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Background: As drug-metabolizing enzyme activities are affected by a variety of factors, such as drug-drug interactions, a method to evaluate drug-metabolizing enzyme activities in real time is needed. In this study, we developed a novel SPECT imaging probe for evaluation of hepatic CYP2D activity. Methods: Iodine-123- and 125-labeled 4-iodobenzylmequitazine (123/125I-BMQ) was synthesized with high labeling and purity. CYP isozymes involved in the metabolism of 125I-BMQ in mouse liver microsomes were evaluated, and the utility of 123/125I-was assessed from biological distribution and SPECT imaging evaluation in normal and CYP2D-inhibited mice. Results: In vitro metabolite analysis using mouse liver microsomes showed that 125I-BMQ is specifically metabolized by CYP2D. Biological distribution and SPECT imaging of 123/125I-BMQ in normal mice showed that injection 123/125I-BMQ accumulated early in the liver and was excreted into the gallbladder and intestines. In CYP2D-inhibited mice, accumulation in the liver was increased, but accumulation in the gallbladder and intestines, the excretory organ, was delayed. Since only metabolites of 125I-BMQ are detected in bile, visualization and measuring of the accumulation of metabolites over time in the intestine, where bile is excreted, could predict the amount of metabolites produced in the body and evaluate CYP2D activity, which would be useful in determining the dosage of various drugs metabolized by CYP2D. Conclusion: 123/125I-BMQ is useful as a SPECT imaging probe for comprehensive and direct assessment of hepatic CYP2D activity in a minimally invasive and simple approach. [ABSTRACT FROM AUTHOR]

Complex networks are pervasive in various fields such as chemistry, biology, and sociology. In chemistry, first-order reaction networks are represented by a set of firstorder differential equations, which can be constructed from the underlying energy landscape. However, as the number of nodes increases, it becomes more challenging to understand complex kinetics across different timescales. Hence, how to construct an interpretable, coarse-graining scheme that preserves the underlying timescales of overall reactions is of crucial importance. Here, we develop a scheme to capture the underlying hierarchical subsets of nodes, and a series of coarse-grained (reduceddimensional) rate equations between the subsets as a function of time resolution from the original reaction network. Each of the coarse-grained representations guarantees to preserve the underlying slow characteristic timescales in the original network. The crux is the construction of a lumping scheme incorporating a similarity measure in deciphering the underlying timescale hierarchy, which does not rely on the assumption of equilibrium. As an illustrative example, we apply the scheme to four-state Markovian models and Claisen rearrangement of allyl vinyl ether (AVE), and demonstrate that the reduced-dimensional representation accurately reproduces not only the slowest but also the faster timescales of overall reactions although other reduction schemes based on equilibrium assumption well reproduce the slowest timescale but fail to reproduce the second-to-fourth slowest timescales with the same accuracy. Our scheme can be applied not only to the reaction networks but also to networks in other fields, which helps us encompass their hierarchical structures of the complex kinetics over timescales. [ABSTRACT FROM AUTHOR]

Release of large amounts of adenosine triphosphate (ATP), a gliotransmitter, into the extracellular space by traumatic brain injury (TBI) is considered to activate the microglia followed by release of inflammatory cytokines resulting in excessive inflammatory response that induces secondary brain injury. The present study investigated whether antagonists of ATP receptors (P2X4 and/or P2X7) on microglia are beneficial for reducing the post-injury inflammatory response that leads to secondary injury, a prognostic aggravation factor of TBI. Adult male Sprague-Dawley rats were subjected to cortical contusion injury (CCI) and randomly assigned to injury and drug treatment conditions, as follows: i) No surgical intervention (naïve group); ii) dimethyl sulfoxide treatment after CCI (CCI-control group); iii) 5-BDBD (antagonist of P2X4 receptor) treatment after CCI (CCI-5-BDBD group); iv) CCI-AZ11645373 (antagonist of P2X7 receptor) treatment after CCI (CCI-AZ11645373 group); v) or 5-BDBD and AZ11645373 treatment after CCI (CCI-5-BDBD + AZ11645373 group). In the CCI-5-BDBD, CCI-AZ11645373, and CCI-5-BDBD + AZ11645373 groups, expression of activated microglia was suppressed in the ipsilateral cortex and hippocampus 3 days after the CCI. Western blotting with ionized calcium-binding adaptor molecule 1 antibody revealed that administration of CCI-5-BDBD and/or CCI-AZ11645373 suppressed expression of microglia and reduced expression of inflammatory cytokine mRNA 3 days after the CCI. Furthermore, the plus maze test, which reflects the spatial memory function and involves the hippocampal function, showed improvement 28 days after secondary injury to the hippocampus. These findings confirmed that blocking the P2X4 and P2X7 receptors, which are ATP receptors central in gliotransmission, suppresses microglial activation and subsequent cytokine expression after brain injury, and demonstrates the potential as an effective treatment for reducing secondary brain injury. [ABSTRACT FROM AUTHOR]

The analytical gradient for the atomic-orbital-based Hartree-Fock-Bogoliubov (HFB) energy functional, the modified form of which was proposed by Staroverov and Scuseria to account for the static electron correlation [J. Chem. Phys. 117, 11107 (2002)], is derived. Interestingly, the Pulay force for the HFB energy is expressed with the same formula as that for the Hartree- Fock method. The efficiency of the present HFB energy gradient is demonstrated in the geometry optimizations of conjugated and biradical systems. The geometries optimized by using the HFB method with the appropriate factor ζ, which controls the degree of static correlation included, are found to show good agreement with those obtained by using a complete active-space selfconsistent field method, although they are significantly dependent on ζ. [ABSTRACT FROM AUTHOR]

Background: Phosphorylated neurofilament heavy subunit (pNF-H) is a constituent protein of the nerve axon, which leaks into the peripheral blood in various central nervous disorders. This study examined the time course of pNF-H value up to 1 month after injury and investigated the correlation with clinical outcome. Methods: Serum pNF-H concentration was measured on admission, and at 24 h, 72 h, 1 week, 2 weeks, and 1 month after injury in 20 patients, 15 males and 5 females aged 35-68 years (mean 52 years), with traumatic brain injury (TBI) transported to our hospital between April 2016 and March 2017. The clinical outcome at discharge was evaluated by Glasgow Outcome Scale. Results: The pNF-H value showed no increase in patients without brain parenchymal injury, but pNF-H value increased depending on the severity of brain damage. pNF-H value peaked at 2 weeks after injury. Two patients with peak value exceeding 10,000 unit had very severe injury and died during hospitalization. Peak pNF-H value was 3210 ± 1073 unit in 12 patients with good outcome and 9884 ± 2353 unit in 8 patients with poor outcome (P = 0.0119). Conclusion: Serum pNF-H level tended to increase and peak at 2 weeks after injury, and the peak pNF-H value was correlated with clinical outcome after TBI. The temporal profile of blood pNF-H seems to be useful to predict the clinical outcome after TBI. [ABSTRACT FROM AUTHOR]

Abstract  To elucidate compositional changes of the prostate with aging, the authors investigated age-related changes of elements in the prostates and the relationships among their elements using Japanese and Thai. After ordinary dissections by students at Nara Medical University and Chiang Mai University were finished, the prostates were resected from the subjects. Fifty-seven Japanese subjects ranged in age from 65 to 101 years (average age = 82.5 ± 7.8 years), whereas 13 Thai subjects ranged in age from 43 to 86 years (average age = 67.9 ± 11.9 years). After ashing with nitric acid and perchloric acid, element contents were determined by inductively coupled plasma–atomic emission spectrometry. It was found that although there were no significant correlations between age and seven element contents, such as Ca, P, S, Mg, Zn, Fe, and Na, in the prostates of Japanese, high contents of Ca (>5 mg/g) and P (>4 mg/g) were contained in one fourth of the prostates of Japanese over 70 years of age. In the prostates of Thai, a significant direct correlation was found between age and Ca content, but it was not found between age and the other element contents, such as P, S, Mg, Zn, Fe, and Na. Regarding the relationships among their elements, extremely significant direct correlations were found among the contents of Ca, P, Mg, Zn, and Na in the prostates of Japanese. In the prostates of Thai, significant direct correlations were found among the contents of Ca, Mg, and Zn, but no significant correlations were found between Ca and P contents and between P and Mg contents. Regarding the relationships among their elements, there were differences between the prostates of Japanese and Thai. To examine whether element contents changed in prostatic hypertrophy, the transverse width of the Japanese prostates was measured. No significant correlations were found between the transverse width and element contents, such as Ca, P, S, Mg, Zn, Fe, and Na, in the Japanese prostates. Therefore, it is unlikely that the increase of elements results in prostatic hypertrophy. [ABSTRACT FROM AUTHOR]

Abstract Purpose  The purpose of the study is to evaluate the feasibility of human estrogen receptor α ligand binding domain (hERL) as a reporter gene in combination with positron emission tomography (PET) probe, 16α-[18F]fluoro-17β-estradiol (FES), in an adenovirus gene delivery system. Methods  An adenoviral vector (test), carrying hERL gene and a model angiogenesis therapeutic gene (human thymidine phosphorylase, hTP) was constructed along with a control vector. In vitro radioligand binding and expression studies were performed on various cell lines. The control and test viruses were injected into contralateral adductor muscles of a rat followed by FES-PET imaging and immunohistochemical staining of resected muscle samples. Results  A high FES uptake accompanied by hERL and hTP expression was obtained both in vitro and in vivo by the test adenovirus infection. Conclusion  Considering the versatile tissue permeability of the probe, highly efficient gene expression, and safeness for human use, we expect our reporter gene system to have favorable characteristics for clinical application. [ABSTRACT FROM AUTHOR]

We have investigated the formation of an ultrathin Ge crystal layer by vacuum annealing of the Al/Ge(111) structure. An hetero-epitaxial Al layer was found to be grown on a Ge(111) substrate by control of Al thickness and deposition rate during thermal evaporation, which the Al surface becomes the template of crystallographic structure of a segregated Ge layer. Then, surface flattening and Ge segregation of the Al/Ge(111) structure by vacuum annealing were evaluated, and the formation of ultrathin segregated-Ge crystals with a thickness below 1 nm on the hetero-epitaxial Al surface have been demonstrated. [ABSTRACT FROM AUTHOR]