Evaluation of the changes in working limits in an automobile assembly line using simulation

The aim of the work presented in this paper consists of the development of a decision-making support system, based on discrete-event simulation models, of an automobile assembly line which was implemented within an Arena simulation environment and focused at a very specific class of production lines with a four closed-loop network configuration. This layout system reflects one of the most common configurations of automobile assembly and preassembly lines formed by conveyors. The sum of the number of pallets on the intermediate buffers, remains constant, except for the fourth closed-loop, which depends on the four-door car ratio (x) implemented between the door disassembly and assembly stations of the car body. Some governing equations of the four closed-loops are not compatible with the capacities of several intermediate buffers for certain values of variable x. This incompatibility shows how the assembly line cannot operate in practice for x0,97 in a stationary regime, due to the starvation phenomenon or the failure of supply to the machines on the production line. We have evaluated the impact of the pallet numbers circulating on the first closed-loop on the performance of the production line, translated into the number of cars produced/hour, in order to improve the availability of the entire manufacturing system for any value of x. Until the present date, these facts have not been presented in specialized literature. © 2012 American Institute of Physics

Magnetic anisotropies in rhombic lanthanide(III) complexes do not conform to Bleaney’s theory

[Abstract] We report a complete set of magnetic susceptibilities of lanthanide complexes with a macrocyclic ligand based on a 3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane platform containing four hydroxyethyl pendant arms (L1). The [LnL1]3+ complexes are isostructural along the lanthanide series from Ce3+ to Yb3+, with the only structural change observed along the series being the monotonous shortening of the Ln–donor distances due to lanthanide contraction. The 1H NMR spectra point to a D2 symmetry of the [LnL1]3+ complexes in aqueous solution, which provides a unique opportunity for analysis of the rhombic magnetic anisotropies with an unequivocal location of the magnetic axes. The contact contributions for the observed paramagnetic shifts have been estimated with density functional theory calculations on the [GdL1]3+ complex. Subsequently, the pseudocontact shifts could be factored out, thereby giving access to the axial and rhombic contributions of the magnetic susceptibility tensor. Our results show that the calculated magnetic anisotropies do not follow the trends predicted by Bleaney’s theory, particularly in the case of Ho3+ and Er3+ complexes.Ministerio de Economía y Competitividad; CTQ2013-43243-PMinisterio de Ciencia e Innovación; CTQ2011-2448

Inert macrocyclic Eu3+ complex with affirmative paraCEST features

[Abstract]: We report on a macrocyclic platform based on an 18-membered macrocycle that forms kinetically highly inert paramagnetic complexes and possesses an excellent outlook for the development of bioresponsive paraCEST (paramagnetic chemical exchange saturation transfer) contrast agents. The investigated europium( III) chelate is non-hydrated and contains four amide groups, each possessing two paramagnetically shifted proton resonances distant from bulk water. The X-ray crystal structure and solution studies indicate that the metal ion is ten-coordinated, being directly bound to the six N atoms of the macrocycle and the four amide O atoms of the pendant arms. The complex presents an excellent inertness with respect to dissociation, being stable under a variety of harsh conditions, including highly acidic and basic media or elevated temperatures. The amide protons are in slow-to-intermediate exchange with bulk water, which gives rise to the generation of a strong CEST effect at low probe concentration and saturation powers (∼25% at 5 mM, B1 = 5 μT, 37 °C). We demonstrate the potential of this platform for mapping pH in its microenvironment and foresee potential for the development of diverse paraCEST probes and sensors.Ministerio de Economía y Competitividad; CTQ2016-76756-PXunta de Galicia; ED431B 2017/59Xunta de Galicia; ED431D 2017/01German Research Foundation; ZA 814/2-

Reinforced Ni(ɪɪ)-Cyclam Derivatives as Dual ¹H/¹⁹F MRI Probes

[Abstract] Reinforced cross-bridged Ni²⁺-cyclam complexes were functionalised with pendant arms containing both amide protons and CF₃ groups that lead to a dual ¹H/¹⁹F response. The resulting complexes possess very high inertness favourable for MRI applications. The paramagnetism of the Ni²⁺ ion shifts the amide resonance 56 ppm away from bulk water favouring the chemical exchange saturation transfer (CEST) effect and shortening the acquisition times in ¹⁹F magnetic resonance imaging (MRI) experiments, thus enhancing the signal-to-noise ratios compared to the fluorinated diamagnetic reference.Authors R. P.-P., D. E.-G. and C. P.-I. thank Ministerio de Economía y Competitividad (CTQ2016-76756-P) and Xunta de Galicia (ED431B 2017/59 and ED431D 2017/01) for generous financial support. R. P.-P. thanks Ministerio de Economía y Competitividad for a PhD FPI grant (BES-2014-068399) and a fellowship for a short term stay in Tuebingen (EEBB-I-17-12213). T. S. thanks the German Academic Exchange Service (DAAD) for the PhD fellowshipXunta de Galicia; ED431B 2017/59Xunta de Galicia; ED431D 2017/0

Understanding the optical and magnetic properties of ytterbium(III) complexes

The absorption and emission spectra of three Yb3+ complexes possessing D3, D2 and C2 symmetries were analyzed with the aid of ab initio calculations based on Complete Active Space Self-Consistent Field (CASSCF) wave functions (CAS(13,7)). The absorption spectra present contributions from both cold and hot bands, involving thermally populated excited sublevels of the 2 F7/2 manifold. The high-resolution emission spectrum of the tris-picolinate complex [Yb(DPA)3] 3- recorded at 77 K presents four components, while the complexes with macrocyclic ligands show both cold and hot emission bands, resulting in more than four components for the 2 F5/2→2 F7/2 transition. The combined information provided by the absorption and emission spectra allowed to identify most of the crystal field sublevels of the 2 F5/2 and 2 F7/2 states. The energies of these crystal field components are well reproduced by the ab initio calculations, with deviations typically lower than 100 cm-1. The crystal field splitting is very sensitive to subtle changes of the Yb3+ coordination environment. The magnetic anisotropy of [Yb(DPA)3] 3- obtained with ab initio calculations was found to be extremely sensitive to changes in the twist angle of the upper and lower faces of the tricapped trigonal prismatic coordination polyhedron. Ab initio ligand field theory (AILFT) provides a straightforward chemical justification for the changes in magnetic anisotropy, which are responsible for the observed pseudocontact shifts in the NMR spectra.Agencia Estatal de Investigación | Ref. CTQ2016-76756-PXunta de Galicia | Ref. ED431B 2017/59Xunta de Galicia | Ref. ED431D 2017/01Deutsche Forschungsgemeinschaft | Ref. SE 1448/6-1Deutsche Forschungsgemeinschaft | Ref. SE 1448/8-1Eberhard Karls Universität Tübingen | Ref. ZUK 6

Lanthanide complexes with 1 H paraCEST and 19 F response for magnetic resonance imaging applications

We present a detailed study of the lanthanide(III) complexes with cyclen-based ligands containing phenylacetamide pen-dants that incorporate CF3 group(s) at different distances from the metal ion. The complexes exhibit square antiprismatic (SAP) coordination in solution, as demonstrated by the analysis of the Yb3+ induced paramagnetic shifts and the X ray structure of the [YbL3] complex. Luminescence lifetime measurements and a detailed 1H and 17O relaxometric characteriza-tion confirmed the presence of an inner-sphere water molecule. The Tm3+ complexes provide Chemical Exchange Satura-tion Transfer (CEST) response upon saturation at the frequency of the amide protons. A 19F relaxation study provided accu-rate estimates of the Ln···F distances that were used to rationalize the efficiency of the complexes as 19F MRI probes, which was tested in vitro using MRI phantom studies.Agencia Estatal de Investigación | Ref. CTQ2016-76756-PXunta de Galicia | Ref. Ref. ED431B 2017/59Xunta de Galicia | Ref. ED431D 2017/01Ministerio de Economía y Competitividad | Ref. BES-2014-068399Ministerio de Economía y Competitividad | Ref. EEBB-I-17-12213Ministerio de Economía y Competitividad | Ref. EEBB-I-18-13075Universitá degli Studi del Piemonte Oriental

(2-{[2-(2-Amino­ethyl­amino)­ethyl­imino]­meth­yl}phenolato-κ4 O,N′,N′′,N′′′)copper(II) perchlorate

The asymmetric unit of the title complex, [Cu(C11H16N3O)]ClO4, consists of two CuII ions coordinated by Schiff base ligands and two perchlorate anions. The Schiff base mol­ecules are linked to the CuII atoms via three N atoms and one O atom, resulting in a square-planar geometry. Inter­molecular hydrogen bonds involving the NH groups as donors and O atoms of the perchlorate anions as acceptors are observed

Stable and inert macrocyclic cobalt(ii) and nickel(ii) complexes with paraCEST response

We report the synthesis of the macrocyclic ligands 3,9 PC2AMH (2,2’-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,9-diyl)diacetamide) and 3,9-PC2AMtBu (2,2’-(3,6,9-triaza-1(2,6)-pyridinacyclodecaphane-3,9-diyl)bis(N-tert-butyl)acetamide) which contain a pyclen platform functionalized with acetamide or tert-butylacetamide pendant arms at positions 3 and 9 of the macrocyclic unit. The corresponding Co(II) and Ni(II) complexes were prepared, isolated and characterised as potential paramagnetic chemical exchange saturation transfer (paraCEST) agents. The X-ray structures of the Ni(II) complexes reveal six-coordination of the ligands to the metal ion. The Co(II) complex with 3,9-PC2AMtBu shows a similar six-coordinate structure in the solid state, while the Co(II) complex with 3,9 PC2AMH contains a seven-coordinate metal ion, seventh coordination being completed by the presence of an inner-sphere water molecule. The structure of the Co(II) complexes was investigated using 1H NMR spectroscopy and computational methods. The complexes present a seven-coordinate structure in solution, as demonstrated by the analysis of the paramagnetic shifts using density functional theory. Ligand protonation constants and stability constants of the complexes with 3,9 PC2AMH were determined using potentiometric titrations (I=0,15 M NaCl). The Co(II) complex was found to be more stable than the Ni(II) analogue (log KCoL = 14.46(5) and log KNiL = 13.15(3)). However, the Ni(II) and Co(II) complexes display similar rate constants characterizing the proton-assisted dissociation mechanism. The presence of highly shifted 1H NMR signals due to the amide protons in slow exchange with bulk water results in sizeable CEST signals, which are observed at +67 and +15 ppm for the Co(II) complex with 3,9 PC2AMH and +42 and +7 ppm for the Ni(II) analogue at 25ºC .Agencia Estatal de Investigación | Ref. CTQ2016-76756-PXunta de Galicia | Ref. ED431B 2020/52Nemzeti Kutatási Fejlesztési és Innovációs Hivatal | Ref. K-120224Nemzeti Kutatási Fejlesztési és Innovációs Hivatal | Ref. K-134694Science and Technology Commission of Shanghai Municipality | Ref. 2019SHZDZX0

Association of the serological status of rheumatoid arthritis patients with two circulating protein biomarkers: a useful tool for precision medicine strategies

[Abstract] Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the joints and presence of systemic autoantibodies, with a great clinical and molecular heterogeneity. Rheumatoid Factor (RF) and anti-citrullinated protein antibodies (ACPA) are routinely used for the diagnosis of RA. However, additional serological markers are needed to improve the clinical management of this disease, allowing for better patient stratification and the desirable application of precision medicine strategies. In the present study, we investigated those systemic molecular changes that are associated with the RF and ACPA status of RA patients. To achieve this objective, we followed a proteomic biomarker pipeline from the discovery phase to validation. First, we performed an iTRAQ-based quantitative proteomic experiment on serum samples from the RA cohort of the Hospital of Santiago de Compostela (CHUS). In this discovery phase, serum samples from the CHUS cohort were pooled according to their RF/ACPA status. Shotgun analysis revealed that, in comparison with the double negative group (RF-/ACPA-), the abundance of 12 proteins was altered in the RF+/ACPA+ pool, 16 in the RF+/ACPA- pool and 10 in the RF-/ACPA+ pool. Vitamin D binding protein and haptoglobin were the unique proteins increased in all the comparisons. For the verification phase, 80 samples from the same cohort were analyzed individually. To this end, we developed a Multiple Reaction Monitoring (MRM) method that was employed in a comprehensive targeted analysis with the aim of verifying the results obtained in the discovery phase. Thirty-one peptides belonging to 12 proteins associated with RF and/or ACPA status were quantified by MRM. In a final validation phase, the serum levels of alpha-1-acid glycoprotein 1 (A1AG1), haptoglobin (HPT) and retinol-binding protein 4 (RET4) were measured by immunoassays in the RA cohort of the Hospital of A Coruña (HUAC). The increase of two of these putative biomarkers in the double seropositive group was validated in 260 patients from this cohort (p = 0.009 A1AG1; p = 0.003 HPT). The increased level of A1AG1 showed association with RF rather than ACPA (p = 0.023), whereas HPT showed association with ACPA rather than RF (p = 0.013). Altogether, this study has allowed a further classification of the RA seropositive patients into two novel clusters: RF+A1AG+ and ACPA+HPT+. The determination of A1AG1 and HPT in serum would provide novel information useful for RA patient stratification, which could facilitate the effective implementation of personalized medicine in routine clinical practice.Instituto de Salud Carlos III; PI16/02124Instituto de Salud Carlos III; PI17/00404Instituto de Salud Carlos III; PI19/01206Instituto de Salud Carlos III; PI20/00793Instituto de Salud Carlos III; RD16/0012/0002Instituto de Salud Carlos III; RD21/0002/0009Xunta de Galicia; IN607A2021/07Xunta de Galicia; IN607D2020/1

Mn2+ complexes containing sulfonamide groups with pH-responsive relaxivity

We present two ligands containing a N-ethyl-4-(trifluoromethyl)benzenesulfonamide group attached to either a 6,6'-(azanediylbis(methylene))dipicolinic acid unit (H3DPASAm) or a 2,2'-(1,4,7-triazonane-1,4-diyl)diacetic acid macrocyclic platform (H3NO2ASAm). These ligands were designed to provide pH-dependent relaxivity response upon complexation with Mn2+ in aqueous solution. The protonation constants of the ligands and the stability constants of the Mn2+ complexes were determined using potentiometric titrations complemented by spectrophotometric experiments. The deprotonation of the sulfonamide groups of the ligands are characterized by protonation constants of logKiH = 10.36 and 10.59 for DPASAm3 and HNO2ASAm2 , respectively. These values decrease dramatically to logKiH = 6.43 and 5.42 in the presence of Mn2+ due to the coordination of the negatively charged sulfonamide groups to the metal ion. The higher logKiH value in [Mn(DPASAm)] is related to the formation of a seven-coordinate complex, while the metal ion in [Mn(NO2ASAm)] is six-coordinated. The X ray crystal structure of Na[Mn(DPASAm)(H2O)]·2H2O confirms the formation of a seven-coordinate complex, where the coordination environment is fulfilled by the donor atoms of the two picolinate groups, the amine N at-om, the N atom of the sulfonamide group and a coordinated water molecule. The lower conditional stability of the [Mn(NO2ASAm)] complex and the lower protonation constant of the sulfonamide group results in complex dissociation at relatively high pH (< 7.0). However, protonation of the sulfonamide group in [Mn(DPASAm)] falls into the physiologically relevant pH window and causes a significant increase in relaxivity from r1p = 3.8 mM 1 s 1 at pH 9.0 to r1p = 8.9 mM 1 s 1 at pH 4.0 (10 MHz, 25 ºC).Agencia Estatal de Investigación | Ref. CTQ2016-76756-PXunta de Galicia | Ref. ED431B 2017/59Xunta de Galicia | Ref. ED431D 2017/01Xunta de Galicia | Ref. ED481A-2018/314Universitá degli Studi del Piemonte OrientaleMinisterio de Ciencia, Innovación y Universidades | Ref. BEAGAL18/0014