Causal discourse in a game of incomplete information

Notions of cause and effect are fundamental to economic explanation. Although concepts such as price effects are intuitive, rigorous foundations justifying causal discourse in the wide range of economic settings remain lacking. We illustrate this deficiency using an N-bidder private-value auction, posing causal questions that cannot be addressed within existing frameworks. We extend the frameworks of Pearl (2000) and White and Chalak (2009) to introduce topological settable systems (TSS), a causal framework capable of delivering the missing answers. Particularly, TSS accommodate choices belonging to general function spaces. Our analysis suggests how TSS enable causal discourse in various areas of economics

H-3 nota Derivatives Possessing Picolyl and Picolinate Pendants for Ga3+ Coordination and Ga-67(3+) Radiolabeling

International audienceWe synthesized, thanks to the regiospecific N-functionalizationusing an orthoamide intermediate, two 1,4,7-triazacyclononane derivativescontaining an acetate arm and either a methylpyridine or a picolinicacid group, respectively, Hnoapy and H-2 noapa, as new Ga3+ chelators for potential usein nuclear medicine. The corresponding Ga3+ complexes weresynthesized and structurally characterized in solution by H-1 and C-13 NMR. The [Ga(noapy)](2+) complex appears to exist in solution as two diasteroisomeric pairsof enantiomers, as confirmed by density functional theory (DFT) calculations,while for [Ga(noapa)](+), a single species ispresent in solution. Solid-state investigations were possible forthe [Ga(noapa)](+) complex, which crystallizedfrom water as a pair of enantiomers. The average length of the N-Gabonds of 2.090 and ANGS; is identical with that found for the [Ga(nota)] complex, showing that the presence of the picolinatearm does not hinder the coordination of the ligand to the metal ion.Protonation constants of noapy ( - ) and noapa ( 2- ) weredetermined by potentiometric titrations, providing an overall basicity n-ary sumation log K ( i ) (H) (i = 1-4) that increases in the order noapy ( - ) < noapa ( 2- ) < nota ( 3- ) with increases in the negative charge of theligand. Stability constants determined by pH-potentiometric titrationssupplemented with Ga-71 NMR data show that the stabilitiesof [Ga(noapy)](2+) and [Ga(noapa)](+) are lower compared to that of [Ga(nota)] but higher than those of other standards such as [Ga(aazta)](-). Ga-67 radiolabeling studies wereperformed in order to demonstrate the potential of these chelatorsfor Ga-67/68-based radiopharmaceuticals. The labelings ofHnoapy and H-2 noapa were nearlyidentical, outperforming H-3 nota. Stabilitystudies were conducted in phosphate-buffered saline and in the presenceof human serum transferrin, revealing no significant decomplexationof [Ga-67][Ga(noapy)](2+) and [Ga-67][Ga(noapa)](+) compared to [Ga-67][Ga(nota)]. Finally, all complexes were foundto be highly hydrophilic, with calculated log D (7.4) values of -3.42 and PLUSMN; 0.05, -3.34 and PLUSMN;0.04, and -3.00 and PLUSMN; 0.23 for Hnoapy, H-2 noapa, and H-3 nota, respectively,correlating with the charge of each complex and the electrostaticpotentials obtained with DFT. Hnoapy and H-2 noapa havebeen synthesized and studied as H-3 nota alternativesfor the complexation of Ga3+ and Ga-67/68, providingenhanced stability of the radiocomplex while maintaining good coordinationproperties

<i>N</i>,<i>N</i>‑Alkylation Clarifies the Role of <i>N</i>- and <i>O</i>‑Protonated Intermediates in Cyclen-Based ⁶⁴Cu Radiopharmaceuticals

Radioisotopes of Cu, such as 64Cu and 67Cu, are alluring targets for imaging (e.g., positron emission tomography, PET) and radiotherapeutic applications. Cyclen-based macrocyclic polyaminocarboxylates are one of the most frequently examined bifunctional chelators in vitro and in vivo, including the FDA-approved 64Cu radiopharmaceutical, Cu(DOTATATE) (Detectnet); however, connections between the structure of plausible reactive intermediates and their stability under physiologically relevant conditions remain to be established. In this study, we share the synthesis of a cyclen-based, N,N-alkylated spirocyclic chelate, H2DO3AC4H8, which serves as a model for N-protonation. Our combined experimental (in vitro and in vivo) and computational studies unravel complex pH-dependent speciation and enable side-by-side comparison of N- and O-protonated species of relevant 64Cu radiopharmaceuticals. Our studies suggest that N-protonated species are not inherently unstable species under physiological conditions and demonstrate the potential of N,N-alkylation as a tool for the rational design of future radiopharmaceuticals

IMMATURE CIRCULATING NEUTROPHILS IN SEPSIS HAVE IMPAIRED PHAGOCYTOSIS AND CALCIUM SIGNALING

Patients with sepsis commonly develop leukocytosis, which is presumed to reflect a host response to infection. Effective phagocytosis by neutrophils is crucial in the clearance of invading microbes. However, efficacy of phagocytosis in sepsis is controversial. We hypothesized that host phagocytic capacity in sepsis can be affected by immature neutrophils that are released into the circulation. Circulating neutrophils were evaluated in 16 patients with severe sepsis and 5 healthy donors. Immature neutrophils were identified by the cell morphology. Phagocytosis was evaluated by micromanipulation technique and simultaneous cytosolic-free Ca2+ imaging. Leukocytosis was present in 12 of 16 patients. Nine of the 12 patients with leukocytosis and 3 of 4 patients with normal white blood cell counts had increased circulating immature neutrophils (mean, 39.3% ± 20.7%; normal ≤5%). Quantification of the phagocytic activity revealed a significantly reduced phagocytic index of immature neutrophils as compared with mature neutrophils from both sepsis patients and healthy donors (25% ± 5% vs. 69% ± 8% and 42% ± 6%; P < 0.05). As compared with mature neutrophils, the number of internalized zymosan particles within immature neutrophils was also significantly lower. Mature neutrophils from patients and healthy donors displayed a single rapid transient Ca2+ signal during phagocytosis in contrast with weak signals from immature neutrophils. Our preliminary results show that phagocytic capacity of immature neutrophils is lower as compared with mature neutrophils. An increase in immature neutrophils in severe sepsis may undermine the overall phagocytic efficacy of a host despite observed leukocytosis