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The effects of hydrogen absorption on the local lattice structure in palladium (Pd) were investigated by means of positron annihilation lifetime spectroscopy (PALS) and time-differential perturbed angular correlation (TDPAC) spectroscopy. The PALS measurements demonstrated that dislocations and vacancies formed in the preparation process of a pristine Pd plate can be clearly removed by vacuum annealing at 1073 K and the subsequent absorption of a large quantity of hydrogen, resulting in the production of the β-phase hydride PdH0.62, induces the formation of the open-volume defects again. It was also found that the absorbed hydrogen atoms remain in the Pd sample at 323 K but they are completely evacuated during 5 h heating at 383 K. In addition to the overall thermal behavior, an atomic scale observation of the hydrogen dynamics was carried out by means of TDPAC spectroscopy, indicating the nuclear quadrupole relaxation of the present (111m,111Pd → 111Ag→)111Cd probe, which evidently suggests that the hydrogen atoms show fast dynamic motion around the probe. From the temperature-dependent nuclear quadrupole relaxation rate, we obtained an activation energy of 41(4) meV for the motion. [ABSTRACT FROM AUTHOR]

Membrane binding is a crucial mechanism for many proteins, but understanding the specific interactions between proteins and membranes remains a challenging endeavor. Coagulation factor Va (FVa) is a large protein whose membrane interactions are complicated due to the presence of multiple anchoring domains that individually can bind to lipid membranes. Using molecular dynamics simulations, we investigate the membrane binding of FVa and identify the key mechanisms that govern its interaction with membranes. Our results reveal that FVa can either adopt an upright or a tilted molecular orientation upon membrane binding. We further find that the domain organization of FVa deviates (sometimes significantly) from its crystallographic reference structure, and that the molecular orientation of the protein matches with domain reorganization to align the C2 domain toward its favored membrane-normal orientation. We identify specific amino acid residues that exhibit contact preference with phosphatidylserine lipids over phosphatidylcholine lipids, and we observe that mostly electrostatic effects contribute to this preference. The observed lipid-binding process and characteristics, specific to FVa or common among other membrane proteins, in concert with domain reorganization and molecular tilt, elucidate the complex membrane binding dynamics of FVa and provide important insights into the molecular mechanisms of protein-membrane interactions. An updated version of the HMMM model, termed extHMMM, is successfully employed for efficiently observing membrane bindings of systems containing the whole FVa molecule. Author summary: Understanding the intricacies of protein-membrane interaction is essential for fleshing out the functional roles of membrane proteins. Substantial evidence indicates that the binding of some proteins, such as coagulation factor Va, proceeds in a multi-step manner requiring some form of rearrangements within the structure and dynamics of the protein, as well as in the protein's orientation relative to the membrane surface. In the case of factor Va, the intricate binding process can be attributed to the presence of multiple membrane-anchoring domains. In order to feasibly study the dynamics of these mechanisms, we employ an enhanced membrane-mimetic model, HMMM, capable of capturing such processes and rearrangements and making new discoveries possible using the molecular dynamics technique. The successful execution of these studies demanded several modifications to the original implementation of the HMMM. Our exploration not only improves our understanding of FVa's membrane binding dynamics but also contributes to the broader molecular mechanisms governing protein-membrane interactions. [ABSTRACT FROM AUTHOR]

Yasoo Sugiura,1 Etsuo Nemoto,1 Osamu Kawai,2 Yasuyuki Ohkubo,2 Hisae Fusegawa,2 Shizuka Kaseda1 1Department of Pulmonary and Thoracic Surgery, 2Department of Respiratory Medicine, Kanagawa National Hospital, Hadano, Japan Background: Gefitinib is known as one of the agents for treating patients with both advanced lung cancer and an epidermal growth-factor receptor mutation. In the epidermal growth-factor receptor-mutant advanced non-small-cell lung cancer population, gefitinib therapy has been associated with increased response rate, longer progression-free survival, and better quality of life compared to other anticancer drugs. However, gefitinib has to be discontinued for patients in whom adverse events occur, even if it is still effective. Here, we retrospectively assessed the clinical course of patients receiving gefitinib therapy, with a particular focus on liver damage. Patients and methods: Of 24 Asian patients treated with 250 mg gefitinib daily at Kanagawa National Hospital, Japan, between January 2008 and June 2012, grade 3 liver damage (Common Terminology Criteria for Adverse Events, version 4.0) occurred in nine and were eligible for our assessment. The regimen was subsequently changed to alternate-day administration. The relationships between liver damage and each clinical factor were retrospectively examined using Fisher’s exact test. Results: Of the nine patients with liver damage, seven had previous exposure to another anticancer drug. There was a significant relationship between the incidence of liver damage and previous chemotherapy (P = 0.009). The objective response rates of patients treated with daily gefitinib 250 mg and alternate-day gefitinib following liver damage were 66.7% and 46.7%, respectively; these were not significantly different (P = 0.597). Conclusion: Gefitinib for advanced adenocarcinoma patients who have previously undergone chemotherapy should be used cautiously and liver function monitored closely, because it frequently induces significant liver damage. The alternate-day administration of gefitinib may be a suitable option for patients in whom daily gefitinib therapy induces liver damage. Keywords: gefitinib, liver damage, adjuvant chemotherapy, previous chemotherapy, alternate-day administration

Shinji Makino, Yuko Ohkubo, Hironobu TampoDepartment of Ophthalmology, Jichi Medical University, Shimotsuke, Tochigi, JapanAbstract: We report the first case in the literature of chorioretinal atrophy involving the macula in an 11-year-old girl with Alagille syndrome, as examined by optical coherence tomography, and fundus autofluorescence imaging. Funduscopy revealed diffuse choroidal hypopigmentation with increased visibility of the choroidal vessels and symmetric, well circumscribed macular discoloration. Anomalous oblique configuration of the optic disc and peripapillary tortuous vessels were also detected. Optical coherence tomography demonstrated decreased retinal thickness, especially the outer retinal layer, and the photoreceptor inner segment/outer segment junctions were irregular and discontinued, corresponding to macular discoloration. Fundus autofluorescence imaging clearly defined hypofluorescent areas in the peripapillary regions that extended along the macula and had a sleep mask appearance. We suggest that transient hypovitaminosis due to Alagille syndrome early in life might contribute to the retinal degeneration seen in this case.Keywords: Alagille syndrome, chorioretinal atrophy, optical coherence tomography, fundus autofluorescence imaging, hypovitaminosis

Thermally activated association and dissociation behaviors of indium impurities in Zinc oxide (ZnO) were observed on an atomic scale by means of time-differential perturbed angular correlation spectroscopy with the radioactive 111In(→111Cd) probe. We found that In impurities associate in the process of thermal diffusion to form nanoscale clusters in the ZnO matrix under thermal treatment in air, and their structures depend on the concentration of In ions introduced. Heat treatment under vacuum, however, causes dissociation of part of the clusters, suggesting that In ions leave the clusters and migrate into the ZnO matrix. Positron annihilation lifetime spectroscopy performed for the In-doped ZnO also suggests that In ions as impurities migrate into the ZnO matrix by thermal diffusion to settle themselves in Zn vacancies. Dependences of thermal behavior of In impurities on their concentration, treatment temperature, and atmospheric condition are discussed based on the results observed by the nuclear spectroscopic techniques. [ABSTRACT FROM AUTHOR]

Magnetite (Fe3O4) was doped with radioactive 111mCd and 111In ions as impurities, and their residence sites and thermal stability were investigated by means of time-differential perturbed angular correlation (TDPAC) spectroscopy. Well-defined TDPAC spectra unequivocally show their sites: Cd ions are stably located only in the tetrahedral A site in all the temperature range of the present observation (77 K-873 K); In ions also specifically occupy the A site at low temperature, but at high temperature part of them select the B site in a reversible fashion. The energy difference between the A and B sites for the accommodation of In was experimentally determined to be 0.119 (9) eV by assuming a Boltzmann distribution for the populations of the 111In probe in the respective sites. The element-dependent thermal stabilities observed for Cd and In were well corroborated by density functional theory calculations. The successful observation of thermally activated site-tosite displacement of impurity In ions in Fe3O4 is reported. [ABSTRACT FROM AUTHOR]