Bridging gaps in traditional research training with iBiology Courses.

iBiology Courses provide trainees with just-in-time learning resources to become effective researchers. These courses can help scientists build core research skills, plan their research projects and careers, and learn from scientists with diverse backgrounds.

Mammalian endoplasmic reticulum stress sensor IRE1 signals by dynamic clustering.

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), an intracellular signaling pathway that adjusts the protein folding capacity of the ER according to need. If homeostasis in the ER protein folding environment cannot be reestablished, cells commit to apoptosis. The ER-resident transmembrane kinase-endoribonuclease inositol-requiring enzyme 1 (IRE1) is the best characterized UPR signal transduction molecule. In yeast, Ire1 oligomerizes upon activation in response to an accumulation of misfolded proteins in the ER. Here we show that the salient mechanistic features of IRE1 activation are conserved: mammalian IRE1 oligomerizes in the ER membrane and oligomerization correlates with the onset of IRE1 phosphorylation and RNase activity. Moreover, the kinase/RNase module of human IRE1 activates cooperatively in vitro, indicating that formation of oligomers larger than four IRE1 molecules takes place upon activation. High-order IRE1 oligomerization thus emerges as a conserved mechanism of IRE1 signaling. IRE1 signaling attenuates after prolonged ER stress. IRE1 then enters a refractive state even if ER stress remains unmitigated. Attenuation includes dissolution of IRE1 clusters, IRE1 dephosphorylation, and decline in endoribonuclease activity. Thus IRE1 activity is governed by a timer that may be important in switching the UPR from the initially cytoprotective phase to the apoptotic mode.

Framework for advancing rigorous research.

There is a pressing need to increase the rigor of research in the life and biomedical sciences. To address this issue, we propose that communities of 'rigor champions' be established to campaign for reforms of the research culture that has led to shortcomings in rigor. These communities of rigor champions would also assist in the development and adoption of a comprehensive educational platform that would teach the principles of rigorous science to researchers at all career stages.

A CHOP-regulated microRNA controls rhodopsin expression.

Using genome-wide microribonucleic acid (microRNA [miRNA]) expression profiling, bioinformatics, and biochemical analyses, we identified miR-708, an endoplasmic reticulum (ER) stress-inducible miRNA whose expression is regulated by the transcription factor CCAAT enhancer-binding protein homologous protein (CHOP) in vertebrates. miR-708 is encoded within an intron of the CHOP-regulated gene Odz4, a member of the highly conserved teneurin family of developmental regulators. Odz4 and mir-708 expression is coregulated by CHOP, and the two transcripts are coexpressed in the brain and eyes of mice, suggesting common physiological functions in these tissues. We validated rhodopsin as a target of miR-708 through loss- and gain-of-function experiments. Together, our data implicate miR-708 in the homeostatic regulation of ER function in mammalian rod photoreceptors, whereby miR-708 may help prevent an excessive rhodopsin load from entering the ER. Hence, miR-708 may function analogously to other unfolded protein response controls that throttle protein influx into the ER to avoid ER stress through mechanisms, such as general translational attenuation by protein kinase RNA-like ER kinase or membrane-bound messenger RNA decay by inositol-requiring enzyme 1.

Antimyeloma Effects of the Heat Shock Protein 70 Molecular Chaperone Inhibitor MAL3-101.

Multiple myeloma (MM) is the second most common hematologic malignancy and remains incurable, primarily due to the treatment-refractory/resistant nature of the disease. A rational approach to this compelling challenge is to develop new drugs that act synergistically with existing effective agents. This approach will reduce drug concentrations, avoid treatment resistance, and also improve treatment effectiveness by targeting new and nonredundant pathways in MM. Toward this goal, we examined the antimyeloma effects of MAL3-101, a member of a new class of non-ATP-site inhibitors of the heat shock protein (Hsp) 70 molecular chaperone. We discovered that MAL3-101 exhibited antimyeloma effects on MM cell lines in vitro and in vivo in a xenograft plasmacytoma model, as well as on primary tumor cells and bone marrow endothelial cells from myeloma patients. In combination with a proteasome inhibitor, MAL3-101 significantly potentiated the in vitro and in vivo antimyeloma effects. These data support a preclinical rationale for small molecule inhibition of Hsp70 function, either alone or in combination with other agents, as an effective therapeutic strategy for MM.