Excitability of the Primary Motor Cortex Increases More Strongly with Slow- than with Normal-Speed Presentation of Actions

Introduction: The aim of the present study was to investigate how the speed of observed action affects the excitability of the primary motor cortex (M1), as assessed by the size of motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS). Copyright:Methods: Eighteen healthy subjects watched a video clip of a person catching a ball, played at three different speeds (normal-, half-, and quarter-speed). MEPs were induced by TMS when the model\u27s hand had opened to the widest extent just before catching the ball ("open") and when the model had just caught the ball ("catch"). These two events were locked to specific frames of the video clip ("phases"), rather than occurring at specific absolute times, so that they could easily be compared across different speeds. MEPs were recorded from the thenar (TH) and abductor digiti minimi (ADM) muscles of the right hand.Results: The MEP amplitudes were higher when the subjects watched the video clip at low speed than when they watched the clip at normal speed. A repeated-measures ANOVA, with the factor VIDEO-SPEED, showed significant main effects. Bonferroni\u27s post hoc test showed that the following MEP amplitude differences were significant: TH, normal vs. quarter; ADM, normal vs. half; and ADM, normal vs. quarter. Paired t-tests showed that the significant MEP amplitude differences between TMS phases under each speed condition were TH, "catch" higher than "open" at quarter speed; ADM, "catch" higher than "open" at half speed.Conclusions: These results indicate that the excitability of M1 was higher when the observed action was played at low speed. Our findings suggest that the action observation system became more active when the subjects observed the video clip at low speed, because the subjects could then recognize the elements of action and intention in others

Changes in Cerebral Hemodynamics during Complex Motor Learning by Character Entry into Touch-Screen Terminals

Introduction Studies of cerebral hemodynamics during motor learning have mostly focused on neurorehabilitation interventions and their effectiveness. However, only a few imaging studies of motor learning and the underlying complex cognitive processes have been performed. Methods We measured cerebral hemodynamics using near-infrared spectroscopy (NIRS) in relation to acquisition patterns of motor skills in healthy subjects using character entry into a touchscreen terminal. Twenty healthy, right-handed subjects who had no previous experience with character entry using a touch-screen terminal participated in this study. They were asked to enter the characters of a randomly formed Japanese syllabary into the touchscreen terminal. All subjects performed the task with their right thumb for 15 s alternating with 25 s of rest for 30 repetitions. Performance was calculated by subtracting the number of incorrect answers from the number of correct answers, and gains in motor skills were evaluated according to the changes in performance across cycles. Behavioral and oxygenated hemoglobin concentration changes across task cycles were analyzed using Spearman\u27s rank correlations. Results Performance correlated positively with task cycle, thus confirming motor learning. Hemodynamic activation over the left sensorimotor cortex (SMC) showed a positive correlation with task cycle, whereas activations over the right prefrontal cortex (PFC) and supplementary motor area (SMA) showed negative correlations. Conclusions We suggest that increases in finger momentum with motor learning are reflected in the activity of the left SMC. We further speculate that the right PFC and SMA were activated during the early phases of motor learning, and that this activity was attenuated with learning progress

Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive acute myeloid leukemia

Aggressive therapy-resistant and refractory acute myeloid leukemia (AML) has an extremely poor outcome. By analyzing a large number of genetically complex and diverse, primary high-risk poor-outcome human AML samples, we identified specific pathways of therapeutic vulnerability. Through drug screens followed by extensive in vivo validation and genomic analyses, we found inhibition of cytosolic and mitochondrial anti-apoptotic proteins XIAP, BCL2 and MCL1, and a key regulator of mitosis, AURKB, as a vulnerability hub based on patient-specific genetic aberrations and transcriptional signatures. Combinatorial therapeutic inhibition of XIAP with an additional patient-specific vulnerability eliminated established AML in vivo in patient-derived xenografts (PDXs) bearing diverse genetic aberrations, with no signs of recurrence during off-treatment follow-up. By integrating genomic profiling and drug-sensitivity testing, this work provides a platform for a precision-medicine approach for treating aggressive AML with high unmet need

Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive acute myeloid leukemia

Aggressive therapy-resistant and refractory acute myeloid leukemia (AML) has an extremely poor outcome. By analyzing a large number of genetically complex and diverse, primary high-risk poor-outcome human AML samples, we identified specific pathways of therapeutic vulnerability. Through drug screens followed by extensive in vivo validation and genomic analyses, we found inhibition of cytosolic and mitochondrial anti-apoptotic proteins XIAP, BCL2 and MCL1, and a key regulator of mitosis, AURKB, as a vulnerability hub based on patient-specific genetic aberrations and transcriptional signatures. Combinatorial therapeutic inhibition of XIAP with an additional patient-specific vulnerability eliminated established AML in vivo in patient-derived xenografts (PDXs) bearing diverse genetic aberrations, with no signs of recurrence during off-treatment follow-up. By integrating genomic profiling and drug-sensitivity testing, this work provides a platform for a precision-medicine approach for treating aggressive AML with high unmet need

Human Leukocyte Antigen DRB1 Alleles Predict Risk and Disease Progression of Immunoglobulin A Nephropathy in Han Chinese

The role of human leukocyte antigen (HLA) class II polymorphisms in the pathogenesis and progression of primary immunoglobulin A nephropathy (pIgAN) is unclear. This study aimed to explore the relationship of HLA-DRB1 alleles with the susceptibility and disease progression of pIgAN in Han Chinese. A PCR-based genotyping technique was used to detect HLA-DRB1 alleles in 139 patients with pIgAN and 143 healthy subjects. A total of 37 HLA-DRB1 alleles were detected, of which 30 were found in pIgAN patients and 29 in healthy subjects. In pIgAN patients, the frequencies of HLA-DRB1∗140501 (belonging to DR∗14) were significantly increased, while the frequencies of HLA-DRB1∗070101 (belonging to DR∗7) were significantly reduced compared with the healthy individuals. Further stratification analysis revealed that the frequencies of HLA-DRB1∗030101 in pIgAN patients with normal renal function were significantly higher than those in patients with renal dysfunction. These findings suggest that HLA-DRB1 polymorphisms are related to the occurrence and disease progression of pIgAN patients in Han Chinese, with HLA-DRB1∗140501 being a susceptible allele and HLA-DRB1∗070101 a resistant allele. HLA-DRB1∗030101 may serve as a predictor of disease progression and renal damage of pIgAN in Han Chinese. Further studies are warranted to explore the immunological mechanisms for the genotype-disease phenotype relationship