On the origin of the extremely different solubilities of polyethers in water

The solubilities of polyethers are surprisingly counter-intuitive. The best-known example is the difference between polyethylene glycol ([–CH2–CH2–O–]n) which is infinitely soluble, and polyoxymethylene ([–CH2–O–]n) which is completely insoluble in water, exactly the opposite of what one expects from the C/O ratios of these molecules. Similar anomalies exist for oligomeric and cyclic polyethers. To solve this apparent mystery, we use femtosecond vibrational and GHz dielectric spectroscopy with complementary ab initio calculations and molecular dynamics simulations. We find that the dynamics of water molecules solvating polyethers is fundamentally different depending on their C/O composition. The ab initio calculations and simulations show that this is not because of steric effects (as is commonly believed), but because the partial charge on the O atoms depends on the number of C atoms by which they are separated. Our results thus show that inductive effects can have a major impact on aqueous solubilities

Detecting intratumoral heterogeneity of EGFR activity by liposome-based in vivo transfection of a fluorescent biosensor

Despite decades of research in the epidermal growth factor receptor (EGFR) signalling field, and many targeted anti-cancer drugs that have been tested clinically, the success rate for these agents in the clinic is low, particularly in terms of the improvement of overall survival. Intratumoral heterogeneity is proposed as a major mechanism underlying treatment failure of these molecule-targeted agents. Here we highlight the application of fluorescence lifetime microscopy (FLIM)-based biosensing to demonstrate intratumoral heterogeneity of EGFR activity. For sensing EGFR activity in cells, we used a genetically encoded CrkII-based biosensor which undergoes conformational changes upon tyrosine-221 phosphorylation by EGFR. We transfected this biosensor into EGFR-positive tumour cells using targeted lipopolyplexes bearing EGFR-binding peptides at their surfaces. In a murine model of basal-like breast cancer, we demonstrated a significant degree of intratumoral heterogeneity in EGFR activity, as well as the pharmacodynamic effect of a radionuclide-labeled EGFR inhibitor in situ. Furthermore, a significant correlation between high EGFR activity in tumour cells and macrophage-tumour cell proximity was found to in part account for the intratumoral heterogeneity in EGFR activity observed. The same effect of macrophage infiltrate on EGFR activation was also seen in a colorectal cancer xenograft. In contrast, a non-small cell lung cancer xenograft expressing a constitutively active EGFR conformational mutant exhibited macrophage proximity-independent EGFR activity. Our study validates the use of this methodology to monitor therapeutic response in terms of EGFR activity. In addition, we found iNOS gene induction in macrophages that are cultured in tumour cell-conditioned media as well as an iNOS activity-dependent increase in EGFR activity in tumour cells. These findings point towards an immune microenvironment-mediated regulation that gives rise to the observed intratumoral heterogeneity of EGFR signalling activity in tumour cells in vivo

The mode of school transportation in pre-pubertal children does not influence the accrual of bone mineral or the gain in bone size - two year prospective data from the paediatric osteoporosis preventive (POP) study

<p>Abstract</p> <p>Background</p> <p>Walking and cycling to school are one source of regular physical activity. The aim of this two years observational study in pre-pubertal children was to evaluate if walking and cycling to school was associated with higher total amount of physical activity and larger gain in bone mineral content (BMC) and bone width than when going by car or bus.</p> <p>Methods</p> <p>133 boys and 99 girls aged 7-9 years were recruited to the Malmö Prospective Paediatric Osteoporosis Prevention (POP) study. BMC (g) was measured by dual X-ray absorptiometry (DXA) in total body, lumbar spine (L2-L4) and femoral neck (FN) at baseline and after 24 months. Bone width was measured in L2-L4 and FN. Skeletal changes in the 57 boys and 48 girls who consistently walked or cycled to school were compared with the 24 boys and 17 girls who consistently went by bus or car. All children remained in Tanner stage I. Level of everyday physical activity was estimated by accelerometers worn for four consecutive days and questionnaires. Comparisons were made by independent student's t-tests between means and Fisher's exact tests. Analysis of covariance (ANCOVA) was used to adjust for group differences in age at baseline, duration of organized physical activity, annual changes in length and BMC or bone width if there were differences in these traits at baseline.</p> <p>Results</p> <p>After the adjustments, there were no differences in the annual changes in BMC or bone width when comparing girls or boys who walked or cycled to school with those who went by car or bus. Furthermore, there were no differences in the levels of everyday physical activity objectively measured by accelerometers and all children reached above the by the United Kingdom Expert Consensus Group recommended level of 60 minutes moderate to vigorous physical activity per day.</p> <p>Conclusion</p> <p>A physical active transportation to school for two years is in pre-pubertal children not associated with a higher accrual of BMC or bone width than a passive mode of transportation, possibly due to the fact that the everyday physical activity in these pre-pubertal children, independent of the mode of school transportation, was high.</p

Aerobic nonylphenol degradation and nitro-nonylphenol formation by microbial cultures from sediments

Nonylphenol (NP) is an estrogenic pollutant which is widely present in the aquatic environment. Biodegradation of NP can reduce the toxicological risk. In this study, aerobic biodegradation of NP in river sediment was investigated. The sediment used for the microcosm experiments was aged polluted with NP. The biodegradation of NP in the sediment occurred within 8 days with a lag phase of 2 days at 30°C. During the biodegradation, nitro-nonylphenol metabolites were formed, which were further degraded to unknown compounds. The attached nitro-group originated from the ammonium in the medium. Five subsequent transfers were performed from original sediment and yielded a final stable population. In this NP-degrading culture, the microorganisms possibly involved in the biotransformation of NP to nitro-nonylphenol were related to ammonium-oxidizing bacteria. Besides the degradation of NP via nitro-nonylphenol, bacteria related to phenol-degrading species, which degrade phenol via ring cleavage, are abundantly present

Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial

Funding Information: The FOAM study was an investigator-initiated study funded by ZonMw, The Netherlands organization for Health Research and Development (project number 837001504). ZonMw funded the whole project. IQ Medical Ventures provided the ExEm-foamVR kits free of charge. The funders had no role in study design, collection, analysis and interpretation of the data. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.Peer reviewedPublisher PD

Karakterizacija solvatomorfa metotreksata pomoću termoanalitičkih i drugih metoda

Identification and characterization of different forms of methotrexate were carried out by crystallization from different solvents. Five different forms of the drug were obtained. Appearance of a desolvation endotherm in the DSC accompanied by mass loss in TGA for forms I, II, IV and V showed these forms to be acetonitrile solvate hydrate (form I), trihydrate (forms II and IV) and dimethylformamide solvate (form V), respectively. However, the desolvation peak was absent in form III (obtained from methanol) indicating the absence of any solvent of crystallization. This form was found to be partially crystalline by its XRPD pattern. Solution calorimetry was further used to differentiate between the forms as they differ in lattice energy, resulting in different enthalpies of solution. The dissolution and solubility profiles were correlated with the enthalpy of solution and subsequently with crystallinity of all the forms; the least endothermic form (form III) had the highest dissolution rate.U radu je provedena identifikacija i karakterizacija pet različitih formi metotreksata dobivenih kristalizacijom iz različitih otapala. Desolvatacijska izoterma u DSC popraćena gubitkom mase u TGA za forme I, II, IV i V ukazuje da su te forme solvati s acetonitrilom: hidrat (forma I), trihidrat (forma II i IV) i solvat s dimetilformamidom (forma V). Međutim, desolvatacijski pik je odsutan u formi III (dobivenoj iz metanola) što ukazuje na odsutnost otapala u kristalnoj formi. Ta forma je parcijalno kristalna i pokazuje odgovarajući XRPD uzorak. Energija kristalne ćelije je za različite forme različita, što ima za posljedicu različite entalpije otapanja te omogućava primjenu kalorimetrije otopine za diferencijaciju formi. Topljivost je korelirana s entalpijom otopine i kristaliničnosti svih formi. Najmanje endotermna forma (forma III) je najbolje topljiva

Comparison of gene transfection and cytotoxicity mechanisms of linear poly(amidoamine) and branched poly(ethyleneimine) polyplexes

Purpose: This study aimed to further explore the mechanisms behind the ability of certain linear polyamidoamines (PAAs) to transfect cells with minimal cytotoxicity. Methods: The transfection efficiency of DNA complexed with a PAA of a molecular weight over 10 kDa or 25 kDa branched polyethyleneimine (BPEI) was compared in A549 cells using a luciferase reporter gene assay. The impact of endo/lysosomal escape on transgene expression was investigated by transfecting cells in presence of bafilomycin A1 or chloroquine. Cytotoxicity caused by the vectors was evaluated by measuring cell metabolic activity, lactate dehydrogenase release, formation of reactive oxygen species and changes in mitochondrial membrane potential. Results: The luciferase activity was 3-fold lower after transfection with PAA polyplexes than with BPEI complexes at the optimal polymer to nucleotide ratio (RU:Nt). However, in contrast to BPEI vectors, PAA polyplexes caused negligible cytotoxic effects. The transfection efficiency of PAA polyplexes was significantly reduced in presence of bafilomycin A1 while chloroquine enhanced or decreased transgene expression depending on the RU:Nt. Conclusions: PAA polyplexes displayed a pH-dependent endo/lysosomal escape which was not associated with cytotoxic events, unlike observed with BPEI polyplexes. This is likely due to their greater interactions with biological membranes at acidic than neutral pH