Gait-combined closed-loop brain stimulation can improve walking dynamics in Parkinsonian gait disturbances: a randomised-control trial

日本発、歩行リハビリテーションの未来への一歩 パーキンソン病に新たな光明. 京都大学プレスリリース. 2023-06-23.[Objective] Gait disturbance lowers activities of daily living in patients with Parkinson’s disease (PD) and related disorders. However, the effectiveness of pharmacological, surgical and rehabilitative treatments is limited. We recently developed a novel neuromodulation approach using gait-combined closed-loop transcranial electrical stimulation (tES) for healthy volunteers and patients who are post-stroke, and achieved significant entrainment of gait rhythm and an increase in gait speed. Here, we tested the efficacy of this intervention in patients with Parkinsonian gait disturbances. [Methods] Twenty-three patients were randomly assigned to a real intervention group using gait-combined closed-loop oscillatory tES over the cerebellum at the frequency of individualised comfortable gait rhythm, and to a sham control group. [Results] Ten intervention sessions were completed for all patients and showed that the gait speed (F(1, 21)=13.0, p=0.002) and stride length (F(1, 21)=8.9, p=0.007) were significantly increased after tES, but not after sham stimulation. Moreover, gait symmetry measured by swing phase time (F(1, 21)=11.9, p=0.002) and subjective feelings about freezing (F(1, 21)=14.9, p=0.001) were significantly improved during gait. [Conclusions] These findings showed that gait-combined closed-loop tES over the cerebellum improved Parkinsonian gait disturbances, possibly through the modulation of brain networks generating gait rhythms. This new non-pharmacological and non-invasive intervention could be a breakthrough in restoring gait function in patients with PD and related disorders

The Hippo Signaling Pathway Components Lats and Yap Pattern Tead4 Activity to Distinguish Mouse Trophectoderm from Inner Cell Mass

Outside cells of the preimplantation mouse embryo form the trophectoderm (TE), a process requiring the transcription factor Tead4. Here, we show that transcriptionally active Tead4 can induce Cdx2 and other trophoblast genes in parallel in embryonic stem cells. In embryos, the Tead4 coactivator protein Yap localizes to nuclei of outside cells, and modulation of Tead4 or Yap activity leads to changes in Cdx2 expression. In inside cells, Yap is phosphorylated and cytoplasmic, and this involves the Hippo signaling pathway component Lats. We propose that active Tead4 promotes TE development in outside cells, whereas Tead4 activity is suppressed in inside cells by cell contact- and Lats-mediated inhibition of nuclear Yap localization. Thus, differential signaling between inside and outside cell populations leads to changes in cell fate specification during TE formation

Nano-Scale Alignment of Proteins on a Flexible DNA Backbone

<div><p>Nano-scale alignment of several proteins with freedom of motion is equivalent to an enormous increase in effective local concentration of proteins and will enable otherwise impossible weak and/or cooperative associations between them or with their ligands. For this purpose, a DNA backbone made of six oligodeoxynucleotide (ODN) chains is designed in which five double-stranded segments are connected by four single-stranded flexible linkers. A desired protein with an introduced cysteine is connected covalently to the 5′-end of azido-ODN by catalyst-free click chemistry. Then, six protein-ODN conjugates are assembled with their complementary nucleotide sequences into a single multi-protein-DNA complex, and six proteins are aligned along the DNA backbone. Flexible alignment of proteins is directly observed by high-speed AFM imaging, and association of proteins with weak interaction is demonstrated by fluorescence resonance energy transfer between aligned proteins.</p> </div

(A) Monomeric (A206K) and (B) dimeric (S208F/V224L) mutant of CFP and YFP were placed at adjacent position (left) and opposite ends (right).

<p>Fluorescence spectra were measured without (red) or with (blue) EcoRI treatment. Inset shows intensity ratio of 520 nm/480 nm as an indicator of FRET efficiency. The spectra are normalized to the value of 480 nm of the EcoRI-treated sample.</p

Flexible DNA backbone.

<p>(A) Hybridization of four 55 nt ODNs (numbered 1, 2, 4 and 5) and two 26 nt ODNs (numbered 3 and 6). Five 26 bp dsDNA segments are connected by ssDNA (three thymines). The restriction sites are also shown. (B) AFM images of flexible DNA backbone.</p

Sequence of ODNs used in this study. Primary amine (NH2) was attached to 5′-end via (CH₂)₆ spacer. Underlines indicate restriction enzyme sites.

<p>Sequence of ODNs used in this study. Primary amine (NH2) was attached to 5′-end via (CH₂)₆ spacer. Underlines indicate restriction enzyme sites.</p