Acetylation changes tau interactome to degrade tau in Alzheimer’s disease animal and organoid models

Alzheimer's disease (AD) is an age‐related neurodegenerative disease. The most common pathological hallmarks are amyloid plaques and neurofibrillary tangles in the brain. In the brains of patients with AD, pathological tau is abnormally accumulated causing neuronal loss, synaptic dysfunction, and cognitive decline. We found a histone deacetylase 6 (HDAC6) inhibitor, CKD‐504, changed the tau interactome dramatically to degrade pathological tau not only in AD animal model (ADLP^APT) brains containing both amyloid plaques and neurofibrillary tangles but also in AD patient‐derived brain organoids. Acetylated tau recruited chaperone proteins such as Hsp40, Hsp70, and Hsp110, and this complex bound to novel tau E3 ligases including UBE2O and RNF14. This complex degraded pathological tau through proteasomal pathway. We also identified the responsible acetylation sites on tau. These dramatic tau‐interactome changes may result in tau degradation, leading to the recovery of synaptic pathology and cognitive decline in the ADLP^APT mice.     

Verification of accuracy and validity of gait phase detection system using motion sensors for applying walking assistive FES

In this study, we have analysed heel strike (HS) and toe off (TO) of normal individuals and hemiplegic patients, taking advantage of output curves acquired from various sensors, and verified the validity of sensor detection methods and their effectiveness when they were used for hemiplegic gaits. Gait phase detections using three different motion sensors were valid, since they all had reliabilities more than 95%, when compared with foot velocity algorithm. Results showed that the tilt sensor and the gyrosensor could detect gait phase more accurately in normal individuals. Vertical acceleration could detect HS most accurately in hemiplegic patient group A. The gyrosensor could detect HS and TO most accurately in hemiplegic patient groups A and B. The detection of TO from all sensor signals was valid in both the patient groups A and B. However, the vertical acceleration detected HS validly in patient group A and the gyrosensor detected HS validly in patient group B.     

Delphinidin induces antiproliferation and apoptosis of endometrial cells by regulating cytosolic calcium levels and mitochondrial membrane potential depolarization

Endometriosis is a benign gynecological disease of women of reproductive ages, wherein endometrial cells grow ectopically, decreasing their quality of life due to chronic pelvic pain and severe dysmenorrhea. Although surgery and hormone therapies are gold standards for treating endometriosis, side effects are common and the recurrence rate is nearly 50%. Recent studies are exploring phytochemicals as pharmacological adjuvants for treating endometriosis. Delphinidin is an anthocyanin with anti-inflammatory, antioxidative, and anticancerous properties. In this study, delphinidin showed antiproliferative and apoptotic effects on human endometrial cells. Additionally, treatment with delphinidin decreased the mitochondrial membrane potential and increased cytosolic calcium levels in VK2/E6E7 and End1/E6E7 cells. Delphinidin decreased the phosphorylation of proliferative signaling molecules, including ERK1/2, AKT, P70S6K, and S6, while increasing the phosphorylation of P38 MAPK and P90RSK. These results imply that delphinidin is a novel therapeutic agent for treating and managing endometriosis, and has fewer side effects.     

Pretreatment of corn stover by aqueous ammonia

Corn stover was pretreated with aqueous ammonia in a flow-through column reactor, a process termed ammonia recycled percolation (ARP). This method was highly effective in delignifying of the biomass, reducing the lignin content by 70-85%. Most lignin removal occurred within the first 20 min of the process. Lignin removal by ARP was further confirmed by FTIR analysis and lignin staining. The ARP process solubilized 40-60% of the hemicellulose but left the cellulose intact. The solubilized carbohydrate existed in oligomeric form. Carbohydrate decomposition during the pretreatment was insignificant. Corn stover treated for 90 min exhibited enzymatic digestibility of 99% with 60 FPU/g of glucan enzyme loading, and 92.5% with 10 FPU/g of glucan. The digestibility of ARP treated corn stover was substantially higher than that of alpha-cellulose. The enzymatic digestibility was related with the removal of lignin and hemicellulose, perhaps due to increased surface area and porosity. The SEM pictures indicated that the biomass structure was deformed and its fibers exposed by the pretreatment. The crystallinity index increased with pretreatment reflecting removal of the amorphous portion of biomass. The crystalline structure of the cellulose in the biomass, however, was not changed by the ARP treatment.     

Isolation and characterization of proteoglycans from growing antlers of wapiti (Cervus elaphus)

Proteoglycans were extracted with 4 M guanidine–HCl from the zone of maturing chondrocytes, the site of endochondral ossification of growing antlers of wapiti (Cervus elaphus). Proteoglycans were isolated by DEAE-Sephacel chromatography and separated by Sepharose CL-4B chromatography into three fractions. Fraction I contained a high molecular mass (>1000 kDa) chondroitin sulfate proteoglycan capable of interacting with hyaluronic acid. Its amino acid composition resembled that of the cartilage proteoglycan, aggrecan. Fraction II contained proteoglycans with intermediate molecular weight which were recognized by monoclonal antibodies specific to chondroitin sulfate and keratan sulfate. Fraction III contained a low molecular mass (<160 kDa) proteoglycan, decorin, with a glucuronate-rich glycosaminoglycan chain.     

Glucosylation of the flavonoid, astragalin by Leuconostoc mesenteroides B-512FMCM dextransucrase acceptor reactions and characterization of the products

Astragalin (kaempferol-3-O-β-d-glucopyranoside, Ast) glucosides were synthesized by the acceptor reaction of a dextransucrase produced by Leuconostoc mesenteroides B-512FMCM with astragalin and sucrose. Each glucoside was purified and their structures were assigned as kaempferol-3-O-β-d-glucopyranosyl-(1 → 3)-O-α-d-glucopyranoside (or kaempferol-3-O-β-d-nigeroside, Ast-G1′) and kaempferol-3-O-β-d-glucopyranosyl-(1 → 6)-O-α-d-glucopyranoside (or kaempferol-3-O-β-d-isomaltoside, Ast-G1) for one glucose transferred, and kaempferol-3-O-β-d-isomaltooligosacharide (Ast-IMO or Ast-Gn; n = 2-8). The astragalin glucosides exhibited 8.3-60.6% higher inhibitory effects on matrix metalloproteinase-1 expression, 18.8-20.3% increased antioxidant effects, and 3.8-18.8% increased inhibition activity of melanin synthesis compared to control (without the addition of compound), depending on the number of glucosyl residues linked to astragalin. These novel compounds could be used to further expand the industrial applications of astragalin glucosides, in particular in the cosmetics industry.     

Bright light exposure before bedtime impairs response inhibition the following morning: a non-randomized crossover study

Introduction: Bright light exposure in the late evening can affect cognitive function the following morning either by changing the biological clock and/or disturbing sleep, but the evidence for this effect is scarce, and the underlying mechanism remains unknown. In this study, we first aimed to evaluate the effect of bright light exposure before bedtime on frontal lobe activity the following morning using near-infrared spectroscopy (NIRS) during a Go/NoGo task. Second, we aimed to evaluate the effects of bright light exposure before bedtime on polysomnographic measures and on a frontal lobe function test the following morning.

Methods: Twenty healthy, young males (mean age, 25.5 years) were recruited between September 2013 and August 2014. They were first exposed to control light (150 lux) before bedtime (from 20:00 h to 24:00 h) for 2 days and then to bright light (1,000 lux) before bedtime for an additional 5 days. We performed polysomnography (PSG) on the final night of each light exposure period (on nights 2 and night 7) and performed NIRS, which measures the concentrations of oxygenated and deoxygenated hemoglobin (OxyHb and DeoxyHb, respectively), coupled with a Go/NoGo task the following morning (between 09:30 h and 11:30 h). The participants also completed frontal lobe function tests the following morning.

Results: NIRS showed decreased hemodynamic activity (lower OxyHb and a tendency toward higher DeoxyHb concentration) in the right frontal lobe during the NoGo block after 1000-lux light exposure compared with that during the NoGo block after 150-lux light exposure. The commission error rate (ER) during the Go/NoGo task was higher after 1000-lux light exposure than that during the Go/NoGo task after 150-lux light exposure (1.24 ± 1.09 vs. 0.6 ± 0.69, P = 0.002), suggesting a reduced inhibitory response.

Conclusion: This study shows that exposure to bright light before bedtime for 5 days impairs right frontal lobe activation and response inhibition the following morning.     

Effect of Immunotherapy on Seizure Outcome in Patients with Autoimmune Encephalitis: A Prospective Observational Registry Study

Objective

To evaluate the seizure characteristics and outcome after immunotherapy in adult patients with autoimmune encephalitis (AE) and new-onset seizure.

Methods

Adult (age ≥18 years) patients with AE and new-onset seizure who underwent immunotherapy and were followed-up for at least 6 months were included. Seizure frequency was evaluated at 2–4 weeks and 6 months after the onset of the initial immunotherapy and was categorized as “seizure remission”, “> 50% seizure reduction”, or “no change” based on the degree of its decrease.

Results

Forty-one AE patients who presented with new-onset seizure were analysed. At 2–4 weeks after the initial immunotherapy, 51.2% of the patients were seizure free, and 24.4% had significant seizure reduction. At 6 months, seizure remission was observed in 73.2% of the patients, although four patients died during hospitalization. Rituximab was used as a second-line immunotherapy in 12 patients who continued to have seizures despite the initial immunotherapy, and additional seizure remission was achieved in 66.6% of them. In particular, those who exhibited partial response to the initial immunotherapy had a better seizure outcome after rituximab, with low adverse events.

Conclusion

AE frequently presented as seizure, but only 18.9% of the living patients suffered from seizure at 6 months after immunotherapy. Aggressive immunotherapy can improve seizure outcome in patients with AE.