Compression and fracture of ordered and disordered droplet rafts

We simulate a two-dimensional array of droplets being compressed between two walls. The droplets are adhesive due to an attractive depletion force. As one wall moves toward the other, the droplet array is compressed and eventually induced to rearrange. The rearrangement occurs via a fracture, where depletion bonds are quickly broken between a subset of droplets. For monodisperse, hexagonally ordered droplet arrays, this fracture is preceded by a maximum force exerted on the walls, which drops rapidly after the fracture occurs. In small droplet arrays a fracture is a single well-defined event, but for larger droplet arrays, competing fractures can be observed. These are fractures nucleated nearly simultaneously in different locations. Finally, we also study the compression of bidisperse droplet arrays. The addition of a second droplet size further disrupts fracture events, showing differences between ideal crystalline arrays, crystalline arrays with a small number of defects, and fully amorphous arrays. These results are in good agreement with previously published experiments.Comment: 14 pages, 14 figure

Design and Synthesis of Hydroxyferroquine Derivatives with Antimalarial and Antiviral Activities

Three ferroquine (FQ) derivatives, closely mimicking the antimalarial drug hydroxychloroquine (HCQ), have been prepared. Whereas these organometallic compounds provide the expected reduced cytotoxic effects compared to FQ, they inhibit in vitro growth of Plasmodium falciparum far better than chloroquine (CQ). Moreover, this new class of bioorganometallic compounds exert antiviral effects with some selectivity toward SARS-CoV infection. These new drugs may offer an interesting alternative for Asia where SARS originated and malaria has remained endemic

Self-organisation and convection of confined magnetotactic bacteria

Funder: Natural Sciences and Engineering Research Council of Canada; doi: http://dx.doi.org/10.13039/501100000038Funder: École Supérieure de Physique et de Chimie Industrielles de la Ville de Paris; doi: http://dx.doi.org/10.13039/501100003068Abstract: Collective motion is found at all scales in biological and artificial systems, and extensive research is devoted to describing the interplay between interactions and external cues in collective dynamics. Magnetotactic bacteria constitute a remarkable example of living organisms for which motion can be easily controlled remotely. Here, we report a new type of collective motion where a uniform distribution of magnetotactic bacteria is rendered unstable by a magnetic field. A new state of “bacterial magneto-convection” results, wherein bacterial plumes emerge spontaneously perpendicular to an interface and develop into self-sustained flow convection cells. While there are similarities to gravity driven bioconvection and the Rayleigh–Bénard instability, these rely on a density mismatch between layers of the fluids. Remarkably, here no external forces are applied on the fluid and the magnetic field only exerts an external torque aligning magnetotactic bacteria with the field. Using a theoretical model based on hydrodynamic singularities, we capture quantitatively the instability and the observed long-time growth. Bacterial magneto-convection represents a new class of collective behaviour resulting only from the balance between hydrodynamic interactions and external alignment

GORAB scaffolds COPI at the trans-Golgi for efficient enzyme recycling and correct protein glycosylation

COPI is a key mediator of protein trafficking within the secretory pathway. COPI is recruited to the membrane primarily through binding to Arf GTPases, upon which it undergoes assembly to form coated transport intermediates responsible for trafficking numerous proteins, including Golgi-resident enzymes. Here, we identify GORAB, the protein mutated in the skin and bone disorder gerodermia osteodysplastica, as a component of the COPI machinery. GORAB forms stable domains at the trans-Golgi that, via interactions with the COPI-binding protein Scyl1, promote COPI recruitment to these domains. Pathogenic GORAB mutations perturb Scyl1 binding or GORAB assembly into domains, indicating the importance of these interactions. Loss of GORAB causes impairment of COPI-mediated retrieval of trans-Golgi enzymes, resulting in a deficit in glycosylation of secretory cargo proteins. Our results therefore identify GORAB as a COPI scaffolding factor, and support the view that defective protein glycosylation is a major disease mechanism in gerodermia osteodysplastica.Peer reviewe

Platinum (II) and palladium (II) complexes with (N,N') and (C,N,N') ligands derived from pyrazole as anticancer and antimalarial agents: synthesis, characterization and in vitro activities

The study of the reactivity of three 1-(2-dimethylaminoethyl)-1H-pyrazole derivatives of general formula [1-(CH2)2NMe2}-3,5-R2-pzol] {where pzol represents pyrazole and Rdouble bond; length as m-dashH (1a), Me (1b) or Ph (1c)} with [MCl2(DMSO)2] (Mdouble bond; length as m-dashPt or Pd) under different experimental conditions allowed us to isolate and characterize cis-[M{κ2-N,N′-{[1-(CH2)2NMe2}-3,5-R2-pzol])}Cl2] {MMdouble bond; length as m-dashPtPt (2a-2c) or Pd (3a-3c)} and two cyclometallated complexes [M{κ3-C,N,N′-{[1-(CH2)2NMe2}-3-(C5H4)-5-Ph-pzol])}Cl] {Mdouble bond; length as m-dashPt(II) (4c) or Pd(II) (5c)}. Compounds 4c and 5c arise from the orthometallation of the 3-phenyl ring of ligand 1c. Complex 2a has been further characterized by X-ray crystallography. Ligands and complexes were evaluated for their in vitro antimalarial against Plasmodium falciparum and cytotoxic activities against lung (A549) and breast (MDA MB231 and MCF7) cancer cellular lines. Complexes 2a-2c and 5c exhibited only moderate antimalarial activities against two P. falciparum strains (3D7 and W2). Interestingly, cytotoxicity assays revealed that the platinacycle 4c exhibits a higher toxicity than cisplatin in the three human cell lines and that the complex 2a presents a remarkable cytotoxicity and selectivity in lung (IC50 = 3 μM) versus breast cancer cell lines (IC50 > 20 μM). Thus, complexes 2c and 4c appear to be promising leads, creating a novel family of anticancer agents. Electrophoretic DNA migration studies in presence of the synthesized compounds have been performed, in order to get further insights into their mechanism of action

Recognition of methylated DNA through methyl-CpG binding domain proteins

DNA methylation is a key regulatory control route in epigenetics, involving gene silencing and chromosome inactivation. It has been recognized that methyl-CpG binding domain (MBD) proteins play an important role in interpreting the genetic information encoded by methylated DNA (mDNA). Although the function of MBD proteins has attracted considerable attention and is well characterized, the mechanism underlying mDNA recognition by MBD proteins is still poorly understood. In this article, we demonstrate that the methyl-CpG dinucleotides are recognized at the MBD–mDNA interface by two MBD arginines through an interplay of hydrogen bonding and cation-π interaction. Through molecular dynamics and quantum-chemistry calculations we investigate the methyl-cytosine recognition process and demonstrate that methylation enhances MBD–mDNA binding by increasing the hydrophobic interfacial area and by strengthening the interaction between mDNA and MBD proteins. Free-energy perturbation calculations also show that methylation yields favorable contribution to the binding free energy for MBD–mDNA complex

In vitro and in vivo antischistosomal activity of ferroquine derivatives

Schistosomiasis is a neglected tropical disease and drug-repurposing is a useful strategy to fill its exhausted drug development pipeline. The ferrocenyl analogue of chloroquine, ferroquine, is an antimalarial in late-stage drug development. The aim of the present work was to study the antischistosomal activity of ferroquine against Schistosoma mansoni adult worms and newly transformed schistosomula (NTS) in vitro and in vivo. Hydroxyl-ferroquine and ruthenoquine were included to study the potential role of reactive oxygen species in the antischistosomal activity. Chloroquine and mefloquine, the later described for its antischistosomal properties, served as comparators.; All metal complexes were shown to be moderately cytotoxic on human cervix HeLa cancer cells and human fetal lung fibroblasts MRC-5. 72 hours post-incubation NTS exposed to 33.3 µM ruthenoquine had died, while ferroquine and hydroxyl-ferroquine treated worms were strongly affected. No activity was observed treating NTS with chloroquine at 33.3 µM. Incubation of adult S. mansoni with 33.3 µM of the organometallic derivatives were highly affected in viability but were still alive 72 hours post-incubation. Mefloquine showed the highest activity against NTS and adult S. mansoni. Low total worm burden reductions of 0-36% were observed following oral administration of 200-800 mg/kg of the ferroquine derivatives to S. mansoni-infected mice.; The organometallic compounds evaluated in this study revealed moderate in vitro activity against both larval and adult stages of S. mansoni but low in vivo activity. No correlation can be drawn between the antimalarial and antischistosomal activity of chloroquine analogues and oxidative shock does not seem to play a role in the activity of these compounds against S. mansoni

Ferroquine: a new weapon in the fight against malaria

Malaria remains the first world-wide parasitic disease with an estimated 2.7 million deaths per year, most of them occurring in Africa. The parasite, Plasmodium falciparum, has demonstrated its extreme skill at adapting to all drugs currently in use (like chloroquine (CQ)) and resistance to these drugs has spread almost all over the world. Therefore (multi)drug resistance has become one of the most important problems. Whereas the discovery of an antimalarial compound with no possibility of resistance seems utopian, new strategies have been developed to overcome the situation. The most promising results come from the new area of bioorganometallic chemistry with the synthetic compound Ferroquine (FQ). In vitro, FQ inhibits at nanomolar concentrations the growth of chloroquino-resistant strains and isolates P. falciparum. Its schizontocidal activity was confirmed in murine models. Chemical modifications of FQ were attempted to correlate structure with activity. Some physicochemical properties of FQ were investigated to elucidate its mechanism of action. This strategy, based on incorporation of an organometallic moiety into the "standard" drug, offers new possibilities in reversal of resistance and therapeutic application. The review will conclude by presenting the present industrial development of FQ. © 2004 Bentham Science Publishers Ltd.SCOPUS: re.jinfo:eu-repo/semantics/publishe

Avancées dans la compréhension des mécanismes d'action d'agents anti-apicomplexes (de la conception à l'imagerie in vitro)

Les apicomplexes sont des organismes intracellulaires intervenant dans de nombreuses pathologies humaines. Parmi celles-ci le fléau du paludisme continue de tuer plus de 600000 personnes chaque année. Malgré tous les efforts déployés par les autorités de santé, le parasite du paludisme a développé de nombreuses résistances à tous les antipaludiques. Les alternatives aux traitements actuels sont donc très attendues. Le développement efficace de nouvelles molécules doit passer par la compréhension complète des mécanismes d action des molécules actuelles et par la connaissance des mécanismes de résistance développés par le parasite. Dans ce travail de thèse, nous nous sommes intéressés à la compréhension du mécanisme d action de la Ferroquine, un candidat médicament en développement par la Sanofi. Nous avons étudié l impact de sa structure originale et de ses propriétés physico-chimiques sur son activité antipaludique. D autre part, des études d imagerie ont permis d étudier l accumulation et la localisation de cette molécule. Dans une seconde partie, nous nous sommes intéressés au développement d analogues de la ciprofloxacine. Dans des études antérieures de pharmacomodulation ont montré que la transformation de la ciprofloxacine en prodrogue et l insertion d un ferrocène dans sa structure permettent une augmentation de l activité. Ces travaux de thèse ont permis d étudier l influence du ferrocène sur l activité de ces molécules. Des études d imagerie ont également été mises en oeuvre sur cette famille de composés.Apicomplexa parasites are intracellular organisms involved in many human diseases. Among them the scourge of malaria continues to kill over 600,000 people each year. Despite all efforts of health authorities, the malaria parasite has developed resistance to all antimalarial drugs and alternatives to current treatments are eagerly awaited. The development of effective new drugs must go through a complete understanding of molecular mechanisms of action of current drug and knowledge of resistance mechanisms developed by the parasite. In this thesis, we were interested in understanding the mechanism of action of Ferroquine, a drug candidate in development by Sanofi. We studied the impact of its original structure and its physico-chemical properties on its antimalarial activity. On the other hand, imaging studies have investigated the accumulation and localization of this molecule. In the second part, we were interested in developing analogues of ciprofloxacin. Previous pharmacomodulation studies showed that the transformation of ciprofloxacin into a prodrug and the insertion of a ferrocene into its structure allow an increase in activity. This thesis has investigated the influence of ferrocene on the activity of these molecules. Imaging studies were also carried out on this family of compounds.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF