Discovery and characterization of stereodefined PMO-gapmers targeting tau.

Antisense oligonucleotides (ASOs) are an important class of therapeutics to treat genetic diseases, and expansion of this modality to neurodegenerative disorders has been an active area of research. To realize chronic administration of ASO therapeutics to treat neurodegenerative diseases, new chemical modifications that improve activity and safety profiles are still needed. Furthermore, it is highly desirable to develop a single stereopure ASO with a defined activity and safety profile to avoid any efficacy and safety concerns due to the batch-to-batch variation in the composition of diastereomers.

Total Synthesis of Eribulin, a Macrocyclic Ketone Analogue of Halichondrin B, via Prins Macrocyclization.

An entirely chromium-free synthesis of eribulin, a fully synthetic macrocyclic ketone analogue of the marine natural product halichondrin B, was achieved through iterative sulfone fragment couplings followed by an intramolecular Prins reaction involving a C.26 homoallenyl alcohol and a C.27 aldehyde acetal.

Comparing effects of wearable robot-assisted gait training on functional changes and neuroplasticity: A preliminary study.

Robot-assisted gait training (RAGT) is a promising technique for improving the gait ability of elderly adults and patients with gait disorders by enabling high-intensive and task-specific training. Gait functions involve multiple brain regions and networks. Therefore, RAGT is expected to affect not just gait performance but also neuroplasticity and cognitive ability.

Energy-Based Domain Adaptation Without Intermediate Domain Dataset for Foggy Scene Segmentation.

Robust segmentation performance under dense fog is crucial for autonomous driving, but collecting labeled real foggy scene datasets is burdensome in the real world. To this end, existing methods have adapted models trained on labeled clear weather images to the unlabeled real foggy domain. However, these approaches require intermediate domain datasets (e.

Pharmacologic Activation of STING in the Bladder Induces Potent Antitumor Immunity in Non-Muscle Invasive Murine Bladder Cancer.

Stimulator of interferon genes (STING) is an innate immune receptor activated by natural or synthetic agonists to elicit antitumoral immune response via type I IFNs and other inflammatory cytokines. Bacillus Calmette-Guerin (BCG) is the standard of care as intravesical therapy for patients with high-risk non-muscle invasive bladder cancer (NMIBC). There are limited options available for patients with NMIBC who developed BCG unresponsiveness.

MRI-Based Classification of Neuropsychiatric Systemic Lupus Erythematosus Patients With Self-Supervised Contrastive Learning.

Introduction/purpose: Systemic lupus erythematosus (SLE) is a chronic auto-immune disease with a broad spectrum of clinical presentations, including heterogeneous neuropsychiatric (NP) syndromes. Structural brain abnormalities are commonly found in SLE and NPSLE, but their role in diagnosis is limited, and their usefulness in distinguishing between NPSLE patients and patients in which the NP symptoms are not primarily attributed to SLE (non-NPSLE) is non-existent. Self-supervised contrastive learning algorithms proved to be useful in classification tasks in rare diseases with limited number of datasets.

E7766, a Macrocycle-Bridged Stimulator of Interferon Genes (STING) Agonist with Potent Pan-Genotypic Activity.

A strategy for creating potent and pan-genotypic stimulator of interferon genes (STING) agonists is described. Locking a bioactive U-shaped conformation of cyclic dinucleotides by introducing a transannular macrocyclic bridge between the nucleic acid bases leads to a topologically novel macrocycle-bridged STING agonist (MBSA). In addition to substantially enhanced potency, the newly designed MBSAs, exemplified by clinical candidate E7766, exhibit broad pan-genotypic activity in all major human STING variants.

Prediction of Transporter-Mediated Drug-Drug Interactions and Phenotyping of Hepatobiliary Transporters Involved in the Clearance of E7766, a Novel Macrocycle-Bridged Dinucleotide.

E7766 represents a novel class of macrocycle-bridged dinucleotides and is under clinical development for immuno-oncology. In this report, we identified mechanism of systemic clearance E7766 and investigated the hepatobiliary transporters involved in the disposition of E7766 and potential drug interactions of E7766 as a victim of organic anion-transporting polypeptide (OATP) inhibitors. In bile-duct cannulated rats and dogs, E7766 was mainly excreted unchanged in bile (>80%) and to a lesser extent in urine (<20%).

Prediction of motor recovery using indirect connectivity in a lesion network after ischemic stroke.

Background: Recovery prediction can assist in the planning for impairment-focused rehabilitation after a stroke. This study investigated a new prediction model based on a lesion network analysis. To predict the potential for recovery, we focused on the next link-step connectivity of the direct neighbors of a lesion.

Biomechanics of Long Cane Use.

Introduction: The modern long cane has been used by people who are blind for traveling for decades. This article describes parameters surrounding the collection of over 10,000 trials of people walking with the long cane to detect drop-offs or obstacles.

Methods: The data include 10,069 trials representing 101 different participants in 366 conditions over 11 studies spanning the 9 years from 2007 to 2016.

Obstacle Detection with the Long Cane: Effect of Cane Tip Design and Technique Modification on Performance.

Introduction: The purpose of this study was to investigate the effect of cane tip design and cane technique modification on obstacle detection performance as they interact with the size, height, and position of obstacles.

Methods: A repeated-measures design with block randomization was used for the study. In experiment one, participants attempted to detect obstacles with either a marshmallow tip or a bundu basher tip.

An Intersection Database Facilitates Access to Complex Signalized Intersections for Pedestrians with Vision Disabilities.

A growing number of intersections and crosswalks pose barriers to pedestrians with vision disabilities. This project investigated the effects of providing verbal descriptions of intersections and crosswalks on the performance of street-crossing subtasks by individuals who are totally blind. The authors designed an intersection database containing information relevant to crossing subtasks such as finding and aligning with the crosswalk, deciding when to cross, remaining in the crosswalk, and recognizing the end of a crossing.

Synthesis of a Polycyclic Halichondrin C1-C14 Fragment via Intermolecular Oxy-Michael/ Trans-Ketalization.

Syntheses of a crystalline polycyclic halichondrin C1-C14 building block starting from a d-gulono-1,4-lactone-derived intermediate in the current Halaven manufacturing process are described. Key features of the syntheses include an acid-catalyzed tandem intermolecular oxy-Michael/intramolecular trans-ketalization reaction and stereoselective Kishi reductions.

Synthesis of the Halichondrin C1-C15 Fragment from a Halaven C27-C35 Byproduct: Stereospecific Intramolecular Kishi Reduction.

A byproduct from a Halaven C27-C35 manufacturing process was transformed into a crystalline halichondrin C1-C15 building block by employing a stereospecific intramolecular Kishi reduction as the key step.

Alteration and Role of Interhemispheric and Intrahemispheric Connectivity in Motor Network After Stroke.

This study investigated local and global changes in the motor network using longitudinal resting-state functional magnetic resonance imaging (rs-fMRI). Motor impairment was measured in 81 stroke patients using Fugl-Meyer assessment on the same day as rs-fMRI acquisition at both 2 weeks and 3 months post-stroke. The relationships between network measures and motor function scores were assessed.

Modulating Brain Connectivity by Simultaneous Dual-Mode Stimulation over Bilateral Primary Motor Cortices in Subacute Stroke Patients.

Repetitive transcranial magnetic stimulation (rTMS) or transcranial direct current stimulation (tDCS) has been used for the modulation of stroke patients' motor function. Recently, more challenging approaches have been studied. In this study, simultaneous stimulation using both rTMS and tDCS (dual-mode stimulation) over bilateral primary motor cortices (M1s) was investigated to compare its modulatory effects with single rTMS stimulation over the ipsilesional M1 in subacute stroke patients.

Beaconing Signalization Substantially Reduces Blind Pedestrians' Veer on Snow-Covered Pavement.

Veering outside of crosswalks is a common problem experienced by individuals who are blind. One technology found to be effective for reducing this veer when other guidance cues are absent is audible beaconing. However, veering in general and veering from crosswalks in particular have been studied primarily on smooth, flat walking surfaces such as clear pavement.

Effect of cane length and swing arc width on drop-off and obstacle detection with the long cane.

A repeated-measures design with block randomization was used for the study, in which 15 adults with visual impairments attempted to detect the drop-offs and obstacles with the canes of different lengths, swinging the cane in different widths (narrow vs wide). Participants detected the drop-offs significantly more reliably with the standard-length cane (79.5% ± 6.

Prins Reaction of Homoallenyl Alcohols: Access to Substituted Pyrans in the Halichondrin Series.

Prins reaction of homoallenyl alcohols with aldehyde dimethylacetals in the presence of methoxyacetic acid directly affords tetrasubstituted pyrans relevant to halichondrins with complete control of the C27 stereogenic center. Regioselective Tsuji reduction of the resultant allylic acetates stereoselectively establishes the C25 stereogenic center and C26 exocyclic olefin. Building upon these findings, we achieved concise access to the halichondrin C14-C38 and eribulin C14-C35 fragments.

Reconstruction of Arm Movement Directions from Human Motor Cortex Using fMRI.

Recent advances in functional magnetic resonance imaging (fMRI) have been used to reconstruct cognitive states based on brain activity evoked by sensory or cognitive stimuli. To date, such decoding paradigms were mostly used for visual modalities. On the other hand, reconstructing functional brain activity in motor areas was primarily achieved through more invasive electrophysiological techniques.

Hierarchical ordering with partial pairwise hierarchical relationships on the macaque brain data sets.

Hierarchical organizations of information processing in the brain networks have been known to exist and widely studied. To find proper hierarchical structures in the macaque brain, the traditional methods need the entire pairwise hierarchical relationships between cortical areas. In this paper, we present a new method that discovers hierarchical structures of macaque brain networks by using partial information of pairwise hierarchical relationships.

A new primary mobility tool for the visually impaired: A white cane-adaptive mobility device hybrid.

This article describes pilot testing of an adaptive mobility device-hybrid (AMD-H) combining properties of two primary mobility tools for people who are blind: the long cane and adaptive mobility devices (AMDs). The long cane is the primary mobility tool used by people who are blind and visually impaired for independent and safe mobility and AMDs are adaptive devices that are often lightweight frames approximately body width in lateral dimension that are simply pushed forward to clear the space in front of a person. The prototype cane built for this study had a wing apparatus that could be folded around the shaft of a cane but when unfolded, deployed two wheeled wings 25 cm (9.

A pumpless multi-organ-on-a-chip (MOC) combined with a pharmacokinetic-pharmacodynamic (PK-PD) model.

A multi-organ-on-a-chip (MOC), also known as a human-on-a-chip, aims to simulate whole body response to drugs by connecting microscale cell cultures of multiple tissue types via fluidic channels and reproducing the interaction between them. While several studies have demonstrated the usefulness of MOC at a proof-of-concept level, improvements are needed to enable wider acceptance of such systems; ease of use for general biological researchers, and a mathematical framework to design and interpret the MOC systems. Here, we introduce a pumpless, user-friendly MOC which can be easily assembled and operated, and demonstrate the use of a PK-PD model for interpreting drug's action inside the MOC.

Drop-off detection with the long cane: effect of cane shaft weight and rigidity on performance.

Most travellers who are blind rely on a long cane to detect drop-offs on their walking paths. We examined how different cane shaft materials affect drop-off detection performance through providing different vibrotactile and proprioceptive feedbacks to the cane user. Results of the study showed a significant interaction between cane shaft weight and how the cane is used.