Imidazo[1,2-a]pyridine and Imidazo[1,5-a]pyridine: Electron Donor Groups in the Design of D-π-A Dyes.

This work investigates the electron-donating capabilities of two 10-π electron nitrogen bridgehead bicyclic [5,6]-fused ring systems, imidazo[1,2-a]pyridine and imidazo[1,5-a]pyridine rings. Eight compounds with varying positions of electron-withdrawing moieties (TCF or DCI) coupled to the imidazopyridine ring were synthesized and studied. DCI-containing compounds (Ib-IVb) exhibited a purely dipolar nature with broad absorption bands, weak fluorescence, large Stokes shifts, and strong solvatochromism. In contrast, TCF-containing compounds (Ia-IVa) demonstrated diverse properties. Imidazo[1,2-a]pyridine derivatives Ia and IIa were purely dipolar, while imidazo[1,5-a]pyridine derivatives IIIa and IVa displayed a cyanine-like character with intense absorption and higher quantum yields of emission. The observed gradual red shift in optical properties with changing electron-donor groups (IIb < Ib < IIIb < IVb) and (IIa < Ia < IIIa < IVa) underscores the stronger electron-donor character of imidazo[1,5-a]pyridine compared to that of imidazo[1,2-a]pyridine. Furthermore, crystalline powders of imidazo[1,2-a]pyridine derivatives exhibited fluorescence despite minimal emission in solution. Two compounds (Ib and IVa) were successfully formulated into nanoparticles for potential in vivo imaging applications in zebrafish embryos.

Development of targeted photodynamic therapy drugs by combining a zinc phthalocyanine sensitizer with TSPO or EGFR binding groups: the impact of the number of targeting agents on biological activity.

Drug-targeted delivery has become a top priority in the world of medicine in order to develop more efficient therapeutic agents. This is important as a critical underlying problem in cancer therapy stems from the inability to deliver active therapeutic substances directly to tumor cells without causing collateral damage. In this work, zinc(II) phthalocyanine (ZnPc) was selected as a sensitizer and was linked to different targeting agents, which would be recognized by overexpressed proteins in cancer cells. As targeting agents, we first selected the two ligands (DAA1106, PK11195) of the translocator protein (TSPO) and then Erlotinib a binding group of the ATP domain of tyrosine kinase in epidermal growth factor (EGFR). ZnPc was connected via an ethylene glycol chain to either one (n = 1) or four (n = 4) targeting agents. The biological activity of these conjugates ZnPc(ligand)n was investigated on MDA-MB-231 breast human cancer cells and human hepatoma HepG2 cells, first in the dark (cytotoxicity) and then under irradiation (photodynamic therapy). The dark cytotoxicity was extremely low (IC50 ≥ 50 µM) for all of these compounds, which is a required criterion for further photodynamic application. After irradiation at 650 nm, only the conjugates bearing one targeting ligand such as ZnPc-[DAA1106]1, ZnPc-[PK11195]1, and ZnPc-[Erlo]1 showed photodynamic activity, while those linked to 4 targeting agents were inactive. Importantly, fluorescence imaging microscopy showed the colocalization of ZnPc-[DAA1106]1, ZnPc-[PK11195]1 and ZnPc-[erlo]1, at mitochondria, a result that justifies the observed photodynamic activity of these conjugates. This study first shows the impact of the number and the mode of organization of targeting agents on the ability of the sensitizer to cross the cell membrane. When zinc(II) phthalocyanine carries a single targeting agent, a significant photodynamic activity on MDA-MB-231 breast human cancer cells was measured and localization at the mitochondria was demonstrated by fluorescence imaging, thus proving the potential of the sensitizer linked to a targeting agent to improve selectivity. Another important conclusion from this study for the design of future effective PDT drugs using multivalence effects is to control the arrangement of the targeting agents in order to design molecules that will be able to pass the cell membrane barriers.

Determination of the Rituximab Binding Site to the CD20 Epitope Using SPOT Synthesis and Surface Plasmon Resonance Analyses.

Antibodies not only play a major role in clinical diagnostics and biopharmaceutical analysis but also are a class of drugs that are regularly used to treat numerous diseases. The identification of antibody-epitope binding sites is then of great interest to many emerging medical and bioanalytical applications, particularly to design monoclonal antibodies (mAb) mimics taking advantage of amino acid residues involved in the binding. Among relevant antibodies, the monoclonal antibody rituximab has received significant attention as it is exploited to treat several cancers including non-Hodgkin's lymphoma and chronic lymphocytic leukemia, as well as some autoimmune disorders such as rheumatoid arthritis. The binding of rituximab to the targeted cells occurs via the recognition of the CD20 epitope. A crystallographic study has shown that the binding area, named paratope, is located at the surface of rituximab. Combining the SPOT method and the complementary surface plasmon resonance technique allowed us to detect an extended recognition domain buried in the pocket of the rituximab Fab formed by four ß-sheets. More generally, the present study offers a comprehensive approach to identify antibody-epitope binding sites.

Pyclen-Based Ln(III) Complexes as Highly Luminescent Bioprobes for In Vitro and In Vivo One- and Two-Photon Bioimaging Applications.

In addition to the already described ligand L4a, two pyclen-based lanthanide chelators, L4b and L4c, bearing two specific picolinate two-photon antennas (tailor-made for each targeted metal) and one acetate arm arranged in a dissymmetrical manner, have been synthesized, to form a complete family of lanthanide luminescent bioprobes: [EuL4a], [SmL4a], [YbL4b], [TbL4c], and [DyL4c]. Additionally, the symmetrically arranged regioisomer L4a' was also synthesized as well as its [EuL4a'] complex to highlight the astonishing positive impact of the dissymmetrical N-distribution of the functional chelating arms. The investigation clearly shows the high performance of each bioprobe, which, depending on the complexed lanthanide, could be used in various applications. Each presents high brightness, quantum yields, and lifetimes. Staining of the complexes into living human breast cancer cells was observed. In addition, in vivo two-photon microscopy was performed for the first time on a living zebrafish model with [EuL4a]. No apparent toxicity was detected on the growth of the zebrafish, and images of high quality were obtained.

PEPOP 2.0: new approaches to mimic non-continuous epitopes.

BACKGROUND: Bioinformatics methods are helpful to identify new molecules for diagnostic or therapeutic applications. For example, the use of peptides capable of mimicking binding sites has several benefits in replacing a protein which is difficult to produce, or toxic. Using peptides is less expensive. Peptides are easier to manipulate, and can be used as drugs. Continuous epitopes predicted by bioinformatics tools are commonly used and these sequential epitopes are used as is in further experiments. Numerous discontinuous epitope predictors have been developed but only two bioinformatics tools have been proposed so far to predict peptide sequences: Superficial and PEPOP 2.0. PEPOP 2.0 can generate series of peptide sequences that can replace continuous or discontinuous epitopes in their interaction with their cognate antibody. RESULTS: We have developed an improved version of PEPOP (PEPOP 2.0) dedicated to answer to experimentalists' need for a tool able to handle proteins and to turn them into peptides. The PEPOP 2.0 web site has been reorganized by peptide prediction category and is therefore better formulated to experimental designs. Since the first version of PEPOP, 32 new methods of peptide design were developed. In total, PEPOP 2.0 proposes 35 methods in which 34 deal specifically with discontinuous epitopes, the most represented epitope type in nature. CONCLUSION: Through the presentation of its user-friendly, well-structured new web site conceived in close proximity to experimentalists, we report original methods that show how PEPOP 2.0 can assist biologists in dealing with discontinuous epitopes.

Topological Requirements for CI-M6PR-Mediated Cell Uptake.

The 300 kDa cation-independent M6P receptor (CI-MPR) mediates ligand internalization and trafficking to the endolysosomal compartments. Because of its endocytotic nature, it has been recognized as a promising class of receptors for target component delivery. Its cellular uptake involves the simultaneous binding of two protein units resulting in the formation of receptor dimers. While many multivalent glycoconjugates have been reported to date, little is known about the topological requests to induce an effective recruitment of CI-MPRs. We herein describe the synthesis and cell uptake ability of a set of highly organized glycoclusters bearing one to three saccharide units. The spatial arrangement of carbohydrate ligands is ensured by a heterocyclic γ-peptide central core.

A "Multi-Heavy-Atom" Approach toward Biphotonic Photosensitizers with Improved Singlet-Oxygen Generation Properties.

Two trispicolinate 1,4,7-triazacyclonane (TACN)-based ligands bearing three picolinate biphotonic antennae were synthetized and their Yb3+ and Gd3+ complexes isolated. One series differs from the other by the absence (L1 )/presence (L2 ) of bromine atoms on the antenna backbone, offering respectively improved optical and singlet-oxygen generation properties. Photophysical properties of the ligands, complexes and micellar Pluronic suspensions were investigated. Complexes exhibit high two-photon absorption cross-section combined either with NIR emission (Yb) or excellent 1 O2 generation (Gd). The very large intersystem crossing efficiency induced by the combination of bromine atom and heavy rare-earth element was corroborated with theoretical calculations. The 1 O2 generation properties of L2 Gd micellar suspension under two-photon activation leads to tumour cell death, suggesting the potential of such structures for theranostic applications.

Synthesis and Anticancer Activity of Gold Porphyrin Linked to Malonate Diamine Platinum Complexes.

Recently, gold(III) porphyrins have gained great interest as anticancer drugs not only for the stability of gold(III) but also for the functionalization of the porphyrin to allow bridging with another metal such as platinum(II). We report here, for the first time, the synthesis of three new bimetal compounds containing a gold(III) porphyrin conjugated to a platinum diamine moiety through malonate bridging to obtain enhanced cytotoxicity from both metals combined with the phototoxicity of the porphyrin. The three complexes differ in the type of diamine ligand around platinum(II): ammonia (NH3), cyclohexanediamine (CyDA), and pyridylmethylamine (Py). The synthesis was carried out using the complexation of activated malonic acid derivatives with aquadiaminoplatinum(II) complexes, and the products were characterized by IR, NMR, mass spectra, and elementary analysis. The cytotoxic activity of the conjugates was screened in both healthy cell lines and cancer cell lines, human fibroblast cells (FS-68) and human breast cancer cells (MCF-7), and was compared to that of the corresponding platinum(II) complexes. The cyclohexyldiamine (CyDA) derivative exhibited the greatest cytotoxic effect among the series. The results showed that Au(III)/Pt(II) conjugates are more potent by 2-5.6-fold than the corresponding platinum complexes. Moreover, the dyad AuP-PtCyDA is 18% more potent and also more selective toward cancer cells than the parent gold porphyrin substituted with malonic acid. On the other hand, the IC50 of the dyad AuP-PtCyDA is 43% lower than that of AuTPP but is more selective toward healthy cells. Singlet oxygen measurements indicated that gold(III) porphyrin derivatives are poor oxygen sensitizers and cell death occurred potentially due to generation of other reactive oxygen species (ROS) upon reductive quenching of the gold porphyrin excited state. In addition, the increase in cancer cell death obtained after light irradiation is totally absent in healthy cells, demonstrating the specificity of this PDT treatment on cancer cells. Our findings imply that the incorporation of two different cytotoxic metals in the same molecule represents a remarkable cytotoxic effect in comparison to traditional homometallic Pt(II) drugs.

Efficient Photodynamic Therapy of Prostate Cancer Cells through an Improved Targeting of the Cation-Independent Mannose 6-Phosphate Receptor.

The aim of the present work is the development of highly efficient targeting molecules to specifically address mesoporous silica nanoparticles (MSNs) designed for the photodynamic therapy (PDT) of prostate cancer. We chose the strategy to develop a novel compound that allows the improvement of the targeting of the cation-independent mannose 6-phosphate receptor, which is overexpressed in prostate cancer. This original sugar, a dimannoside-carboxylate (M6C-Man) grafted on the surface of MSN for PDT applications, leads to a higher endocytosis and thus increases the efficacy of MSNs.

Encapsulation of Upconversion Nanoparticles in Periodic Mesoporous Organosilicas.

(1) Background: Nanomedicine has recently emerged as a promising field, particularly for cancer theranostics. In this context, nanoparticles designed for imaging and therapeutic applications are of interest. We, therefore, studied the encapsulation of upconverting nanoparticles in mesoporous organosilica nanoparticles. Indeed, mesoporous organosilica nanoparticles have been shown to be very efficient for drug delivery, and upconverting nanoparticles are interesting for near-infrared and X-ray computed tomography imaging, depending on the matrix used. (2) Methods: Two different upconverting-based nanoparticles were synthesized with Yb3+-Er3+ as the upconverting system and NaYF4 or BaLuF5 as the matrix. The encapsulation of these nanoparticles was studied through the sol-gel procedure with bis(triethoxysilyl)ethylene and bis(triethoxysilyl)ethane in the presence of CTAB. (3) Results: with bis(triethoxysilyl)ethylene, BaLuF5: Yb3+-Er3+, nanoparticles were not encapsulated, but anchored on the surface of the obtained mesoporous nanorods BaLuF5: Yb3+-Er3+@Ethylene. With bis(triethoxysilyl)ethane, BaLuF5: Yb3+-Er3+ and NaYF4: Yb3+-Er3+nanoparticles were encapsulated in the mesoporous cubic structure leading to BaLuF5: Yb3+-Er3+@Ethane and NaYF4: Yb3+-Er3+@Ethane, respectively. (4) Conclusions: upconversion nanoparticles were located on the surface of mesoporous nanorods obtained by hydrolysis polycondensation of bis(triethoxysilyl)ethylene, whereas encapsulation occurred with bis(triethoxysilyl)ethane. The later nanoparticles NaYF4: Yb3+-Er3+@Ethane or BaLuF5: Yb3+-Er3+@Ethane were promising for applications with cancer cell imaging or X-ray-computed tomography respectively.

Malaria Hyperendemicity and Risk for Artemisinin Resistance among Illegal Gold Miners, French Guiana.

To assess the prevalence of malaria among illegal gold miners in the French Guiana rainforest, we screened 205 miners during May-June 2014. Malaria prevalence was 48.3%; 48.5% of cases were asymptomatic. Patients reported self-medication with artemisinin-based combination therapy. Risk for emergence and spread of artemisinin resistance among gold miners in the rainforest is high.

How exogenous ligand enhances the efficiency of cadmium phytoextraction from soils?

Many experiments showed that exogenous ligands could enhance cadmium (Cd) phytoextraction efficiency in soils. Previous studies suggested that the dissociation and the apoplastic uptake of Cd complex could not fully explain the increase of root Cd uptake. Two hypotheses are evaluated to explain enhanced Cd uptake in the presence of ligand: i) enhanced apoplastic uptake of complex due to reduced apoplastic resistance and ii) complex internalization by membrane transporters. RESULTS: show that the ligand affinity for Cd is a key characteristic determining the potential mechanism for enhanced Cd uptake. When low molecular weight organic acids are applied, the complex dissociation could generally be fast (> 10-3.3 s-1) and result in the increased Cd uptake. When hydrophilic aminopolycarboxylic acids (APCAs) are applied in experiments without water or temperature stresses to the plant, the root water uptake flux could very likely be high (> 10-7.8 dm s-1), and the strong apoplastic complex uptake could enhance the root Cd uptake. When lipophilic APCAs are applied, the strong internalization of the complex by membrane transporters could result in the increased Cd uptake if the maximum internalization rate is high (> 10-12 mol dm-2 s-1). However, the complex internalization by membrane transporters must be experimentally confirmed.

Cadmium partitioning between hulls and kernels in three sunflower varieties: consequences for food/feed chain safety.

Contamination of sunflower seeds with soil Cd is an important issue for food and feed because this species strongly accumulates this metal. The present work reports that seeds from three sunflower varieties (ES Biba, Extrasol, Vellox) cultivated in the field in a calcareous agricultural soil having a moderately high Cd content (1 mg Cd/kg) had Cd contents of 0.84, 0.88 and 0.76 mg Cd/kg, respectively, all exceeding the regulation limit of 0.5 mg Cd/kg seeds for human food. On average, for the three varieties, washing seeds did not affect their total Cd contents but slightly increased the Cd in the kernels at the expense of that in hulls. Despite the Cd content of the whole seeds not differing between the varieties, the Cd fraction in the edible kernel differed significantly between varieties from 78 to 87% of the total seed Cd. The results of this study suggest that (i) the size of the kernel, relative to that of the hull, may affect the dilution of Cd in kernel tissues and (ii) there might be genetic variability for the capacity of transfer of Cd from the hull to the kernel. This opens the perspective to increase food safety by selecting sunflower genotypes that retain more Cd into the hull and transfer less of it to the edible kernel.

Exceptional anticancer photodynamic properties of [1,4-Bis(3,6,9,12-Tetraoxatridec-1-yloxy)phthalocyaninato]zinc(II).

Phthalocyanines have been described as effective photosensitizers for photodynamic therapy and are therefore, being studied for their biomedical applications. The metalation of photosensitizers can improve their photodynamic therapy potential. Here, we focus on the biological properties of [1,4-Bis(3,6,9,12-Tetraoxatridec-1-yloxy)phthalocyaninato]zinc(II) (ZnPc(αEG4)2) and demonstrate its exceptional anticancer activity upon light stimulation to kill preferentially cancer cells with a start of efficiency at 10 pM. Indeed, in this work we highlighted the high selectivity of ZnPc(αEG4)2 for cancer cells compared with healthy ones and we establish its mechanism of action, enabling us to conclude that ZnPc(αEG4)2 could be a powerful tool for cancer therapy.

Amphiphilic Single-Chain Polymer Nanoparticles as Imaging and Far-Red Photokilling Agents for Photodynamic Therapy in Zebrafish Embryo Xenografts.

This work introduces rationally designed, improved amphiphilic single-chain polymer nanoparticles (SCNPs) for imaging and photodynamic therapy (PDT) in zebrafish embryo xenografts. SCNPs are ultrasmall polymeric nanoparticles with sizes similar to proteins, making them ideal for biomedical applications. Amphiphilic SCNPs result from the self-assembly in water of isolated synthetic polymeric chains through intrachain hydrophobic interactions, mimicking natural biomacromolecules and, specially, proteins (in size and when loaded with drugs, metal ions or fluorophores also in function). These ultrasmall, soft nanoparticles have various applications, including catalysis, sensing, and nanomedicine. Initial in vitro experiments with nonfunctionalized, amphiphilic SCNPs loaded with a photosensitizing Zn phthalocyanine with four nonperipheral isobutylthio substituents, ZnPc, showed promise for PDT. Herein, the preparation of improved, amphiphilic SCNPs containing ZnPc as highly efficient photosensitizer encapsulated within the nanoparticle and surrounded by anthracene units is disclosed. The amount of anthracene groups and ZnPc molecules within each single-chain nanoparticle controls the imaging and PDT properties of these nanocarriers. Critically, this work opens the way to improved PDT applications based on amphiphilic SCNPs as a first step toward ideal, long-term artificial photo-oxidases (APO).

Variation in Pyrethroid Resistance Phenotypes in Anopheles darlingi in an Area with Residual Malaria Transmission: Warning of Suspected Resistance in French Guiana.

Anopheles darlingi is the main vector of malaria in South America. In French Guiana, malaria transmission occurs inland and along the rivers with a regular reemergence in the lower Oyapock area. Control against malaria vectors includes indoor residual spraying of deltamethrin and the distribution of long-lasting impregnated bednets. In this context, the level of resistance to pyrethroids was monitored for 4 years using CDC bottle tests in An. darlingi populations. A loss of susceptibility to pyrethroids was recorded with 30-minute knock-down measured as low as 81%. However, no pyrethroid molecular resistance was found by sequencing a 170 base pair fragment of the S6 segment of domain II of the voltage-gated sodium channel gene. Fluctuation of resistance phenotypes may be influenced by the reintroduction of susceptible alleles from sylvatic populations or by other mechanisms of metabolic resistance.

Novel Biocompatible Trianglamine Networks for Efficient Iodine Capture.

Herein, we report for the first time a biocompatible cross-linked trianglamine (Δ) network for the efficient iodine removal from the vapor phase, water, and seawater. In the vapor phase, the cross-linked network could capture 6 g g-1 of iodine, ranking among the most performant materials for iodine vapor capture. In the liquid phase, this cross-linked network is also capable of capturing iodine at high rates from aqueous media (water and seawater). This network displayed fast adsorption kinetics, and they are fully recyclable. This study reveals the high affinity of iodine for the intrinsic cavity of the trianglamine. The synthesized materials are extremely interesting since they are environmentally friendly and inexpensive and the synthesis could easily be scaled up to be used as the material of choice in response to accidents in the nuclear industry.

Two-Photon Light Trigger siRNA Transfection of Cancer Cells Using Non-Toxic Porous Silicon Nanoparticles.

The concept of using two-photon excitation in the NIR for the spatiotemporal control of biological processes holds great promise. However, its use for the delivery of nucleic acids has been very scarcely described and the reported procedures are not optimal as they often involve potentially toxic materials and irradiation conditions. This work prepares a simple system made of biocompatible porous silicon nanoparticles (pSiNP) for the safe siRNA photocontrolled delivery and gene silencing in cells upon two-photon excitation. PSiNP are linked to an azobenzene moiety, which possesses a lysine group (pSiNP@ICPES-azo@Lys) to efficiently complex siRNA. Non-linear excitation of the two-photon absorber system (pSiNP) followed by intermolecular energy transfer (FRET) to trans azobenzene moiety, result in the photoisomerization of the azobenzene from trans to cis and in the destabilization of the azobenzene-siRNA complex, thus inducing the delivery of the cargo siRNA to the cytoplasm of cells. Efficient silencing in MCF-7 expressing stable firefly luciferase with siRNAluc against luciferase is observed. Furthermore, siRNA against inhibitory apoptotic protein (IAP) leads to over 70% of MCF-7 cancer cell death. The developed technique using two-photon light allows a unique high spatiotemporally controlled and safe siRNA delivery in cells in few seconds of irradiation.

Psychological distress and post-traumatic growth in France during the COVID-19 pandemic: A mediation model of psychosocial safety climate as a determinant of work performance.

The psychosocial safety climate (PSC) reflects workers' perceptions of senior management's concern for mental health. Because the COVID-19 pandemic has exacerbated organizational issues, PSC could be a target for interventions attempting to preserve both the psychological health of employees and the economic health of companies. This study examines the direct and indirect relationships between PSC and work performance through two indicators of psychological health, psychological distress and post-traumatic growth, during a health crisis, i.e., prior to the second confinement in France. To this end, 2,004 participants from the French workforce completed a survey in October 2020. The results of mediation analyses indicate that PSC has a direct and positive influence on post-traumatic growth (PTG) and performance, as well as a direct negative influence on psychological distress. PSC also has an indirect positive influence on performance via psychological distress. Organizations that wish to jointly address mental health and performance at work would benefit from optimizing PSC.

Do DOM optical parameters improve the prediction of copper availability in vineyard soils?

Accumulation of copper (Cu) in soils due to the application of fungicides may be toxic for organisms and hence affect winegrowing sustainability. Soil parameters such as pH and dissolved organic matter (DOM) are known to affect the availability of Cu. In this study, we investigated the contribution of chromophoric and fluorescent DOM properties to the prediction of Cu availability in 18 organic vineyard soils in the Bordeaux winegrowing area (France). The DOM parameters, assessed through absorbance and fluorescence analyses, and proxies for Cu availability (total soluble Cu and free ionic Cu2+) were measured in 0.01 M KCl extracts. Total soluble Cu (CuKCl) varied 23-fold while free ionic Cu2+ varied by a factor of 4600 among the soils. DOC concentrations were similar among the soils, but the samples differed in the quality of DOM as assessed by optical spectroscopy. Multilinear regression models with and without DOM quality parameters were investigated to predict Cu availability. The best model for CuKCl successfully explained 83% of variance and included pH, CuT, and two DOM fluorescence quality indices, the FI fluorescence index, which distinguishes between microbial and higher plant origins, and the HIX humification index. For the prediction of Cu2+, pH alone explained 88% of variance and adding DOM parameters did not improve modelling. The two Cu availability proxies were related to pH. This study confirms the prominent role of pH in Cu availability and underlines the importance of DOM quality to better predict Cu solubility.