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A metal complex bearing 1,3,5-triaza-7-phosphaadamantane and terpyridine scaffolds as a single polydentate ligand was used as a recyclable catalyst for synthesizing the nylon precursor, KA oil.

This study examines the differences in using two primary methods for adsorbing TMPO onto acid catalysts and their influence on the NMR spectra of TMPO-loaded zeolites. The findings show that TMPO molecules interact with both Brønsted and Lewis acid sites, and that the amount of (TMPO)2H+ dimers formed increases with the amount of TMPO added. The use of dichloromethane as a solvent inhibits the formation of dimers and crystalline TMPO but may lead to inaccurate estimations of acid site strength and quantification due to interactions with residual solvent molecules. The gas-phase method is preferred for adsorbing TMPO onto zeolites, but caution is needed to avoid forming a high number of dimers that make interpretation of the NMR spectra challenging. published

The identification of acid and nonacid species at the external surface of zeolites remains a major challenge, in contrast to the extensively-studied internal acid sites. Here, it is shown that the synthesis of zeolite ZSM-5 samples with distinct particle sizes, combined with solid-state NMR and computational studies of trimethylphosphine oxide (TMPO) adsorption, provides insight into the chemical species on the external surface of the zeolite crystals. 1 H-31 P HETCOR NMR spectra of TMPO-loaded zeolites exhibit a broad correlation peak at δP ∼35-55 ppm and δH ∼5-12 ppm assigned to external SiOH species. Pore-mouth Brønsted acid sites exhibit 31 P and 1 H NMR resonances and adsorption energies close to those reported for internal acid sites interacting with TMPO. The presence of an external tricoordinate Al-Lewis site interacting strongly with TMPO is suggested, resulting in 31 P resonances that overlap with the peaks usually ascribed to the interaction of TMPO with Brønsted sites. published

Magnetic Resonance Imaging (MRI) T

The correct parametrization of lanthanide complexes is of the utmost importance for their characterization using computational tools such as molecular dynamics simulations. This allows the optimization of their properties for a wide range of applications, including medical imaging. Here we present a systematic study to establish the best strategies for the correct parametrization of lanthanide complexes using [Gd(DOTA)]

Increased life expectancy leads to older and frailer surgical patients. Co-management between medical and surgical specialities has proven favourable in complex situations. Selection of patients for co-management is full of difficulties. The aim of this study was to develop a clinical decision support tool to select surgical patients for co-management.Clinical data was collected from patient electronic health records with an ICD-9 code for colorectal surgery from January 2012 to December 2015 at a hospital in Lisbon. The outcome variable consists in co-management signalling. A dataset from 344 patients was used to develop the prediction model and a second data set from 168 patients was used for external validation.Using logistic regression modelling the authors built a five variable (age, burden of comorbidities, ASA-PS status, surgical risk and recovery time) predictive referral model for co-management. This model has an area under the curve (AUC) of 0.86 (95% CI: 0.81 - 0.90), a predictive Brier score of 0.11, a sensitivity of 0.80, a specificity of 0.82 and an accuracy of 81.3%.Early referral of high-risk patients may be valuable to guide the decision on the best level of post-operative clinical care. We developed a simple bedside decision tool with a good discriminatory and predictive performance in order to select patients for comanagement.A simple bed-side clinical decision support tool of patients for co-management is viable, leading to potential improvement in early recognition and management of postoperative complications and reducing the 'failure to rescue'. Generalizability to other clinical settings requires adequate customization and validation.Introdução: O aumento da esperança média de vida leva a que a população cirúrgica seja cada vez mais velha e frágil. Os modelos colaborativos de co-gestão entre especialidades médicas e cirúrgicas têm demonstrado ser favoráveis em situações complexas. A selecção de doentes para co-gestão está repleta de dificuldades. O objectivo deste estudo foi construir uma ferramenta de apoio à decisão para selecionar doentes de submetidos a cirurgia colo-rectal para co-gestão. Material e Métodos: A informação clínica foi colhida dos processos clínicos electrónicos de doentes que tiveram um código ICD-9 de cirurgia colo-rectal no período de janeiro 2012 a dezembro 2015, num hospital em Lisboa. A variável resposta consiste na sinalização para co-gestão. Um conjunto de dados de 344 doentes foi usado para o desenvolvimento do modelo predictivo e, um segundo conjunto de dados de 168 doentes foi usado para a validação externa do modelo. Resultados: Os autores construíram um modelo predictivo, de regressão logística, com cinco variáveis clínicas (idade, carga de co-morbilidades, ASA-PS status, risco cirúrgico e tempo de recobro) para predizer a selecção de doentes para co-gestão. O modelo tem uma área sob a curva (AUC) de 0,86 (95% IC: 0,81 - 0,90), um score predictivo de Brier de 0,11, uma sensibilidade de 0,80, uma especificidade de 0,82 e uma precisão de classificação de 81,3%. Discussão: A sinalização precoce dos doentes de alto risco ajuda a definir o melhor nível de cuidados ao doente operado. Desenvolvemos uma ferramenta de apoio à decisão, simples, aplicável à cabeceira do doente com uma boa capacidade discriminativa e preditiva para seleccionar os doentes para co-gestão. Conclusão: A selecção de doentes para co-gestão entre a cirurgia e a medicina interna permite o reconhecimento e a correcção precoce de complicações pós-operatórias reduzindo o ‘failure to rescue’. A ferramenta, uma vez customizada e validada, poderá ser aplicada em outros cenários clínicos.

International audience; Amyloid forms of many different proteins have been long identified as relevant biomarkers in important pathologies with high societal impact, including Aβ in Alzheimer's disease, amylin in type 2 diabetes, α-synuclein in Parkinson's disease, etc. With over eighty novel complexes reported in the last six years, metal-based agents designed for the detection of such amyloid fibrils represent a rapidly growing field in molecular imaging. While the majority of these examples are radiocomplexes for nuclear imaging and focus on the detection of Aβ in Alzheimer's disease, there is increasing interest in other peptides and pathologies, and few studies are also directed at magnetic resonance imaging probes. In this review, we survey the recent literature according to the chemical nature of the amyloid recognition moieties, most of which are derived from a few basic structures, including benzothiazole, benzofuran or stilbene. Relationships between chemical structure and amyloid binding properties and biodistribution, in particular brain delivery and brain clearance, are outlined in order to help further work in this emerging area of research.

International audience; The photophysical properties of Eu3+ and Tb3+ complexes of DOTAGA and DO3A-monoamide conjugates of the Pittsburgh compound B (PiB) chromophore, prepared using linkers of different lengths and flexibilities, and which form stable negatively charged (LnL1), and uncharged (LnL2) complexes, respectively, were studied as potential probes for optical detection of amyloid aggregates. The phenylbenzothiazole (PiB) moiety absorbs light at wavelengths longer than 330 nm with a high molar absorption coefficient in both probes, and acts as an antenna in these systems. The presence of the luminescent Ln3+ ion quenches the excited states of PiB through an energy transfer process from the triplet state of PiB to the metal centre, and structured emission is seen from Eu3+ and Tb3+. The luminescence study indicates the presence of a 5D4 → T1 back transfer process in the Tb3+ complexes. It also provides insights on structural properties of the Eu3+ complexes, such as the high symmetry environment of the Eu3+ ion in a single macrocyclic conformation and the presence of one water molecule in its inner coordination sphere. The overall quantum yield of luminescence of EuL1 is higher than for EuL2. However, their low values reflect the low overall sensitization efficiency of the energy transfer process, which is a consequence of the large distances between the metal center and the antenna, especially in the EuL2 complex. DFT calculations confirmed that the most stable conformation of the Eu3+ complexes involves a combination of a square antiprismatic (SAP) geometry of the chelate and an extended conformation of the linker. The large calculated average distances between the metal center and the antenna point to the predominance of the Förster energy transfer mechanism, especially for EuL2. This study provides insights into the behavior of amyloid-targeted Ln3+ complexes as optical probes, and contributes towards their rational design.

Extracellular pH is an important biomarker in many diseases yet a routine method for imaging tissue pH has not been established in the clinic. Paramagnetic chemical exchange saturation transfer (paraCEST) agents are well-suited for imaging tissue pH because the basis of CEST, chemical exchange, is inherently sensitive to pH. Several previous pH-sensitive paraCEST agents were based upon with an exchanging Ln 3+ bound water molecule as the CEST antenna but this design often added additional line-broadening of the bulk water signal due to T 2 exchange. We report here a pH-sensitive paraCEST agent that lacks an inner-sphere water molecule but contains one Ln-bound -OH group for CEST activation. The Yb 3+ - complex, Yb( 1 ), displayed a single, highly-shifted CEST peak originating from the exchangeable Yb-OH proton, the frequency of which changed over the biologically relevant pH range. CEST images of phantoms ranging in pH from 6-8 demonstrate the potential of this agent for imaging pH. Initial rodent imaging studies showed that Gd( 1 ) remains in the vascular system much longer than anticipated but is cleared slowing via renal filtration.

RATIONALE AND OBJECTIVES Liver inflammation is associated with nonalcoholic steatohepatitis and other pathologies, but noninvasive methods to assess liver inflammation are limited. Inflammation causes endothelial disruption and leakage of plasma proteins into the interstitial space and can result in extravascular coagulation with fibrin deposition. Here we assess the feasibility of using the established fibrin-specific magnetic resonance probe EP-2104R for the noninvasive imaging of fibrin as a marker of liver inflammation. METHODS Weekly 100 mg/kg diethylnitrosamine (DEN) dosing was used to generate liver fibrosis in male rats; control animals received vehicle. Magnetic resonance imaging at 1.5 T with EP-2104R, a matched non-fibrin-binding control linear peptide, or the collagen-specific probe EP-3533 was performed at 1 day or 7 days after the last DEN administration. Imaging data were compared with quantitative histological measures of fibrosis and inflammation. RESULTS After 4 or 5 DEN administrations, the liver becomes moderately fibrotic, and fibrosis is the same if the animal is killed 1 day (Ishak score, 3.62 ± 0.31) or 7 days (Ishak score, 3.82 ± 0.25) after the last DEN dose, but inflammation is significantly higher at 1 day compared with 7 days after the last DEN dose (histological activity index from 0-4, 3.54 ± 0.14 vs 1.61 ± 0.16, respectively; P < 0.0001). Peak EP-2104R signal enhancement was significantly higher in animals imaged at 1 day post-DEN compared with 7 days post-DEN or control rats (29.0% ± 3.2% vs 22.4% ± 2.0% vs 17.0% ± 0.2%, respectively; P = 0.017). Signal enhancement with EP-2104R was significantly higher than control linear peptide at 1 day post-DEN but not at 7 days post-DEN indicating specific fibrin binding during the inflammatory phase. Collagen molecular magnetic resonance with EP-3533 showed equivalent T1 change when imaging rats 1 day or 7 days post-DEN, consistent with equivalent fibrosis. CONCLUSIONS EP-2104R can specifically detect fibrin associated with inflammation in a rat model of liver inflammation and fibrosis.

A supported gold nanoparticle-catalyzed strategy has been utilized to promote a click chemistry reaction for the synthesis of 1,2,3-triazoles via the azide-alkyne cycloaddition (AAC) reaction. While the advent of effective non-copper catalysts (i.e., Ru, Ag, Ir) has demonstrated the catalysis of the AAC reaction, additional robust catalytic systems complementary to the copper catalyzed AAC remain in high demand. Herein, Au nanoparticles supported on Al2O3, Fe2O3, TiO2 and ZnO, along with gold reference catalysts (gold on carbon and gold on titania supplied by the World Gold Council) were used as catalysts for the AAC reaction. The supported Au nanoparticles with metal loadings of 0.7–1.6% (w/w relative to support) were able to selectively obtain 1,4-disubstituted-1,2,3-triazoles in moderate yields up to 79% after 15 min, under microwave irradiation at 150 °C using a 0.5–1.0 mol% catalyst loading through a one-pot three-component (terminal alkyne, organohalide and sodium azide) procedure according to the “click” rules. Among the supported Au catalysts, Au/TiO2 gave the best results.

The introduction of new diagnostic imaging modalities in parallel with recent developments in nanomaterial science has led to the development of an explosive number of nanoplatforms for diagnostic molecular imaging applications. This chapter describes in a systematic way the types of nanomaterials used for imaging, based on their physicochemical properties. It further correlates them with the corresponding imaging modalities where they can be applied by describing the physical basis of their imaging contrast effects. Their advantages and disadvantages are described and the ways they can be optimally combined into multimodal probes for recently developed hybrid imaging techniques are discussed. Selected in vivo applications of single and multimodal nanoprobes are described. The bodistribution, excretion, and toxicity of nanoparticles, which can limit their success in clinical translation, are also explored. Finally, a few cases undergoing clinical translation are presented and discussed.

Background Excessive lactate production, a hallmark of cancer, is largely formed by the reduction of pyruvate via lactate dehydrogenase (LDH) to l-lactate. Although d-lactate can also be produced from glucose via the methylglyoxal pathway in small amounts, less is known about the amount of d-lactate produced in cancer cells. Since the stereoisomers of lactate cannot be distinguished by conventional 1H NMR spectroscopy, a chiral NMR shift reagent was used to fully resolve the 1H NMR resonances of d- and l-lactate. Methods The production of l-lactate from glucose and d-lactate from methylglyoxal was first demonstrated in freshly isolated red blood cells using the chiral NMR shift reagent, YbDO3A-trisamide. Then, two different cell lines with high GLO1 expression (H1648 and H 1395) were selected from a panel of over 80 well-characterized human NSCLC cell lines, grown to confluence in standard tissue culture media, washed with phosphate-buffered saline, and exposed to glucose in a buffer for 4 h. After 4 h, a small volume of extracellular fluid was collected and mixed with YbDO3A-trisamide for analysis by 1H NMR spectroscopy. Results A suspension of freshly isolated red blood cells exposed to 5mM glucose produced l-lactate as expected but very little d-lactate. To evaluate the utility of the chiral NMR shift reagent, methylglyoxal was then added to red cells along with glucose to stimulate the production of d-lactate via the glyoxalate pathway. In this case, both d-lactate and l-lactate were produced and their NMR chemical shifts assigned. NSCLC cell lines with different expression levels of GLO1 produced both l- and d-lactate after incubation with glucose and glutamine alone. A GLO1-deleted parental cell line (3553T3) showed no production of d-lactate from glucose while re-expression of GLO1 resulted in higher production of d-lactate. Conclusions The shift-reagent-aided NMR technique demonstrates that d-lactate is produced from glucose in NSCLC cells via the methylglyoxal pathway. The biological role of d-lactate is uncertain but a convenient method for monitoring d-lactate production could provide new insights into the biological roles of d- versus l-lactate in cancer metabolism.

Elucidating the nature, strength, and siting of acid sites in zeolites is fundamental to fathom their reactivity and catalytic behavior. Despite decades of research, this endeavor remains a major challenge. Trimethylphosphine oxide (TMPO) has been proposed as a reliable probe molecule to study the acid properties of solid acid catalysts, allowing the identification of distinct Brønsted and Lewis acid sites and the assessment of Brønsted acid strengths. Recently, doubts have been raised regarding the assignment of the 31P NMR resonances of TMPO-loaded zeolites. Here, it is shown that a judicious control of TMPO loading combined with two-dimensional 1H-31P HETCOR solid-state NMR, DFT, and ab initio molecular dynamics (AIMD)-based computational modeling provides an unprecedented atomistic description of the host-guest and guest-guest interactions of TMPO molecules confined within HZSM-5 molecular-sized voids. 31P NMR resonances usually assigned to TMPO molecules interacting with Brønsted sites of different acid strength arise instead from both changes in the probe molecule confinement effects at ZSM-5 channel system and the formation of protonated TMPO dimers. Moreover, DFT/AIMD shows that the 1H and 31P NMR chemical shifts strongly depend on the siting of the framework aluminum atoms. This work overhauls the current interpretation of NMR spectra, raising important concerns about the widely accepted use of probe molecules for studying acid sites in zeolites. published

The thermodynamic, kinetic, and structural properties of Ln3+ complexes with the bifunctional DO3A-ACE4− ligand and its amide derivative DO3A-BACE4− (modelling the case where DO3A-ACE4− ligand binds to vector molecules) have been studied in order to confirm the usefulness of the corresponding Gd3+ complexes as relaxation labels of targeted MRI contrast agents. The stability constants of the Mg2+ and Ca2+ complexes of DO3A-ACE4− and DO3A-BACE4− complexes are lower than for DOTA4− and DO3A3−, while the Zn2+ and Cu2+ complexes have similar and higher stability than for DOTA4− and DO3A3− complexes. The stability constants of the Ln(DO3A-BACE)− complexes increase from Ce3+ to Gd3+ but remain practically constant for the late Ln3+ ions (represented by Yb3+). The stability constants of the Ln(DO3A-ACE)4− and Ln(DO3A-BACE)4− complexes are several orders of magnitude lower than those of the corresponding DOTA4− and DO3A3− complexes. The formation rate of Eu(DO3A-ACE)− is one order of magnitude slower than for Eu(DOTA)−, due to the presence of the protonated amine group, which destabilizes the protonated intermediate complex. This protonated group causes the Ln(DO3A-ACE)− complexes to dissociate several orders of magnitude faster than Ln(DOTA)− and its absence in the Ln(DO3A-BACE)− complexes results in inertness similar to Ln(DOTA)− (as judged by the rate constants of acid assisted dissociation). The 1H NMR spectra of the diamagnetic Y(DO3A-ACE)− and Y(DO3A-BACE)− reflect the slow dynamics at low temperatures of the intramolecular isomerization process between the SA pair of enantiomers, R-Λ(λλλλ) and S-Δ(δδδδ). The conformation of the Cα-substituted pendant arm is different in the two complexes, where the bulky substituent is further away from the macrocyclic ring in Y(DO3A-BACE)− than the amino group in Y(DO3A-ACE)− to minimize steric hindrance. The temperature dependence of the spectra reflects slower ring motions than pendant arms rearrangements in both complexes. Although losing some thermodynamic stability relative to Gd(DOTA)−, Gd(DO3A-BACE)− is still quite inert, indicating the usefulness of the bifunctional DO3A-ACE4− in the design of GBCAs and Ln3+-based tags for protein structural NMR analysis., This research was funded by the Hungarian National Research, Development and Innovation Office (Projects NKFIH K-128201, K-134694, and FK-134551).

International audience; Given their potential in a better characterization and diagnosis of major pathologies like cancer or chronic inflammation, redox-activated Magnetic Resonance Imaging (MRI) probes have recently attracted much interest from chemists. Such redox responsive probes are capable of reporting on specific biomarkers that are related to tissue redox potential disruption or hypoxia. Lately, this research area has experienced remarkable development, including redox-responsive metal complexes and nanoparticles. Here we critically review the progress with a specific focus on metal-based probes and some nanoparticle examples. We demonstrate, via representative cases, the different molecular mechanisms that can generate a redox-modulated MRI response. They can be based on the redox activity of either the ligand or the metal center, provided the different oxidation states of the metal ion are endowed with different magnetic properties. A particular emphasis is given to recent advances and to the imaging probes that have attained in vivo validation. In overall, we aim to provide the reader with a comprehensive view of how intracellular or extracellular redox buffer systems can be assessed by using MRI contrast agents based on lanthanide or transition metal ions using T1-weighted, T2-weighted, paraCEST 1H or 19F MRI.

Magnetic resonance imaging (MRI) is a powerful non-invasive diagnostic tool that enables distinguishing healthy from pathological tissues, with high anatomical detail. Nevertheless, MRI is quite limited in the investigation of molecular/cellular biochemical events, which can be reached by fluorescence-based techniques. Thus, we developed bimodal nanosystems consisting in hydrophilic quantum dots (QDs) directly conjugated to Gd(III)-DO3A monoamide chelates, a Gd(III)-DOTA derivative, allowing for the combination of the advantages of both MRI and fluorescence-based tools. These nanoparticulate systems can also improve MRI contrast, by increasing the local concentration of paramagnetic chelates. Transmetallation assays, optical characterization, and relaxometric analyses, showed that the developed bimodal nanoprobes have great chemical stability, bright fluorescence, and high relaxivities. Moreover, fluorescence correlation spectroscopy (FCS) analysis allowed us to distinguish nanosystems containing different amounts of chelates/QD. Also, inductively coupled plasma optical emission spectrometry (ICP – OES) indicated a conjugation yield higher than 75%. Our nanosystems showed effective longitudinal relaxivities per QD and per paramagnetic ion, at least 5 times [per Gd(III)] and 100 times (per QD) higher than the r1 for Gd(III)-DOTA chelates, suitable for T1-weighted imaging. Additionally, the bimodal nanoparticles presented negligible cytotoxicity, and efficiently labeled HeLa cells as shown by fluorescence. Thus, the developed nanosystems show potential as strategic probes for fluorescence analyses and MRI, being useful for investigating a variety of biological processes.

International audience; For the development of redox responsive MRI probes based on the MnIII/MnII couple, stable complexation of both reduced and oxidized forms of the metal ion and appropriate tuning of the redox potential in the biologically relevant range are key elements. The water soluble fluorinated Mn-porphyrin derivative Mn-3 satisfies both requirements. In aqueous solutions, it can reversibly switch between MnIII/MnII oxidation states. In the presence of ascorbic acid or beta-mercaptoethanol, the MnIII form undergoes reduction, which is slowly but fully reversed in the presence of air oxygen. A UV-Vis kinetic study of MnIII/MnII reduction under oxygen-free conditions yielded second-order rate constants, k2, of 46.1 M-1 s-1 and 13.8 M-1 s-1 for the reaction with ascorbic acid and beta-mercaptoethanol, respectively. This could correspond, in the absence of oxygen, to a half-life of a few minutes in blood plasma and a few seconds in circulating immune cells where ascorbic acid reaches 20-40 muM and a few mM concentrations, respectively. In contrast to expectations based on the redox potential, reduction with glutathione or cysteine does not occur. It is prevented by the coordination of the glutathione carboxylate group(s) to MnIII in the axial position, as was evidenced by NMR data. Therefore, MnIII-3 acts as an ascorbate specific turn-on MRI probe, which in turn can be re-oxidized by oxygen. The relaxivity increase from the oxidized to the reduced form is considerably improved at medium frequencies (up to 80 MHz) with respect to the previously studied Mn-TPPS4 analogues; at 20 MHz, it amounts to 150%. No in vitro cytotoxicity is detectable for Mn-3 in the typical MRI concentration range. Finally, 19F NMR resonances of MnIII-3 are relatively sharp which could open further opportunities to exploit such complexes as paramagnetic 19F NMR probes.

Two-dimensional 1H–31P heteronuclear correlation NMR of trimethylphosphine oxide (TMPO) adsorbed in zeolites, in tandem with DFT calculations, challenges previous one-dimensional 31P NMR assignments, enabling the unambiguous discrimination of Bronsted and Lewis acid sites, extending the understanding of TMPO:Bronsted complexes formed with distinct stoichiometries at the HZSM-5 zeolite surface, and the proton-transfer mechanism.

Cancer is one of the most prevalent and deadly diseases in the world, to which conventional treatment options, such as chemotherapy and radiotherapy, have been applied to overcome the disease or used in a palliative manner to enhance the quality of life of the patient. However, there is an urgent need to develop new preventive and treatment strategies to overcome the limitations of the commonly used approaches. The field of cancer nanomedicine, and more recently the field of nanotheranostics, where imaging and therapeutic agents are combined in a single platform, provide new opportunities for the treatment and the diagnosis of cancer. This combination could bring us closer to a more personalized and cared-for therapy, in opposition to the conventional and standardized approaches. Gene therapy is a promising strategy for the treatment of cancer that requires a transport system to efficiently deliver the genetic material into the target cells. Hence, the main purpose of this work was to review recent findings and developments regarding theranostic nanosystems that incorporate both gene therapy and imaging agents for cancer treatment.

International audience; Metal chelates targeted to amyloid peptides are widely explored as diagnostic tools or therapeutic agents. The attachment of a metal complex to amyloid recognition units typically leads to a decrease in peptide affinity. We show here that by separating a macrocyclic GdL chelate and a PiB targeting unit with a long hydrophobic C10 linker, it is possible to attain nanomolar affinities for both Aβ 1‐40 ( K d = 4.4 nM) and amylin ( K d = 4.5 nM), implicated respectively in Alzheimer’s disease and diabetes. The Scatchard analysis of surface plasmon resonance data obtained for a series of amphiphilic, PiB derivative GdL complexes indicate that their Aβ 1‐40 or amylin binding affinity varies with their concentration, thus micellar aggregation state. The GdL chelates also affect peptide aggregation kinetics, as probed by thioflavin‐T fluorescence assays. A 2D NMR study allowed identifying that the hydrophilic region of Aβ 1‐40 is involved in the interaction between the monomer peptide and the Gd 3+ complex. Finally, ex vivo biodistribution experiments were conducted in healthy mice by using 111 In labelled analogues. Their pancreatic uptake, ~3%ID/g, is promising to envisage amylin imaging in diabetic animals.

Funding: This work was partially support by CEAUL (funded by FCT – Fundação para a Ciência e a Tecnologia, Portugal, through the project UIDB/00006/2020). This manuscript brings attention to inaccurate epidemiological concepts that emerged during the COVID-19 pandemic. In social media and scientific journals, some wrong references were given to a "normal epidemic curve" and also to a "log-normal curve/distribution". For many years, textbooks and courses of reputable institutions and scientific journals have disseminated misleading concepts. For example, calling histogram to plots of epidemic curves or using epidemic data to introduce the concept of a Gaussian distribution, ignoring its temporal indexing. Although an epidemic curve may look like a Gaussian curve and be eventually modelled by a Gauss function, it is not a normal distribution or a log-normal, as some authors claim. A pandemic produces highly-complex data and to tackle it effectively statistical and mathematical modelling need to go beyond the "one-size-fits-all solution". Classical textbooks need to be updated since pandemics happen and epidemiology needs to provide reliable information to policy recommendations and actions. Publisher PDF

The NMR relaxivities of the decatungstolanthanoate core-shell nanoparticles, prepared by encapsulating [Ln(W5O18)2]9− polyoxometalates (LnPOM) within amorphous silica shells (K9[Ln(W5O18)2]@SiO2), were studied along the Ln series. The relaxivity of GdPOM is slightly higher than for Gd-DTPA due to second-sphere relaxation effects, but the values for the other paramagnetic LnPOMs are much smaller due to the short T1e values of their Ln3+-ions. The NPs have core-shell spherical structures, with LnPOM-containing cores with 9.5–28 nm diameters, and 4.0–11.0 nm thick amorphous silica shells. In water suspensions, the NPs have negative zeta potentials (−32.5 to −40.0 mV) and time-dependent hydrodynamic diameters (31–195 nm) reflecting the formation of aggregates. The relaxivities of GdPOM@SiO2 NPs suspensions (r1=10.97 (mM Gd)−1 s−1, r2=12.02 (mM Gd)−1 s−1, 0.47 T, 25 °C) are considerably larger than for the GdPOM solutions, indicating that their silica shell is significantly porous to water. This increase is limited by the agglomeration of the complexes in the NPs core, limiting their access to water to those at the core surface. Replacing half of the Gd3+ ions by Eu3+ decreases the NPs r1 and r2 relaxivities at 0.47 T to 20 % and 35 % of their initial values, which are still considerable, but does not affect the efficient luminescence properties of the Eu3+ centers. This indicates that the mixed NPs have potential as dual modality MRI/optical imaging contrast agents.

This work reports the mastered design of novel water-dispersible superparamagnetic iron oxide nanomaterials with enhanced magnetic properties and reduced size. A straightforward cost-effective aqueous coprecipitation route was developed, based on the use of three new coprecipitation agents: the polydentate bases diethanolamine, triethanolamine and triisopropanolamine. Through the selection of these alkanolamines which presented different complexing properties, an improvement of the surface spin order could be achieved upon the reduction of the nanomaterial dimensions (from 8.7 to 3.8 nm) owing to the complexation of the polydentate bases with the subcoordinated iron cations on the particle surface. In particular, the alkanolamine with the highest chelating ability (triethanolamine) led to the nanomaterial with the smallest size and the thinnest magnetic "dead" layer. In order to evaluate the importance of the dual control of size and magnetism, the relaxometric properties of the nanomaterials were investigated, whereby maximum values of transverse relaxivity r

The diagnosis of multiple myeloma (MM) has a significant impact on patients. This study analyzed the mediating role of patients’ unmet needs in the relationship between psychological morbidity/social support and quality of life (QoL). Methods This study included 213 patients with MM recruited from the outpatient medical oncology and clinical hematology services from five hospitals. Patients who meet the study criteria were referred by physicians and invited to participate in the study by the researcher. All participants answered the following questionnaires: Hospital Anxiety and Depression Scale, Satisfaction with Social Support Scale, Short-Form Survivor Unmet Needs Survey, and The European Organization for Research and Treatment of Cancer’s Multiple Myeloma Module. Descriptive statistics, bivariate correlations, and structural equation modeling were performed to analyze the data. Results The indirect effect of psychological morbidity on patients’ future perspectives (MYFP) was partially mediated by information unmet needs (INF), while the indirect effect of psychological morbidity on treatment side effects (MYSE) was partially mediated by relationship and emotional unmet needs (REH). In turn, the indirect effect of psychological morbidity on disease symptoms (MYDS) was fully mediated by REH. Social support had an indirect effect on MYDS and MYSE fully mediated by REH. Conclusion Intervention programs tailored to promote MM patients’ QoL should specifically address information and emotional needs, raising awareness and training health professionals, caregivers, and family members to attend MM patients’ unmet needs., This study was supported by a grant from the Portuguese Association against Leukemia and the Portuguese Association of Leukemias and Lymphomas funded by Celgene

We report a synthetic strategy to combine different moieties in a single structure using cyanuric chloride (2,4,6-trichlorotriazine) as a starting platform for preparing potential bioimaging agents. This reacted with macrocycles of the porphyrin family and DOTA type metal chelators through mono-, di- and tri- substitution of its chlorine atoms by appropriate nucleophiles, controlling the stepwise by temperature, to produce a system that opens the potential for biomedicinal applications. Porphyrins were chosen as one of the sensing arms, based on their rich structural chemistry, and excellent photophysical properties, while DO3A was used since it can form a versatile aminopropionate functionalized metal ion chelator. All new compounds were fully characterized, both spectroscopically and photophysically. Keywords: Porphyrins, Aza-chelates, Sulfonation, Fluorescence, Biomedicinal applications, Cyanuric chloride

Although nowadays there is a renewed and growing interest in Mn-based contrast agents, there are only few studies dealing with Mn-based lipophilic nanoparticles and how they may be optimized as MRI contrast agents. Three amphiphilic paramagnetic Mn(II) complexes based on derivatives of EDTA and 1,4-DO2A were used for the preparation of lipidic nanoparticles. The length and position of the aliphatic chains were found to control whether either vesicular liposomes, nonvesicular bicelles, or a mixture of both was produced as well as the size and morphology of phospholipid-based self-assembling nanoaggregates. These differences determine whether hydrophilic Gd-based contrast agents or fluorescent dyes can be entrapped in the aqueous core of the nanoaggregate. Structural characterization was performed by cryo-TEM. Detailed

Background Site-specific multimodal nanoplatforms with fluorescent-magnetic properties have great potential for biological sciences. For this reason, we developed a multimodal nanoprobe (BNPs-Tf), by covalently conjugating an optical-magnetically active bimodal nanosystem, based on quantum dots and iron oxide nanoparticles, with the human holo-transferrin (Tf). Methods The Tf bioconjugation efficiency was evaluated by the fluorescence microplate assay (FMA) and the amount of Tf immobilized on BNPs was quantified by fluorescence spectroscopy. Moreover, relaxometric and fluorescent properties of the BNPs-Tf were evaluated, as well as its ability to label specifically HeLa cells. Cytotoxicity was also performed by Alamar Blue assay. Results The FMA confirmed an efficient bioconjugation and the fluorescence spectroscopy analysis indicated that 98% of Tf was immobilized on BNPs. BNPs-Tf also presented a bright fluorescence and a transversal/longitudinal relaxivities ratio (r2/r1) of 65. Importantly, the developed BNPs-Tf were able to label, efficiently and specifically, the Tf receptors in HeLa cells, as shown by fluorescence and magnetic resonance imaging assays. Moreover, this multimodal system did not cause noteworthy cytotoxicity. Conclusions The prepared BNPs-Tf hold great promise as an effective and specific multimodal, highly fluorescent-magnetic, nanoplatform for fluorescence analyses and T2-weighted images. General significance This study developed an attractive and versatile multimodal nanoplatform that has potential to be applied in a variety of in vitro and in vivo studies, addressing biological processes, diagnostic, and therapeutics. Moreover, this work opens new possibilities for designing other efficient multimodal nanosystems, considering other biomolecules in their composition able to provide them important functional properties.

Partial symmetry, i.e., the presence of more than one molecule in the asymmetric unit of a crystal, is a relatively rare phenomenon in small-molecule crystallography, but is quite common in protein crystallography, where it is typically known as non-crystallographic symmetry (NCS). Several papers in literature propose molecular determinants such as crystal contacts, thermal factors, or TLS parameters as an explanation for the phenomenon of intrinsic asymmetry among molecules that are in principle equivalent. Nevertheless, are all of the above determinants the cause or are they rather the effect? In the general frame of the NCS often observed in crystals of biomolecules, this paper deals with nickel(II)-substituted human carbonic anhydrase(II) (hCAII) and its SAD structure determination at the nickel edge. The structure revealed two non-equivalent molecules in the asymmetric unit, the presence of a secondary nickel-binding site at the N-terminus of both molecules (which had never been found before in the nickel-substituted enzyme) and two different coordination geometries of the active site nickel (hexa-coordinated in one molecule and mainly penta-coordinated in the other). The above-mentioned standard molecular crystallographic determinants of this asymmetry are analyzed and presented in detail for this particular case. From these considerations, we speculate on the existence of a fundamental, although yet unknown, common cause for the partial symmetry that is so often encountered in X-ray structures of biomolecules.

Ethnopharmacological relevance Leaves extracts from Cymbopogon citratus (DC) Stapf. are widely used in traditional medicine exhibiting several in vivo biological activities, including antidiabetic. Several flavonoids, including aglycones and glycosides, were reported in this plant and previous studies suggested that flavonoids may interact with targets related to diabetes. Aim of the study Evaluated the hypoglycemic activity of C. citratus flavonoids through α-glucosidase inhibition and assess the structure-activity relationship using molecular docking studies. Material and methods An infusion of C. citratus leaves and its flavonoid-rich fraction were prepared. Five flavonoids from this fraction were isolated and structurally characterized by UV spectral analysis with shift reagents, HPLC-PDA-ESI/MSn and 1H NMR. The antidiabetic potential of C. citratus infusion, its flavonoid-rich fraction, glycosylated flavonoids and aglycones was evaluated trough the in vitro inhibition of yeast α-glucosidase. Posteriorly, molecular docking of the tested flavonoids was performed to investigate its possible interactions with the α-glucosidase pocket. Results The infusion of C. citratus, its flavonoid-rich fraction, luteolin and five flavone glycosides namely, luteolin 6-C-β-glucopyranoside (isoorientin), luteolin 7-O-neohesperidoside (ionicerin), luteolin 7-O-β-glucopyranoside (cynaroside), Luteolin 2″-O-rhamnosyl-C-(6-deoxy-ribo-hexos-3-ulosyl) (cassiaoccidentalin B), luteolin 6-C-α-arabinofuranosil-(1→2)-α-L-rhamnopyranoside (kurilesin A) showed higher inhibitory activity than the reference drug. This activity increased by the addition of a sugar moiety. However, the di-glycosides were less active than mono-glycosides. The docking studies showed interactions of sugar moieties and A or B rings with the catalytic pocket mainly through hydrogen bonds. Conclusions Our results corroborate the potential of C. citratus as a medicinal plant for the treatment of diabetes and revealed that its flavonoid glycosides has hypoglycemic effect and can be explored as drug candidates to act as α-glucosidase inhibitors in the treatment of diabetes.

Mn(III) porphyrins have great potential as Gd-free MRI contrast agents because both the cation and the ligand have interesting properties. The redox properties of the Mn(III)-ion can be exploited for the preparation of reactive oxygen species for therapy. Moreover, the porphyrin ligand allows these complexes to have a high affinity for tumor tissues. The inherent properties of the porphyrin ligands make these systems attractive for photothermal, photodynamic, and sonodynamic therapies. Therefore, these systems are attractive for the development of theranostics for MRI-guided therapy. For the magnetic field strengths at which most clinical MRI machines operate at present (0.5–1.5 T), the longitudinal relativity of low-molecular-weight complexes is even higher than that of the classical Gd-based contrast agents. This review gives an overview of the developments in the field of Mn(III) porphyrin contrast agents during the last 30 years.

Purpose To determine the relationship of liver fibrosis, inflammation, and steatosis with the magnetic resonance (MR) viscoelastic and diffusion parameters in patients with chronic liver disease and to compare the diagnostic accuracy of the imaging parameters in staging liver fibrosis. Materials and Methods Consecutive patients with chronic liver disease scheduled for liver biopsy were prospectively recruited from November 2010 to October 2012 for this institutional review board-approved study after they provided written informed consent. Sixty-eight patients underwent three-dimensional MR elastography and intravoxel incoherent motion diffusion-weighted MR imaging with a 1.5-T MR system. Fibrosis, inflammation, and steatosis were assessed with the METAVIR and steatosis, activity, and fibrosis (or SAF) scoring systems. Spearman correlation and multiple regression analyses were performed to determine the relationship between liver fibrosis, inflammation, steatosis, and alanine aminotransferase (ALT) levels and viscoelastic and diffusion parameters. The accuracy of three-dimensional MR elastography and diffusion-weighted MR imaging in the determination of fibrosis stage was assessed with Obuchowski measures. Results At multiple regression analysis, fibrosis was the only variable associated with viscoelastic parameters (β = 0.6, P < .001, R2 = 0.33 for shear modulus; β = 0.6, P < .001, R2 = 0.32 for elasticity). Fibrosis had a weaker independent association with the apparent diffusion coefficient (β = -0.3, P = .02, R2 = 0.33) than did steatosis (β = -0.5, P < .001, R2 = 0.33). Steatosis was the only factor independently associated with the pure diffusion coefficient (β = -0.4, P = .002, R2 = 0.22). Inflammation and ALT level were not associated with the viscoelastic or diffusion parameters. The diagnostic accuracy of fibrosis staging was significantly higher when measuring the shear modulus rather than the apparent diffusion coefficient (Obuchowski measures, 0.82 ± 0.04 vs 0.30 ± 0.06; P < .001). Conclusion Fibrosis is independently associated with the MR viscoelastic parameters and is less associated with the diffusion parameters than is steatosis. These results and those of diagnostic accuracy suggest that MR elastography should be preferred over diffusion-weighted MR imaging in the staging of liver fibrosis. © RSNA, 2016.

The number of scientific reports on the field of imaging in biomedical sciences is rising massively, with the emergence of “noninvasive” in vivo imaging technologies, of which Magnetic Resonance Imaging (MRI) is considered to be among the top techniques in modern Medical Imaging. These techniques manage to detect events at molecular and cellular levels, providing a faster diagnostic evaluation to oncology patients and consequently hastening drug development processes. Of the many contrast agents developed by Organic Chemists during the last decades, tetrapyrrolic macrocycles like porphyrins and related compounds, like phthalocyanines, represent some of the oldest, most widely studied chemical structures in biomedical applications. These macrocyclic structures display intrinsic affinity for tumor localization, and their well-described photosensitizing and photophysical features allured many scientists toward their potential use as contrast agents in a variety of in vivo imaging technologies, namely in the MRI technique. Furthermore, a special emphasis is put on the development of multimodal contrast agents, which may be the future of Medical Imaging. This review intends to give an insight on developments on MRI technologies involving tetrapyrrolic-based contrast agents for cancer detection. It is a Chemist’s view, regarding the synthesis of the crucial contrast agents, selecting influential milestones over the last few decades on this field, along with pertinent reflections pointing to future guidelines.

International audience; Aggregation of misfolded proteins and progressive polymerization of otherwise soluble proteins is a common hallmark of a wide range of highly debilitating and increasingly prevalent diseases, including amyotrophic lateral sclerosis, cerebral amyloid angiopathy, type II diabetes and Parkinson's, Huntington's and Alzheimer's diseases. There is a growing interest in creating imaging agents to detect such aggregates in various imaging modalities, including PET, SPECT and MRI. We present here an overview of recent efforts from the perspective of early diagnosis of amyloid diseases, with a major focus on Aβ detection and metal complexes bearing PiB units.

[Abstract] In the periodical system, the lanthanides (the 15 elements in the periodic table between barium and hafnium) are unique in the sense that their trivalent cations have their valence electrons hidden behind the 5s and 5p electrons. They show a gradual decrease in ionic radius with increasing atomic number (also known as the lanthanide contraction). The resulting steric effects determine to a large extent the geometries of complexes of these ions. Here, we discuss these effects, particularly upon the properties of the complexes in aqueous solution, for selected families of Ln3+-complexes of oxycarboxylate and aminocarboxylate ligands. The physical properties of the cations are very different, which is very useful for the elucidation of the configuration, conformation and the dynamics of the complexes by X-ray techniques, NMR spectroscopy, and optical techniques. Often the structural analysis is assisted by computational methods.

The recent derivation, based on pure quantum chemistry (QC) first-principles, of the pseudocontact shifts (PCSs) caused by a paramagnetic metal center on far away nuclei has cast doubts on the validity of the semiempirical (SE) theory, predicting PCSs to arise from the metal magnetic susceptibility anisotropy. The SE theory has been used and applied countless times, especially in the last 2 decades, to obtain structural information on proteins containing paramagnetic metal ions. We show here that the QC and SE predictions can be directly tested against experiments, provided a suitable macromolecular system is used. The SE approach yields a good prediction of the experimental PCSs while the QC one does not. It appears that the classic theory is able to grasp satisfactorily the underlying physics.