Roundup is a glyphosate-based herbicide used worldwide, including on most genetically modified plants that have been designed to tolerate it. Its residues may thus enter the food chain, and glyphosate is found as a contaminant in rivers. Some agricultural workers using glyphosate have pregnancy problems, but its mechanism of action in mammals is questioned. Here we show that glyphosate is toxic to human placental JEG3 cells within 18 hr with concentrations lower than those found with agricultural use, and this effect increases with concentration and time or in the presence of Roundup adjuvants. Surprisingly, Roundup is always more toxic than its active ingredient. We tested the effects of glyphosate and Roundup at lower nontoxic concentrations on aromatase, the enzyme responsible for estrogen synthesis. The glyphosate-based herbicide disrupts aromatase activity and mRNA levels and interacts with the active site of the purified enzyme, but the effects of glyphosate are facilitated by the Roundup formulation in microsomes or in cell culture. We conclude that endocrine and toxic effects of Roundup, not just glyphosate, can be observed in mammals. We suggest that the presence of Roundup adjuvants enhances glyphosate bioavailability and/or bioaccumulation.

The ability to create a 3D tissue structure from individual cells and then to stimulate it at will is a major goal for both the biophysics and regenerative medicine communities. Here we show an integrated set of magnetic techniques that meet this challenge using embryonic stem cells (ESCs). We assessed the impact of magnetic nanoparticles internalization on ESCs viability, proliferation, pluripotency and differentiation profiles. We developed magnetic attractors capable of aggregating the cells remotely into a 3D embryoid body. This magnetic approach to embryoid body formation has no discernible impact on ESC differentiation pathways, as compared to the hanging drop method. It is also the base of the final magnetic device, composed of opposing magnetic attractors in order to form embryoid bodies in situ, then stretch them, and mechanically stimulate them at will. These stretched and cyclic purely mechanical stimulations were sufficient to drive ESCs differentiation towards the mesodermal cardiac pathway.

Emerging advances in extracellular vesicle (EV) research brings along new promises for tailoring clinical treatments in order to meet specific disease features of each patient in a personalized medicine concept. EVs may act as regenerative effectors conveying endogenous therapeutic factors from parent cells or constitute a bio-camouflaged delivery system for exogenous therapeutic agents. Physical stimulation may be an important tool in the field of EVs for personalized therapy by powering EV production, loading and therapeutic properties. Physically-triggered EV production is inspired by naturally occurring EV release by shear stress in blood vessels. Bioinspired physically-triggered EV production technologies may bring along high yield advantages combined to scalability assets. Physical stimulation may also provide new prospects for highefficient EV loading. Additionally, physically-triggered EV theranostic properties brings new hopes for spatiotemporal controlled therapy combined to tracking. Technological considerations related to EV-based personalized medicine and the input of physical stimulation on EV production, loading and theranostic properties will be overviewed herein.2

Microbial pathogens commonly escape the human immune system by varying surface proteins. We investigated the mechanisms used for that purpose by Pneumocystis jirovecii. This uncultivable fungus is an obligate pulmonary pathogen that in immunocompromised individuals causes pneumonia, a major life-threatening infection. Long-read PacBio sequencing was used to assemble a core of subtelomeres of a single P. jirovecii strain from a bronchoalveolar lavage fluid specimen from a single patient. A total of 113 genes encoding surface proteins were identified, including 28 pseudogenes. These genes formed a subtelomeric gene superfamily, which included five families encoding adhesive glycosylphosphatidylinositol (GPI)-anchored glycoproteins and one family encoding excreted glycoproteins. Numerical analyses suggested that diversification of the glycoproteins relies on mosaic genes created by ectopic recombination and occurs only within each family. DNA motifs suggested that all genes are expressed independently, except those of the family encoding the most abundant surface glycoproteins, which are subject to mutually exclusive expression. PCR analyses showed that exchange of the expressed gene of the latter family occurs frequently, possibly favored by the location of the genes proximal to the telomere because this allows concomitant telomere exchange. Our observations suggest that (i) the P. jirovecii cell surface is made of a complex mixture of different surface proteins, with a majority of a single isoform of the most abundant glycoprotein, (ii) genetic mosaicism within each family ensures variation of the glycoproteins, and (iii) the strategy of the fungus consists of the continuous production of new subpopulations composed of cells that are antigenically different.

Ultra-small ZnGa2 O4 :Cr(3+) nanoparticles (6 nm) that exhibit near-infrared (NIR) persistent luminescence properties are synthesized by using a non-aqueous sol-gel method assisted by microwave irradiation. The nanoparticles are pegylated, leading to highly stable dispersions under physiological conditions. Preliminary in vivo studies show the high potential for these ultra-small ZnGa2 O4 :Cr(3+) nanoparticles to be used as in vivo optical nanotools as they emit without the need for in situ excitation and, thus, avoid the autofluorescence of tissues.

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Summary From the rat C6 glioma cell line in culture, we selected camptothecin-resistant variants by growth in the presence of increasing amounts of this drug (C6 CPT10 , C6 CPT50 and C6 CPT100 , growing respectively with 10, 50 and 100 ng ml -1 camptothecin). The degree of resistance to camptothecin ranged between 15-fold (C6 CPT10 ) and 30-fold (C6 CPT50 and C6 CPT100 ). The C6 CPT10 cell line presented a collateral sensitivity to etoposide (3.6-fold), while the C6 CPT50 and C6 CPT100 cell lines were cross-resistant to etoposide (1.8-fold) The resistant lines were characterised by a two-fold reduced content and catalytic activity of topoisomerase I, and C6 CPT50 and C6 CPT100 presented a significant increase in topoisomerase IIα content and catalytic activity and a marked overexpression of P-glycoprotein. We explored the cytotoxicity of combinations of a topoisomerase I inhibitor (camptothecin) and a topoisomerase II inhibitor (doxorubicin or etoposide) at several molar ratios, allowing the evaluation of their synergistic or antagonistic effects on cell survival using the median effect principle. The simultaneous combination of camptothecin and doxorubicin or etoposide was additive or antagonistic in C6 cells, slightly synergistic in the C6 CPT10 line and never more than additive in the C6 CPT50 and C6 CPT100 cell lines. The sequential combination of doxorubicin and camptothecin gave additivity in the order camptothecin → doxorubicin and antagonism in the order doxorubicin → camptothecin. Clinical protocols combining a topoisomerase I and a topoisomerase II inhibitor should be considered with caution because antagonistic effects have been observed with combinations of camptothecin and doxorubicin.