Donor Set Research Articles

A-168 Comparison of Two Different Lupus Anticoagulant Hexagonal Phase Phospholipid Confirmatory Assays on an Automated Coagulation Analyzer

Abstract Background Antiphospholipid syndrome (aPS) is an autoimmune disorder resulting in venous and/or arterial thrombosis, characterized by presence of lupus anticoagulants (LA) in patient plasma, also referred to as antiphospholipid antibodies. Depending on clinical history and symptoms, or if an unexpected elevated routine aPTT result is observed, LA laboratory testing would be performed, if appropriate. According to published clinical guidelines, LA tests should use aPTT-based and dRVVT-based screening (low phospholipid) and confirmatory (high phospholipid) methods, run in parallel. aPS diagnosis is confirmed from both clinical and laboratory criteria. Laboratory criteria are met if either the aPTT or dRVVT confirmatory test results are positive, and if lab positivity is confirmed following repeated testing 12 weeks following initial results. Due to the multiple tests used, and different manufacturers’ reagents, analysis of comparative performance allows users to identify the optimal tests to use. Objectives of the study were 1) compare intra-run and total precision of two different aPTT-based LA confirmatory tests on a newly available automated coagulation instrument equipped with improved pipetting methodology and preanalytical sample integrity detection and 2) correlate results from the two different aPTT-based LA confirmatory test assays. Methods CRYOcheck Hex LA (Precision BioLogic, Inc., Dartmouth, NS, Canada) and Staclot LA (Diagnostica Stago, Inc., Parsippany, NJ, USA) were run on a STA R Max3 automated coagulation analyzer (Diagnostica Stago, Inc.), using manufacturer recommended protocols. For intra-run precision and total precision analysis, replicates of 5 quality control samples were used (STA Control LA 1+2, Diagnostica Stago, Inc.). For the correlation studies, 20 different LA positive samples were used, supplied by the Specimen Access Team (SAT) from Laboratory Corporation of America Holdings, Burlington, NC, USA. LA positivity was defined as positive by CRYOcheck Hex LA delta result > 11 seconds, which was the cutoff determined at LabCorp’s facility. CRYOcheck Normal Donor Set plasmas were used for normal samples (Precision BioLogic, Inc.). Samples were run in batches containing 5 normal samples and 5 abnormal samples, with quality control run at the beginning and end of each batch. Results Intra-run precision was superior for Staclot LA compared to CRYOcheck Hex LA, with the exception of the high phospholipid “LA Correct” positive tube from CRYOcheck Hex LA. Total precision was either comparable or superior for Staclot LA compared to CRYOcheck Hex LA. In addition, correlation data showed Staclot LA recovered the same result between 3 different aliquots of the same patient mother tube, whereas CRYOcheck Hex LA recovered varying results between runs, when using manufacturer recommended cutoffs. Conclusions Analysis of intra-run and total precision, along with result correlation and recovery between multiple sample aliquots is recommended for when coagulation laboratories evaluate different manufacturers’ reagents. Our data indicate Staclot LA demonstrates superior performance to the CRYOcheck Hex LA on the STA R Max3 automated coagulation analyzer.

A square planar cobalt(II)-thiosemicarbazone complex. Synthesis, characterization, antiviral and anti-inflammatory potential

Considering the possible antiviral effect of cobalt compounds and known pharmacological potential of thiosemicarbazones, a new combination containing cobalt(II) ions and tetradentate thiosemicarbazone was synthesized and structurally analyzed. In the complex structure (Co1), the cobalt ion is in 2+ oxidation state and is coordinated with ONNO donor set on the thiosemicarbazone backbone. The complex molecule crystallizes in the space group P21/m and the environment of the cobalt center tends to square planar geometry. The inhibitory performance of SARS-CoV-2 and the anti-inflammatory impact of the complex molecule were investigated. It was found that Co1 has high inhibitory effects on the SARS-CoV-2 virus's 3CL main protease enzyme, ACE2:SARS-CoV2 Spike RBD interaction, and IL8. Also, it showed significant anti-inflammatory effects on the release of IL6, IL8, IL10, and TGFβ1 cytokines and wound healing during in vitro TNF-α-induced inflammation. Experimental evidence demonstrates that Co1 diminishes both IL8 gene expression and protein levels. According to in silico and experimental results, it has a drug potential. Assessing the in vivo impacts of Co1 might contribute to understanding its potential as an antiviral and anti-inflammatory agent.

Metal Center-Tuned Photocatalytic Carbon Dioxide Reduction for Frameworks with the Tetraphenylethene-Imidazole Ligand.

As heterogeneous photocatalysts that can effectively transform CO2 to CO, two MOFs with different metal centers, namely, [M(tipe)(H2O)2](ClO4)2·solvent (M = Ni named as Ni-MOF and M = Co referred to as Co-MOF), were synthesized by reactions of 1,1,2,2-tetrakis(4-(imidazole-1-yl)phenyl)ethene (tipe) with the corresponding metal perchlorate. Both Ni-MOF and Co-MOF have 3D structures, in which the metal centers have the same coordination environment with the N4O2 donor set. Driven by visible light, the CO production catalyzed by Co-MOF is 6734.1 μmol g-1 with 45.3% selectivity, and in contrast, Ni-MOF has 4601.3 μmol g-1 CO production with 97.6% selectivity in 5 h. Through photoelectrochemical characterization, DFT calculations, and in situ FT-IR measurements, the photocatalytic CO2 reduction process catalyzed by Ni-MOF and Co-MOF was investigated. The results show that the metal center of the MOF is crucial for photocatalytic CO2 reduction. This work offers an innovative approach for controlling the performance of photocatalytic CO2 reduction through tuning the metal centers of architectures.

Illuminating the Performance of Electron Withdrawing Groups in Halogen Bonding.

Throughout the halogen bonding literature, electron withdrawing groups are relied upon heavily for tuning the in- teraction strength between the halogen bond donor and acceptor; however, the interplay of electronic effects associated with various substituents is less of a focus. This work utilizes computational techniques to study the degree ofσ- andπ- electron donating/accepting character of electron withdrawing groups in a prescribed set of halo-alkyne, halo-benzene, and halo-ethynyl benzene halogen bond donors. We examine how these factors affect theσ-hole magnitude of the donors as well as the binding strength of the corresponding complexes with an ammonia acceptor. Statistical analyses aid the interpretation of how these substituents influence the properties of the halogen bond donors and complexes, and show that the electron withdrawing groups that are bothσ- andπ-electron accepting form the strongest halogen bond complexes.

Comparing transplant outcomes in ALL patients after myeloablative conditioning in mismatch-related or unrelated donor settings.

The optimal myeloablative conditioning regimen for ALL patients undergoing hematopoietic cell transplant (HCT) with an alternative donor is unknown. We analyzed HCT outcomes ALL patients (n = 269) who underwent HCT at our center from 2010 to 2020 in complete remission (CR) after FTBI-etoposide and CNI-based GvHD prophylaxis for matched donor HCT (ETOP-package; n = 196) or FTBI-Fludarabine and post-transplant cyclophosphamide (PTCy)-based prophylaxis for HLA- mismatched (related or unrelated) donors (FLU-package; n = 64). Patients in FLU-package showed a significant delay in engraftment (p < 0.001) and lower cumulative incidence (CI) of any and extensive chronic GVHD (p = 0.009 and 0.001, respectively). At the median follow up of 4.6 years (range 1-12 years); non-relapse mortality, overall or leukemia-free survival and GVHD-free/relapse-free survival were not significantly impacted by the choice of conditioning. However, in patients at CR2 or with measurable residual disease (MRD+), there was a trend towards higher relapse after FLU-package (p = 0.08 and p = 0.07, respectively), while patients at CR1 regardless of MRD status had similar outcomes despite the package/donor type (p = 0.9 and 0.7, respectively). Our data suggests that FLU-package for alternative donors offers comparable outcomes to ETOP-package for matched donor HCT to treat ALL. Disease status and depth of remission at HCT were independent predictors for better outcomes.

Local stability in kidney exchange programs

When each patient of a kidney exchange program has a preference ranking over its set of compatible donors, questions naturally arise surrounding the stability of the proposed exchanges. We extend recent work on stable exchanges by introducing and underlining the relevance of a new concept of locally stable, or L-stable, exchanges. We show that locally stable exchanges in a compatibility digraph are exactly the so-called local kernels (L-kernels) of an associated blocking digraph (whereas the stable exchanges are the kernels of the blocking digraph), and we prove that finding a nonempty L-kernel in an arbitrary digraph is NP-complete. Based on these insights, we propose several integer programming formulations for computing an L-stable exchange of maximum size. We conduct numerical experiments to assess the quality of our formulations and to compare the size of maximum L-stable exchanges with the size of maximum stable exchanges. It turns out that nonempty L-stable exchanges frequently exist in digraphs which do not have any stable exchange. All the above results and observations carry over when the concept of (locally) stable exchanges is extended to the concept of (locally) strongly stable exchanges.

Coordination chemistry of 4-aminopyrazole: Structure and physicochemical properties of cobalt(II) chlorido complexes, and amino group reactivity towards a ketone to yield an imine bond

An outline of the in situ construction of a coordination polymer by reacting a mononuclear cobalt(II) complex, functionalised with an amine substituent, with acetone is given. The methodology involved 4-amino-3,5-diisopropyl-1-pyrazole (denoted as L1pzHNH2) as the precursor, putative linker molecule. Reaction of the ligand with anhydrous cobalt(II) chloride, yielded a four-coordinated cobalt(II) chlorido complex, [CoCl2(L1pzHNH2)2]. When the complex was reacted with acetone, a four-coordinated cobalt(II) chlorido coordination polymer, [CoCl2{L1pzHN=C(CH3)2}]n, with an imine bond, was obtained. The complexes were characterised by various spectroscopic techniques. X-ray crystallography shows [CoCl2(L1pzHNH2)2]·2(thf) to comprise a tetrahedrally coordinated cobalt(II) centre with the donors being two chlorido and two pyrazolyl-N atoms. Similarly, [CoCl2{L1pzHN=C(CH3)2}]n features a Cl2N2 donor set defining an approximately tetrahedral geometry with the imine-N donors being derived from a pyrazolyl ring and a symmetry related exocyclic imine-N atom with the result that a one-dimensional coordination polymer with a helical topology is formed. When the uncoordinated precursor molecule, L1pzHNH2, was reacted with acetone, the formation of the imine was confirmed by 1H NMR measured in (CD3)2CO solution. However, from the 1H NMR measured for the imine in CDCl3 solution, a 70:30 equilibrium between the imine and amine was established. It is concluded that the nucleophilicity of the amine group is enhanced by the binding of cobalt(II) to the pyrazole nitrogen in [CoCl2(L1pzHNH2)2]·2(thf), thereby favouring irreversible imine formation. The facile formation of [CoCl2{L1pzHN=C(CH3)2}]n in the solid-state also correlates with the reduced solubility of the coordination polymer structure in organic solvents.

P-492 Providing implications counselling to SA anonymous oocyte donors donating to Australian recipients raising Australian DCC in an open- donor-identity context?

Abstract Study question How do counsellors manage mismatched expectations of stakeholders involved in cross-border oocyte donation between Australia and South Africa with different socio-legal frameworks regarding donor anonymity? Summary answer Cross-border oocyte donation can produce mismatched expectations due to different socio-legal frameworks around donor anonymity between two countries. Counsellors should alert stakeholders to these implications What is known already The demand for oocyte donation in Australia exceeds supply, influencing Australian women to undertake cross-border oocyte donation in South Africa. In Australia, oocyte donation is altruistic and open identity with guaranteed identity release. Conversely, South African oocyte donors are compensated and anonymous. The widespread utilisation of direct to consumer (DTC) ancestry DNA testing and internet-based forums to assist in the interpretation of these results has enabled recipients and donor conceived people (DCPs) to learn the identity of previously anonymous gamete donors. To better prepare stakeholders, some regulatory authorities require counsellors to discuss these implications with donors and recipients. Study design, size, duration Semi-structured in-depth interviews (lasting 45-60 mins) were conducted via zoom and in person in 2022 and 2023. The study included 9 South African infertility counsellors, 16 South African oocyte donors and 12 Australian recipients of cross-border oocyte donation in South Africa. Interviews were recorded and transcribed and transcripts were coded using NVivo software. Data were analysed using thematic analysis Participants/materials, setting, methods Infertility counsellors (9) were recruited through networks of SA fertility professionals. Research participant Australian recipients (12) were recruited through a Facebook peer fertility forum for recipients planning or having completed oocyte donation in SA. Research participant SA oocyte donors were recruited through Facebook advertisements and through snowball sampling resulting from recruitment advertisements placed in clinics and oocyte donor agencies Main results and the role of chance South African oocyte donors anticipated that they would remain anonymous. Some indicated that they would be open to contact should the legal framework in South Africa allow it. As Australian recipients were not required to undergo implications counselling with South African counsellors, the South African counsellors were not aware that recipients pursued the identity of their donors. The counsellors did not alert South African oocyte donors that Australian recipients and DCPs may engage in measures to determine their identity, including via DTC DNA testing and online sleuthing through forums. The Australian recipients believed donor conceived children had a right to know the donor’s identity and donor siblings’ identity, with some wanting early contact. Some recipients took steps to determine their donor’s identity and/or to discover whether their donor conceived children had donor siblings. They suggested that their children could pursue DNA testing in the future, if they wanted to know about their genetic origins. Limitations, reasons for caution The study findings are from 9 SA counsellors, 16 SA oocyte donors and 12 Australian recipients who agreed to be interviewed. They may not represent the views of all stakeholders involved in cross-border oocyte donation between Australia and South Africa. Wider implications of the findings Stakeholders involved in cross-border oocyte donation between anonymous donor and open identity settings should receive implications counselling to avoid a mismatch in the consequences of donor-conception. Trial registration number not applicable

Distance-dependent mating but considerable pollen immigration in an isolated Quercus rubra planting in Germany

AbstractGene flow affects the genetic diversity and structure of tree species and can be influenced by stress related to changing climatic conditions. The study of tree species planted in locations outside their natural range, such as arboreta or botanical gardens, allows us to analyse the effect of severe fragmentation on patterns and distances of gene flow. Paternity analysis based on microsatellite marker genotyping was used to analyse how fragmentation affects gene flow among individuals of Quercus rubra L. distributed in a small isolated group of trees (15 trees) planted in the arboretum on the North Campus of the University of Göttingen. For paternity analysis, 365 seedlings from four seed parents were selected and genotyped using 16 microsatellites. The analysis revealed the majority of pollen (84.89%) originated from trees within the site and identified three large full-sib families consisting of 145, 63 and 51 full-sibs. The average pollen dispersal distance for the four seed parents ranged from 17.3 to 103.6 meters. We observed substantial genetic differentiation among effective pollen clouds of the four seed parents (G’’ST = 0.407) as a result of cross pollination between neighboring trees. No self-fertilization was observed. Gene dispersal via pollen followed the expected distance-dependent pattern, and we observed a significant influx of external pollen (15.11%, ranging from 8.64 to 26.26% for individual seed parents) from a diverse set of donors (30). Long-distance pollen dispersal could explain the presence of significant genetic variation even in isolated natural Q. rubra populations.

Two Zn(II) complexes based on bis(benzimidazole) and different dicarboxylate anions: synthesis, structures, and fluorescent properties

Two new zinc(II) complexes, [Zn2(PBM)2(terephthalate)(formate)2] (1) and {[Zn(PBM)(fumarate)]∙H2O}n (2), were synthesized using 1,3-bis(1H-benzo[d]imidazol-2-yl)propane (PBM) and two different dicarboxylic acids under solvothermal conditions. Complexes 1 and 2 have been characterized by infrared spectroscopy, elemental analysis, and single-crystal X-ray diffraction analysis. The structural analysis showed that 1 was a binuclear structure and then formed a 3D supramolecular network structure through hydrogen bond and π-π conjugation, while 2 was a one-dimensional coordination polymer. In 1 and 2, the zinc ions were four-coordinate with an N2O2 donor set and a slightly distorted tetrahedral geometry. The solid-state fluorescence properties indicate that the fluorescence peaks belong to the π*-π transition of the ligand PBM, which has a significant red shift and enhancement with the order being 1 > 2 > PBM. The stronger fluorescence of the complexes than the ligand is due to the immobilization of the ligand through coordination, which reduces the energy loss of thermal vibration. The π∙∙∙π conjugation in 1 results in a stronger fluorescence of 1 than 2. Therefore, coordination and π∙∙∙π conjugation will affect the fluorescence of complexes.

Experimental and Computational Studies on the Interaction of DNA with Hesperetin Schiff Base CuII Complexes.

The interactions with calf thymus DNA (CT-DNA) of three Schiff bases formed by the condensation of hesperetin with benzohydrazide (HHSB or L1H3), isoniazid (HIN or L2H3), or thiosemicarbazide (HTSC or L3H3) and their CuII complexes (CuHHSB, CuHIN, and CuHTSC with the general formula [CuLnH2(AcO)]) were evaluated in aqueous solution both experimentally and theoretically. UV-Vis studies indicate that the ligands and complexes exhibit hypochromism, which suggests helical ordering in the DNA helix. The intrinsic binding constants (Kb) of the Cu compounds with CT-DNA, in the range (2.3-9.2) × 106, from CuHTSC to CuHHSB, were higher than other copper-based potential drugs, suggesting that π-π stacking interaction due to the presence of the aromatic rings favors the binding. Thiazole orange (TO) assays confirmed that ligands and Cu complexes displace TO from the DNA binding site, quenching the fluorescence emission. DFT calculations allow for an assessment of the equilibrium between [Cu(LnH2)(AcO)] and [Cu(LnH2)(H2O)]+, the tautomer that binds CuII, amido (am) and not imido (im), and the coordination mode of HTSC (O-, N, S), instead of (O-, N, NH2). The docking studies indicate that the intercalative is preferred over the minor groove binding to CT-DNA with the order [Cu(L1H2am)(AcO)] > [Cu(L2H2am)(AcO)] ≈ TO ≈ L1H3 > [Cu(L3H2am)(AcO)], in line with the experimental Kb constants, obtained from the UV-Vis spectroscopy. Moreover, dockings predict that the binding strength of [Cu(L1H2am)(AcO)] is larger than [Cu(L1H2am)(H2O)]+. Overall, the results suggest that when different enantiomers, tautomers, and donor sets are possible for a metal complex, a computational approach should be recommended to predict the type and strength of binding to DNA and, in general, to macromolecules.

Obesity and the cerebral cortex: Underlying neurobiology in mice and humans

Obesity is a major modifiable risk factor for Alzheimer’s disease (AD), characterized by progressive atrophy of the cerebral cortex. The neurobiology of obesity contributions to AD is poorly understood. Here we show with in vivo MRI that diet-induced obesity decreases cortical volume in mice, and that higher body adiposity associates with lower cortical volume in humans. Single-nuclei transcriptomics of the mouse cortex reveals that dietary obesity promotes an array of neuron-adverse transcriptional dysregulations, which are mediated by an interplay of excitatory neurons and glial cells, and which involve microglial activation and lowered neuronal capacity for neuritogenesis and maintenance of membrane potential. The transcriptional dysregulations of microglia, more than of other cell types, are like those in AD, as assessed with single-nuclei cortical transcriptomics in a mouse model of AD and two sets of human donors with the disease. Serial two-photon tomography of microglia demonstrates microgliosis throughout the mouse cortex. The spatial pattern of adiposity-cortical volume associations in human cohorts interrogated together with in silico bulk and single-nucleus transcriptomic data from the human cortex implicated microglia (along with other glial cells and subtypes of excitatory neurons), and it correlated positively with the spatial profile of cortical atrophy in patients with mild cognitive impairment and AD. Thus, multi-cell neuron-adverse dysregulations likely contribute to the loss of cortical tissue in obesity. The dysregulations of microglia may be pivotal to the obesity-related risk of AD.

Syntheses, characterizations and crystal structures of two Ni(II) complexes [Ni2(neoc)4(H2O)(CO3)](NO3)2·3H2O and [Ni(bapa)2](NO3)2·H2O and magnetic properties of the carbonato complex

By the reaction of nickel(II) nitrate hexahydrate with 2,9-dimethyl-1,10-phenanthroline (neoc) and bis(3-aminopropyl)amine (bapa) two novel complexes were isolated, namely [Ni2(neoc)4(H2O)(CO3)](NO3)2·3H2O (1) and [Ni(bapa)2](NO3)2·H2O (2). Both structures are ionic and comprise hexacoordinated Ni(II) central atoms. Complex 1 is built up of dinuclear [Ni2(neoc)4(H2O)(CO3)]2+ complex cation, nitrate anions and water solvate molecules. The dinuclear complex cation is centrosymmetric and the two Ni(II) atoms are linked by a μ3-bridging-chelating carbonato ligand which, due to the presence of an inversion centre, exhibits two orientations with equal probability. The coordination sphere of Ni(II) atom is heteroleptic with an N4O2 donor set formed by two chelating neoc ligands and two O-donor atoms from bridging carbonato and aqua ligands. The carbonato ligand was formed by transformation of absorbed carbon dioxide from air (single crystals) or from dry ice (bulk sample). The crystal structure of 2 is formed by [Ni(bapa)2]2+ complex cation, nitrate anions and water solvate molecule. The coordination sphere of Ni(II) atom in 2 is homoleptic with N6 donor set. Both bapa ligands act as double chelating 3 N-donor ligands and are coordinated in mer-fashion. The study of the magnetic response of 1 in the temperature range 1.8–300 K revealed that the system can be considered as a system of antiferromagnetic S = 1 spin dimers with exchange interaction J/hc = -13.86 cm−1 (J/kB = -19.96 K) and axial single-ion anisotropy D/hc = -4.94 cm−1 (D/kB = -7.12 K). The experimental magnetic results were corroborated by ab initio and DFT calculations.

Synthesis, Spectroscopy, X-ray Structures, DNA Binding and Photocatalytic Properties of Two Ni(II) and Co(II) Complexes of a Pyrazolyl Schiff-base Ligand

Two new nickel(II) and cobalt(II) complexes, [Ni(MPAFA)3](BF4)2 (I) and [Co(MPAFA)3](BF4)2 (II) were synthesized from a pyrazole containing ‘NN’ bidentate Schiff-base ligand, N-(furan-2-ylmethyl)-1-(5-methyl-1H-pyrazol-3-yl)methanimine, (MPAFA) (L). The complexes I and II were characterized by various physico-chemical and spectral parameters. Both I and II were 1:3 (M:L) coordination complexes and behaving as 1:2 electrolytes. Single crystal X-ray diffraction studies revealed that both of them were distorted octahedral in nature with a N6 donor set. The binding interactions of the complexes with CT-DNA were studied by UV-Vis and fluorescence spectroscopic methods. I was found to bind with CT-DNA in a partial intercalative mode, whereas II bound via the groove-like manner in solutions. The ligand and the complexes were shown to have potential photocatalytic activity in degrading methylene-blue (MB) under UV-Vis light irradiation.

Robotic kidney transplantation.

Kidney transplantation is the best treatment option for patients with end-stage renal disease owing to improved survival and quality of life compared with dialysis. The surgical approach to kidney transplantation has been somewhat stagnant in the past 50 years, with the open approach being the only available option. In this scenario, evidence of reduced surgery-related morbidity after the introduction of robotics into several surgical fields has induced surgeons to consider robot-assisted kidney transplantation (RAKT) as an alternative approach to these fragile and immunocompromised patients. Since 2014, when the RAKT technique was standardized thanks to the pioneering collaboration between the Vattikuti Urology Institute and the Medanta hospital (Vattikuti Urology Institute-Medanta), several centres worldwide implemented RAKT programmes, providing interesting results regarding the safety and feasibility of this procedure. However, RAKT is still considered an alternative procedure to be offered mainly in the living donor setting, owing to various possible drawbacks such as prolonged rewarming time, demanding learning curve, and difficulties in carrying out this procedure in challenging scenarios (such as patientswith obesity, severe atherosclerosis of the iliac vessels, deceased donor setting, or paediatric recipients). Nevertheless, the refinement of robotic platforms through the implementation of novel technologies as well as the encouraging results from multicentre collaborations under the umbrella of the European Association of Urology Robotic Urology Section are currently expanding the boundaries of RAKT, making this surgical procedure a real alternative to the open approach.

Bis[S-octyl 3-(2-methyl-propyl-idene)di-thio-carb-az-ato-κ2N3,S]nickel(II).

The central NiII atom in the title complex, [Ni(C13H25N2S2)2], is located on an inversion center and adopts a roughly square-planar coordination environment defined by two chelating N,S donor sets of two symmetry-related ligands in a trans configuration. The Ni-N and Ni-S bond lenghts are 1.9193 (14) and 2.1788 (5) Å, respectively, with a chelating N-Ni-S bond angle of 86.05 (4)°. These data are compared with those measured for similar di-thio-carbazato ligands that bear n-octyl or n-hexyl alkyl chains. Slight differences are observed with respect to the phenyl-ethyl-idene derivative where the ligands are bound cis relative to one another.

Probing the Mechanism of Action of Bis(phenolato) Amine (ONO Donor Set) Titanium(IV) Anticancer Agents.

The need for anticancer therapies that overcome metallodrug resistance while minimizing adverse toxicities is targeted, herein, using titanium coordination complexes. Octahedral titanium(IV) trans,mer-[Ti{R1N(CH2-2-MeO-4-R1-C6H2)2}2] [R1 = Et, allyl, n-Pr, CHO, F, CH2(morpholino), the latter from the formyl derivative; R2 = Me, Et; not all combinations] are attained from Mannich reactions of commercial 2-methoxyphenols (27-74% overall yield, 2 steps). These crystalline (four X-ray structures) Ti(IV)-complexes are active against MCF-7, HCT-116, HT-29, PANC-1, and MDA-MB-468 cancer cell lines (GI50 = 0.5-38 μM). Their activity and cancer selectivity (vs nontumor MRC-5 cells) typically exceeds that of cisplatin (up to 16-fold). Proteomic analysis (in MCF-7) supported by other studies (G2/M cell cycle arrest, ROS generation, γH2AX production, caspase activation, annexin positivity, western blot, and kinase screens in MCF-7 and HCT-116) suggest apoptosis elicited by more than one mechanism of action. Comparison of these data to the modes of action proposed for salan Ti(IV) complexes is made.

Technical evaluation and standardization of the human thyroid microtissue assay.

The success and sustainability of U.S. EPA efforts to reduce, refine, and replace in vivo animal testing depends on the ability to translate toxicokinetic and toxicodynamic data from in vitro and in silico new approach methods (NAMs) to human-relevant exposures and health outcomes. Organotypic culture models employing primary human cells enable consideration of human health effects and inter-individual variability but present significant challenges for test method standardization, transferability, and validation. Increasing confidence in the information provided by these in vitro NAMs requires setting appropriate performance standards and benchmarks, defined by the context of use, to consider human biology and mechanistic relevance without animal data. The human thyroid microtissue (hTMT) assay utilizes primary human thyrocytes to reproduce structural and functional features of the thyroid gland that enable testing for potential thyroid-disrupting chemicals. As a variable-donor assay platform, conventional principles for assay performance standardization need to be balanced with the ability to predict a range of human responses. The objectives of this study were to (1) define the technical parameters for optimal donor procurement, primary thyrocyte qualification, and performance in the hTMT assay, and (2) set benchmark ranges for reference chemical responses. Thyrocytes derived from a cohort of 32 demographically diverse euthyroid donors were characterized across a battery of endpoints to evaluate morphological and functional variability. Reference chemical responses were profiled to evaluate the range and chemical-specific variability of donor-dependent effects within the cohort. The data-informed minimum acceptance criteria for donor qualification and set benchmark parameters for method transfer proficiency testing and validation of assay performance.

A genome-wide association study of social trust in 33,882 Danish blood donors

Social trust is a heritable trait that has been linked with physical health and longevity. In this study, we performed genome-wide association studies of self-reported social trust in n = 33,882 Danish blood donors. We observed genome-wide and local evidence of genetic similarity with other brain-related phenotypes and estimated the single nucleotide polymorphism-based heritability of trust to be 6% (95% confidence interval = (2.1, 9.9)). In our discovery cohort (n = 25,819), we identified one significantly associated locus (lead variant: rs12776883) in an intronic enhancer region of PLPP4, a gene highly expressed in brain, kidneys, and testes. However, we could not replicate the signal in an independent set of donors who were phenotyped a year later (n = 8063). In the subsequent meta-analysis, we found a second significantly associated variant (rs71543507) in an intergenic enhancer region. Overall, our work confirms that social trust is heritable, and provides an initial look into the genetic factors that influence it.

A comparison of structure, bonding and non-covalent interactions of aryl halide and diarylhalonium halogen-bond donors.

Halogen bonding permeates many areas of chemistry. A wide range of halogen-bond donors including neutral, cationic, monovalent, and hypervalent have been developed and studied. In this work we used density functional theory (DFT), natural bond orbital (NBO) theory, and quantum theory of atoms in molecules (QTAIM) to analyze aryl halogen-bond donors that are neutral, cationic, monovalent and hypervalent and in each series we include the halogens Cl, Br, I, and At. Within this diverse set of halogen-bond donors, we have found trends that relate halogen bond length with the van der Waals radii of the halogen and the non-covalent or partial covalency of the halogen bond. We have also developed a model to calculate ΔG of halogen-bond formation by the linear combination of the % p-orbital character on the halogen and energy of the σ-hole on the halogen-bond donor.