MP-Align: Alignment of Metabolic Pathways

Background Comparing the metabolic pathways of different species is useful for understanding metabolic functions and can help in studying diseases and engineering drugs. Several comparison techniques for metabolic pathways have been introduced in the literature as a first attempt in this direction. The approaches are based on some simplified representation of metabolic pathways and on a related definition of a similarity score (or distance measure) between two pathways. More recent comparative research focuses on alignment techniques that can identify similar parts between pathways. Results We propose a methodology for the pairwise comparison and alignment of metabolic pathways that aims at providing the largest conserved substructure of the pathways under consideration. The proposed methodology has been implemented in a tool called MP-Align, which has been used to perform several validation tests. The results showed that our similarity score makes it possible to discriminate between different domains and to reconstruct a meaningful phylogeny from metabolic data. The results further demonstrate that our alignment algorithm correctly identifies subpathways sharing a common biological function. Conclusion The results of the validation tests performed with MP-Align are encouraging. A comparison with another proposal in the literature showed that our alignment algorithm is particularly well-suited to finding the largest conserved subpathway of the pathways under examination

High sensitivity detection of nanoparticles permeation through polymer membranes: A physico-chemical and nuclear imaging measurement approach

Diffusion cells are devices made of donor and acceptor compartments (DC and AC), separated by a membrane. They are widely used in pharmaceutical, cosmetic, toxicology, and protective equipment tests (e.g., gloves) to measure the kinetics of permeants (molecules and nanoparticles) across biological membranes as the skin. However, rarely is the concentration of permeants in the AC measured in continuous or in real-time, and this limitation leads to significant discrepancies in the calculations of kinetic parameters that define the permeation mechanisms. In this study, a diffusion cell compatible with positron emission tomography was used to measure the permeation kinetics of nanoparticles across glove membranes. The technology allows for the measurement of nanoparticle concentration in real-time in the two compartments (DC and AC) and at a detection sensitivity several orders of magnitude higher compared with conventional spectroscopies, thus allowing a much more precise extraction of kinetic parameters. Ultra-small (<10 nm) gold nanoparticles were used as a model nanoparticle contaminant. They were radiolabeled, and their diffusion kinetics was measured in continuous through latex and nitrile polymer membranes. Permeation profiles were recorded at sub-nanomolar sensitivity and in real-time, thus allowing the high precision extraction of kinetic permeation parameters. The technology, methodology, and data extraction process developed in this work could be applied to measure in real-time the kinetics of diffusion of a whole range of potentially toxic molecules and nanoparticles across polymer membranes, including glove membranes

High-sensitivity permeation analysis of ultra-small nanoparticles across the skin by positron emission tomography (PET)

Ultrasmall nanoparticles (US-NPs; <20 nm in hydrodynamic size) are now included in a variety of pharmacological and cosmetic products, and new technologies are needed to detect at high sensitivity the passage of small doses of these products across biological barriers such as the skin. In this work, a diffusion cell adapted to positron emission tomography (PET), a highly sensitive imaging technology, was developed to measure the passage of gold NPs (AuNPs) in skin samples in continuous mode. US-AuNPs (3.2 nm diam.; TEM) were functionalized with deferoxamine (DFO) and radiolabeled with 89Zr(IV) (half-life: 3.3 days, matching the timeline of diffusion tests). The physicochemical properties of the functionalized US-AuNPs (US-AuNPs-PEG-DFO) were characterized by FTIR (DFO grafting; hydroxamate peaks: 1629.0 cm–1, 1569.0 cm–1), XPS (presence of the O═C–N C 1s peak of DFO at 287.49 eV), and TGA (organic mass fraction). The passage of US-AuNPs-PEG-DFO-89Zr(IV) in skin samples was measured by PET, and the diffusion parameters were extracted thereby. The signals of radioactive US-AuNPs-PEG-DFO-89Zr(IV) leaving the donor compartment, passing through the skin, and entering the acceptor compartment were detected in continuous at concentrations as low as 2.2 nM of Au. The high-sensitivity acquisitions performed in continuous allowed for the first time to extract the lag time to the start of permeation, the lag time to start of the steady state, the diffusion coefficients, and the influx data for AuNPs permeating into the skin. PET could represent a highly valuable tool for the development of nanoparticle-containing topical formulations of drugs and cosmetics

The Montbelleux intrusion-related Sn-W ore deposit: a witness of an underestimated Cambrian metallogenic event in the Armorican massif (France)?

International audienceDespite significant outcropping surfaces and favourable geology, pre-Variscan ore deposits remain scarce in France. This is particularly true in the north of the Armorican massif where the Neoproterozoic Cadomian orogeny is well preserved. There, the largest Cadomian terrane, the Fougères unit, is composed of turbiditic sediments affected by a low-grade metamorphism and intruded by granitoids. These metasediments are strongly folded presenting a steeply axial-plane cleavage and both bedding and cleavage strike N40°E. This deformation event is constrained at ca. 560-540 Ma (Ballèvre et al., 2001). Post-dating the folding, granodioritic plutons intrude sediments generating large contact metamorphism aureoles. Intrusions consists of large peraluminous Crd-Bt-granodiorite plutons emplaced at ca 540 Ma as well as scarce and small younger Bt-Ms-leucogranites. Finally, the Fougères unit is affect by a Cambrian extensional event marked by a local NE-SW-trending rifting, associated ash-flow Caldeiras and felsic volcanism (Le Gall, 1995). Close to the town of Fougères, several small Crd-Bt-granites and Bt-Ms-granites intrude the Fougères unit. Numerous occurrences of wolframite and cassiterite are spatially associated with these granites but only one W-Sn ore deposit has been found. This is the Montbelleux W-Sn ore deposit, constituted by at least 2 small and elongated Bt-Ms-granitic sills extended by 5 main quartz lodes (Chauris et al., 1989). The mineralisation, 17000 t Sn+WO3 of measured resources, is hosted by a quartz veins stockwork within the granite and quartz lodes within metasediments. Zircons from the Montbelleux sills have been dated by LA-ICP-MS and provide an age of 538.2 ± 6.1 Ma. Hydrothermal apatite associated with the ore stage, provide an U/Pb age of 524 ± 13 Ma, undistinguishable within error from the age of the sill intrusions. Whole-rock geochemical results show that the Montbelleux deposit belong to ore-bearing peraluminous granites (Nb/Ta)

A diffusion cell adapted to nuclear imaging instruments for the measurement of molecular release and pharmacokinetics across membranes

Diffusion cells are routinely used in pharmacology to measure the permeation of pharmaceutical compounds and contaminants across membranes (biological or synthetic). They can also be used to study drug release from excipients. The device is made of a donor (DC) and an acceptor (AC) compartment, separated by a membrane. Usually, permeation of molecules across membranes is measured by sampling from the AC at different time points. However, this process disturbs the equilibrium of the cell. Furthermore, analytical techniques used in association with diffusion cells sometimes lack either accuracy, sensitivity, or both. This work reports on the development of nuclear imaging – compatible diffusion cells. The cell is made of a polymer transparent to high-energy photons typically detected in positron emission tomography (PET). It was tested in a finite-dose set-up experiment with a pre-clinical PET system. Porous cellulose membranes (3.5, 25 and 300 kDa), a common excipient in pharmacology, as well as for dialysis membranes, were used as test membranes. The radioisotope 89Zr chelated with deferoxamine B (DFO; 0.65 kDa), was used as an imaging probe (7–10 MBq; 0.2–0.3 nMol 89Zr-DFO). In medicine, DFO is also commonly used for iron removal treatments and pharmacological formulations often require the association of this molecule with cellulose. Permeation profiles were obtained by measuring the radioactivity in the DC and AC for up to 2 weeks. The kinetic profiles were used to extract lag time, influx, and diffusion coefficients of DFO across porous cellulose membranes. A sensitivity threshold of 0.005 MBq, or 3.4 fmol of 89Zr-DFO, was revealed. The lag time to permeation (τ) measured in the AC compartment, was found to be 1.33, 0.5, and 0.19 h with 3.5, 25, and 300 kDa membranes, respectively. Diffusion coefficients of 3.65 × 10−6, 8.33 × 10−6, and 4.74 × 10−5 cm2 h−1 where revealed, with maximal pseudo steady-state influx values (Jpss) of 6.55 × 10−6, 1.76 × 10−5, and 1.29 × 10−5 nmol cm−2 h−1. This study confirms the potential of the technology for monitoring molecular diffusion and release processes at low concentrations, high sensitivities, in real time and in a visual manner. © 2021 Elsevier B.V

Structural control, magmatic-hydrothermal evolution and formation of hornfels-hosted, intrusion-related gold deposits: Insight from the Thaghassa deposit in Eastern Anti-Atlas, Morocco.

International audienceIn the Moroccan Eastern Anti-Atlas, the Thaghassa intrusion-related gold deposit is hosted in hornfelsed metasedimentary rocks that lie adjacent to the Ikniwn granodiorite. Fields studies reveal three tectono-magmatic stages controlling the formation of the deposit. i) The first stage refers to the top-to-the-south asymmetry and the syn-kinematic Ikniwn pluton emplacement controlled by a compressional or transpressional strain regime. ii) The second stage is characterized, from older to younger and further away from the intrusion, by: metatexite with leucocratic stromatic bands, aplo-pegmatite sills, intermediate veinlets composed of quartz, K-feldspar and muscovite, and then gold-bearing striped foliation-veins. All these features are assumed to have been emplaced during a large-scale ENE-WSW dextral shearing process that results from an ESE-WNW shortening direction during transtensive tectonics. We suggest that the progressive and continuous shearing was initiated since the aplo-pegmatite stage and achieved during the hydrothermal phase. The existence of intermediate veins characterized by quartz-rich core and apatite-muscovite-feldspar-rich rims demonstrates the progressive evolution from the magmatic to the hydrothermal stage and evidence for the persistence of the magmatic character, at least until the onset of the hydrothermal process. iii) The late stage developed large volcanic dyke swarm and brittle faulting.Zircon U-Pb LA-ICP-MS dating yields a Concordia age of 563.5 ± 6.3 Ma for the Ikniwn granodiorite intrusion. The fluid inclusions data besides the mineral thermometry indicate that two main types of fluids can been highlighted: i) a hot aquo-carbonic (H2O-NaCl-CO2) fluid with N2 and CH4, evolving from vapour-rich N2 and CH4 inclusions for the magmatic stage (∼550°C) to CH4-CO2 biphased inclusions for the ongoing hydrothermal stage (∼450-300°C) and ii) an always secondary low T (∼200°C) saline aqueous type (probably NaCl) free from volatiles, with very variable salinity. Eventually, we highlight that in the hornfels-hosted IRG deposits, fluid sources may originate from both magmatic processes and devolatization of the metamorphic host rocks