Continuous Monitoring of Changes in Heart Rate during the Periprocedural Course of Carotid Artery Stenting Using a Wearable Device: A Prospective Observational Study.

This prospective observational study will evaluate the change in heart rate (HR) during the periprocedural course of carotid artery stenting (CAS) via continuous monitoring using a wearable device. The participants were recruited from our outpatient clinic between April 2020 and March 2023. They were instructed to continuously wear the device from the last outpatient visit before admission to the first outpatient visit after discharge. The changes in HR of interest throughout the periprocedural course of CAS were assessed. In addition, the Bland-Altman analysis was adopted to compare the HR measurement made by the wearable device during CAS with that made by the electrocardiogram (ECG). A total of 12 patients who underwent CAS were included in the final analysis. The time-series analysis revealed that a percentage change in HR decrease occurred on day 1 following CAS and that the most significant HR decrease rate was 12.1% on day 4 following CAS. In comparing the measurements made by the wearable device and ECG, the Bland-Altman analysis revealed the accuracy of the wearable device with a bias of -1.12 beats per minute (bpm) and a precision of 3.16 bpm. Continuous HR monitoring using the wearable device indicated that the decrease in HR following CAS could persist much longer than previously reported, providing us with unique insights into the physiology of carotid sinus baroreceptors.

GDNF rescues the fate of neural progenitor grafts by attenuating Notch signals in the injured spinal cord in rodents.

Neural progenitor cell (NPC) transplantation is a promising strategy for the treatment of spinal cord injury (SCI). In this study, we show that injury-induced Notch activation in the spinal cord microenvironment biases the fate of transplanted NPCs toward astrocytes in rodents. In a screen for potential clinically relevant factors to modulate Notch signaling, we identified glial cell-derived neurotrophic factor (GDNF). GDNF attenuates Notch signaling by mediating delta-like 1 homolog (DLK1) expression, which is independent of GDNF's effect on cell survival. When transplanted into a rodent model of cervical SCI, GDNF-expressing human-induced pluripotent stem cell-derived NPCs (hiPSC-NPCs) demonstrated higher differentiation toward a neuronal fate compared to control cells. In addition, expression of GDNF promoted endogenous tissue sparing and enhanced electrical integration of transplanted cells, which collectively resulted in improved neurobehavioral recovery. CRISPR-induced knockouts of the DLK1 gene in GDNF-expressing hiPSC-NPCs attenuated the effect on functional recovery, demonstrating that this effect is partially mediated through DLK1 expression. These results represent a mechanistically driven optimization of hiPSC-NPC therapy to redirect transplanted cells toward a neuronal fate and enhance their integration.

YAP-dependent necrosis occurs in early stages of Alzheimer's disease and regulates mouse model pathology.

The timing and characteristics of neuronal death in Alzheimer's disease (AD) remain largely unknown. Here we examine AD mouse models with an original marker, myristoylated alanine-rich C-kinase substrate phosphorylated at serine 46 (pSer46-MARCKS), and reveal an increase of neuronal necrosis during pre-symptomatic phase and a subsequent decrease during symptomatic phase. Postmortem brains of mild cognitive impairment (MCI) rather than symptomatic AD patients reveal a remarkable increase of necrosis. In vivo imaging reveals instability of endoplasmic reticulum (ER) in mouse AD models and genome-edited human AD iPS cell-derived neurons. The level of nuclear Yes-associated protein (YAP) is remarkably decreased in such neurons under AD pathology due to the sequestration into cytoplasmic amyloid beta (Aß) aggregates, supporting the feature of YAP-dependent necrosis. Suppression of early-stage neuronal death by AAV-YAPdeltaC reduces the later-stage extracellular Aß burden and cognitive impairment, suggesting that preclinical/prodromal YAP-dependent neuronal necrosis represents a target for AD therapeutics.

Carbohydrate recognition by the rhamnose-binding lectin SUL-I with a novel three-domain structure isolated from the venom of globiferous pedicellariae of the flower sea urchin Toxopneustes pileolus.

The globiferous pedicellariae of the venomous sea urchin Toxopneustes pileolus contains several biologically active proteins. We have cloned the cDNA of one of the toxin components, SUL-I, which is a rhamnose-binding lectin (RBL) that acts as a mitogen through binding to carbohydrate chains on target cells. Recombinant SUL-I (rSUL-I) was produced in Escherichia coli cells, and its carbohydrate-binding specificity was examined with the glycoconjugate microarray analysis, which suggested that potential target carbohydrate structures are galactose-terminated N-glycans. rSUL-I exhibited mitogenic activity for murine splenocyte cells and toxicity against Vero cells. The three-dimensional structure of the rSUL-I/l-rhamnose complex was determined by X-ray crystallographic analysis at a 1.8 Å resolution. The overall structure of rSUL-I is composed of three distinctive domains with a folding structure similar to those of CSL3, a RBL from chum salmon (Oncorhynchus keta) eggs. The bound l-rhamnose molecules are mainly recognized by rSUL-I through hydrogen bonds between its 2-, 3-, and 4-hydroxy groups and Asp, Asn, and Glu residues in the binding sites, while Tyr and Ser residues participate in the recognition mechanism. It was also inferred that SUL-I may form a dimer in solution based on the molecular size estimated via dynamic light scattering as well as possible contact regions in its crystal structure.

cDNA cloning and characterization of a rhamnose-binding lectin SUL-I from the toxopneustid sea urchin Toxopneustes pileolus venom.

The globiferous pedicellariae of the venomous sea urchin Toxopneustes pileolus contain several biologically active proteins. Among these, a galactose-binding lectin SUL-I isolated from the venom in the large globiferous pedicellariae shows several activities such as mitogenic, chemotactic, and cytotoxic activities through binding to the carbohydrate chains on the cells. We cloned cDNA encoding SUL-I by reverse transcription-PCR using the degenerate primers designed on the basis of the N-terminal amino acid sequence of the protein and expressed the recombinant SUL-I (rSUL-I) in Escherichia coli cells. The SUL-I gene contains an open reading frame of 927 nucleotides corresponding to 308 amino acid residues, including 24 residues of a putative signal sequence. The mature protein with 284 residues is composed of three homologous regions, each showing similarity with the carbohydrate-recognition domains of the rhamnose-binding lectins, which have been mostly found in fish eggs. While rSUL-I exhibited binding activity for several galactose-related sugars, the highest affinity was found for l-rhamnose among carbohydrates tested, confirming that SUL-I is a rhamnose-binding lectin. rSUL-I also showed hemagglutinating activity toward rabbit erythrocytes, indicating the existence of more than one carbohydrate-binding site to cross-link the carbohydrate chains on the cell surface, which may be closely related to its biological activities.