Structure-activity relationships of middle-size cyclic peptides, KRAS inhibitors derived from an mRNA display.

Cyclic peptides are attracting attention as therapeutic agents due to their potential for oral absorption and easy access to tough intracellular targets. LUNA18, a clinical KRAS inhibitor, was transformed-without scaffold hopping-from the initial hit by using an mRNA display library that met our criteria for drug-likeness. In drug discovery using mRNA display libraries, hit compounds always possess a site linked to an mRNA tag.

Intraoperative and Postoperative Ultrasonographic Spinal Cord Evaluation of Cervical Double-Door Laminoplasty.

Background: Ultrasonography is a useful tool for the localization, morphology, and characterization of lesions and is increasingly being applied to spinal cord evaluation in cervical spine diseases. However, in conventional cervical laminoplasty, detailed evaluation is difficult because of ultrasound attenuation. Therefore, the purpose of this study was to perform a cervical laminoplasty using a modified surgical technique and evaluate the spinal cord.

Validation of a New Methodology to Create Oral Drugs beyond the Rule of 5 for Intracellular Tough Targets.

Establishing a technological platform for creating clinical compounds inhibiting intracellular protein-protein interactions (PPIs) can open the door to many valuable drugs. Although small molecules and antibodies are mainstream modalities, they are not suitable for a target protein that lacks a deep cavity for a small molecule to bind or a protein found in intracellular space out of an antibody's reach. One possible approach to access these targets is to utilize so-called middle-size cyclic peptides (defined here as those with a molecular weight of 1000-2000 g/mol).

Preliminary Clinical Experience with a High-Definition Three Dimensional Exoscope for Spinal Surgery.

We retrospectively evaluated spinal surgeries performed using the high-definition three-dimensional exoscopic system, which became available at our institution in August 2020. Eleven patients (4 with cervical disease and 7 with lumbar disease) underwent surgery with the system. There were no surgical complications related to the system, and the results were satisfactory.

Development of Orally Bioavailable Peptides Targeting an Intracellular Protein: From a Hit to a Clinical KRAS Inhibitor.

Cyclic peptides as a therapeutic modality are attracting a lot of attention due to their potential for oral absorption and accessibility to intracellular tough targets. Here, starting with a drug-like hit discovered using an mRNA display library, we describe a chemical optimization that led to the orally available clinical compound known as LUNA18, an 11-mer cyclic peptide inhibitor for the intracellular tough target RAS. The key findings are as follows: (i) two peptide side chains were identified that each increase RAS affinity over 10-fold; (ii) physico-chemical properties (PCP) including log can be adjusted by side-chain modification to increase membrane permeability; (iii) restriction of cyclic peptide conformation works effectively to adjust PCP and improve bio-activity; (iv) cellular efficacy was observed in peptides with a permeability of around 0.

A Modified Sliding-Lengthening Approach to Tendon Lengthening with a Locking Mechanism Suture: A Technical Note.

There are various techniques used for tendon lengthening, of which Z-lengthening and sliding-lengthening are the most frequently performed. In patients with cerebral palsy, tendon lengthening may often be necessary at multiple sites. However, they can cause various complications, such as inaccurate extension, overextension, and a lack of tendon continuity.

Computed Tomographic Epidurography in Patients with Low Back Pain and Leg Pain: A Single-Center Observational Study.

This study was conducted to analyze the findings and benefits of computed tomography (CT) epidurography in patients with low back and leg pain and compare these findings with those of magnetic resonance imaging (MRI) images. In total, 495 intervertebral discs from 99 patients with low back and leg pain who underwent percutaneous epidural adhesiolysis (epidural neuroplasty or percutaneous adhesiolysis) were examined. The axial views of CT epidurography were classified into six types to examine each intervertebral disc: round type, ellipse type, spike type, Benz mark, incomplete block, complete block, and non-contrast.

Femoral varus derotational osteotomy without pelvic osteotomy in nonambulatory children with cerebral palsy: Minimum 5 years follow-up.

Whether femoral varus derotational osteotomy (VDRO) alone or a combination of femoral and pelvic osteotomies should be performed for hip dislocation in nonambulatory children with cerebral palsy (CP) remains controversial. Few studies have reported radiographical results after the surgical treatment in nonambulatory children with CP. This study aimed to assess the results and determine predictors indicating progressive hip subluxation and redislocation after VDRO without pelvic osteotomy.

Angulated Salter osteotomy in the treatment of developmental dysplasia of the hip.

Salter osteotomy is widely used to improve acetabular coverage in the treatment of developmental dysplasia of the hip. Herein we describe angulated Salter osteotomy (ASO) as the modified Salter osteotomy, which creates a two-point contact between the proximal and distal fragments and better stabilizes the fixation of the fragments. We reported our results of ASO and compared it with that of Salter osteotomy performed previously by us.

Influence of Stochastic Resonance on Manual Dexterity in Children With Developmental Coordination Disorder: A Double-Blind Interventional Study.

There is increasing evidence that the stochastic resonance (SR) phenomenon provided by subthreshold mechanical noise stimulation improves the sensory-motor system. However, the effect of SR on children with developmental coordination disorder (DCD) is unclear. The purpose of this study was to assess whether SR activated by subthreshold vibrotactile noise stimulation of the wrist influences manual dexterity in children with DCD.

In Vivo Evaluation of the Mechanical Strength of a Slide Lengthening Technique With a Locking Mechanism Using a Rabbit Model.

Background There are many reports of Achilles tendon lengthening procedures for equinus deformity of the ankle. We previously modified an Achilles tendon lengthening to prevent overextension with a locking mechanism suture before performing a sliding lengthening. The purpose of this study was to compare the biomechanical properties of the locking mechanism suture with sliding lengthening (L-SL) and Z-lengthening (ZL) using a rabbit model.

Electron-Rich Gold Clusters Stabilized by Poly(vinylpyridines) as Robust and Active Oxidation Catalysts.

In this report, we introduced poly(-vinylpyridine) (PVP, = 2, 4) as an electron-donating stabilizer for small (<2 nm) Au clusters and elucidated how coordinating pyridines affect the physical, optical, chemical, and catalytic properties of Au clusters. Spectroscopic measurements and theoretical calculation suggested the high electron-donating ability of PVP. PVP-stabilized Au clusters improved robustness in aerobic oxidation of alcohols compared to poly(-vinyl-2-pyrrolidone)-stabilized ones, while retaining catalytic activities.

Subthreshold Vibrotactile Noise Stimulation Immediately Improves Manual Dexterity in a Child With Developmental Coordination Disorder: A Single-Case Study.

Developmental coordination disorder (DCD) is the most common childhood movement disorder. It is characterized by clumsiness of fine and gross motor skills in developing children. Children with DCD have low ability to effectively use tactile information for movements, instead relying on visual information.

Stochastic resonance improves visuomotor temporal integration in healthy young adults.

Mechanical and electrical noise stimulation to the body is known to improve the sensorimotor system. This improvement is related to stochastic resonance (SR), a phenomenon described as a "noise benefit" to various sensory and motor systems. The current study investigated the influence of SR on visuomotor temporal integration and hand motor function under delayed visual feedback in healthy young adults.

Identification of a selective inhibitor of transforming growth factor β-activated kinase 1 by biosensor-based screening of focused libraries.

Transforming growth factor-β activated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase family, plays an essential role in mediating signals from various pro-inflammatory cytokines and therefore may be a good target for developing anti-inflammation agents. Herein, we report our efforts to identify TAK1 inhibitors with a good selectivity profile with which to initiate medicinal chemistry. Instead of resorting to a high-throughput screening campaign, we performed biosensor-based biophysical screening for a limited number of compounds by taking advantage of existing knowledge on kinase inhibitors.

Incongruence between Verbal and Non-Verbal Information Enhances the Late Positive Potential.

Smooth social communication consists of both verbal and non-verbal information. However, when presented with incongruence between verbal information and nonverbal information, the relationship between an individual judging trustworthiness in those who present the verbal-nonverbal incongruence and the brain activities observed during judgment for trustworthiness are not clear. In the present study, we attempted to identify the impact of incongruencies between verbal information and facial expression on the value of trustworthiness and brain activity using event-related potentials (ERP).

Factors Contributing to Satisfaction with Changes in Physical Function after Orthopedic Surgery for Musculoskeletal Dysfunction in Patients with Cerebral Palsy.

Background: The recognition of required treatments for cerebral palsy (CP) patients, including orthopedic surgery, differs according to region. This study was performed to identify factors associated with satisfactory changes in physical function after orthopedic surgery.

Methods: 358 patients were selected for the questionnaire survey.

The influence of repeated pain stimulation on the emotional aspect of pain: a preliminary study in healthy volunteers.

Purpose: Pain is a multidimensional experience with sensory-discriminative, cognitive-evaluative, and affective-motivational components. Emotional factors, such as unpleasantness or anxiety, are known to have influence on pain in humans. Repeated painful stimulation has been reported to reduce subjective pain intensity.

Effects of self-action observation on standing balance learning: A change of brain activity detected using functional near-infrared spectroscopy.

Background: Studies suggest that the observation of others' actions leads to enhanced motor skill learning.

Objective: We examined whether others' or self-action observation is effective for standing balance learning. In addition, we examined cortical activation during action observation using functional near-infrared spectroscopy.

Changes in the equilibrium of standing on one leg at various life stages.

The ability to maintain a one-leg standing position and the relation between plantar two-point discrimination and standing time on one leg were assessed. Participants were 1,241 apparently healthy people aged 2-92 years. Participants were asked to stand on one leg with eyes open (EO group) or closed (EC group) for up to 120 seconds.

Effectiveness of the gaze direction recognition task for chronic neck pain and cervical range of motion: a randomized controlled pilot study.

We developed a mental task with gaze direction recognition (GDR) by which subjects observed neck rotation of another individual from behind and attempted to recognize the direction of gaze. A randomized controlled trial was performed in test (n = 9) and control (n = 8) groups of subjects with chronic neck pain undergoing physical therapy either with or without the GDR task carried out over 12 sessions during a three-week period. Primary outcome measures were defined as the active range of motion and pain on rotation of the neck.

Effects of peripheral sensory nerve stimulation plus task-oriented training on upper extremity function in patients with subacute stroke: a pilot randomized crossover trial.

Objective: To investigate the feasibility of peripheral sensory nerve stimulation combined with task-oriented training in patients with stroke during inpatient rehabilitation.

Design: A pilot randomized crossover trial.

Setting: Two rehabilitation hospitals.

Influence of transcranial direct current stimulation of the dorsolateral prefrontal cortex on pain related emotions: a study using electroencephalographic power spectrum analysis.

Pain is a multidimensional experience with sensory-discriminative, cognitive-evaluative and affective-motivational components. Emotional factors such as unpleasantness or anxiety are known to have influence on pain in humans. The aim of this single-blinded, cross over study was to evaluate the effects of transcranial direct current stimulation (tDCS) on emotional aspects of pain in pain alleviation.