Structural and Functional Analysis of the Allosteric Inhibition of IRE1α with ATP-Competitive Ligands.

The accumulation of unfolded proteins under endoplasmic reticulum (ER) stress leads to the activation of the multidomain protein sensor IRE1α as part of the unfolded protein response (UPR). Clustering of IRE1α lumenal domains in the presence of unfolded proteins promotes kinase trans-autophosphorylation in the cytosol and subsequent RNase domain activation. Interestingly, there is an allosteric relationship between the kinase and RNase domains of IRE1α, which allows ATP-competitive inhibitors to modulate the activity of the RNase domain.

Allosteric inhibition of the IRE1α RNase preserves cell viability and function during endoplasmic reticulum stress.

Depending on endoplasmic reticulum (ER) stress levels, the ER transmembrane multidomain protein IRE1α promotes either adaptation or apoptosis. Unfolded ER proteins cause IRE1α lumenal domain homo-oligomerization, inducing trans autophosphorylation that further drives homo-oligomerization of its cytosolic kinase/endoribonuclease (RNase) domains to activate mRNA splicing of adaptive XBP1 transcription factor. However, under high/chronic ER stress, IRE1α surpasses an oligomerization threshold that expands RNase substrate repertoire to many ER-localized mRNAs, leading to apoptosis.

Vespa tropica venom suppresses lipopolysaccharide-mediated secretion of pro-inflammatory cyto-chemokines by abrogating nuclear factor-κ B activation in microglia.

Objective And Design: The present study was aimed to evaluate the anti-inflammatory potentials of Vespa tropica (VT) venom and its isolated peptides. Effects of whole venom and its two peptides (Vt1512 and Vt1386) on lipopolysaccharide (LPS) challenged BV-2 murine microglial cells was evaluated.

Materials: Mouse microglial cell line, BV-2 and crude venom extract as well as purified peptides from VT along with LPS from Salmonella enterica were used for the studies.

Development of potent and selective Plasmodium falciparum calcium-dependent protein kinase 4 (PfCDPK4) inhibitors that block the transmission of malaria to mosquitoes.

Malaria remains a major health concern for a large percentage of the world's population. While great strides have been made in reducing mortality due to malaria, new strategies and therapies are still needed. Therapies that are capable of blocking the transmission of Plasmodium parasites are particularly attractive, but only primaquine accomplishes this, and toxicity issues hamper its widespread use.

Epigenetic regulation of self-renewal and fate determination in neural stem cells.

Differentiation and self-renewal are two primary properties that characterize stem cells. Differentiation of neural stem/precursor cells (NSPCs) gives rise to multiple neural lineages, including neurons, astrocytes, and oligodendrocytes. Self-renewal, by definition, signifies the progressive growth of cells, while preserving an undifferentiated state.