Non-Canonical Targets of MicroRNAs: Role in Transcriptional Regulation, Disease Pathogenesis and Potential for Therapeutic Targets.

MicroRNAs are a class of regulatory, non-coding small ribonucleic acid (RNA) molecules found in eukaryotes. Dysregulated expression of microRNAs can lead to downregulation or upregulation of their target gene. In general, microRNAs bind with the Argonaute protein and its interacting partners to form a silencing complex. This silencing complex binds with fully or partial complementary sequences in the 3'-UTR of their cognate target mRNAs and leads to degradation of the transcripts or translational inhibition, respectively. However, recent developments point towards the ability of these microRNAs to bind to the promoters, enhancers or coding sequences, leading to upregulation of their target genes. This review briefly summarizes the various non-canonical binding sites of microRNA and their regulatory roles in various diseased conditions.

Multi-dimensional role of gangliosides in modulating cancer hallmarks and their prospects in targeted cancer therapy.

Gangliosides are glycosphingolipids with prevalence in nervous tissue and their involvement in certain neuronal diseases have been widely known. Interestingly, many recent studies highlighted their importance in the development and progression of various cancers through orchestration of multiple attributes of tumorigenesis, i.e., promoting migration, invasion, escaping the host immune system, and influencing other cancer hallmarks. Therefore, the multidimensional role of gangliosides in different cancers has established them as potential cancer targets. However, the tremendous structural complexity and functional heterogeneity are the major challenges in ganglioside research. Moreover, despite numerous immunotherapeutic attempts to target different gangliosides, it has failed to yield consistent results in clinical trials owing to their poor immunogenicity, a broad range of cross-reactivity, severe side effects, lack of uniform expression as well as heterogeneity. The recent identification of selective O-acetylated ganglioside expression in cancer tissues, but not in normal tissues, has strengthened their potential as a better and specific target for treating cancer patients. It was further supported by reduced cross-reactivity and side effects in clinical trials, although poor immunogenicity remains a major concern. Therefore, in addition to characterization and identification of the biological importance of O-acetylated gangliosides, their specific and efficient targeting in cancer through engineered antibodies is an emerging area of glycobiology research. This review highlights the modulatory effect of select gangliosides on different hallmarks of cancer and presents the overall development of ganglioside targeted immunotherapies along with recent progress. Here, we have also discussed its potential for future modifications aimed towards improvement in ganglioside-based cancer therapies.

Constructing Expertise: Surmounting Performance Plateaus by Tasks, by Tools, and by Techniques.

Acquiring expertise in a task is often thought of as an automatic process that follows inevitably with practice according to the log-log law (aka: power law) of learning. However, as Ericsson, Chase, and Faloon (1980) showed, this is not true for digit-span experts and, as we show, it is certainly not true for Tetris players at any level of expertise. Although some people may simply "twitch" faster than others, the limit to Tetris expertise is not raw keypress time but the techniques acquired by players that allow them to use the tools provided by the hardware and software to compensate for the game's relentlessly increasing drop speed. Unfortunately, these increases in drop speed between Tetris levels make performance plateaus very short and quickly followed by game death. Hence, a player's success at discovering, exploring, and practicing new techniques for the tasks of board preparation, board maintenance, optimal placement discovery, zoid rotation, lateral movement of zoids, and other tasks important to expertise in Tetris is limited. In this paper, we analyze data collected from 492 Tetris players to reveal the challenges they confronted while constructing expertise via the discovery of new techniques for gameplay at increasingly difficult levels of Tetris.