Motoyama, K. | bioRxiv Science

bioRxiv2024

Speed amplitude and period affect gait variability and step followability under sinusoidal speed changing conditions

BackgroundThe time courses of the joint elevation angles of the thigh, shank, and foot in one stride during walking can be well approximated by a "plane" in a triaxial space. This intersegmental coordination (IC) of the lower limb elevation angles is called planar covariation law. Thickness of the IC plane is associated with gait variability. This study aimed to examine how anteroposterior and lateral gait variabilities are influenced by sinusoidal speed changes with different amplitudes ({+/-}0.33 vs. {+/-}0.67 m{middle dot}s-1) and periods (30 vs. 60 s). We also questioned which limbs are responsible for the step variabilities in these conditions. MethodsEighteen young adults walked on a treadmill under sinusoidal speed-changing conditions with different amplitudes ({+/-}0.33 vs. {+/-}0.67 m{middle dot}s-1) and periods (30-vs. 60-s). Using 3D motion analysis system, we quantified the IC plane thickness, coefficient of variance of step width (CVSW), time delay of step length (TDSL), and step frequency (TDSF). We applied 2-way statistical parametric mapping for the time courses of each limb angle during the acceleration and deceleration phases. ResultsThe IC plane thickness was greater in the {+/-}0.67 m{middle dot}s-1 condition than in the {+/-}0.33 m{middle dot}s-1 condition. Periods and amplitudes did not affect CVSW, TDSL, and TDSF. In the middle gait cycle, the thigh and shank were delayed in the greater amplitude condition during the acceleration phase but proceeded in the same condition during the deceleration phase. DiscussionSinusoidal speed amplitude influenced anteroposterior gait variability, but not lateral gait variability, regardless of period, even in healthy young adults. More distal limbs were delayed in the greater speed amplitude condition during the acceleration phase, whereas more proximal limbs proceeded in that condition during the deceleration phase, indicating that these different behaviors of the lower limb segments could be related to step variabilities.

physiology↗

bioRxiv2024

Targeted Degradation of CDK9 Potently Disrupts the MYC Transcriptional Network

Cyclin-dependent kinase 9 (CDK9) coordinates signaling events that regulate RNA polymerase II (Pol II) pause-release states. It is an important co-factor for transcription factors, such as MYC, that drive aberrant cell proliferation when their expression is deregulated. CDK9 modulation offers an approach for attenuating dysregulation in such transcriptional programs. As a result, numerous drug development campaigns to inhibit CDK9 kinase activity have been pursued. More recently, targeted degradation has emerged as an attractive approach. However, comprehensive evaluation of degradation versus inhibition is still critically needed to assess the biological contexts in which degradation might offer superior therapeutic benefits. We validated that CDK9 inhibition triggers a compensatory mechanism that dampens its effect on MYC expression and found that this feedback mechanism was absent when the kinase is degraded. Importantly, CDK9 degradation is more effective than its inhibition for disrupting MYC transcriptional regulatory circuitry likely through the abrogation of both enzymatic and scaffolding functions of CDK9. Highlights- KI-CDK9d-32 is a highly potent and selective CDK9 degrader. - KI-CDK9d-32 leads to rapid downregulation of MYC protein and mRNA transcripts levels. - KI-CDK9d-32 represses canonical MYC pathways and leads to a destabilization of nucleolar homeostasis. - Multidrug resistance ABCB1 gene emerged as the strongest resistance marker for the CDK9 PROTAC degrader.

cancer biology↗