Unique Interplay between Sugar and Lipid in Determining the Antigenic Potency of Bacterial Antigens for NKT Cells

Structural and biophysical studies reveal the induced-fit mechanism underlying the stringent specificity of invariant natural killer T cells for unique glycolipid antigens from the pathogen Streptococcus pneumoniae

Auditory statistical learning during concurrent physical exercise and the tolerance for pitch, tempo, and rhythm changes

Previous studies suggest that statistical learning is preserved when acoustic changes are made to auditory sequences. However, statistical learning effects can vary with and without concurrent exercise. The present study examined how concurrent physical exercise influences auditory statistical learning when acoustic and temporal changes are made to auditory sequences. Participants were presented with 500-tone sequences based on a Markov chain while cycling or resting in ignored and attended conditions. Learning effects were evaluated using a familiarity test with four types of short tone series: tone series in which stimuli were same as 500-tone sequence and three tone series in which frequencies, tempo, or rhythm was changed. We suggested that, regardless of attention, concurrent exercise interferes with tolerance in statistical learning for rhythm, rather than tempo changes. There may be specific relationships among statistical learning, rhythm perception, and motor system underlying physical exercise

Physical fitness modulates incidental but not intentional statistical learning of simultaneous auditory sequences during concurrent physical exercise

In real-world auditory environments, humans are exposed to overlapping auditory information such as those made by human voices and musical instruments even while routine physical activities such as walking and cycling. The present study investigated how concurrent physical exercise affects performance of incidental and intentional learning of overlapping auditory streams, and whether physical fitness modulates the performances of learning. Participants were grouped with 11 participants with lower and higher fitness each, based on their Vo2max value. They were presented simultaneous auditory sequences with a distinct statistical regularity each other (i.e., statistical learning), while they were pedaling on the bike and seating on a bike at rest. In experiment 1, they were instructed to attend to one of the two sequences and ignore to the other sequence. In experiment 2, they were instructed to attend to both of the two sequences. After exposure to the sequences, learning effects was evaluated by familiarity test. In the experiment 1, performance of statistical learning of ignored sequences while concurrently pedaling could be higher in the participants with high than low physical fitness, whereas in attended sequence, there was no significant difference in performance of statistical learning between high than low physical fitness. Furthermore, there was no significant effect of physical fitness on learning while resting. In the experiment 2, the both participants with high and low physical fitness could perform intentional statistical learning of two simultaneous sequences in the both exercise and rest sessions. The improvement of physical fitness might facilitate incidental but not intentional statistical learning of simultaneous auditory sequences while concurrent physical exercise

Salt-Inducible Kinase inhibition suppresses acute myeloid leukemia progression in vivo

Lineage-defining transcription factors (TFs) are compelling targets for leukemia therapy, yet they are among the most challenging proteins to modulate directly with small molecules. We previously used CRISPR screening to identify a Salt-Inducible Kinase 3 (SIK3) requirement for the growth of acute myeloid leukemia (AML) cell lines that overexpress the lineage TF MEF2C. In this context, SIK3 maintains MEF2C function by directly phosphorylating histone deacetylase 4 (HDAC4), a repressive cofactor of MEF2C. Here, we evaluated whether inhibition of SIK3 with the tool compound YKL-05-099 can suppress MEF2C function and attenuate disease progression in animal models of AML. Genetic targeting of SIK3 or MEF2C selectively suppressed the growth of transformed hematopoietic cells under in vitroand in vivoconditions. Similar phenotypes were obtained when exposing cells to YKL-05-099, which caused cell cycle arrest and apoptosis in MEF2C-expressing AML cell lines. An epigenomic analysis revealed that YKL-05-099 rapidly suppressed MEF2C function by altering the phosphorylation state and nuclear localization of HDAC4. Using a gatekeeper allele of SIK3, we found that the anti-proliferative effects of YKL-05-099 occurred through on-target inhibition of SIK3 kinase activity. Based on these findings, we treated two different mouse models of MLL-AF9 AML with YKL-05-099, which attenuated disease progression in vivoand extended animal survival at well-tolerated doses. These findings validate SIK3 as a therapeutic target in MEF2C-addicted AML and provide a rationale for developing drug-like inhibitors of SIK3 for definitive pre-clinical investigation and for studies in human patients