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Describes a graduate quantum mechanics projects in which students write a computer program that performs ab initio calculations on the electronic structure of a simple molecule. Theoretical potential energy curves are produced. (MLH)

Outcome expectations of direct pulp capping in carious teeth are obscured by a clinically unknown infiltration and breakdown of the dental pulp tissue. Histologic studies showed that this soft tissue breakdown is related to the innate immune system. We hypothesized 1) that a neutrophil biomarker could predict the outcome of direct pulp capping and 2) that using sodium hypochlorite (NaOCl) as a lavage solution to remove necrotized infected pulp tissue could improve it. In this randomized trial in mature posterior teeth causing no or mild discomfort with carious pulpal exposures, pulpal fluid was collected to assess neutrophil gelatinase (matrix metalloproteinase 9 [MMP-9]) per total protein (TP) levels as a predictive local biomarker. Subsequently, the dentin-pulp wound was randomly washed with a 2.5% NaOCl or a physiologic saline solution (1:1 allocation), capped with mineral trioxide aggregate, and the tooth was immediately restored with a resin-based composite restoration. Ninety-six patients were included, and 84 individuals could be followed up to treatment failure or clinically confirmed pulp survival after a minimum of 1 y. The entire data were fitted to a Cox proportional hazards model to assess the influence of the observational variables MMP-9/TP and discomfort with the randomized lavage treatment on pulp survival. The Kaplan-Meier pulp survival rates after 1 y were 55% for saline and 89% for NaOCl lavage. The inflammatory state of the pulp tissue as reflected by MMP-9/TP levels and NaOCl lavage had a highly significant ( P

Aluminyl anions are low-valent, anionic, and carbenoid aluminum species commonly found stabilized with potassium cations from the reaction of Al-halogen precursors and alkali compounds. These systems are very reactive toward the activation of σ-bonds and in reactions with electrophiles. Various research groups have detected that the potassium atoms play a stabilization role via electrostatic and cation ⋯ π interactions with nearby (aromatic)-carbocyclic rings from both the ligand and from the reaction with unsaturated substrates. Since stabilizing K⋯H bonds are witnessed in the activation of this class of molecules, we aim to unveil the role of these metals in the activation of the smaller and less polarizable H2 molecule, together with a comprehensive characterization of the reaction mechanism. In this work, the activation of H2 utilizing a NON-xanthene-Al dimer, [K{Al(NON)}]2 (D) and monomeric, [Al(NON)]- (M) complexes are studied using density functional theory and high-level coupled-cluster theory to reveal the potential role of K+ atoms during the activation of this gas. Furthermore, we aim to reveal whether D is more reactive than M (or vice versa), or if complicity between the two monomer units exits within the D complex toward the activation of H2 . The results suggest that activation energies using the dimeric and monomeric complexes were found to be very close (around 33 kcal mol-1 ). However, a partition of activation energies unveiled that the nature of the energy barriers for the monomeric and dimeric complexes are inherently different. The former is dominated by a more substantial distortion of the reactants (and increased interaction energies between them). Interestingly, during the oxidative addition, the distortion of the Al complex is minimal, while H2 distorts the most, usually over 0.77 Δ E d i s t ≠ . Overall, it is found here that electrostatic and induction energies between the complexes and H2 are the main stabilizing components up to the respective transition states. The results suggest that the K+ atoms act as stabilizers of the dimeric structure, and their cooperative role on the reaction mechanism may be negligible, acting as mere spectators in the activation of H2 . Cooperation between the two monomers in D is lacking, and therefore the subsequent activation of H2 is wholly disengaged.

A series of reactions between Lewis bases and an imidazole-based dithione dimer (1) has been investigated. Both cyclic(alkyl)(amino)carbene (CAAC) (2) and N-heterocyclic carbene (NHC) (4), in addition to N-heterocyclic silylene (NHSi) (6), demonstrate the capability to cleave the sulphur-sulphur bonds in 1, giving carbene-stabilized dithiolene (L0 ) zwitterions (3 and 5) and a spirocyclic silicon-dithiolene compound (7), respectively. The bonding nature of 3, 5, and 7 are probed by both experimental and theoretical methods.

Vanadium forms binuclear complexes with a variety of ligands often containing V≡V triple bonds. Many tetragonal divanadium paddlewheel complexes with bridging bidentate ligands have been experimentally characterized. This research exhaustively treats model tetragonal, trigonal, and digonal paddlewheel-type divanadium complexes V2 Lx (L=formamidinate, guanidinate, and carboxylate; x=2, 3, 4), each in the three lowest-energy spin states. The V-V formal bond orders are obtained from metal-metal MO diagrams for representative structures. A number of short V-V multiple bonds of order 3, 3.5, and 4 are found in these model complexes. The short V≡V triple bonds and singlet ground state predicted here for the model tetragonal complexes correspond well with the limited experimental results for the series of known tetragonal paddlewheels. Digonal divanadium lanterns with very short V-V quadruple bonds are predicted as interesting synthetic targets. The V-V bond distances are categorized into distinct ranges according to the formal bond order values from 0.5 to 4. These bond length ranges are compared with the ranges compiled for other divanadium complexes including carbonyl complexes.

Enhancer of zeste homolog 2 (EZH2) is the catalytic core of polycomb repressive complex 2 (PRC2), which primarily methylates lysine 27 on histone H3 (H2K27me3), generating transcriptionally suppressed heterochromatin. Since EZH2 suppresses expression of genes involved in dentin formation, we examined the role of EZH2 in tooth development. Intriguingly, microCT analysis of teeth from mice with conditional Ezh2 knockout in uncommitted mesenchymal cells showed hyper-mineralization of enamel, which is produced by the epithelial-lineage cells, ameloblasts. Scanning electron microscopy analysis and nano-indentation of the incisor enamel from knockout mice revealed smaller inter-rod spaces and higher hardness compared to wild type enamel, respectively. Interestingly, expression of the calcium channel subunit gene, Orai2, was decreased compared to its competitor, Orai1, both in knockout mouse incisors and the ex vivo culture of ameloblasts with the surrounding tissues under EZH2 inhibition. Moreover, histological analysis of incisor from knockout mice showed decreased ameloblastin and expedited KLK4 expression in the ameloblasts. These observations suggest that EZH2 depletion in dental mesenchymal cells reduces enamel matrix formation and increases enamel protease activity from ameloblasts, resulting in enamel hyper-mineralization. This study demonstrates the significant role of the suppressive H3K27me3 mark for heterochromatin on enamel formation.

In 2019, Diaz-Urrutia and Ott developed a high-yield method for direct conversion of methane to methanesulfonic acid and proposed a cationic chain reaction mechanism. However, Roytman and Singleton questioned this mechanism, and they favored a free-radical mechanism. In the present paper, we studied both the cationic chain and radical mechanisms and found the radical mechanism is more favorable, since it has a much lower energy barrier. However, the radical mechanism has not considered the effect of ions for the reaction taking place in oleum. Thus, we studied a simple model of a protonated radical mechanism, which further lowers the energy barrier. Although the true mechanism for the CH4 + SO3 reaction could be more complicated in electrolyte solutions, this model should be helpful for the further study of the mechanism of this reaction.

Important recent experimental studies have allowed the isomer-selective identification of the 2-, 3-, and 4-picolyl radicals. The picolyl radicals and their valence isoelectronic P, As, Sb, and Bi congeners are investigated here. For the three observed parent radicals, the theoretical ionization potentials agree with experiment to within 0.02 eV. Two rules are proposed for predicting vertical ionization potentials (EVIE) and relative energies. The EVIE values for these radicals will be higher when large percentages of the SOMO orbitals are distributed on the atoms with greater electronegativities. The cations of these systems were also studied along with the closed-shell methylpyridines and their P, As, Sb, and Bi analogs. The energies for the cationic species will lie lower when high percentages of π natural localized molecular orbitals occur on the more electronegative atoms. The structures of the 2- and 4-isomers strongly depend upon the heteroatoms, with the C-C linkages adopting a single-double alternating bond manner when the heteroatoms become heavier. The 3-isomers adopt roughly equal C-C bond distances with small changes from N to Bi.

Recent experimental research by Cummins and co-workers has established the existence of a tetrahedrane molecule with one CH moiety replaced by phosphorus. We present here the first theoretical studies of the entire Pn(CH)3 (Pn = N, P, As, Sb, Bi) class of molecules. Geometries are obtained at the highly reliable CCSD(T)/aug-cc-pwCVTZ(-PP) level of theory. Harmonic vibrational frequencies are determined and analyzed to confirm the nature of each stationary point and provide helpful findings that may aid in the detection of each species. Most notable is the result that the geometric parameters associated with the (CH)3 moiety in the tetrahedranes exhibit little change under pnictogen substitution, while the Pn-C bonds and C-Pn-C bond angles greatly increase and decrease, respectively. Strain energies are predicted and range from 122.3 kcal mol-1 (N(CH)3) to 99.4 kcal mol-1 (Bi(CH)3) at the DF-CCSD(T)//B3LYP-D3/aug-cc-pV(T+d)Z(-PP) level of theory. The obtained geometries are further analyzed with Natural Bond Orbital (NBO) methods to understand the bonding and electronic structure of each species. We also provide insight into how different substituents can help make the tetrahedrane structure more energetically favorable due to electron delocalization into substituent antibonding orbitals. The effect of additional delocalization also weakens the Pn-C bonds, especially for the heavier pnictogens. This work concludes with a list of considerations that summarize our key findings and motivate future work aimed at producing novel pnictogen-substituted tetrahedrane molecules.

The utility of high energy density materials (HEDMs) comes from their thermodynamic properties which arise from specific structural features that contribute to energy storage. Studies of such structural features seek to increase our understanding of these energy storage mechanisms in order to further enhance their properties. High-nitrogen-containing HEDMs are of particular interest because they are less toxic than traditional HEDMs. Pentazole is the largest of the nitrogen rings which has been synthesized and considered for an HEDM; however, few experimental studies exist due to the difficulty involved in the synthesis, and most previous theoretical studies employed composite methods where lower level geometries were used with higher level methods. Here, the decomposition reaction of pentazole is studied. Geometries, fundamental frequencies, and energies for each of the stationary points of the decomposition pathway are computed using ab initio methods up to CCSDT(Q). Decomposition rates are calculated over a range of temperatures using canonical transition state theory in order to determine the kinetic stability of pentazole. Based on the present results, it would be difficult for pentazole to act as an HEDM, requiring temperatures close to 200 K to achieve a suitable level of stability.

Purpose Transforming growth factor β (TGFβ) promotes cell survival by endorsing DNA damage repair and mediates an immunosuppressive tumor microenvironment. Thus, TGFβ activation in response to radiation therapy is potentially targetable because it opposes therapeutic control. Strategies to assess this potential in the clinic are needed. Methods and Materials We evaluated positron emission tomography (PET) to image 89Zr -fresolimumab, a humanized TGFβ neutralizing monoclonal antibody, as a means to detect TGFβ activation in intracranial tumor models. Pathway activity of TGFβ was validated by immunodetection of phosphorylated SMAD2 and the TGFβ target, tenascin. The contribution of TGFβ to radiation response was assessed by Kaplan-Meier survival analysis of mice bearing intracranial murine tumor models GL261 and SB28 glioblastoma and brain-adapted 4T1 breast cancer (4T1-BrA) treated with TGFβ neutralizing monoclonal antibody, 1D11, and/or focal radiation (10 Gy). Results 89Zr-fresolimumab PET imaging detected engineered, physiological, and radiation-induced TGFβ activation, which was confirmed by immunostaining of biological markers. GL261 glioblastoma tumors had a greater PET signal compared with similar-sized SB28 glioblastoma tumors, whereas the widespread PET signal of 4T1-BrA intracranial tumors was consistent with their highly dispersed histologic distribution. Survival of mice bearing intracranial tumors treated with 1D11 neutralizing antibody alone was similar to that of mice treated with control antibody, whereas 1D11 improved survival when given in combination with focal radiation. The extent of survival benefit of a combination of radiation and 1D11 was associated with the degree of TGFβ activity detected by PET. Conclusions This study demonstrates that 89Zr-fresolimumab PET imaging detects radiation-induced TGFβ activation in tumors. Functional imaging indicated a range of TGFβ activity in intracranial tumors, but TGFβ blockade provided survival benefit only in the context of radiation treatment. This study provides further evidence that radiation-induced TGFβ activity opposes therapeutic response to radiation.

The geometries and energies of mononuclear and binuclear octafluorocyclohexadiene iron carbonyl derivatives have been studied using density functional theory. The lowest energy C6F8Fe(CO)3 tricarbo...

Background:: To investigate dynamic live tissue organophosphorus nerve agent uptake and distribution fates resulting in acetylcholinesterase inhibition, we recently reported the first-in-class fluorine-18 [18F] radiolabeled Positron Emission Tomography (PET) imaging tracer known as [18F]O-(2-fluoroethyl)-O-(p-nitrophenyl)methylphosphonate. This tracer has been initially studied in live rats with PET imaging. Objective.: We sought to evaluate the PET tracer in vivo using a new dose formulation of saline, ethanol and L-ascorbic acid, and compare the influence of this formulation on in vivo tracer performance to previous data collected using a CH3CN:PBS formulation. Methods:: A high molar activity [18F]tracer radiosynthesis was used. Doses were formulated as saline, ethanol (≤ 1%) and L-ascorbic acid (0.1%), pH 4.0-4.5. Stability was evaluated to 6 h. Dose injection (i.v.) into male rats was followed by either ex vivo biodistribution profiling at 5, 30, 90 min, or dynamic 90 min PET imaging. Rat biodistribution and PET imaging data were compared. Results and Discussion:: An optimized radiosynthesis (8 ± 2 % RCY) resulted in stable doses for 6 h (>99%). Arterial blood included a tracer and a single metabolite. The ex vivo biodistribution and live tissue PET imaging data revealed rapid radioactivity uptake and distributed tissue levels: heart and lung, highest; liver, moderate; and brain, lowest. Conclusions:: Imaging and biodistribution data were highly correlated with expected radioactivity tissue uptake and distribution in target organs. Lower brain radioactivity levels by PET imaging were found for the new formulation (saline, 1% L-ascorbic acid, < 1% ethanol) as compared to the established CH3CN:PBS formulation. Overall, we found that the i.v. dose formulation changed the in vivo profile of an organophosphorus PET tracer that is considered an important finding for future organophosphorus PET tracer studies.

The cyano radical (CN) is an abundant, open-shell molecule found in a variety of environments, including the atmosphere, the interstellar medium and combustion processes. In these environments, it often reacts with small, closed-shell molecules via hydrogen abstraction. Both carbon and nitrogen atoms of the cyano radical are reactive sites, however the carbon is more reactive with reaction barrier heights generally between 2–15 kcal mol−1 lower than those of the analogous nitrogen. The CN + HX → HCN/HNC + X, with X = H, CH3, NH2, OH, F, SiH3, PH2, SH, Cl, C2H, CN reactions have been studied at a high-level of theory, including CCSD(T)-F12a. Furthermore, kinetics were obtained over the 100–1000 K temperature range, showing excellent agreement with those rate constants that have been determined experimentally.

Four different reaction pathways are initially located for the reaction of Cl atom plus water trimer Cl + (H2O)3 → HCl + (H2O)2OH using a standard DFT method. As found for the analogous fluorine reaction, the geometrical and energetic results for the four chlorine pathways are closely related. However, the energetics for the Cl reaction are very different from those for fluorine. In the present paper, we investigate the lowest-energy chlorine pathway using the “gold standard” CCSD(T) method in conjunction with correlation-consistent basis sets up to cc-pVQZ. Structurally, the stationary points for the water trimer reaction Cl + (H2O)3 may be compared to those for the water monomer reaction Cl + H2O and water dimer reaction Cl + (H2O)2. Based on the CCSD(T) energies, the title reaction is endothermic by 19.3 kcal mol−1, with a classical barrier height of 16.7 kcal mol−1 between the reactants and the exit complex. There is no barrier for the reverse reaction. The Cl⋯(H2O)3 entrance complex lies 5.3 kcal mol−1 below the separated reactants. The HCl⋯(H2O)2OH exit complex is bound by 8.6 kcal mol−1 relative to the separated products. The Cl + (H2O)3 reaction is somewhat similar to the analogous Cl + (H2O)2 reaction, but qualitatively different from the Cl + H2O reaction. It is reasonable to expect that the reactions between the chlorine atom and larger water clusters may be similar to the Cl + (H2O)3 reaction. The potential energy profile for the Cl + (H2O)3 reaction is radically different from that for the valence isoelectronic F + (H2O)3 system, which may be related to the different bond energies between HCl and HF.

While the 1 : 1 reaction of 3 with an N-heterocyclic carbene ({(Me)CN(i-Pr)}2C:) in THF resulted in ligand-substituted product 4, the corresponding 1 : 2 reaction (in the presence of H2O) gives the first structurally characterized germanium tris(dithiolene)dianion 5 as the major product and the "naked" dithiolene radical 6˙ as a minor by-product. The structure and bonding of 4 and 5 were probed by experimental and theoretical methods. Our study suggests that carbene-mediated partial hydrolysis may represent a new method to access tris(dithiolene) complexes of main-group elements.

[Image: see text] Organophosphorus esters (OPs) were originally developed as pesticides but were repurposed as easily manufactured, inexpensive, and highly toxic chemical warfare agents. Acute OP toxicity is primarily due to inhibition of acetylcholinesterase (AChE), an enzyme in the central and peripheral nervous system. OP inhibition of AChE can be reversed using oxime reactivators but many show poor CNS penetration, indicating a need for new clinically viable reactivators. However, challenges exist on how to best measure restored AChE activity in vivo and assess the reactivating agent efficacy. This work reports the development of molecular imaging tools using radiolabeled OP analog tracers that are less toxic to handle in the laboratory, yet inhibit AChE in a similar fashion to the actual OPs. Carbon-11 and fluorine-18 radiolabeled analog tracers of VX and sarin OP agents were prepared. Following intravenous injection in normal Sprague–Dawley rats (n = 3–4/tracer), the tracers were evaluated and compared using noninvasive microPET/CT imaging, biodistribution assay, and arterial blood analyses. All showed rapid uptake and stable retention in brain, heart, liver, and kidney tissues determined by imaging and biodistribution. Lung uptake of the sarin analog tracers was elevated, 2-fold and 4-fold higher uptake at 5 and 30 min, respectively, compared to that for the VX analog tracers. All tracers rapidly bound to red blood cells (RBC) and blood proteins as measured in the biodistribution and arterial blood samples. Analysis of the plasma soluble activity (nonprotein/cell bound activity) showed only 1–6% parent tracer and 88–95% of the activity in the combined solid fractions (RBC and protein bound) as early as 0.5 min post injection. Multivariate analysis of tracer production yield, molar activity, brain uptake, brain area under the curve over 0–15 min, and the amount of parent tracer in the plasma at 5 min revealed the [(18)F]VX analog tracer had the most favorable values for each metric. This tracer was considered the more optimal tracer relative to the other tracers studied and suitable for future in vivo OP exposure and reactivation studies.

Sulfur dioxide and hypohalous acids (HOX, X = F, Cl, Br, I) are ubiquitous molecules in the atmosphere that are central to important processes like seasonal ozone depletion, acid rain, and cloud nucleation. We present the first theoretical examination of the HOX···SO 2 binary complexes and the associated trends due to halogen substitution. Reliable geometries were optimized at the CCSD(T)/aug-cc-pV(T+d)Z level of theory for HOF and HOCl complexes. The HOBr and HOI complexes were optimized at the CCSD(T)/aug-cc-pV(D+d)Z level of theory with the exception of the Br and I atoms which were modeled with an aug-cc-pwCVDZ-PP pseudopotential. 27 HOX···SO 2 complexes were characterized and the focal point method was employed to produce CCSDT(Q)/CBS interaction energies. Natural Bond Orbital analysis and Symmetry Adapted Perturbation Theory were used to classify the nature of each principle interaction. The interaction energies of all HOX···SO 2 complexes in this study ranged from 1.35 to 3.81 kcal mol -1 . The single-interaction hydrogen bonded complexes spanned a range of 2.62 to 3.07 kcal mol -1 , while the single-interaction halogen bonded complexes were far more sensitive to halogen substitution ranging from 1.35 to 3.06 kcal mol -1 , indicating that the two types of interactions are extremely competitive for heavier halogens. Our results provide insight into the interactions between HOX and SO 2 which may guide further research of related systems.

Reaction of the lithium dithiolene radical 2(•) with the imidazolium salt [{(Me)CN(i-Pr)}(2)CH](+)[Cl](−) (in a 1:1 molar ratio) gives the first stable naked anionic dithiolene radical 3(•), which, when coupled with hexasulfide, [{(Me)CN(i-Pr)}(2)CH](+)(2)[S(6)](2−) (4), and N-heterocyclic silylene 5, unexpectedly results in synergic THF ring-opening via a radical mechanism.

Non-invasive methods to study glucocorticoid receptor (GR) signaling are urgently needed to reveal the complexity of GR signaling in normal physiology and human disorders, as well as to identify selective GR modulators to treat diseases. Here, we report evidence supporting translational studies with (±)-[11C]-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f ]-quinoline (named as (±)-[11C]YJH08), a radioligand for positron emission tomography (PET) that engages the ligand binding domain on GR. Methods: (±)-[11C]YJH08 was synthesized by reacting the phenol precursor with [11C]methyl iodide. The biodistribution was studied in vivo with PET/CT and autoradiography. A library of analogues were synthesized and studied in vitro and in vivo to understand the (±)-[11C]YJH08 structure activity relationship. Rodent dosimetry studies were performed to estimate the human equivalent doses of (±)-[11C]YJH08. Results: (±)-[11C]YJH08 was synthesized by reaction of the phenolic precursor with [11C]methyl iodide giving a radiochemical yield of 51.7 ± 4.7% (decay corrected to starting [11C]methyl iodide). An analysis of the (±)-YJH08 structure-activity relationship with molecular dynamics simulations showed that (R)- and (S)-enantiomers occupy the ligand binding domain on GR with different binding modes and have indistinguishable patterns of biodistribution in vivo. Moreover, a focused chemical screen of analogues revealed that the aryl fluoride motif on YJH08 is essential for high affinity GR binding in vitro, high tissue uptake in vivo, and passage across the blood brain barrier. Lastly, we performed dosimetry studies in rodents, from which we showed estimated human equivalent doses of (±)-[11C]YJH08 to be commensurate with widely used carbon-11 and fluorine-18 tracers. Conclusion: In summary, these studies reveal the molecular determinants of a high affinity and selectivity ligand-receptor interaction and support the use of (±)-[11C]YJH08 PET to make the first measurements of GR expression in human subjects.

Methicillin-resistant Staphylococcus aureus (MRSA) infections cause significant mortality and morbidity globally. MRSA resistance to β-lactam antibiotics is mediated by two divergons that control levels of a β-lactamase, PC1, and a penicillin-binding protein poorly acylated by β-lactam antibiotics, PBP2a. Expression of genes encoding these proteins is controlled by two integral membrane proteins, BlaR1 and MecR1, which both have an extracellular β-lactam–binding sensor domain. Here, we solved the X-ray crystallographic structures of the BlaR1 and MecR1 sensor domains in complex with avibactam, a diazabicyclooctane β-lactamase inhibitor at 1.6–2.0 A resolution. Additionally, we show that S. aureus SF8300, a clinically relevant strain from the USA300 clone of MRSA, responds to avibactam by up-regulating the expression of the blaZ and pbp2a antibiotic-resistance genes, encoding PC1 and PBP2a, respectively. The BlaR1–avibactam structure of the carbamoyl-enzyme intermediate revealed that avibactam is bound to the active-site serine in two orientations ∼180° to each other. Although a physiological role of the observed alternative pose remains to be validated, our structural results hint at the presence of a secondary sulfate-binding pocket that could be exploited in the design of future inhibitors of BlaR1/MecR1 sensor domains or the structurally similar class D β-lactamases. The MecR1–avibactam structure adopted a singular avibactam orientation similar to one of the two states observed in the BlaR1–avibactam structure. Given avibactam up-regulates expression of blaZ and pbp2a antibiotic resistance genes, we suggest further consideration and research is needed to explore what effects administering β-lactam–avibactam combinations have on treating MRSA infections.

The high stability of the experimentally known homoleptic 1-norbornyl derivative (nor)4Fe of iron in the unusual +4 oxidation state is a consequence of the high reaction barriers of the singlet or triplet potential surfaces constrained by the global dispersion attraction and the great steric demands of the norbornyl groups. The much more limited stability of the corresponding cyclohexyl derivative (cx)4Fe may result from the conical intersection between the singlet potential surface and the quintet spin potential surface arising from the weaker dispersion attraction and the reduced steric effect of the cyclohexyl groups relative to the 1-norbornyl groups. In contrast, the high stability of the likewise experimentally known (cx)4M (M = Ru or Os) structures results from the larger ligand field splitting (Δ) of the d-orbital energies for the second and third-row transition metals ruthenium and osmium relative to that of the first-row transition metal iron. The cyclohexyl derivative (cx)4Fe is predicted to be reactive toward carbon monoxide to insert CO into up to two Fe-C bonds. However, the dispersion effect as well as the much larger size of the 1-norbornyl substituents prevents similar reactivity of (nor)4Fe with carbon monoxide.

This research reports a search for peculiar monobridged structures of the E2H2 molecules (E = Be, Mg, Ca, Sr, Ba). For Be2H2 and Mg2H2, the monobridged geometry is not an equilibrium but rather a t...

Ortho-benzyne has been well studied by both experiment and theory. Its substituted variants, however, have been less carefully examined. Benchmark data are computed for unsubstituted ortho-benzyne using several density functional theory functionals and basis sets, up to cc-pVQZ. Optimized geometries for the substituted ortho-benzyne as well as harmonic vibrational frequencies and singlet-triplet splittings are computed using the benchmarked functionals. A proximal (syn)OH substitution causes a mean θ1 distortion of +8.1 ± 1.4° from ortho-benzyne. Substituting in the proximal position with F shifts the singlet-triplet splitting by +4.5 ± 0.4 kcal mol-1 from ortho-benzyne. Natural bond orbital analysis, including natural Coulomb electrostatics, elucidates the presence of three influences from the selected substituents: hyperconjugative, resonance, and electrostatic effects.

Oxime antidotes regenerate organophosphate-inhibited acetylcholinesterase (AChE). Although they share a common mechanism of AChE reactivation, the rate and amount of oxime that enters the brain are critical to the efficacy, a process linked to the oxime structure and charge. Using a platform based on the organophosphate [18 F]-VXS as a positron emission tomography tracer for active AChE, the in vivo distribution of [18 F]-VXS was evaluated after an LD50 dose (250 μg/kg) of the organophosphate paraoxon (POX) and following oximes as antidotes. Rats given [18 F]-VXS tracer alone had significantly higher radioactivity (two- to threefold) in the heart and lung than rats given LD50 POX at 20 or 60 min prior to [18 F]-VXS. When rats were given LD50 POX followed by 2-PAM (cationic), RS194b (ionizable), or monoisonitrosoacetone (MINA) (neutral), central nervous system (CNS) radioactivity returned to levels at or above untreated naive rats (no POX), whereas CNS radioactivity did not increase in rats given the dication oximes HI-6 or MMB-4. MINA showed a significant, pairwise increase in CNS brain radioactivity compared with POX-treated rats. This new in vivo dynamic platform using [18 F]-VXS tracer measures and quantifies peripheral and CNS relative changes in AChE availability after POX exposure and is suitable for comparing oxime delivery and AChE reactivation in rats.

Lithiation of an imidazole-based monothiolate, 2, by excess n-butyllithium gives a white powder containing both a lithiated product and an nBuLi contaminant (in a ca. 1:1 molar ratio). This white p...

The histamine H(3) receptor (H(3)R) represents a highly attractive drug target for the treatment of various central nervous system disorders, but the discovery of novel H(3)R targeting compounds relies on the assessment of highly amplified intracellular signaling events that do not only reflect H(3)R modulation and carry the risk of high false-positive and -negative screening rates. To address these limitations, we designed an intramolecular H(3)R biosensor based on the principle of bioluminescence resonance energy transfer (BRET) that reports the receptor's real-time conformational dynamics and provides an advanced tool to screen for both H(3)R agonists and inverse agonists in a live cell screening-compatible assay format. This conformational G-protein-coupled receptor (GPCR) sensor allowed us to characterize the pharmacological properties of known and new H(3) receptor ligands with unprecedented accuracy. Interestingly, we found that one newly developed H(3) receptor ligand possesses even stronger inverse agonistic activity than reference H(3)R inverse agonists including the current gold standard pitolisant. Taken together, we describe here the design and validation of the first screening-compatible H(3)R conformational biosensor that will aid in the discovery of novel H(3)R ligands and can be employed to gain deeper insights into the (in-)activation mechanism of this highly attractive drug target.

ObjectiveTo investigate whether vitamin D, smoking, and anti-Epstein-Barr virus (EBV) antibody concentrations predict long-term cognitive status and neuroaxonal injury in multiple sclerosis (MS).MethodsThis study was conducted among 278 patients with clinically isolated syndrome who participated in the clinical trial BENEFIT (Betaferon/Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) and completed the 11-year assessment (BENEFIT-11). We measured serum 25-hydroxyvitamin-D (25(OH)D), cotinine (smoking biomarker), and anti-Epstein-Barr virus nuclear antigen 1 (EBNA-1) immunoglobulin G (IgG) at baseline and at months 6, 12, and 24 and examined whether these biomarkers contributed to predict Paced Auditory Serial Addition Test (PASAT)-3 scores and serum neurofilament light chain (NfL) concentrations at 11 years. Linear and logistic regression models were adjusted for sex, baseline age, treatment allocation, steroid treatment, multifocal symptoms, T2 lesions, and body mass index.ResultsHigher vitamin D predicted better, whereas smoking predicted worse cognitive performance. A 50-nmol/L higher mean 25(OH)D in the first 2 years was related to 65% lower odds of poorer PASAT performance at year 11 (95% confidence intervals [95% CIs]: 0.14–0.89). Standardized PASAT scores were lower in smokers and heavy smokers than nonsmokers (ptrend = 0.026). Baseline anti–EBNA-1 IgG levels did not predict cognitive performance (ptrend = 0.88). Associations with NfL concentrations at year 11 corroborated these findings—a 50-nmol/L higher mean 25(OH)D in the first 2 years was associated with 20% lower NfL (95% CI: −36% to 0%), whereas smokers had 20% higher NfL levels than nonsmokers (95% CI: 2%–40%). Anti–EBNA-1 antibodies were not associated with NfL.ConclusionsLower vitamin D and smoking after clinical onset predicted worse long-term cognitive function and neuronal integrity in patients with MS.

The histamine H4 receptor (H4R) activates Gαi-mediated signaling and recruits β-arrestin2 upon stimulation with histamine. β-Arrestins play a regulatory role in G protein-coupled receptor (GPCR) signaling by interacting with phosphorylated serine and threonine residues in the GPCR C-terminal tail and intracellular loop 3, resulting in receptor desensitization and internalization. Using bioluminescence resonance energy transfer (BRET)-based biosensors, we show that G protein-coupled receptor kinases (GRK) 2 and 3 are more quickly recruited to the H4R than β-arrestin1 and 2 upon agonist stimulation, whereas receptor internalization dynamics toward early endosomes was slower. Alanine-substitution revealed that a serine cluster at the distal end of the H4R C-terminal tail is essential for the recruitment of β-arrestin1/2, and consequently, receptor internalization and desensitization of G protein-driven extracellular-signal-regulated kinase (ERK)1/2 phosphorylation and label-free cellular impedance. In contrast, alanine substitution of serines and threonines in the intracellular loop 3 of the H4R did not affect β-arrestin2 recruitment and receptor desensitization, but reduced β-arrestin1 recruitment and internalization. Hence, β-arrestin recruitment to H4R requires the putative phosphorylated serine cluster in the H4R C-terminal tail, whereas putative phosphosites in the intracellular loop 3 have different effects on β-arrestin1 versus β-arrestin2. Mutation of these putative phosphosites in either intracellular loop 3 or the C-terminal tail did not affect the histamine-induced recruitment of GRK2 and GRK3 but does change the interaction of H4R with GRK5 and GRK6, respectively. Identification of H4R interactions with these proteins is a first step in the understanding how this receptor might be dysregulated in pathophysiological conditions.