The trunk-tail junctional region in Ciona larvae autonomously expresses tail-beating bursts at ∼20 second intervals.

Swimming locomotion in aquatic vertebrates, such as fish and tadpoles, is expressed through neuron networks in the spinal cord. These networks are arranged in parallel, ubiquitously distributed and mutually coupled along the spinal cord to express undulation patterns accommodated to various inputs into the networks. While these systems have been widely studied in vertebrate swimmers, their evolutionary origin along the chordate phylogeny remains unclear. Ascidians, representing a sister group of vertebrates, give rise to tadpole larvae that swim freely in seawater. In the present study, we examined the locomotor ability of the anterior and posterior body fragments of larvae of the ascidian Ciona that had been cut at an arbitrary position. Examination of more than 200 fragments revealed a necessary and sufficient body region that spanned only ∼10% of the body length and included the trunk-tail junction. 'Mid-piece' body fragments, which included the trunk-tail junctional region, but excluded most of the anterior trunk and posterior tail, autonomously expressed periodic tail-beating bursts at ∼20 s intervals. We compared the durations and intervals of tail-beating bursts expressed by mid-piece fragments, and also by whole larvae under different sensory conditions. The results suggest that body parts outside the mid-piece effect shortening of swimming intervals, particularly in the dark, and vary the burst duration. We propose that Ciona larvae express swimming behaviors by modifying autonomous and periodic locomotor drives that operate locally in the trunk-tail junctional region.

Black rice bran intake reduces phosphorylated tau levels and enhances insulin signaling in the brain of aged normal mice.

This study reports that black rice bran (BRB) intake for 50-52 consecutive weeks (∼12 months) reduces tau phosphorylation with a concomitant activation of insulin signaling and subsequent PI3K/AKT pathway in the brain of aged normal mice. BRB holds promise for preventing the formation of neurofibrillary tangles consisting of hyperphosphorylated tau, a pathological hallmark of Alzheimer's disease.

Efficacy of endoscopic gallbladder drainage in patients with acute cholecystitis.

BACKGROUND: Early cholecystectomy is recommended for patients with acute cholecystitis. However, emergency surgery may not be indicated due to complications and disease severity. Patients requiring drainage are usually treated with percutaneous transhepatic gallbladder drainage (PTGBD), whereas patients with biliary duct stones undergo endoscopic stones removal followed by endoscopic gallbladder drainage (EGBD). Herein, we investigated the efficacy of EGBD in patients with acute cholecystitis. METHODS: Overall, 101 patients receiving laparoscopic cholecystectomy between September 2019 and September 2020 in our department were retrospectively analyzed. RESULTS: The patients (n = 101) were divided into three groups: control group that did not undergo drainage (n = 68), a group that underwent EGBD (n = 7), and a group that underwent PTGBD (n = 26). Median surgery time was 107, 166, and 143 min, respectively. Control group had a significantly shorter surgery time, whereas it did not significantly differ between EGBD and PTGBD groups. The median amount of bleeding was 5 g, 7 g, and 7.5 g, respectively, and control group had significantly less bleeding than the drainage group. We further divided patients into the following subgroups: patients requiring a 5 mm clip to ligate the cystic duct, patients requiring a 10 mm clip due to the thickness of the cystic duct, patients requiring an automatic suturing device, and patients undergoing subtotal cholecystectomy due to impossible cystic duct ligation. There was no significant difference between EGBD and PTGBD regarding the clip used or the need for an automatic suturing device and subtotal cholecystectomy. CONCLUSIONS: There was no significant difference between EGBD and PTGBD groups regarding surgery time or bleeding amount when surgery was performed after gallbladder drainage for acute cholecystitis. Therefore, EGBD was considered a useful preoperative drainage method requiring no drainage bag.

Pharmacological interventions versus placebo, no treatment or usual care for osteoporosis in people with chronic kidney disease stages 3-5D.

BACKGROUND: Chronic kidney disease (CKD) is an independent risk factor for osteoporosis and is more prevalent among people with CKD than among people who do not have CKD. Although several drugs have been used to effectively treat osteoporosis in the general population, it is unclear whether they are also effective and safe for people with CKD, who have altered systemic mineral and bone metabolism. OBJECTIVES: To assess the efficacy and safety of pharmacological interventions for osteoporosis in patients with CKD stages 3-5, and those undergoing dialysis (5D). SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 25 January 2021 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials comparing any anti-osteoporotic drugs with a placebo, no treatment or usual care in patients with osteoporosis and CKD stages 3 to 5D were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed their quality using the risk of bias tool, and extracted data. The main outcomes were the incidence of fracture at any sites; mean change in the bone mineral density (BMD; measured using dual-energy radiographic absorptiometry (DXA)) of the femoral neck, total hip, lumbar spine, and distal radius; death from all causes; incidence of adverse events; and quality of life (QoL). Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference (MD) for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: Seven studies involving 9164 randomised participants with osteoporosis and CKD stages 3 to 5D met the inclusion criteria; all participants were postmenopausal women. Five studies included patients with CKD stages 3-4, and two studies included patients with CKD stages 5 or 5D. Five pharmacological interventions were identified (abaloparatide, alendronate, denosumab, raloxifene, and teriparatide). All studies were judged to be at an overall high risk of bias. Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture (RR 0.52, 95% CI 0.39 to 0.69; low certainty evidence). Anti-osteoporotic drugs probably makes little or no difference to the risk of clinical fracture (RR 0.91, 95% CI 0.79 to 1.05; moderate certainty evidence) and adverse events (RR 0.99, 95% CI 0.98 to 1.00; moderate certainty evidence). We were unable to incorporate studies into the meta-analyses for BMD at the femoral neck, lumbar spine and total hip as they only reported the percentage change in the BMD in the intervention group. Among patients with severe CKD stages 5 or 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture (RR 0.33, 95% CI 0.01 to 7.87; very low certainty evidence). It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low (MD 0.01, 95% CI 0.00 to 0.02). Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine (MD 0.03, 95% CI 0.03 to 0.04, low certainty evidence). No adverse events were reported in the included studies. It is uncertain whether anti-osteoporotic drug reduces the risk of death (RR 1.00, 95% CI 0.22 to 4.56; very low certainty evidence). AUTHORS' CONCLUSIONS: Among patients with CKD stages 3-4, anti-osteoporotic drugs may reduce the risk of vertebral fracture in low certainty evidence. Anti-osteoporotic drugs make little or no difference to the risk of clinical fracture and adverse events in moderate certainty evidence. Among patients with CKD stages 5 and 5D, it is uncertain whether anti-osteoporotic drug reduces the risk of clinical fracture and death because the certainty of this evidence is very low. Anti-osteoporotic drug may slightly improve the BMD at the lumbar spine in low certainty evidence. It is uncertain whether anti-osteoporotic drug improves the BMD at the femoral neck because the certainty of this evidence is very low. Larger studies including men, paediatric patients or individuals with unstable CKD-mineral and bone disorder are required to assess the effect of each anti-osteoporotic drug at each stage of CKD.

Association between conscientiousness and peritoneal dialysis-related peritonitis.

AIM: Peritonitis is a critical complication in patients undergoing peritoneal dialysis. Patient characteristics, especially conscientiousness, potentially influence self-care activity. This study aimed to examine the relationship between the peritonitis risk and the patient conscientiousness. METHODS: This retrospective observational study was conducted at three Japanese medical centres in 2018. Adult patients undergoing peritoneal dialysis were evaluated for conscientiousness with the Japanese version of the Ten-Item Personality Inventory. We followed the patients from peritoneal dialysis induction retrospectively on chart review. The primary outcome was time to first episode of peritonitis after initiation of peritoneal dialysis in the entire observation period. Hazard ratios were estimated using a Cox model adjusted for potential confounders. RESULTS: Among 111 patients enrolled, 32 experienced peritonitis. The patients were divided into the more conscientious group (n = 64) and less conscientious group (n = 47) based on a mean conscientiousness score of 3.991. Additionally, less conscientious patients tended to be at higher risk for peritonitis during the entire study period (hazard ratio adjusted for age and sex, 1.99; 95% confidence interval, 0.98-4.03; p = .057). The increased risk in the less conscientious group was statistically significant in the first year (adjusted hazard ratio, 6.98; 95% confidence interval, 1.42-34.40; p = .017). CONCLUSION: Less conscientious patients significantly have shorter peritonitis-free survival in the early phase after peritoneal dialysis induction although not significantly during the entire study period. Personality trait assessment using the Ten-Item Personality Inventory could be helpful in educating and following up patients undergoing peritoneal dialysis.

Important agronomic characteristics of yielding ability in common buckwheat; ecotype and ecological differentiation, preharvest sprouting resistance, shattering resistance, and lodging resistance.

Common buckwheat is recognized as a healthy food because its seed contains large amounts of protein, minerals, and rutin. However, the yielding ability of common buckwheat is lower than that of other major crops. The short growing period, moisture injury, occurrence of sterile seeds due to lack of flower-visiting insects, and yield loss due to lodging and shattering cause low and unstable grain yield. Therefore, many common buckwheat breeders have tried to increase yielding ability by improving various characteristics. Recently, new breeding objectives for improving yielding ability by increasing preharvest sprouting resistance; reducing shattering loss; introducing self-compatibility; the ecotype, and semidwarf have been reported. In this review, we introduce the research on the important agronomic characteristics, preharvest sprouting resistance, ecotype and ecological differentiation, shattering resistance, and lodging resistance in common buckwheat.

Genetic analysis of photoperiod sensitivity associated with difference in ecotype in common buckwheat.

Ecotype breeding is a key technology in common buckwheat (Fagopyrum esculentum Moench) for the breeding of highly adaptive cultivars and their introduction to other cultivation areas. However, the details of the relationship between photoperiod sensitivity and ecotype remain unclear. Here, we evaluated photoperiod sensitivity in 15 landraces from different parts of Japan, and analyzed quantitative trait loci (QTLs) for photoperiod sensitivity using two F2 segregating populations derived from the crosses between self-compatible lines ('Kyukei SC2' or 'Buckwheat Norin PL1', early days-to-flowering) and allogamous plants (intermediate or late days-to-flowering). We clarified that (1) photoperiod sensitivity and differences in ecotype are closely related; (2) photoperiod sensitivity is controlled by several QTLs common among population of different ecotypes; and (3) orthologues of GIGANTEA and EARLY FLOWERING 3 will be useful markers in future detailed elucidation of the photoperiod sensitivity mechanism in common buckwheat. This study provides the basis for genomics-assisted breeding for local adaptation and ecotype breeding in common buckwheat.

Correlation Between Skeletal Muscle Mass Deficit and Poor Functional Outcome in Patients with Acute Ischemic Stroke.

BACKGROUND AND AIMS: To date, the correlation between sarcopenia, which exists before a stroke, and acute stroke outcome remains partially understood. This study aims to evaluate the skeletal muscle mass deficit using the bioelectrical impedance analysis in patients with acute ischemic stroke. METHODS: We enrolled 164 geriatric patients with acute ischemic stroke (108 males and 56 females) who underwent the bioelectrical impedance analysis. We evaluated clinical outcomes and their impact on patients with the skeletal muscle mass deficit determined using the skeletal muscle mass index. RESULTS: The skeletal muscle mass deficit was obtained using the bioelectrical impedance analysis in 101 patients. Patients with the skeletal muscle mass deficit determined by the skeletal muscle mass index exhibited severe neurological impairment and functional status on admission; moreover, they tended to display poor functional outcome and prolonged hospital stay. Logistic regression analysis revealed that the skeletal muscle mass deficit remained an independent poor outcome predictor. CONCLUSIONS: This study establishes the presence of the skeletal muscle mass deficit in over half patients with acute ischemic stroke. Furthermore, the skeletal muscle mass deficit correlates with neurological impairment owing to stroke with poorer functional prognosis.

Intra-Dialytic Hemoglobin Changes and Cardiovascular Events: A Cohort Study on Dialysis Outcomes and Practice Patterns in Japan.

BACKGROUND: Ultrafiltration during hemodialysis (HD) causes hemoconcentration. Little is known about the relationships between intra-dialytic changes in hemoglobin concentration and cardiovascular events. Thus, this study aimed to elucidate the relationships between intra-dialytic changes in hemoglobin concentration and cardiovascular events among HD patients. METHODS: This prospective cohort study was based on the Japanese Dialysis Outcomes and Practice Pattern Study phases 4 and 5. The predictor was the ratio of post-dialysis hemoglobin concentration to pre-dialysis hemoglobin concentration (post-Hb/pre-Hb) at baseline. The primary outcome was major adverse cardiovascular events (MACEs). Hazard ratios (HRs) were estimated using a Cox model for the association between post-Hb/pre-Hb and MACEs, adjusting for potential confounders. RESULTS: A total of 865 patients were enrolled. During a median follow-up of 2.6 years, 145 (16.8%) patients developed MACEs. Patients were divided into 4 categories according to baseline post-Hb/pre-Hb (<1.0, ≥1.0 to <1.1, ≥1.1 to <1.2, and ≥1.2). The multivariable-adjusted HRs for MACEs were 1.69 (95% CI 1.36-2.10), 1.29 (95% CI 1.10-1.51), and 1.31 (95% CI 1.02-1.68) in patients with post-Hb/pre-Hb ratios of <1.0, ≥1.0 to <1.1, and ≥1.2, respectively, compared with the reference post-Hb/pre-Hb ratio of ≥1.1 to <1.2. Cubic spline analyses revealed a U-shaped association between post-Hb/pre-Hb and MACEs. CONCLUSION: High and low intra-dialytic changes in hemoglobin concentration are associated with a high risk of MACEs in patients undergoing HD.

Creutzfeldt-Jakob disease with Alzheimer pathology, presenting with status epilepticus following repeated partial seizures: a case report and literature review.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease. Common first symptoms are dementia, cerebellar ataxia, visual disturbance, and psychiatric symptoms. Seizure as the first symptom of CJD is a very rare finding. CASE PRESENTATION: We experienced an elderly woman who presented initially with status epilepticus following repeated partial seizures in the course of Alzheimer disease (AD) dementia. Anti-convulsive therapy had no effect. Autopsy revealed definite CJD with AD pathology. COCLUSIONS: This is the first reported CJD case presenting with status epilepticus in the course of AD dementia.

Synthesis and Properties of 7-Deazapurine- and 8-Aza-7-deazapurine-Locked Nucleic Acid Analogues: Effect of the Glycosidic Torsion Angle.

Conformationally restricted nucleoside analogues 2',4'-BNA/LNA-7-deazaguanine (LNA-7cG) and 2',4'-BNA/LNA-8-aza-7-deazaguanine (LNA-8n7cG), which avoid extra hydrogen bond formation at the 7-position of the guanine nucleobase, were successfully synthesized and incorporated into oligonucleotides. While the LNA-7cG-containing oligonucleotides show high duplex-forming ability with complementary DNA and RNA similar to LNA-G, the LNA-8n7cG-containing oligonucleotide has lower binding affinity than that of natural 2'-deoxyguanosine. This disparity in thermostability is also observed in 7-deazaadenosine analogues (LNA-7cA, LNA-8n7cA). Thermodynamic parameters and computational chemistry revealed that an inappropriate glycosidic torsion angle χ of 2',4'-BNA/LNA-8-aza-7-deazapurine analogues destabilizes duplex formation in contrast to 2',4'-BNA/LNA-7-deazapurine analogues. This result indicates that the nucleobase rotation angle plays an important role in duplex binding affinity. In addition, LNA-7cG-modified oligonucleotide effectively suppresses aggregation even in a guanine-rich sequence.

Effects of super-hard rice bread blended with black rice bran on amyloid ß peptide production and abrupt increase in postprandial blood glucose levels in mice.

Alzheimer's disease and type 2 diabetes are very serious diseases with the latter having been suggested to cause the former. We prepared super-hard rice bread blended with black rice bran (SRBBB), which contained a high amount of resistant starch that showed strong inhibitory activities against ß-secretase and acetylcholinesterase even after heating. Black rice bran showed greater ß-secretase inhibitory activity (3.6-fold) than Koshihikari rice. The bran contained more oleic acid and anthocyanin, meaning that it is potentially a biofunctional food with a high antioxidant capacity. Furthermore, aged mice, which were fed a SRBBB diet for four weeks, showed lower amyloid ß 40 peptide in the blood than mice fed a commercial diet (p < 0.01). Additionally, their initial blood glucose levels (BGLs) after 12 weeks of being fed SRBBB were significantly lower than those in the control group. Taken together, our results indicate SRBBB shows promise for inhibiting not only amyloid ß production, but also abrupt increases in postprandial BGLs.

A calcium-dependent protease as a potential therapeutic target for Wolfram syndrome.

Wolfram syndrome is a genetic disorder characterized by diabetes and neurodegeneration and considered as an endoplasmic reticulum (ER) disease. Despite the underlying importance of ER dysfunction in Wolfram syndrome and the identification of two causative genes, Wolfram syndrome 1 (WFS1) and Wolfram syndrome 2 (WFS2), a molecular mechanism linking the ER to death of neurons and ß cells has not been elucidated. Here we implicate calpain 2 in the mechanism of cell death in Wolfram syndrome. Calpain 2 is negatively regulated by WFS2, and elevated activation of calpain 2 by WFS2-knockdown correlates with cell death. Calpain activation is also induced by high cytosolic calcium mediated by the loss of function of WFS1. Calpain hyperactivation is observed in the WFS1 knockout mouse as well as in neural progenitor cells derived from induced pluripotent stem (iPS) cells of Wolfram syndrome patients. A small-scale small-molecule screen targeting ER calcium homeostasis reveals that dantrolene can prevent cell death in neural progenitor cells derived from Wolfram syndrome iPS cells. Our results demonstrate that calpain and the pathway leading its activation provides potential therapeutic targets for Wolfram syndrome and other ER diseases.

Analysis of genetic diversity of rapeseed genetic resources in Japan and core collection construction.

Diversity analysis of rapeseed accessions preserved in the Japanese Genebank can provide valuable information for breeding programs. In this study, 582 accessions were genotyped with 30 SSR markers covering all 19 rapeseed chromosomes. These markers amplified 311 alleles (10.37 alleles per marker; range, 3-39). The genetic diversity of Japanese accessions was lower than that of overseas accessions. Analysis of molecular variance indicated significant genetic differentiation between Japanese and overseas accessions. Small but significant differences were found among geographical groups in Japan, and genetic differentiation tended to increase with geographical distance. STRUCTURE analysis indicated the presence of two main genetic clusters in the NARO rapeseed collection. With the membership probabilities threshold, 227 accessions mostly originating from overseas were assigned to one subgroup, and 276 accessions mostly originating from Japan were assigned to the other subgroup. The remaining 79 accessions are assigned to admixed group. The core collection constructed comprises 96 accessions of diverse origin. It represents the whole collection well and thus it may be useful for rapeseed genetic research and breeding programs. The core collection improves the efficiency of management, evaluation, and utilization of genetic resources.

Synthesis and biological evaluation of novel imidazol-1-ylacetic acid derivatives as non-brain penetrant bombesin receptor subtype-3 (BRS-3) agonists.

Novel compounds based on 1a were synthesized with the focus of obtaining agonists acting upon peripheral BRS-3. To identify potent anti-obesity compounds without adverse effects on the central nervous system (CNS), a carboxylic acid moiety and a labile carboxylic ester with an antedrug functionality were introduced. Through the extensive synthetic exploration and the pharmacokinetic studies of intravenous administration in mice, the ester 2b was selected owing to its most suitable pharmacological profile. In the evaluation of food intake suppression in C57BL/6N mice, 2b showed significant in vivo efficacy and no clear adverse effects on blood pressure change in dogs administered the compound by intravenous infusion.

Synthesis and biological evaluation of novel chiral diazepine derivatives as bombesin receptor subtype-3 (BRS-3) agonists incorporating an antedrug approach.

Novel compounds based on the lead BRS-3 agonists from our HTS compounds 2a and 2b have been synthesized with the focus on obtaining peripheral BRS-3 agonists. To identify potent anti-obesity compounds without adverse effects on the central nerve system, a labile carboxylic ester with an antedrug functionality was introduced onto the terminal position. Through the extensive synthetic exploration and the pharmacokinetic studies of oral administration in mice, the phenol ester 17c was selected due to the most suitable pharmacological profile. In the evaluation of food intake suppression in B6 mice, 17c showed significant in vivo efficacy and no clear adverse effect on heart rate and blood pressure change in dog iv infusion. Our study paved the way for development of anti-diabetes and obesity drugs with a safer profile.

Discovery of novel chiral diazepines as bombesin receptor subtype-3 (BRS-3) agonists with low brain penetration.

The discovery and optimization of a novel series of BRS-3 agonists are described. We explored a potent BRS-3 agonist with low brain penetration to avoid an adverse effect derived from central nervous system exposure. Through the derivatization process, chiral diazepines 9f and 9g were identified as possessing low brain penetration as well as potent in vitro activity against human and mouse BRS-3s.

Identification of a Serratia marcescens virulence factor that promotes hemolymph bleeding in the silkworm, Bombyx mori.

Injection of culture supernatant of Serratia marcescens, a Gram-negative bacterium pathogenic to a wide range of host animals including insects and mammals, into the hemolymph of silkworm (Bombyx mori) larvae led to continuous flow of the hemolymph (blood of insects) from the injection site. The amount of hemolymph lost within 60 min reached 15-20% of the total larval weight. Using a bioassay with live silkworms, we purified Serralysin, a metalloprotease that requires divalent cations for its activity, as the factor responsible for the promotion of hemolymph bleeding from the culture supernatant of S. marcescens. Recombinant protein also induced hemolymph bleeding in silkworms. Moreover, the culture supernatant of an S. marcescens disruption mutant of the ser gene showed attenuated ability to promote hemolymph bleeding. In addition, this bleeding-promoting activity of the S. marcescens culture supernatant was attenuated by disruption of the wecA gene, which is involved in the biosynthesis of the lipopolysaccharide O-antigen. These findings suggest that Serralysin metalloprotease contributes to the pathogenesis of S. marcescens by inhibiting wound healing, which leads to a massive loss of hemolymph from silkworm larvae.

Rapid genotyping with DNA micro-arrays for high-density linkage mapping and QTL mapping in common buckwheat (Fagopyrum esculentum Moench).

For genetic studies and genomics-assisted breeding, particularly of minor crops, a genotyping system that does not require a priori genomic information is preferable. Here, we demonstrated the potential of a novel array-based genotyping system for the rapid construction of high-density linkage map and quantitative trait loci (QTL) mapping. By using the system, we successfully constructed an accurate, high-density linkage map for common buckwheat (Fagopyrum esculentum Moench); the map was composed of 756 loci and included 8,884 markers. The number of linkage groups converged to eight, which is the basic number of chromosomes in common buckwheat. The sizes of the linkage groups of the P1 and P2 maps were 773.8 and 800.4 cM, respectively. The average interval between adjacent loci was 2.13 cM. The linkage map constructed here will be useful for the analysis of other common buckwheat populations. We also performed QTL mapping for main stem length and detected four QTL. It took 37 days to process 178 samples from DNA extraction to genotyping, indicating the system enables genotyping of genome-wide markers for a few hundred buckwheat plants before the plants mature. The novel system will be useful for genomics-assisted breeding in minor crops without a priori genomic information.