Targeting pre-mRNA splicing in cancers: roles, inhibitors, and therapeutic opportunities

Accumulating evidence has indicated that pre-mRNA splicing plays critical roles in a variety of physiological processes, including development of multiple diseases. In particular, alternative splicing is profoundly involved in cancer progression through abnormal expression or mutation of splicing factors. Small-molecule splicing modulators have recently attracted considerable attention as a novel class of cancer therapeutics, and several splicing modulators are currently being developed for the treatment of patients with various cancers and are in the clinical trial stage. Novel molecular mechanisms modulating alternative splicing have proven to be effective for treating cancer cells resistant to conventional anticancer drugs. Furthermore, molecular mechanism-based combination strategies and patient stratification strategies for cancer treatment targeting pre-mRNA splicing must be considered for cancer therapy in the future. This review summarizes recent progress in the relationship between druggable splicing-related molecules and cancer, highlights small-molecule splicing modulators, and discusses future perspectives of splicing modulation for personalized and combination therapies in cancer treatment

IMPROVEMENT OF EXPERIMENTTAL THEME ON EXPERIMENTS IN ATERIALS ENGINEERING

長岡工業高等専門学校物質工学科では，1年生から5年生までの各学年において学生実験（物質工学実験）を行っている．特に1年生で実施される物質工学実験（化学）は，基礎的かつ重要な実験項目や技法を習得する実験と位置付けられる．一般に化学系実験で定量分析を行うときには，0.0001gまではかることのできる直示天秤を使用する．その使用法を身につけるための実験を一年生時に行っている．以前は，四塩化炭素の分子量を測定する実験を行っていたが，四塩化水素の毒性とともに，実験にかかる時間が2時間以上と長いことが問題であった．そこで，比較的安全性を有し，かつ1時間程度でできる実験が必要になった．一方，2年生の実験の際，こぼれた水酸化ナトリウムが解けた潮解の現象を見て驚く学生がいた．そこで，水酸化ナトリウムが潮解するときの質量変化を利用した直示天秤の実験を組み立てることに取り組んだ

Mutant SOD1 impairs axonal transport of choline acetyltransferase and acetylcholine release by sequestering KAP3

Mutations in the superoxide dismutase 1 (sod1) gene cause familial amyotrophic lateral sclerosis (FALS), likely due to the toxic properties of misfolded mutant SOD1 protein. Here we demonstrated that, starting from the pre-onset stage of FALS, misfolded SOD1 species associates specifically with kinesin-associated protein 3 (KAP3) in the ventral white matter of SOD1G93A-transgenic mouse spinal cord. KAP3 is a kinesin-2 subunit responsible for binding to cargos including choline acetyltransferase (ChAT). Motor axons in SOD1G93A-Tg mice also showed a reduction in ChAT transport from the pre-onset stage. By employing a novel FALS modeling system using NG108-15 cells, we showed that microtubule-dependent release of acetylcholine was significantly impaired by misfolded SOD1 species. Furthermore, such impairment was able to be normalized by KAP3 overexpression. KAP3 was incorporated into SOD1 aggregates in human FALS cases as well. These results suggest that KAP3 sequestration by misfolded SOD1 species and the resultant inhibition of ChAT transport play a role in the dysfunction of ALS

A casual conversation system using modality and word associations retrieved from the web

In this paper we present a textual dialogue system that uses word associations retrieved from the Web to create propositions. We also show experiment results for the role of modality generation. The proposed system automatically extracts sets of words related to a conversation topic set freely by a user. After the extraction process, it generates an utterance, adds a modality and verifies the semantic reliability of the proposed sentence. We evaluate word associations extracted form the Web, and the results of adding modality. Over 80% of the extracted word associations were evaluated as correct. Adding modality improved the system significantly for all evaluation criteria. We also show how our system can be used as a simple and expandable platform for almost any kind of experiment with human-computer textual conversation in Japanese. Two examples with affect analysis and humor generation are given

Straight thinking straight from the net - on the web-based intelligent talking toy development

This paper introduces an early stage of a smart toy development project which combines several techniques to achieve a level of conversational skills and knowledge higher than currently available robots for children. We describe our ideas and achievements for three modules which we treat as the most important - topic unlimited talking engine, emotions recognizer and the moral behavior analyzer. We will also mention our novel evaluation method for freely speaking agents and possibilities of adding another module - an automatic joke generator. Index Terms—Intelligent systems, common sense, affect analysis, machine ethic

When Your Users Are Not Serious : Using Web-based Associations, Affect and Humor for Generating Appropriate Utterances for Inappropriate Input

In this paper we propose a method for generating simple but semantically correct replies to user inputs which are not related to a given task of a task-oriented information kiosk or any other natural language interface placed in a public place. We describe our method for retrieving meaningful associations from the Web and adding modality based on chatlog data. After showing the results of the evaluation experiments, we introduce an implementation of an affect analysis algorithm and pun generator to increase users’ satisfaction level

Affect-as-Information Approach to a Sentiment Analysis Based Evaluation of Conversational Agents

In this paper we propose a novel method forautomatic evaluation of conversational agents. Themethod is based on analyzing the user’s affectconveyed in utterances. From analyzing: the user’sgeneral emotional engagement in the conversation andthe emotion types conveyed by the user in theconversation, a simple psychological reasoning isderived about the user’s sentiment about the agent’sperformance. The evaluation experiment on twoJapanese-speaking conversational agents showed thesame tendencies in the results returned by the systemconstructed on the proposed method and the user’sopinion about the two agents checked in the afterwardsurvey. Thus the method can be used for evaluation ofJapanese-speaking conversational agents