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Graves' orbitopathy (GO), an extrathyroidal manifestation of Graves' disease, can seriously threaten a patient's quality of life. Given that immunosuppressive treatment during the early active phase of GO has been found to reduce both disease activity and severity, sensitive screening tests are needed.The present study included 86 patients with GO, in whom serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (T3), free thyroxine, thyroid-stimulating antibody, TSH receptor antibody, thyroid peroxidase antibody, thyroglobulin, and thyroglobulin antibody were measured within 2 months before magnetic resonance imaging (MRI) for orbit assessment.The thyroid-stimulating antibody/TSH receptor antibody ratio was able to distinguish MRI results with a correct classification rate of 81%. When focusing on patients without T3 predominant Graves' diseases, the ratio distinguished MRI results at a rate of 92%. Receiver operating characteristic curve analysis revealed a cutoff antibody ratio of 87, which yielded a sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 91%, 95%, 18.2, and 0.0957, respectively, for distinguished MRI results.The thyroid-stimulating antibody/TSH receptor antibody ratio is a highly sensitive and specific indicator for active GO, especially in patients without T3 predominance, and serves as a good screening test for active GO in primary care settings.

We present the experimental visualization of the valence-electron-density distribution in benzene and its kinetically stabilized heavier-element analogues, i.e., 1,2-disilabenzene and 1,2-digermabenzene.

We examine the effects of fusing two benzofurans to s-indacene (indacenodibenzofurans, IDBFs) and dicyclopenta[b,g]naphthalene (indenoindenodibenzofurans, IIDBFs) to control the strong antiaromaticity and diradical character of these core units. Synthesis via 3-functionalized benzofuran yields syn-IDBF and syn-IIDBF. syn-IDBF possesses a high degree of paratropicity, exceeding that of the parent hydrocarbon, which in turn results in strong diradical character for syn-IIDBF. In the case of the anti-isomers, synthesized via 2-substituted benzofurans, these effects are decreased; however, both derivatives undergo an unexpected ring-opening reaction during the final dearomatization step. All the results are compared to the benzothiophene-fused analogues and show that the increased electronegativity of oxygen in the syn-fused derivatives leads to enhancement of the antiaromatic core causing greater paratropicity. For syn-IIDBF increased diradical character results from rearomati-zation of the core naphthalene unit in order to relieve this paratropicity.

We investigate the singlet fission (SF) dynamics of a slip-stack-like pentacene ring-shaped aggregate model, which is constructed by rotating each pentacene unit around its longitudinal axis in an H-aggregate ring. The aggregate size (N) and rotation angle (α) dependences of SF rates and double triplet (TT) yields are clarified using the quantum master equation method. It is found that there exist optimal ranges of the rotation angle α for each N, yielding efficient SF with high SF rates and TT yields. For example, in an 8-mer model, SF rates at α = 23 and 43° are 18.9 and 38.6 times as high as that at α = 30°, respectively, and the TT yields are as high as 0.871, 0.988, and 0.882 at α = 23, 30, and 43°, respectively. Analysis of the relative relaxation factors shows that the many-to-many relaxation paths from adiabatic Frenkel exciton (FE)-like states to TT-like states are opened by tuning α at relevant aggregate sizes, causing fast and high-TT-yield SF, and efficient SF occurs at α = 40° for medium N (7 ≤ N ≤ 10) or at α = 30° for large N (>10). This mechanism is interpreted by the second-order perturbation theory for electronic couplings. Namely, the inequality in the energies of charge-transfer states [CA and AC states, where the cation (C) and anion (A) are located at two neighboring sites in anticlockwise and clockwise directions, respectively] and the change in the amplitude and sign of the couplings between the FE, CT, and TT states are found to cause quantum superposition of the FE and TT states, which contribute to the high TT yield and SF rate. The present results contribute to a deeper understanding of SF dynamics in ring-shaped aggregates as well as to the development of their new design guidelines.

The singlet open-shell character and antiaromaticity are intriguing features in π-conjugated carbocycles. These two exhibit similar chemical and physical properties. However, they rarely coexist in the same molecule. Understanding the interrelation between the open-shell and antiaromatic characteristics in the same molecule is crucial to control the electronic properties. Herein we describe the synthesis and characterization of a new member of diareno[a,f]pentalene, benzo[a]naphtho[2,3-f]pentalene 6. Unlike its isomer 5 with a closed-shell ground state, 6 exhibits an appreciable open-shell character and a moderate antiaromatic feature. The behaviors of the open-shell index (y0 ) against the difference of the proton chemical signal (Δδ(H1 )) between pentalenide dianions/neutral pentalenes for our reported pentalenes 1, 4, 5, and 6 give a thought-provoking conclusion about the interrelation between open-shell and antiaromatic characteristics in this series. The mode of the incorporated quinoidal moiety and the formal molecular symmetry are critical to balance these two characteristics.

We theoretically investigate the role of charge-transfer (CT) states being stabilized by surrounding environments on singlet fission (SF) dynamics in a pentacene crystal. Using a polarizable force ...

We investigate the effect of applying an external static electric field on the singlet fission (SF) dynamics of pentacene dimer models using quantum chemical calculations and exciton dynamics simulations. It is found that the excitation energies of anion-cation (AC) and cation-anion (CA) pair exciton states in the SF process are significantly stabilized and destabilized, respectively, by applying an external static electric field (F) in the intermolecular direction. As a result, this change of excitation energies is found to accelerate the SF dynamics in pentacene dimer models. In particular, in the tilted- and parallel-type pentacene dimer models, SF rates at F = 0.001 a.u. are predicted to be about 2.3 and 3.0 times as large as those at F = 0.0 a.u. while keeping the TT yields large. The present result contributes to paving the way for novel physical and chemical controls, that is, an external static electric field application and donor/acceptor substitution on SF molecules, of SF dynamics.

The preparation of a series of dibenzo- and tetrabenzo-fused fluoreno[3,2-b]fluorenes is disclosed, and the diradicaloid properties of these molecules are compared with those of a similar, previously reported series of anthracene-based diradicaloids. Insights on the diradical mode of delocalization tuning by constitutional isomerism of the external naphthalenes has been explored by means of the physical approach (dissection of the electronic properties in terms of electronic repulsion and transfer integral) of diradicals. This study has also been extended to the redox species of the two series of compounds and found that the radical cations have the same stabilization mode by delocalization that the neutral diradicals while the radical anions, contrarily, are stabilized by aromatization of the central core. The synthesis of the fluorenofluorene series and their characterization by electronic absorption and vibrational Raman spectroscopies, X-ray diffraction, SQUID measurements, electrochemistry, in situ UV-vis-NIR absorption spectroelectrochemistry, and theoretical calculations are presented. This work attempts to unify the properties of different series of diradicaloids in a common argument as well as the properties of the carbocations and carbanions derived from them.

We investigate the potential of sumanene-fused acenes as a novel class of highly efficient singlet fission (SF) candidates by density functional theory (DFT) calculations and exciton dynamics simul...

We describe an autopsied patient with familial parkinsonism and unclassified four repeat-tau (4R-tau) aggregation. She presented with bradykinesia, truncal dystonia, and mild amnesia at the age of 61 and then exhibited body weight loss (15 kg over 8 months), sleep disturbances, and progressive respiratory failure with CO2 narcosis. She died of respiratory failure at the age of 62, 14 months after disease onset. Her brother also showed parkinsonism at the age of 58 and suddenly died 6 months later. Postmortem examination revealed 4R-tau aggregation, which was characterized by neuronal globose-type tangles or pretangles, bush-like or miscellaneous astrocytic inclusions, and coiled bodies. The temporal tip, the striatum, the substantia nigra, the tegmentum of the midbrain, the medullary reticular formation, and the spinal cord were severely involved with tau aggregation. Argyrophilic grains and ballooned neurons were also found in the medial temporal structures, however, extensions of the 4R-aggregations in the case were clearly broader than those of the argyrophilic grains. Western blot analysis of sarkosyl-insoluble fractions from brain lysates revealed prominent bands of tau at both 33 kDa and 37 kDa. Genetic examinations did not reveal any known pathogenic mutations in MAPT, DCTN-1, PSEN-1, or familial or young-onset parkinsonism-related genes. The clinical manifestations, pathologic findings, and biochemical properties of aggregated tau in our patient cannot be explained by argyrophilic grain disease or other known 4R-tauopathies alone. Our results further extend the clinical and neuropathologic spectra of 4R-tauopathy.

Upon photon absorption, π-conjugated organics are apt to undergo ultrafast structural reorganization via electron-vibrational coupling during non-adiabatic transitions. Ultrafast nuclear motions modulate local planarity and quinoid/benzenoid characters within conjugated backbones, which control primary events in the excited states, such as localization, energy transfer, and so on. Femtosecond broadband fluorescence upconversion measurements were conducted to investigate exciton self-trapping and delocalization in cycloparaphenylenes as ultrafast structural reorganizations are achieved via excited-state symmetry-dependent electron-vibrational coupling. By accessing two high-lying excited states, one-photon and two-photon allowed states, a clear discrepancy in the initial time-resolved fluorescence spectra and the temporal dynamics/spectral evolution of fluorescence spectra were monitored. Combined with quantum chemical calculations, a novel insight into the effect of the excited-state symmetry on ultrafast structural reorganization and exciton self-trapping in the emerging class of π-conjugated materials is provided.

The ability to alter optoelectronic and magnetic properties of molecules at a late stage in their preparation is in general a nontrivial feat. Here, we report the late-stage oxidation of benzothiop...

Summary A fundamental understanding of the inherent electronic and magnetic properties of open-shell diradicaloids is essential so that these properties can be modified to create molecules that meet the potential needs of industry. However, there have been very few attempts to date to systematically accomplish this in diradicaloid compounds. Here, we present the synthetic, spectroscopic, and computational investigation of a series of molecules based on the diindeno[1,2-b:1′,2′-g]anthracene framework. Calculations suggest that by altering the transfer integral term, tab, we are able to manipulate the diradical character and, thus, ΔEST within this series of molecules. Experimentally determined values by superconducting quantum interference device (SQUID) magnetometry show that we can effectively “tune” ΔEST of the five derivatives within a narrow 1.6 kcal mol−1 range.

Non-Markov effects on singlet fission (SF) dynamics of model pentacene dimers are investigated using the second-order time-convolutionless quantum master equation method with state-independent (SI)...

We theoretically investigate significant impacts of diradical character and exchange integral on the first singlet (S1) and triplet (T1) excitation energies related to singlet fission, from which a...

We investigated the capability of simple microfluidic devices with trenches having vertical sidewalls for live-cell fluorescence imaging of adherent cells. An epithelial cell line that forms a two-dimensional (2D) sheet was cultured to adhere to the vertical sidewall so that its vertical section can be imaged directly using ordinal inverted-type laser-scanning microscopy. The material and the structure of the device were characterized. We show that the detailed distribution of intracellular organelles, such as microtubules and mitochondria, and of intercellular apparatus, such as claudin and zonula occludens, can be imaged with high spatio-temporal resolution with a single scan.

In this study, we theoretically investigate the aromatic and open-shell characteristics of carbon nanobelts (CNBs) composed of five- and six-membered rings. We have designed nanobelts composed of indeno[1,2-b]fluorene ([1,2-b]IF) units, which are referred to as [N]IF-CNB (N: the number of five-membered rings). The number of π-electrons, nπ, in neutral [N]IF-CNB is 7N, and thus depending on N and charge states, nπ can be 4n + 2 and 4n. Quantum chemical calculations on neutral [6]IF-CNB and [8]IF-CNB and dicationic [8]IF-CNB2+ have revealed that they are expected to exhibit unique aromatic and open-shell characteristics depending on nπ, there are several analogies of the electronic structures in [N]IF-CNB to those in [N]annulene. Delocalized and intermediate open-shell electronic structures of [N]IF-CNB are also useful to drastically change the third-order nonlinear optical properties. These results suggest that theoretically designed [N]IF-CNB can be attractive and challenging targets of organic synthesis for realizing novel open-shell functional conjugated macrocycles.

Bis-periazulene (cyclohepta[

The dianion and dication of tetramesityl-substituted tetracyclopentatetraphenylene, a circulene consisting of alternating five- and six-membered rings, have been generated by reduction with alkali metals and oxidation with antimony(V) halides, respectively. They are theoretically predicted to adopt double annulenoid structures called annulene-within-an-annulene models in which the outer and inner conjugation circuits are significantly decoupled. The theoretical structures were experimentally proven by X-ray crystallographic analyses and the electronic configurations were supported by MCD spectra. Based on the

BackgroundAdenosine is the effector molecule mediating the antirheumatic effects of methotrexate, but the contributions of synoviocyte adenosine receptors (AdoRs) are unknown. Matrix metalloproteinase 3 (MMP-3) is released by fibroblast-like synoviocytes in response to inflammatory signaling, and serum MMP-3 is elevated during active rheumatoid arthritis. To elucidate the therapeutic mechanisms of methotrexate, we investigated the effects of A2A AdoR activation and inhibition on tumor necrosis factor-alpha (TNFa)-induced MMP-3 release by MH7A human rheumatoid synovial cells.MethodsCultured MH7A cells were treated with 25 pg/ml TNFa or vehicle for 24 h in the presence or absence of the selective A2A AdoR agonist HENECA (10, 50, or 100 nM), and MMP-3 release was measured in the culture supernatant. In other experiments, cells were treated with TNFa plus the cAMP analog dbcAMP or pretreated with the A2A AdoR antagonist ZM241385 prior to TNFa with or without HENECA. Activation of the p38 MAPK signaling pathway was evaluated by western blotting of phosphorylated signaling proteins. Treatment group means were compared by independent samples t-tests.ResultsMH7A cells constitutively expressed membrane-associated A2A AdoRs, and HENECA enhanced intracellular cAMP, indicating that these receptors are functionally coupled to adenylyl cyclase. Stimulation with TNFa markedly enhanced release of MMP-3 from MH7A cells, whereas HENECA partially and dose-dependently inhibited TNFa-evoked MMP-3 release. Similarly, dbcAMP partially inhibited TNFa-induced MMP-3 release. Pretreatment with ZM241385 reversed the inhibitory effects of HENECA. Further, TNFa induced p38 MAPK and ATF-2 phosphorylation, whereas HENECA suppressed p38 MAPK and ATF-2 phosphorylation.ConclusionsAdenosine signaling via A2A AdoRs, adenylyl cyclase, and cAMP reduces (although does not completely block) TNFa-induced MMP-3 production, by interfering with p38 MAPK/ATF-2 activity. Activation of A2A AdoR pathway and suppression of MMP-3 release may explain the antirheumatic effects of methotrexate.

The effect of hydrogen bonds around the active site of Anabaena [2Fe-2S] ferredoxin (Fd) on a vertical ionization potential of the reduced state (IP(red)) is examined based on the density functional theory (DFT) calculations. The results indicate that a single hydrogen bond increases the relative stability of the reduced state, and shifts IP(red) to a reductive side by 0.31–0.33 eV, regardless of the attached sulfur atoms. In addition, the IP(red) value can be changed by the number of hydrogen bonds around the active site. The results also suggest that the redox potential of [2Fe-2S] Fd is controlled by the number of hydrogen bonds because IP(red) is considered to be a major factor in the redox potential. Furthermore, there is a possibility that the redox potentials of artificial iron-sulfur clusters can be finely controlled by the number of the hydrogen bonds attached to the sulfur atoms of the cluster.

Adenosine causes the anti-inflammatory effect of MTX; however, the contributions of synoviocyte adenosine receptors (AdoRs) are unknown, and matrix metalloproteinase 3 (MMP-3) is released by fibroblast-like synoviocytes in response to inflammatory signaling. To understand the mechanism of the clinical observation that the matrix proteinase-3 concentration of patients with rheumatoid arthritis treated successfully with methotrexate does not usually normalize, we investigated the effects of A