogenic pressure.

Summary Background Topotecan is currently the only drug approved in Europe in a second-line setting for the treatment of small-cell lung cancer. This study investigated whether the doublet of carboplatin plus etoposide was superior to topotecan as a second-line treatment in patients with sensitive relapsed small-cell lung cancer. Methods In this open-label, randomised, phase 3 trial done in 38 hospitals in France, we enrolled patients with histologically or cytologically confirmed advanced stage IV or locally relapsed small-cell lung cancer, who responded to first-line platinum plus etoposide treatment, but who had disease relapse or progression at least 90 days after completion of first-line treatment. Eligible patients were aged 18 years or older and had an Eastern Cooperative Oncology Group performance status 0–2. Enrolled patients were randomly assigned (1:1) to receive combination carboplatin plus etoposide (six cycles of intravenous carboplatin [area under the curve 5 mg/mL per min] on day 1 plus intravenous etoposide [100 mg/m2 from day 1 to day 3]) or oral topotecan (2·3 mg/m2 from day 1 to day 5, for six cycles). Randomisation was done using the minimisation method with biased-coin balancing for ECOG performance status, response to the first-line chemotherapy, and treatment centre. The primary endpoint was progression-free survival, which was centrally reviewed and analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , NCT02738346 . Findings Between July 18, 2013, and July 2, 2018, we enrolled and randomly assigned 164 patients (82 in each study group). One patient from each group withdrew consent, therefore 162 patients (81 in each group) were included in the intention-to-treat population. With a median follow-up of 22·7 months (IQR 20·0−37·3), median progression-free survival was significantly longer in the combination chemotherapy group than in the topotecan group (4·7 months, 90% CI 3·9–5·5 vs 2·7 months, 2·3–3·2; stratified hazard ratio 0·57, 90% CI 0·41–0·73; p=0·0041). The most frequent grade 3–4 adverse events were neutropenia (18 [22%] of 81 patients in the topotecan group vs 11 [14%] of 81 patients in the combination chemotherapy group), thrombocytopenia (29 [36%] vs 25 [31%]), anaemia (17 [21%] vs 20 [25%]), febrile neutropenia (nine [11%] vs five [6%]), and asthenia (eight [10%] vs seven [9%]). Two treatment-related deaths occurred in the topotecan group (both were febrile neutropenia with sepsis) and no treatment-related deaths occurred in the combination group. Interpretation Our results suggest that carboplatin plus etoposide rechallenge can be considered as a reasonable second-line chemotherapy option for patients with sensitive relapsed small-cell lung cancer. Funding Amgen and the French Lung Cancer Group (Groupe Francais de Pneumo-Cancerologie).

Simultaneous adsorption of coexisting organic dyes from industrial wastewater is challenging, and the mechanisms of the coadsorption of these dyes remain unclear. Herein, renewable alginate hybridi...

Gold colloidal nanoparticles (NPs) were functionalized in acetonitrile with a Cu(I) complex consisting of one 2,2′-bipyridine ligand possessing a lipoic acid moiety and one 2,9-dimesitylene-1,10-ph...

Natural soil systems usually exhibit complex properties such as fractal geometry, resulting in complex dynamics for the movement of solutes and colloids in soils, such as the well-documented non-Fickian or anomalous diffusion for contaminant transport in saturated soils. The development of robust mathematical models to simulate anomalous diffusion for reactive contaminants at all relevant scales presents a contemporary problem in computational hydrology. This study aims to develop and validate a novel fractional derivative, advection-dispersion-reaction equation (fADRE) with first order decay to quantify nitrate contaminants transport in various soil systems. As an essential nutrient for crop growth, nitrogen in various forms (i.e., fertilizers) is typically applied to agricultural plots but a certain fraction or excess that is converted to nitrate or nitrite will serve as a critical pollutant to surface-water and groundwater. Applications show that the fADRE model can consider both hydrological and biogeochemical processes describing the fate and transport of nitrate in saturated soil. Here “fate” is a commonly used terminology in hydrology to describe the transformation and destination of pollutants in surface and subsurface water systems. The model is tested and validated using the results from three independent studies including: (1) nitrate transport in natural soil columns collected from the North China Plain agricultural pollution zone, (2) nitrate leaching from aridisols and entisols soil columns, and (3) two bacteria (Escherichia coli and Klebsiella sp.) transport through saturated soil columns. The qualitative relationship between model parameters and the target system properties (including soil physical properties, experimental conditions, and nitrate/bacteria physical and chemical properties) is also explored in detail, as well as the impact of chemical reactions on nitrate transport and fate dynamics. Results show that the fADRE can be a reliable mathematical model to quantify non-Fickian and reactive transport of chemicals in various soil systems, and it can also be used to describe other biological degradation and decay processes in soil. Hence, the mathematical model proposed by this study may help provide valuable insight on the quantification of various biogeochemical dynamics in complex soil systems, but needs to be tested in real-world applications in the future.

Bacterial transport and deposition play an important role in the assessment and prediction of subsurface pollution risks. Bacteria transport experiments were performed under unsaturated flow conditions in an aggregated porous medium at the laboratory column scale, to investigate how the inter- and intra-aggregated pore space of this medium could affect transport and deposition under unsaturated flow conditions, where inter- and intra-pore spaces are not fully activated. The results obtained through experimental observations and numerical simulations showed that some intra- and inter-pore space of this medium was excluded from bacteria transport and retention, as confirmed by the non-uniform transport of bacteria pathways in the aggregated porous media under unsaturated flow conditions. Capillary energy was higher the than other forces acting at bacteria air-water-solid interfaces. If this energy should contribute in increasing bacteria deposition under unsaturated conditions, similar to what has been reported for sandy media, similar overall retention of E. coli and R. rhodochrous was obtained under unsaturated flow conditions, suggesting that capillary energy was not the driving force for bacteria deposition.

International audience; The pesticide risk assessment for earthworms is currently performed using standardized tests, the model species Eisenia fetida, and the analyses of the data obtained are performed with ad hoc statistical tools. We assessed the impact of two fungicides on the entire growth pattern of the earthworm species Aporrectodea caliginosa, which is highly representative of agricultural fields. Individuals of three different ages (from hatching to 56 days old) were exposed to Cuprafor micro(R) (copper oxychloride) and Swing(R) Gold (dimoxystrobin and epoxiconazole). Data were analyzed with an energy-based toxicodynamic model coupled with a toxicokinetic model. The copper fungicide caused a drastic growth inhibition once the no effect concentration (NEC), estimated at 65 mg kg(-1) of copper, was exceeded. The Swing(R) Gold negatively affected the growth with NEC values estimated at 0.387 mg kg(-1) and 0.128 mg kg(-1) for the dimoxystrobin and the epoxiconazole in this fungicide formulation, respectively. The time-profile of the effects on A. caliginosa individuals was fully accounted for by the model, whatever their age of exposure. Furthermore, toxicity data analyses, supported by measurements of fungicide concentrations in earthworm at the end of the experiment, allowed bettering understanding of the mechanisms of action of the fungicides towards earthworm growth.

We present the first comprehensive dust provenance and lithogenic flux data set extracted from surface sediments distributed across the polar and subpolar South Pacific. The dataset comprises 230Th-normalized lithogenic fluxes combined with rare earth elements, strontium, neodymium and lead isotope data to determine lithogenic fluxes, spatial distribution and sources of dust (

International audience; We assessed the accuracy of tranexamic acid (TXA) concentrations measured in capillary whole blood using volumetric absorptive micro-sampling (VAMS) devices. Paired venous and VAMS capillary blood samples were collected from 15 healthy volunteers participating in a pharmacokinetic study of alternative routes (oral, IM and IV) of administering TXA. To assess accuracy across a range of concentrations, blood was drawn at different times after TXA administration. We measured TXA concentrations in plasma, whole blood from samples collected by venepuncture and whole blood from venous and capillary samples collected using VAMS devices. TXA was measured using a validated high sensitivity liquid chromatography - mass spectrometry method. We used Bland-Altman plots to describe the agreement between the TXA concentrations obtained with the different methods. In the 42 matched samples, the mean plasma TXA concentration was 14.0 mg/L (range 2.6–36.5 mg/L) whereas the corresponding whole blood TXA concentration was 7.7 mg/L (range 1.6–17.5 mg/L). When comparing TXA concentrations in VAMS samples of venous and capillary whole blood, the average bias was 0.07 mg/L (lower and upper 95% limits of agreement: −2.1 and 2.2 mg/L respectively). When comparing TXA concentrations in venous whole blood and VAMS capillary whole blood, the average bias was 0.7 mg/L (limits of agreement: −2.7 and 4.0 mg/L). Volumetric absorptive micro-sampling devices are sufficiently accurate for use in pharmacokinetic studies of tranexamic acid treatment in the range of plasma concentrations relevant for the assessment of fibrinolysis inhibition. Copyright

Parkinson’s disease (PD) evolves over an extended and variable period in humans; several years prior to the onset of classical motor symptoms, cognitive deficits as well as sleep and biological rhythm disorders develop and worsen with disease progression, significantly impacting the quality of life of patients. The gold standard MPTP macaque model of PD recapitulates the progression of motor and non-motor symptoms over contracted periods of time.Here, this multidisciplinary and multiparametric study follows, in five animals, the steady progression of motor and non-motor symptoms and describes their reversal following bilateral grafts of neural precursors in diverse functional domains of the basal ganglia.Results show unprecedented recovery from cognitive symptoms in addition to a strong clinical motor recuperation. Both motor and cognitive recovery and partial circadian rhythm recovery correlate with the degree of graft integration into the host environment as well as with in-vivo levels of striatal dopaminergic innervation and function.Given inter-individuality of disease progression and recovery the present study underlines the importance of longitudinal multidisciplinary assessments in view of clinical translation and provides empirical evidence that integration of neural precursors following transplantation efficiently restores function at multiple levels in parkinsonian non-human primates.One Sentence SummaryEmpirical evidence that cell therapy efficiently reverts cognitive and clinical motor symptoms in the non-human primate model of Parkinson’s disease.

Background: Beyond-use dates (BUDs) in compounding practice are assigned from stability studies. The United States Pharmacopoeia (USP 42 NF 37) suggested to assign a 6 months BUD for dry oral forms. A new pediatric formula of amiodarone capsules was implemented in our hospital, with 3 dosages (5 mg, 20 mg, and 50 mg). Objective: BUD of these new formulas had to be determined by stability study. Methods: The method for the determination of amiodarone content was validated to be stability indicating, and a stability study was performed. Different excipients commonly used for capsule compounding were compared. Results: We found that, with microcrystalline cellulose as excipient, 50 mg amiodarone capsules were stable for 1 year, whereas 5 mg and 20 mg capsules were not. This difference was studied, and lactose or mannitol were found to be better excipients for 5 mg amiodarone capsules, despite their potential side effects. A potential drug-excipient interaction between microcrystalline cellulose and amiodarone hydrochloride is described. Conclusion: Amiodarone hydrochloride/microcrystalline cellulose capsules have a BUD of 1 month for 5 mg capsules, 6 months for 20 mg, and 1 year for 50 mg.

Continental biogeochemical models are commonly used to prospect the effect of land use, exogenous organic matter input or climate change on soil greenhouse gas emission. However, they can still not be used to investigate the effect of soil contamination while it is known to affect several soil processes and to concern a large fraction of land surface. We implemented a commonly used model estimating soil nitrogen (N) emission, the DeNitrification DeCompostion (DNDC) model, with a function taking into account soil copper (Cu) contamination in nitrate production modulation. Then, we aimed at using this model to predict N-N2O, N-NO2 NOx and N-NH4 emissions in the presence of contamination and in the context of changes in precipitations. For that, incubations of soils were performed at different soil moistures in order to mimic expected rainfall patterns during the next decades and in particular drought and excess of water. The effect of this double stress on soil nitrate production was studied using a bio-assay. Then, data of nitrate production obtained under each moisture treatment were used to parameterize the DNDC model and estimate soil N emission considering the various effect of Cu. Whatever the moisture preincubation, experimental results showed a N-NO3 decreasing production when Cu was added but with different sharpness depending on soil moisture. The DNDC-Cu version we proposed was able to reproduce these observed Cu effects on soil nitrate concentration with r2 > 0.99 and RMSE < 10 % for all treatments in the DNDC-Cu calibration range (> 40 % of the water holding capacity) but showed poor performances for the dry treatments. We modelled a Cu-effect inducing an increase in N-NH4 soil concentration and emissions due to a reduced nitrification activity, and therefore a decrease in N-NO3, N-N2O and N-NOx concentrations and emissions. The effect of added Cu was larger on N-N2 and N-N2O emissions than on the other N species and larger for the soils incubated under constant than variable moisture.

Introduction Advanced non-squamous non-small cell lung cancer (NsqNSCLC) progressing at the induction of a first-line of platin-based chemotherapy is a subgroup of patients with poor prognosis and few second-line treatment options. Materials and Methods This single-stage phase II prospective multicenter open-label trial performed in platin-based refractory (i.e. progressing during induction phase of first-line platin-based chemotherapy) advanced NsqNSCLC assessed the efficacy of the nintedanib-docetaxel combination in second-line treatment. The primary endpoint was progression-free survival (PFS) rates at 12 weeks with a cut-off at 30% for ineffectiveness and 50% for minimal efficacy. Results A total of 59 patients from 23 centers were included (mean age, 58.5 years; male gender, 73.6%; performance status 0–1, 100%; former/current smokers, 92.5%; adenocarcinoma, 92.5%, median platin-based first-line chemotherapy, 2). Nintedanib-docetaxel combination was administered for a median of 4 cycles. The rate of PFS at 12 weeks was 39.6% (95% CI, 28.2–56.8). Median PFS was 2.7 (95% CI, 1.4–4.1) months and one-year PFS was 11.8% (95% CI, 4.8–22.2). Median overall survival (OS) was 6.9 (95% CI, 4.3–8.2) months and 12-month OS was 32.1% (95% CI, 19.8–45.0); 18-month OS was 27.6% (95% CI, 16,1–40.4). Twenty-nine (53.7%) patients reported at least one serious treatment-related adverse events leading to permanent discontinuation of at least one study drug in 12 (22.2%) patients. Conclusion The predefined minimal efficacy was not demonstrated. However, a number of NsqNSCLC patients refractory to first-line platin-based chemotherapy appeared to benefit from this combination.

International audience; Green LED plasmon excitation (525 nm) of colloidal gold nanoparticles (NPs), onto which a copper(ii) complex was grafted, in the presence of nitrobenzaldehyde and nitromethane in DMF lead to the formation of the corresponding nitroaldol with high efficiency. Kinetic studies using H-1 NMR and Raman spectroscopies showed that the reaction was faster under irradiation with green light, especially when in close proximity to the NPs (ca. 100% conversion after 100 min). After reaction completion, it was possible to recover the nanocatalyst and run two subsequent reactions. Green LED excitation of plasmonic nanocatalyst is shown to be a straightforward and efficient method for accelerating the rate of the Henry reaction with a lower energy demand and over a shorter reaction time when compared to the reaction performed under classical conditions.

Salix cortex-containing medicine is used against pain conditions, fever, headaches, and inflammation, which are partly mediated via arachidonic acid-derived prostaglandins (PGs). We used an activity-guided fractionation strategy, followed by structure elucidation experiments using LC-MS/MS, CD-spectroscopy, and 1D/2D NMR techniques, to identify the compounds relevant for the inhibition of PGE2 release from activated human peripheral blood mononuclear cells. Subsequent compound purification by means of preparative and semipreparative HPLC revealed 2′-O-acetylsalicortin (1), 3′-O-acetylsalicortin (2), 2′-O-acetylsalicin (3), 2′,6′-O-diacetylsalicortin (4), lasiandrin (5), tremulacin (6), and cinnamrutinose A (7). In contrast to 3 and 7, compounds 1, 2, 4, 5, and 6 showed inhibitory activity against PGE2 release with different potencies. Polyphenols were not relevant for the bioactivity of the Salix extract but salicylates, which degrade to, e.g., catechol, salicylic acid, salicin, and/or 1-hydroxy-6-oxo-2-cycohexenecarboxylate. Inflammation presents an important therapeutic target for pharmacological interventions, thus, the identification of relevant key drugs in Salix could provide new prospects for the improvement and standardization of existing clinical medicine.

International audience; There is growing interest in developing biologics due to their high target selectivity. The G protein-coupled homo- and heterodimeric metabotropic glutamate (mGlu) receptors regulate many synapses and are promising targets for the treatment of numerous brain diseases. Although subtype-selective allosteric small molecules have been reported, their effects on the recently discovered heterodimeric receptors are often not known. Here, we describe a nanobody that specifically and fully activates homodimeric human mGlu4 receptors. Molecular modeling and mutagenesis studies revealed that the nanobody acts by stabilizing the closed active state of the glutamate binding domain by interacting with both lobes. In contrast, this nanobody does not activate the heterodimeric mGlu2-4 but acts as a pure positive allosteric modulator. These data further reveal how an antibody can fully activate a class C receptor and bring further evidence that nanobodies represent an alternative way to specifically control mGlu receptor subtypes.

In this work, we bring back a rapid way to conceive doxorubicin (DOX) hybrid gold nanoparticles, in which DOX and Au(III) ions were complexed with a hydrochloride-lactose-modified chitosan, named CTL and dicarboxylic acid-terminated polyethylene-glycol (PEG), leading to hybrid polymer-sugar-metal nanoparticles (DOX–AuGSs). All formulations were assessed by spectroscopic techniques (Raman and UV-Vis) and transmission electron microscopy (TEM). To estimate the therapeutic effect of DOX–AuGSs in liver cancer, murine HepG2 cells were used to induce a hepatic carcinoma model in nude mice. The survival time of the tumor-bearing mice, body weight and tumor volume were measured and recorded. The cytokines were used to detect the serum inflammatory factors, and the blood cell analyzer was used to determine the blood cell content of different groups of nude mice. The outcomes demonstrate that DOX–AuGCs significantly suppressed the tumor growth derived from human HepG2 injection and reduce the tumor index without affecting the body weight of mice. Moreover, DOX–AuGCs significantly reduced the serum levels of cytokines IL-6, TNF-α and IL-12 P70. Finally, a histological analysis of the heart tissue sections indicated that DOX–AuGCs significantly reduce the chronic myocardial toxicity of DOX during the period of treatment.

International audience; We study the interaction between one aptamer and its analyte (the MnSOD protein) by the combination of surface-enhanced Raman scattering and multivariate statistical analysis. We observe the aptamer structure and its evolution during the interaction under different experimental conditions (in air or in buffer). Through the spectral treatment by principal component analysis of a large set of SERS data, we were able to probe the aptamer conformations and orientations relative to the surface assuming that the in-plane nucleoside modes are selectively enhanced. We demonstrate that the aptamer orientation and thus its flexibility rely strongly on the presence of a spacer of 15 thymines and on the experimental conditions with the aptamer lying on the surface in air and standing in the buffer. We reveal for the first time that the interaction with MnSOD induces a large loss of flexibility and freezes the aptamer structure in a single conformation.

Bioactive compounds oftentimes bind to several target proteins, thereby exhibiting polypharmacology. Experimentally determining these interactions is however laborious, and structure-based virtual screening (SBVS) of bioactive compounds could expedite drug discovery by prioritizing hits for experimental validation. Here, we present ePharmaLib, a library of 15,148 e-pharmacophores modeled from solved structures of pharmaceutically relevant protein-ligand complexes of the screening Protein Data Bank (sc-PDB). ePharmaLib can be used for target fishing of phenotypic hits, side effect predictions, drug repurposing, and scaffold hopping. In retrospective SBVS, a good balance was obtained between computational efficiency and predictive accuracy. As a proof of concept, we carried out prospective SBVS in conjunction with a photometric assay, which inferred that the mechanism of action of neopterin (an endogenous immunomodulator) putatively stems from its inhibition (IC50 = 18 μM) of the human purine nucleoside phosphorylase. This ready-to-use library is freely available at http://www.pharmbioinf.uni-freiburg.de/epharmalib.

Central micturition control and urine storage involve a multisynaptic neuronal circuit for the efferent control of the urinary bladder. Electrical stimulation of the lateral preoptic area (LPA) at the level of the decussation of the anterior commissure in cats evokes relaxation of the bladder, whereas ventral stimulation of LPA evokes vigorous contraction. Endogenous Angiotensin-(1–7) [(Ang-(1–7)] synthesis depends on ACE-2, and its actions on binding to Mas receptors, which were found in LPA neurons. We aimed to investigate the Ang-(1–7) actions into the LPA on intravesical pressure (IP) and cardiovascular parameters. The gene and protein expressions of Mas receptors and ACE-2 were also evaluated in the LPA. Angiotensin-(1–7) (5 nmol/μL) or A-779 (Mas receptor antagonist, 50 nmol/μL) was injected into the LPA in anesthetized female Wistar rats; and the IP, mean arterial pressure (MAP), heart rate (HR), and renal conductance (RC) were recorded for 30 min. Unilateral injection of Ang-(1–7) into the LPA increased IP (187.46 ± 37.23%) with peak response at ∼23–25-min post-injection and yielded no changes in MAP, HR, and RC. Unilateral or bilateral injections of A-779 into the LPA decreased IP (−15.88 ± 2.76 and −27.30 ± 3.40%, respectively) and elicited no changes in MAP, HR, and RC. The genes and the protein expression of Mas receptors and ACE-2 were found in the LPA. Therefore, the LPA is an important part of the circuit involved in the urinary bladder control, in which the Ang-(1–7) synthetized into the LPA activates Mas receptors for increasing the IP independent on changes in RC and cardiovascular parameters.

The usefulness of anti-inflammatory drugs as an adjunct therapy to improve outcomes in COVID-19 patients is intensely discussed in this paper. Willow bark (Salix cortex) has been used for centuries to relieve pain, inflammation, and fever. Its main active ingredient, salicin, is metabolized in the human body into salicylic acid, the precursor of the commonly used pain drug acetylsalicylic acid (ASA). Here, we report on the in vitro anti-inflammatory efficacy of two methanolic Salix extracts, standardized to phenolic compounds, in comparison to ASA in the context of a SARS-CoV-2 peptide challenge. Using SARS-CoV-2 peptide/IL-1β- or LPS-activated human PBMCs and an inflammatory intestinal Caco-2/HT29-MTX co-culture, Salix extracts, and ASA concentration-dependently suppressed prostaglandin E2 (PGE2), a principal mediator of inflammation. The inhibition of COX-2 enzyme activity, but not protein expression was observed for ASA and one Salix extract. In activated PBMCs, the suppression of relevant cytokines (i.e., IL-6, IL-1β, and IL-10) was seen for both Salix extracts. The anti-inflammatory capacity of Salix extracts was still retained after transepithelial passage and liver cell metabolism in an advanced co-culture model system consisting of intestinal Caco-2/HT29-MTX cells and differentiated hepatocyte-like HepaRG cells. Taken together, our in vitro data suggest that Salix extracts might present an additional anti-inflammatory treatment option in the context of SARS-CoV-2 peptides challenge, however, more confirmatory data are needed.

Water-saturated column experiments were conducted to study the effect of nonwoven geotextiles on bacteria transport and deposition through two sandy porous media with grain sizes 1.05 and 3.25 mm. The breakthrough curves (BTCs) of tracer for the all porous media exhibited an asymmetrical shape with a substantial tailing, indicating that non-equilibrium and dispersive flow patterns in these porous media. The mass recovery of the bacteria from the effluent (Meff) increased with grain size. The retention profiles (RPs) exhibited hyper-exponential behavior, especially in the finer sand. The presence of the geotextiles increased bacteria retention rate. For a given geotextile, greater retention was observed in the surrounding region close to the geotextile. Moreover, the retention of bacteria became more significant in the geotextile with a lower porosity. Results demonstrated that model simulations of bacteria transport and fate need to accurately account for both observed BTC and RP behaviors and also the geotextile placement can impact mechanisms of retention.

Metabotropic glutamate receptors (mGluRs) have been discovered almost four decades ago. Since then, their pharmacology has been largely developed as well as their structural organization. Indeed mGluRs are attractive therapeutic targets for numerous psychiatric and neurological disorders because of their modulating role of synaptic transmission. The more recent drug discovery programs have mostly concentrated on allosteric modulators. However, orthosteric agonists and antagonists have remained unavoidable pharmacological tools as, although not expected, many of them can reach the brain, or can be modified to reach the brain. This review focuses on the most common orthosteric ligands as well as on the few allosteric modulators interacting with the glutamate binding domain. The 3D-structures of these ligands at their binding sites are reported. For most of them, X-Ray structures or docked homology models are available. Because of the high conservation of the binding site, subtype selective agonists were not easy to find. Yet, some were discovered when extending their chemical structures in order to reach selective sites of the receptors.

Two field experiments with onion and garlic were carried out on clay loam soil under different water sources (i.e. fresh, drainage and mixed) in interaction with four rates of N (30%; 45 and 60 kg N fed-1, 60%; 90 and 120 kg N fed-1, 90%; 135 and 180 kg N fed-1 and 120%; 180 and 240 kg N fed-1 of the recommended rate for onion and garlic, respectively) to assess its effects on growth attributes and yield as well as following up the changes of some soil chemical properties after the growing seasons. The side effect of using low water quality on soil properties and water relations was also traced. Drainage and mixed water significantly increased the EC, pH and sodium adsorption ratio (SAR) of the soil under both crops comparing to the fresh water. This was more vigorous under 120% nitrogen rate. In soil irrigated with fresh water, EC were decreased by ~ 26.5% under the initial level on base of over all mean of nitrogen treatments. The low quality waters reflected decrements in EC values by about 10.6% under initial and increments by about 9.7% over the initial for mixed and drainage water, respectively. In meanwhile, the SAR values increased after growing seasons with all water sources, and it affected by water quality where it increased as the low water quality applied, whereas it recorded the highest value with drainage water followed by mixed water. Additionally, the application of 60 and 90% reveal a slight increase in soil chemical properties as the mixed and drainage water were used. Fresh water treatment increased growth and crop yields for both garlic and onion compared to mixed and drainage water treatments. Increasing N rate from 30 up to 120 % of the recommended N rate significantly increased garlic yield by 53.9% and onion yield by 16.3%. The highest WUE for onion (7.44 and 6.79 kg m-3) and for garlic (3.33 and 3.00 kg m-3) resulted from 120 % of the recommended N rate with fresh and mixed water, respectively.

The Antarctic Circumpolar Current is the world’s largest current system connecting all major ocean basins of the global ocean. Its flow, driven by strong westerly winds, is constricted to its narrowest extent in the Drake Passage, located between South America and the Antarctic Peninsula. Due to the remoteness of the area, harsh weather conditions and strong bottom currents, sediment recovery is difficult and data coverage is still inadequate. Here, we report on the composition of 51 surface sediments collected during the R/V Polarstern PS97 expedition (February–April 2016) across the western and central Drake Passage, from the Chilean/Argentinian continental margin to the South Shetland Islands and the Bransfield Strait (water depth: ∼100–4000 m). We studied microfossils (diatoms), bulk sediment composition and geochemical proxies (biogenic opal, organic carbon, calcium carbonate, carbon and nitrogen stable isotopes, sterols and photosynthetic pigments), and evaluated how they respond to, and reflect oceanic domains and polar to subpolar frontal systems in this region. Our multi-proxy approach shows a strong relationship between the composition of surface sediments and ocean productivity, terrigenous input, intensity of ocean currents, and ice proximity, clearly differentiating among 4 biogeographical zones. The Subantarctic Zone was characterized by warmer-water diatoms, high carbonate (>45%) and low organic carbon contents (avg. 0.26%), as well as low concentrations of pigments (avg. 1.75 μg/g) and sterols (avg. 0.90 μg/g). A general N-S transition from carbonate-rich to opal-rich sediment was observed at Drake Passage sites of the Polar Front and Permanently Open Ocean Zone. These sites were characterized by low organic carbon content (0.22%), high relative abundances of heavily silicified diatoms (≥60% Fragilariopsis kerguelensis), and abundant foraminifera at shallower stations. Approaching the Antarctic Peninsula in the Transitional Zone, an increase in the concentrations of pigments and sterols (avg. 2.57 μg/g and 1.44 μg/g, respectively) and a strong decrease in carbonate content was observed. The seasonal Sea-Ice Zone in the southern section of the study area, had the highest contents of biogenic opal (avg. 14.6%) and organic carbon (avg. 0.7%), low carbonate contents (avg. 2.4%), with the occurrence of sea-ice-related diatoms and sterols. In all zones, terrigenous input was detected, although carbon/nitrogen ratios and δ13Corg suggest a predominance of marine-derived organic matter; lower values of δ13Corg occurred south of the Polar Front. The new results presented here constitute a highly valuable reference dataset for the calibration of microfossil and geochemical proxies against observational data and provide a useful regional baseline for future paleo-research.

Cistus ladanifer L. is a shrub present in Mediterranean areas without major use, but which can be incorporated into ruminant diets, improving the digestive efficiency of dietary protein and product quality. The high levels of plant secondary metabolites, including condensed tannins, may be responsible for the beneficial properties of the plant, but can also reduce palatability. In this study, C. ladanifer was incorporated into lambs’ diets, either as aerial parts or as a condensed tannin extract, reaching 1.25% and 2.5% of condensed tannins of dry matter. Saliva was collected and electrophoretic profiles of both whole saliva and saliva after in vitro incubation with C. ladanifer tannins were compared. Animals receiving the aerial parts of C. ladanifer decreased feed ingestion. Differences in salivary protein profiles were observed for animals fed with the higher levels of aerial parts of the plant (CL2.5 group). Most of the lambs’ salivary proteins were present in the precipitate formed after tannin-saliva incubation, and one of the bands increased in CL2.5 group was present in high proportion in the precipitate. None of the protein bands stained pink with Coomassie Brilliant Blue, suggesting the absence, or low amounts, of proline-rich proteins in lamb saliva. The results suggest that the aerial parts of C. ladanifer are poor in palatability and that salivary proteins from lambs, due to their affinity for this plant’s secondary metabolites, can contribute to this. Further protein identification is needed, as well as studies to access the stability of the tannin-protein complexes through the gastrointestinal tract.

Objectives: These practice guidelines for the treatment of alcohol use disorders during pregnancy were developed by members of the International Task Force of the World Federation of Societies of B...

Two field experiments were conducted in the experimental farm, faculty of Agriculture, Cairo university, Giza, Egypt during 2014/2015 and 2015/2016 seasons to evaluate the tolerance of two monogerm sugar beet varieties: Puma and Palace cevek, and two multigerm varieties: Monte Bianko and Ninagri to water depletion levels (25, 50 and 75% of the available soil moisture). Puma variety was the most tolerant sugar beet variety according to stress tolerance index (STI) along with recorded the highest leaf area index (LAI) and plant dry weight at 150, 175 and 200 days after sowing as well as the highest root and sugar yields, followed by Monte Bianko, Ninagri and Palace cevek variety throughout the growing seasons, while the highest sucrose, purity and sugar recovery (SR) percentages resulted from Palace cevek variety. Increasing water depletion level from 25 up to 75% negatively affect beet growth traits and decreased root yield by 17.45 and 17.44% and sugar yield by 11.63 and 9.94% in the first and second seasons, respectively. On the contrary, sucrose, purity and SR significantly increased as water depletion increased, in addition to, the water use efficiency (WUE) increased by 48.3 and 40.1% in the 1st and 2nd seasons, respectively. Puma variety irrigated with 25% water depletion produced the highest LAI, plant dry weight, potassium and sodium content as well as root and sugar yields.

Amaranth is presently an underutilized crop despite its high content of micronutrients/bioactive phytochemicals and its capacity to thrive in harsh environmental condition. The present study aimed at determining the health benefits of Amaranthus cruentus L. in terms of protection against DNA damage induced by the mycotoxin aflatoxin B1 (AFB1) and oxidative stress using comet assay. The antioxidant potential was further investigated using electron paramagnetic resonance spectroscopy (EPR) and an ARE/Nrf2 reporter gene assay in vitro in a human liver model using the HepG2 cell line. Ethanolic extracts from fresh leaves grown under controlled conditions were used and additionally analyzed for their phytochemical content using liquid chromatography-mass spectrometry (LC-MS). The extracts inhibited both AFB1- and oxidative stress-induced DNA damage in a concentration dependent way with a maximum effect of 57% and 81%, respectively. Oxidative stress triggered using ferrous sulfate was blocked by up to 38% (EPR); the potential to induce antioxidant enzymes using ARE/Nrf2-mediated gene expression was also confirmed. Based on these in vitro findings, further studies on the health-protecting effects of A. cruentus are encouraged to fully explore its health promoting potential and provide the scientific basis for encouraging its cultivation and consumption.

For more than two decades the SOHO/SWAN instrument has been monitoring the full-sky hydrogen backscattered Lyman-α emission, and the derived three-dimensional solar wind proton flux. We present a comparison of the time series of the latitude-integrated hydrogen ionization rates (β) derived from the inversion of the SWAN full-sky maps with the integrated coronal electron density derived from the inversion of SOHO/LASCO-C2 white light images. The analysis shows a variable time lag of the SWAN β of a few Carrington rotations, correlated with the solar cycle phase (larger delay during solar maxima compared to minima). This is a direct consequence of the variation of the size of the hydrogen ionization cavity and the time it takes for hydrogen atoms to propagate in the inner heliosphere. This effect should be taken into account in studies of the interstellar neutral populations in interplanetary space.

Catalysis of human phosphoglycerate mutase is dependent on a 2,3-bisphosphoglycerate cofactor (dPGM), whereas the nonhomologous isozyme in many parasitic species is cofactor independent (iPGM). This mechanistic and phylogenetic diversity offers an opportunity for selective pharmacologic targeting of glycolysis in disease-causing organisms. We previously discovered ipglycermide, a potent inhibitor of iPGM, from a large combinatorial cyclic peptide library. To fully delineate the ipglycermide pharmacophore, herein we construct a detailed structure–activity relationship using 280 substituted ipglycermide analogs. Binding affinities of these analogs to immobilized Caenorhabditis elegans iPGM, measured as fold enrichment relative to the index residue by deep sequencing of an mRNA display library, illuminated the significance of each amino acid to the pharmacophore. Using cocrystal structures and binding kinetics, we show that the high affinity of ipglycermide for iPGM orthologs, from Brugia malayi, Onchocerca volvulus, Dirofilaria immitis, and Escherichia coli, is achieved by a codependence between (1) the off-rate mediated by the macrocycle Cys14 thiolate coordination to an active-site Zn2+ in the iPGM phosphatase domain and (2) shape complementarity surrounding the macrocyclic core at the phosphotransferase–phosphatase domain interface. Our results show that the high-affinity binding of ipglycermide to iPGMs freezes these structurally dynamic enzymes into an inactive, stable complex.

Background: The role and timing of whole or stereotaxic brain radiotherapy (BR) in patients with advanced non-small cell lung cancer (aNSCLC) and asymptomatic brain metastases (aBMs) are not well established. This study investigates whether deferring BR until cerebral progression was superior to upfront BR for patients with aNSCLC and aBM. Methods: This open-label, multicenter, phase III trial, randomized (1:1) aNSCLC patients with aBMs to receive upfront BR and chemotherapy: platin–pemetrexed and bevacizumab in eligible patients, followed by maintenance pemetrexed with or without bevacizumab, BR arm, or the same chemotherapy with BR only at cerebral progression, chemotherapy (ChT) arm. Primary endpoint was progression-free survival (PFS), secondary endpoints were overall survival (OS), global, extra-cerebral and cerebral objective response rate (ORR), toxicity, and quality of life [ClinicalTrials.gov identifier: NCT02162537]. Results: The trial was stopped early because of slow recruitment. Among 95 included patients, 91 were randomized in 24 centers: 45 to BR and 46 to ChT arms (age: 60 ± 8.1, men: 79%, PS 0/1: 51.7%/48.3%; adenocarcinomas: 92.2%, extra-cerebral metastases: 57.8%, without differences between arms.) Significantly more patients in the BR-arm received BR compare with those in the ChT arm (87% versus 20%; p Conclusion: The significant BR rate difference between the two arms suggests that upfront BR is not mandatory in aNSCLC with aBM but this trial failed to show that deferring BR for aBM is superior in terms of PFS from upfront BR.

Simple Summary The use of saliva as a biological fluid to assess welfare and health status is gaining interest nowadays since it can be collected by non-invasive methods without specialized staff. The possibility of measuring analytes in saliva by techniques adapted to automated analyzers is cost-effective, reliable, and replicable. These analytes can provide information useful for the evaluation of welfare and health in dairy cows. In this pilot study, a total of 26 salivary analytes were measured in healthy dairy cows along their peripartum period to assess possible changes and associations with their inflammatory, energy, and milk yield status. Salivary analytes related to stress (cortisol, salivary alpha-amylase, butyrylcholinesterase, and total esterase), immunity (adenosine deaminase), oxidative status (Trolox equivalent antioxidant capacity and the advanced oxidation protein products), and general metabolism (creatine kinase, γ-glutamyl transferase, urea, triglycerides, glucose, and lactate) had significant changes throughout this period. This study indicated that the saliva of dairy cows shows changes in its composition during the transition period and potentially can be a source of biomarkers for monitoring health and welfare. Abstract This pilot study aimed to study the possible changes in a profile of 26 salivary analytes in thirteen healthy dairy cows along their peripartum period. Analytes associated with the stress (salivary cortisol, salivary alpha-amylase, butyrylcholinesterase, and total esterase), inflammation (adenosine deaminase), oxidative status (total antioxidant capacity and the advanced oxidation protein products), and general metabolism (creatine kinase, γ-glutamyl transferase, urea, triglycerides, glucose, and lactate) varied along the sampling times. A positive correlation between the white blood cells counts, and the lipase, Trolox equivalent antioxidant capacity, advanced oxidation protein products, and lactate levels in saliva were observed at the delivery. A linear association between selected salivary analytes at different sampling times and the milk yield after calving was observed. In conclusion, in our experimental conditions, it was observed that the peripartum period in dairy cows can induce changes in salivary analytes. Some of them were associated with inflammatory status and the capacity of milk production after calving.

BackgroundHerbal medicinal products have a long-standing history of use in the therapy of common respiratory infections. In the COVID-19 pandemic, they may have the potential for symptom relief in non-severe or moderate disease cases. Here we describe the results derived byin vitroscreening of five herbal medicinal products with regard to their potential to i) interfere with the binding of the human Angiotensin-converting enzyme 2 (ACE2) receptor with the SARS-CoV-2 Spike S1 protein, ii) modulate the release of the human defensin HBD1 and cathelicidin LL-37 from human A549 lung cells upon Spike S1 protein stimulation and iii) modulate the release of IFN-γ from activated human peripheral blood mononuclear cells (PBMC). The investigated extracts were: Sinupret extract (SINx), Bronchipret thyme-ivy (BRO TE), Bronchipret thyme-primrose (BRO TP), Imupret (IMU), and Tonsipret (TOP).MethodsThe inhibitory effect of the herbal medicinal products on the binding interaction of Spike S1 protein and the human ACE2 receptor was measured by ELISA. The effects on intracellular IFN-γ expression in stimulated human PBMCs were measured by flow cytometry. Regulation on HBD1 and LL-37 expression and secretion was assessed in 25d long-term cultured human lung A549 epithelial cells by RT-PCR and ELISA.ResultsIMU and BRO TE concentration-dependently inhibited the interaction between spike protein and the ACE2 Receptor. However, this effect was only observed in the cell-free assay at a concentration range which was later on determined as cytotoxic to human PBMC. SINx, TOP and BRO TP significantly upregulated the intracellular expression of antiviral IFNγ from stimulated PBMC. Co-treatment of A549 cells with IMU or BRO TP together with SARS-CoV-2 spike protein significantly upregulated mRNA expression (IMU) and release (IMU and BRO TP) of HBD1 and LL-37 (BRO TP).ConclusionsThein vitroscreening results provide first evidence for an immune activating potential of some of the tested herbal medicinal extracts in the context of SARS-CoV-2. Whether these could be helpful in prevention of SARS-CoV-2 invasion or supportive in recovery from SARS-CoV-2 infection needs deeper understanding of the observations.

Large protein complexes carry out some of the most complex activities in biology1,2. Such structures are often assembled spontaneously through the process of self-assembly and have characteristic chemical or biological assets in the cellular mechanisms3. Gold-based nanomaterials have attracted much attention in many areas of chemistry, physics and biosciences because of their size- and shape-dependent optic, electric, and catalytic properties. Here we report for the first time a one step synthesis in which Manganese Superoxide Dismutase protein plays a key role in the reduction of gold salts via the use of a Good's buffer (HEPES) to produce gold nanoparticles, compared to other proteins as catalase (CAT) and bovine serum albumin (BSA).We prove that this effect is directly related with the biological activities of the proteins that have an effect on the gold reduction mechanisms. Such synthesis route also induces the integration of proteins directly in the AuNPs that are intrinsically safe by design using a one-step production method. This is an important finding that will have uses in various applications, particularly in the green synthesis of novel nanomaterials.

International audience; Extracellular enzymatic activities constitute the first and limiting step of the whole process of organic matter (OM) cycling in aquatic ecosystems. This study aims to identify the factors controlling prokaryotes ability to hydrolyse OM in an Indo-Pacific tropical mangrove ecosystem (Can Gio, Vietnam). Prokaryotic abundance and leucine-aminopeptidase exo-proteolytic activity (EPA) were measured at vertical (from the sea-surface microlayer to bottom waters), spatial (along a transect within the estuary) and seasonal (wet and dry season) scales. Prokaryotic abundance ranged from 1.2 to 5.7 × 109 cells L−1 and EPA ranged from 24 to 505 nmol L−1 h−1 that was relatively similar to other highly productive ecosystems. The estuary was poorly stratified, most probably because of high water turbulence. Yet, exo-proteolytic activity was significantly higher in bottom waters, where higher loads of suspended particulate matter were measured. Seasonal and spatial differences in EPA suggest that the nature of OM transported by the Can Gio mangrove estuary affect EPA. The latter seems to be increased by two “uncommon” situations: the input of fresh and labile OM (e.g. shrimp farm effluents) or the lack of labile OM and the need to hydrolyse refractory compounds (e.g. during the dry season).

The present work compares the interaction of the antibiotic levofloxacin (LVX) with zwitterionic and anionic liposomes composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol) (DPPG), respectively. By using differential scanning calorimetry (DSC), and with spin labels incorporated into liposomes at two different depths of the bilayers, we investigated the changes induced on the membrane by increasing concentrations of LVX. Further information was obtained using intrinsic LVX fluorescence. Under the conditions used here, all techniques evinced that LVX has little affinity for DPPC zwitterionic membrane. Opposite to that, LVX exhibits a considerable affinity for anionic bilayers, with membrane partition constants Kp = (3.3 ± 0.5) × 102 and (4.5 ± 0.3) × 102, for gel and fluid DPPG membranes, respectively. On binding to DPPG, LVX seems to give rise to the coexistence of LVX -rich and -poor domains on DPPG membranes, as detected by DSC. At the highest LVX concentration used (20 mol%), DSC trace shows an increase in the cooperativity of DPPG gel-fluid transition, also detected by spin labels as an increase in the bilayer packing. Moreover, LVX does not induce pore formation in either DPPG or POPG vesicles. Considering the possible relevance of LVX-membrane interaction for the biological and toxicological action of the antibiotic, the findings discussed here certainly contribute to a better understanding of its action, and the planning of new drugs.