In the search for new therapeutic agents for currently incurable diseases, attention has turned to traditionally "undruggable" targets, and collections of drug-like small molecules with high diversity and quality have become a prerequisite for new breakthroughs. To generate such collections, the diversity-oriented synthesis (DOS) strategy was developed, which aims to populate new chemical space with drug-like compounds containing a high degree of molecular diversity. The resulting DOS-derived libraries have been of great value for the discovery of various bioactive small molecules and therapeutic agents, and thus DOS has emerged as an essential tool in chemical biology and drug discovery. However, the key challenge has become how to design and synthesize drug-like small-molecule libraries with improved biological relevancy as well as maximum molecular diversity. This Perspective presents the development of privileged substructure-based DOS (pDOS), an efficient strategy for the construction of polyheterocyclic compound libraries with high biological relevancy. We envisioned the specific interaction of drug-like small molecules with certain biopolymers via the incorporation of privileged substructures into polyheterocyclic core skeletons. The importance of privileged substructures such as benzopyran, pyrimidine, and oxopiperazine in rigid skeletons was clearly demonstrated through the discovery of bioactive small molecules and the subsequent identification of appropriate target biomolecule using a method called "fluorescence difference in two-dimensional gel electrophoresis". Focusing on examples of pDOS-derived bioactive compounds with exceptional specificity, we discuss the capability of privileged structures to serve as chemical "navigators" toward biologically relevant chemical spaces. We also provide an outlook on chemical biology research and drug discovery using biologically relevant compound libraries constructed by pDOS, biology-oriented synthesis, or natural product-inspired DOS.

This research examines the persuasiveness of destination websites through an investigation of users' first impression. To achieve this goal, it builds on research by Fogg (2003) and by Kim and Fesenmaier (2007) to assess the effect of the design factors of destination websites on first impression formation. The results of this study indicate that the subjects were able to make quick judgments on tourism websites, and that inspiration and usability were the primary drivers evoking a favorable first impression. This research concludes by discussing the implications of these findings and possible directions for future study.

Background: Prognostic factors in locally advanced breast cancer treated with neoadjuvant chemotherapy differ from those of early breast cancer. The purpose of this study was to identify the clinical significance of potential predictive and prognostic factors in breast cancer patients treated by neoadjuvant chemotherapy.

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We revealed the X-ray structure of PPARγ co-crystallized with SR1664 bound to the alternate binding site of PPARγ and confirmed that this blocks the phosphorylation of Ser273.

In this paper we report plasma blob events (plasma density enhancements) that were observed from KOMPSAT‐1 (685‐km altitude, 2250 LT) and from DMSP F15 (840‐km altitude, 2130 LT) in the low‐latitude F region. The blobs were observed mostly along the ±15° magnetic latitudes. Their global distribution showed a seasonal‐longitudinal dependence similar to the distribution of the equatorial plasma bubbles. The blobs drifted upward relative to the ambient plasma, and the electron temperatures and H+ proportions were lower within the blobs compared to those in the background. The characteristics of the plasma blobs were similar to those of the equatorial plasma bubbles. Therefore, it is suggested that the blobs originated from the lower altitudes by a mechanism that drives an upward drift of the plasma bubbles. The blob events did not occur in a correlated way with the magnetic activity or daily variation of solar activity.

Central nerve system (CNS) metastases are a feared complication of breast cancer and are associated with poor prognosis. The purpose of this study is to investigate the clinical characteristics of CNS metastases and to clarify the prognostic factors after CNS metastases in breast cancer at a single institution over a long time period. We retrospectively reviewed the medical records of breast cancer patients diagnosed at Seoul National University Hospital from 1981 to 2009 and identified the patients who experienced CNS metastases. We collected the data, including demographics, clinico-pathologic characteristics, dates of diagnosis of original breast cancer and subsequent metastases, and date of death, and correlated the findings with the clinical outcome. A total of 400 patients were identified, of whom 17 (4.3%) were diagnosed with CNS metastases and primary breast cancer concurrently and 383 (95.7%) experienced CNS metastases subsequent to the diagnosis of primary breast cancer. Further, 318 patients (79.5%) had only brain parenchymal metastases, 30 (7.5%) had only leptomeningeal metastases, and 52 (13%) had both. After the diagnosis of CNS metastasis, 170 patients (42.5%) received systemic chemotherapy (CTx) and 143 (35.8%) received CTx after whole brain radiation therapy (WBRT). The patients with good performance status (PS), initial CNS metastasis as recurrence, absence of extracranial metastases, non-visceral extracranial metastases, longer interval from the date of primary breast cancer to the date of CNS metastasis, and CTx after WBRT and gamma-knife surgery (GKS), had better outcomes in univariate analyses. In multivariate analysis, good PS, systemic CTx after WBRT, GKS, and longer interval to CNS metastasis, were independent prognostic factors for overall survival after CNS metastases. Our results suggest that appropriate palliative systemic therapy after WBRT or GKS, and adequate palliative treatment via combined modalities are helpful for breast cancer patients, even after the detection of CNS metastases.

[1] The 27-day solar modulation of the low-latitude ionosphere is investigated for the solar maximum period using in situ satellite measurement data and the total electron contents (TEC) estimated from the satellite signals of the global positioning system (GPS). Whereas the density and temperature of the topside ionosphere observed at an altitude of 685 km manifest delayed responses to the 27-day variations in the daily F10.7 values, similar to those previously reported for an altitude of 840 km, the nighttime-scale height, obtained by comparing the densities observed at altitudes of 685 and 840 km at similar local times, was shown to vary in accordance with the changes in F10.7 with the same time delay. The oxygen ion fraction measured at an altitude of 840 km shows a similar response regardless of the local time. Moreover, the GPS TEC values, most of which come from the F peak region, also exhibit similar delayed modulations in accordance with solar rotation. The TEC value correlates well with the thermospheric neutral density, and both are observed to be modulated with the solar rotation with time delay, especially when a long-term variation is filtered out. The present result confirms that the whole thermospheric and ionospheric system is modulated with solar rotation.