A novel mPGES-1 inhibitor alleviates inflammatory responses by downregulating PGE2 in experimental models.

We previously reported the strong inhibitory potency of N-phenyl-N'-(4- benzyloxyphenoxycarbonyl)-4-chlorophenylsulfonyl hydrazide (PBCH) on lipopolysaccharide (LPS)-induced prostaglandin E2 (PGE2) production in macrophages. Herein, we characterized PBCH as a microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor and evaluated its anti-inflammatory effects using in vivo experimental models. PBCH inhibited PGE2 production in various activated cells in addition to inhibiting the mPGES-1 activity. In the ear edema and paw edema rat models, PBCH significantly reduced ear thickness and paw swelling, respectively. Besides, in adjuvant-induced arthritis (AIA) rat model, PBCH decreased paw swelling, plasma rheumatoid factor (RF), and receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio. Furthermore, while PBCH reduced the plasma prostaglandin E metabolite (PGEM) levels, it did not affect the plasma levels of prostacyclin (PGI2) and thromboxane A2 (TXA2). Our data suggest that PBCH downregulates PGE2 production by interfering with the mPGES-1 activity, thus reducing edema and arthritis in rat models.

A novel RIPK1 inhibitor that prevents retinal degeneration in a rat glaucoma model.

In glaucoma, retinal ganglion cells (RGCs) are exposed to ischemic stress with elevation of the intraocular pressure and are subsequently lost. Necroptosis, a type of regulated necrosis, is known to play a pivotal role in this loss. We observed that receptor-interacting protein kinase 1 (RIPK1), the key player of necroptosis, was activated by diverse ischemic stresses, including TCZ, chemical hypoxia (CH), and oxygen glucose deprivation (OGD). In this study, we introduce a RIPK1-inhibitory compound (RIC) with a novel scaffold. RIC inhibited downstream events following RIPK1 activation, including necrosome formation and mitochondrial dysfunction in RGC5 cells. Moreover, RIC protected RGCs against ischemic injury in the rat glaucoma model, which was induced by acute high intraocular pressure. However, RIC displayed biochemical characteristics that are distinct from those of previous RIPK1 inhibitors (necrostatin-1; Nec-1 and Compound 27; Cpd27). RIC protected RGCs against OGD insult, while Nec-1 and Cpd27 did not. Conversely, Nec-1 and Cpd27 protected RGCs from TNF-stimulated death, while RIC failed to inhibit the death of RGCs. This implies that RIPK1 activates alternative pathways depending on the context of the ischemic insults.

Design, Synthesis, and Biological Activity of Marinacarboline Analogues as STAT3 Pathway Inhibitors for Docetaxel-Resistant Triple-Negative Breast Cancer.

Metastatic triple-negative breast cancer (mTNBC) is a fatal type of breast cancer (BC), and signal transducer and activator of transcription 3 (STAT3) has emerged as an effective target for mTNBC. In the present study, compound MC0704 was found to be a novel synthetic STAT3 pathway inhibitor, and its potential antitumor activity was demonstrated using in vitro and in vivo models in docetaxel-resistant TNBC cells. Based on marinacarboline (MC), a series ß-carboline derivatives were synthesized and investigated for their antitumor activities against docetaxel-resistant MDA-MB-231 (MDA-MB-231-DTR) cells. Combining antiproliferation and STAT3 inhibitory activities, MC0704 was selected as the most promising ß-carboline compound. MC0704 effectively impeded the metastatic potential of MDA-MB-231-DTR cells in vitro, and the combination of MC0704 and docetaxel exhibited potent antitumor activities in a xenograft mouse model. These findings suggested that MC0704 can be a lead candidate as a target therapeutic agent for TNBC patients with docetaxel resistance.

Regularized Speaker Adaptation of KL-HMM for Dysarthric Speech Recognition.

This paper addresses the problem of recognizing the speech uttered by patients with dysarthria, which is a motor speech disorder impeding the physical production of speech. Patients with dysarthria have articulatory limitation, and therefore, they often have trouble in pronouncing certain sounds, resulting in undesirable phonetic variation. Modern automatic speech recognition systems designed for regular speakers are ineffective for dysarthric sufferers due to the phonetic variation. To capture the phonetic variation, Kullback-Leibler divergence-based hidden Markov model (KL-HMM) is adopted, where the emission probability of state is parameterized by a categorical distribution using phoneme posterior probabilities obtained from a deep neural network-based acoustic model. To further reflect speaker-specific phonetic variation patterns, a speaker adaptation method based on a combination of L2 regularization and confusion-reducing regularization, which can enhance discriminability between categorical distributions of the KL-HMM states while preserving speaker-specific information is proposed. Evaluation of the proposed speaker adaptation method on a database of several hundred words for 30 speakers consisting of 12 mildly dysarthric, 8 moderately dysarthric, and 10 non-dysarthric control speakers showed that the proposed approach significantly outperformed the conventional deep neural network-based speaker adapted system on dysarthric as well as non-dysarthric speech.

Homosexuality in ancient and modern Korea.

This paper examines Korean views on the subject of male homosexuality. Using historical and contemporary sources, it seeks to explain elements of new cultural openness towards homosexuality in modern Korea. Korean people's understanding and knowledge of male homosexuality is ambiguous and limited. In the absence of knowledge and open communication, most Korean people imagine that male homosexuality is an abnormal and impure modern phenomenon. Prejudice and confusion lead most Korean male homosexuals to be estranged from their families, religious communities and non-homosexual peers. Moreover, they are often viewed as the 'carriers' of AIDS and Sexually Transmitted Diseases (STDs). The purpose of this paper is to examine current Korean perspectives on male homosexuality by exploring both the ancient history of the practice of male homosexuality and current thinking about homosexual life among Koreans, which has played an important part in the formation of contemporary attitudes toward homosexuality.