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Abstract Background Maternal preconception overweight status has been reported to be associated with an increased risk of overweight offspring. However, there are no published population-based studies on the association between maternal preconception weight and offspring body fat measured by dual-energy X-ray absorptiometry (DXA). The present population-based retrospective cohort study aimed to examine the association between maternal weight at conception and offspring body fat measured by DXA. Methods The source population consisted of 5th-grade students (1244 students aged 11 years) registered at 8 municipal elementary schools in Kitakata, Fukuroi, Hamamatsu, and Himeji in Japan. The present analyses included 964 participants who provided complete information. Maternal body mass index (BMI) at conception was calculated using records in the Mother and Child Health Handbook (MCHH). Offspring body fat at age 11 years was measured with the same QDR-4500A DXA instrument in a mobile test room that was brought to each school. With regard to the prediction of excess fat in offspring, the area under the curve (AUC) calculated with receiver operating characteristic curve analysis was used to quantify the diagnostic accuracy of maternal BMI at conception. Results Adjusted odds ratios for excess body fat in offspring of the overweight mother group (odds ratios, 4.93 to 15.32) were significantly higher than those in the non-overweight mother group. For the prediction of excess offspring fat, AUCs and 95% confidence intervals for maternal BMI at conception were greater than 0.5. Conclusion Maternal overweight status at conception might be a risk factor for excess body fat in offspring. Maternal BMI values calculated using MCHH data have the potential to distinguish between the presence and absence of excess fat in the next generation.

Abstract A variety of easy-to-use commercial bioelectrical impedance appliances are available. The aim of this study was to examine the usefulness of a commercially available body composition meter using bioelectrical impedance analysis (BIA) by comparing its measurement results with those obtained from dual-energy X-ray absorptiometry (DXA). The participants were 443 children aged from 10 to 14 years (226 boys and 217 girls). Fat mass, fat-free mass, lean body mass, percentage of body fat, and bone mineral contents were evaluated for all participants using BIA and DXA. The agreement in the anthropometric data obtained from both devices was analyzed using correlation analysis, intraclass correlation coefficient (ICC), Lin’s concordance correlation coefficient (CCC), Bland–Altman plots, and ordinary least products regression analysis. Equivalence between both devices was tested by two one-sided t-test. All measured indicators showed strong linear correlations between the two measurement systems (r, 0.853–1.000). Fat mass, fat-free mass, and lean body mass showed absolute concordance (ICC, 0.902–0.972; Lin’s CCC, 0.902–0.972). BIA overestimated bone mineral content (62.7–66.5%) and underestimated percentage of body fat (− 8.9 to − 0.8%), lean body mass (− 3.5 to − 1.8%), and body mass (− 0.8 to − 0.5%). For fat mass and fat-free mass, the overestimate or underestimate varied according to the sex and statistical analysis test. Bland–Altman analysis and ordinary least products analysis showed fixed bias and proportional bias in all indicators. Results according to quartiles of body mass index showed poor agreement for fat mass and percentage of body fat in both boys and girls in the lowest body mass index quartile. The present results revealed strong linear correlations between BIA and DXA, which confirmed the validity of the present single-frequency BIA-derived parameters. Our results suggest that BIA cannot provide the exact same values as DXA for some body composition parameters, but that performance is sufficient for longitudinal use within an individual for daily health management and monitoring.

Neurite outgrowth is a crucial process for organizing neuronal circuits in neuronal development and regeneration after injury. Regenerative failure in the adult mammalian central nervous system (CNS) is attributed to axonal growth inhibitors such as the Nogo protein that commonly binds to Nogo receptor-1 (NgR1). We previously reported that lateral olfactory tract usher substance (LOTUS) functions as an endogenous antagonist for NgR1 in forming neuronal circuits in the developing brain and improving axonal regeneration in the adult injured CNS. However, another molecular and cellular function of LOTUS remains unknown. In this study, we found that cultured retinal explant neurons extend their neurites on the LOTUS-coating substrate. This action was also observed in cultured retinal explant neurons derived from Ngr1-deficient mouse embryos, indicating that the promoting action of LOTUS on neurite outgrowth may be mediated by unidentified LOTUS-binding protein(s). We therefore screened the binding partner(s) of LOTUS by using a liquid chromatography-tandem mass spectrometry (LC-MS/MS). LC-MS/MS analysis and pull-down assay showed that LOTUS interacts with Teneurin-4 (Ten-4), a cell adhesion molecule. RNAi knockdown of Ten-4 inhibited neurite outgrowth on the LOTUS substrate in retinoic acid (RA)-treated Neuro2A cells. Furthermore, a soluble form of Ten-4 attenuates the promoting action on neurite outgrowth in cultured retinal explant neurons on the LOTUS substrate. These results suggest that LOTUS promotes neurite outgrowth by interacting with Ten-4. Our findings may provide a new molecular mechanism of LOTUS to contribute to neuronal circuit formation in development and to enhance axonal regeneration after CNS injury.

Abstract Cellular senescence, a state of irreversible cell-cycle arrest caused by a variety of cellular stresses, is critically involved in age-related tissue dysfunction in various organs. However, the features of cells in the central nervous system that undergo senescence and their role in neural impairment are not well understood as yet. Here, through comprehensive investigations utilising single-cell transcriptome analysis and various mouse models, we show that microglia, particularly in the white matter, undergo cellular senescence in the brain and spinal cord during ageing and in disease models involving demyelination. Microglial senescence is predominantly detected in disease-associated microglia, which appear in ageing and neurodegenerative diseases. We also find that commensal bacteria promote the accumulation of senescent microglia and disease-associated microglia during ageing. Furthermore, knockout of p16 INK4a , a key senescence inducer, ameliorates the neuroinflammatory phenotype in damaged spinal cords in mice. These results advance our understanding of the role of cellular senescence in the central nervous system and open up possibilities for the treatment of age-related neural disorders.

Introduction. Minor head trauma, such as scalp abrasion, is relatively common during vaginal delivery, whereas fatal head trauma is rare. This case report describes the successful repair and management of severe scalp avulsion that occurred during vaginal delivery and consequent hemorrhagic shock in an extremely low birth weight infant. Case Presentation. An extremely low birth weight infant (26 weeks’ gestational age) sustained extensive scalp avulsion during vaginal delivery that exposed the skull. The scalp laceration began in the frontal temporal region and extended bilaterally along the temporal region for 20 cm. The infant experienced hemorrhagic shock soon after birth due to bleeding from the wound and was placed in a closed incubator for intensive care. At 7 h after birth, the wounds were repaired using sutures. Bleeding was quickly controlled, and the infant recovered from hemorrhagic shock. A wet dressing was applied to the wound, and the flap healed without necrosis. Conclusion. We successfully repaired severe scalp avulsion in this case. Scalp avulsion can cause severe bleeding and death. Bleeding control and the preservation of circulation are the most important factors in its repair and maintenance. In this case, suturing the wound effectively controlled the bleeding, and the application of wet dressing and a high-humidity environment thereafter may have contributed to the scalp’s engraftment.

Abstract Aims/Introduction The aim of this study was to develop a scale to evaluate disease stigma in patients with lifestyle‐related chronic non‐communicable diseases (LCNCDs), which we named the Kanden Institute Stigma Scale (KISS), and to consider its possible clinical application for patients with diabetes. Materials and methods An initial 90 questions were drafted and categorized into six subscales according to the manifestations of stigma. The final version of the KISS was developed as a 24‐item questionnaire comprising four items for each subscale. Results A total of 539 outpatients including 452 patients with diabetes and 87 patients without diabetes were recruited. Construct validity was confirmed by assessing the correlation with previously established measures. Confirmatory factor analysis showed the KISS to have good model fitness (adjusted goodness‐of‐fit index = 0.856). Test–retest reproducibility analysis showed that the intraclass coefficient of the first and a second KISS was 0.843 (P

Background: This study aimed to compare the clinical outcomes and patient reported outcome measurement scales (PROMs) between hamstring tendon (HT) or bone-patellar tendon-bone (BTB) grafts in each primary and revision anterior cruciate ligament (ACL) reconstruction. Additionally, the clinical outcomes and PROMs between primary and revision surgeries were compared. Methods: A total of 150 patients (109 primary and 41 revision ACL reconstructions) were enrolled and followed up for an average of 3.9 years (2 years minimum). Knee injury and osteoarthritis outcome scores (KOOS) were examined as PROMs. Side-to-side differences of anterior knee laxity were assessed using KT-1000 and were recorded at the final follow-up. After categorizing patients into HT and BTB reconstruction groups, regression analysis was performed to determine the relationship between revision surgery and changes in KOOS. Results: In patients who underwent primary surgery, there was no significant difference in side-to-side differences of anterior laxity and KOOS between HT and BTB grafts. In those who underwent revision surgery, BTB grafts had a higher KOOS for activities of daily living (ADL) than HT grafts (p = 0.032). Comparing primary and revision surgeries, postoperative side-to-side differences of anterior laxity in the revision group were significantly larger than those in the primary group (p = 0.001). The KOOS for sports after overall revision reconstruction was significantly lower than that after primary reconstruction (p = 0.026). Comparing the KOOS after dividing all patients into HT and BTB reconstruction groups, in the HT reconstruction group, postoperative KOOS results were not different in any subscale from BTB grafts. In contrast, the KOOS for sports (p = 0.008) and QOL (p = 0.039) were significantly lower in revision surgery than in primary surgery. Furthermore, regression analysis including multiple confounders in the HT reconstruction group showed revision surgery using HT graft was correlated with worsened KOOS for symptoms (p = 0.012) and sports (p = 0.010). Revision surgery using BTB graft was not correlated with decreased KOOS. Conclusions: There were no differences between the clinical outcome and KOOS in primary and revision surgery, except for ADL scores following revision ACL reconstruction using BTB graft. Side-to-side difference of anterior laxity and KOOS for sports following revision ACL reconstruction were inferior to those following primary ACL reconstruction.Furthermore, revision ACL reconstruction using HT grafts were correlated with low scores in KOOS for symptoms and sports, while there was no difference of anterior laxity between BTB and HT grafts in revision surgery.

Abstract Background In Japan, height and weight measurements, taken for all children at birth and 1.5- and 3-year health checks, are recorded in the Mother and Child Health (MCH) Handbook, as required by the law. The present population-based retrospective cohort study aimed to evaluate the diagnostic performance of height and weight records in the Handbook for predicting excessive adiposity in adolescents. Methods The source population consisted of 8th grade students (800 students aged 14 years) registered at two public junior high schools. Of these, we excluded students who were born at a gestational age < 37 weeks or > 42 weeks. The present analyses included 435 participants who provided complete information. Body mass index (BMI) was calculated using height and weight records. Body fat mass at 14 years of age was measured by dual-energy X-ray absorptiometry (DXA). Diagnostic performance of BMI calculated from the MCH Handbook records to discriminate between the presence and absence of excessive adiposity at 14 years of age was evaluated using receiver operating characteristic (ROC) curve analysis. The area under the ROC curve (AUC) was used to quantify the diagnostic accuracy of BMI. Results With regard to the prediction of excessive fat at 14 years of age, AUCs and 95% confidence intervals for BMI at 1.5 and 3 years of age were greater than 0.5. Meanwhile, the AUC of BMI at birth was not significantly greater than 0.5. Conclusion The present study findings indicate that BMI values calculated using MCH Handbook data have potential ability to distinguish between the presence and absence of excessive fat at 14 years of age.

Gangliosides, sialic acid-containing glycosphingolipids, are widely involved in regulations of signal transductions to control cellular functions. It has been suggested that GM3, the simplest structure among gangliosides, is involved in insulin resistance, whereas it remains unclear whether insulin signaling diminished by GM3 actually aggravates the pathological conditions in metabolic disorders. Moreover, the functional roles of gangliosides in the regulation of insulin signaling have not yet been fully elucidated in liver or hepatocytes despite that it is one of the major insulin-sensitive organs. To understand physiological roles of GM3 in metabolic homeostasis in liver, we conducted a high fat diet (HFD) loading experiment using double knockout (DKO) mice of GM2/GD2 synthase and GD3 synthase, which lack all gangliosides except GM3, as well as wild-type (WT) mice. DKO mice were strikingly resistant to HFD-induced hepatosteatosis, and hepatic lipogenesis-related molecules including insulin signaling components were down-regulated in HFD-fed DKO. Furthermore, we established primary hepatocyte cultures from DKO and WT mice, and examined their responses to insulin in vitro. Following insulin stimulation, DKO hepatocytes expressing GM3 showed attenuated expression and/or activations in the downstream components compared with WT hepatocytes expressing GM2. While insulin stimulation induced lipogenic proteins in hepatocytes from both genotypes, their expression levels were lower in DKO than in WT hepatocytes after insulin treatment. All our findings suggest that the modified gangliosides, i.e., a shift to GM3 from GM2, might exert a suppressive effect on lipogenesis by attenuating insulin signaling at least in mouse hepatocytes, which might result in protection of HFD-induced hepatosteatosis.

Chronic kidney disease (CKD) prevalence is increasing worldwide, and reducing the number of patients with CKD is of utmost importance. The environment during the fetal, perinatal, and early childhood stages may influence CKD development (developmental origins of health and disease). Under conditions of maternal malnutrition, the glomerular number of infants reduces, and the risk of developing CKD may increase. Nephron progenitor cells and ureteric buds interact with each other to form glomeruli at the tip of the ureteric bud. Thus, the number of glomeruli is determined by the number of ureteric bud branches, which are reportedly decreased due to maternal malnutrition, in turn reducing the glomerular number. Four possible mechanisms can explain the low glomerular number resulting from maternal malnutrition: 1) suppression of c-Ret expression, 2) suppression of nephron formation by renin-angiotensin-aldosterone system inhibition, 3) exposure to excess glucocorticoids, and 4) promotion of apoptosis. Additionally, nephron formation does not continue after birth in humans. Therefore, a low glomerular number at birth is a lifelong burden on the glomeruli and increases the risk of developing CKD. Therefore, it is important to maintain the glomerular number at birth. Accurate glomerular counts are essential for conducting studies on the glomerular number. The dissector/fractionator method is the gold standard; however, it can only be performed at some institutions. Recently, methods have been developed to measure the glomerular number by combining computed tomography and pathological examination and measure the glomerular count using magnetic resonance imaging. Models of decreased and increased glomerular numbers have been developed. Moreover, research regarding the causes of decreased glomerular number and its relationship with development of lifestyle-related diseases and renal dysfunction has significantly progressed, furthering our understanding of the importance of glomerular number.

Although anodization is an essential technology that has supported the aluminum industry for nearly a century, the atomistic structure of the formed alumina films has not completely understood. Here we used NMR spectroscopy to clarify the factors affecting local structure of anodic porous alumina films prepared under various electrolytic conditions. For anion-free amorphous alumina films prepared using chromic acid, the local structure does not depend on electrolytic factors. For films prepared using phosphoric acid, the average coordination number was lower than that of anion-free alumina. On the other hand, films prepared using oxalic and sulfuric acids showed the average coordination numbers higher than that of anion-free alumina. We reveal that aluminum coordination number of anodic porous alumina are affected by anion species and anion content. In addition, the depth of anion incorporation into cell walls, or compositional uniformity, is quite important for accurate interpretation of NMR spectra.

Abstract Aims/Introduction This 6‐month, single‐center, prospective, open‐labeled, randomized trial was designed to investigate whether physicians’ diabetes self‐management education using an education tool developed by the Japan Association of Diabetes Education and Care and a self‐monitoring of blood glucose (SMBG) analyzer improves glycemic control in individuals with type 2 diabetes receiving insulin and SMBG. Materials and Methods Participants were randomized into intervention (I) and control (C) groups. Both groups received physicians’ diabetes self‐management education at each hospital visit, whereas the Japan Association of Diabetes Education and Care education tool and the SMBG readings analyzer was used in group I, but not group C. All participants filled out a diabetes treatment‐related quality of life form and an original questionnaire on SMBG use with five questions (Q1–Q5) before and after the study period. Results A total of 76 individuals were recruited and randomized. Glycated hemoglobin (HbA1c) was significantly improved during the study period in group I, whereas no significant change was observed in group C. The change in HbA1c was greater in group I, although it did not reach statistical significance. The diabetes treatment‐related quality of life total score was not changed in either group. Interestingly, the score of Q1 (“How important is SMBG to you?”) in the SMBG questionnaire was unchanged in group I, whereas it was significantly decreased in group C. HbA1c change was independently associated with changes in insulin dose and SMBG Q1 score. Conclusion Greater HbA1c‐lowering by physicians’ diabetes self‐management education using the Japan Association of Diabetes Education and Care education tool and SMBG analyzer in individuals with type 2 diabetes receiving insulin and SMBG was suggested, but not confirmed.

Abstract To clarify the association between lifestyle changes as a result of coronavirus disease 2019 containment measures and changes in metabolic and glycemic status in patients with diabetes, a cross‐sectional, single‐center, observation study was carried out. A self‐reported questionnaire was provided to ascertain the frequency of various lifestyle activities before and after the coronavirus disease 2019 containment measures in Japan. Among 463 patients, change in glycated hemoglobin was significantly associated with change in bodyweight. After stratification by age 65 years, binary logistic regression analysis showed that increased frequency of snack eating increased bodyweight (odds ratio 1.709, P = 0.007) and glycated hemoglobin (odds ratio 1.420, P = 0.025) in the younger group, whereas in the older patients, reduced walking activities resulted in weight gain (odds ratio 0.726, P = 0.010). In conclusion, changes in eating behavior and physical activity increased bodyweight and reduced glycemic control among diabetes patients, but by different processes depending on age under the coronavirus disease 2019 containment measures in Japan.

Abstract Background Rapid weight gain in early life is associated with adiposity later in life. However, there is limited information on the association between weight gain and body fat mass measured using precise methods. This study aimed to investigate whether weight gain is associated with body fat mass measured by dual-energy X-ray absorptiometry (DXA) in adolescents. Methods Participants of this retrospective cohort study were 423 adolescents born at full-term who were enrolled in the Japan Kids Body-composition Study. Anthropometric measurements related to pregnancy, delivery, and child health were obtained from the Japanese Maternal and Child Health Handbook. Fat mass in adolescents was measured with a DXA scanner. Weight gain was defined as the change in body weight from birth to age 1.5 years. Associations between birthweight and fat mass, and between weight gain and fat mass, were evaluated using multiple regression analysis. Results There was a significant positive association between weight gain from birth to age 1.5 years and fat mass in adolescents (boys: standardized regression coefficient (β) = 0.253, p

Abstract Background The Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study was launched to investigate risk factors for osteoporotic fractures, interactions of osteoporosis with other non-communicable chronic diseases, and effects of fracture on QOL and mortality. Methods FORMEN baseline study participants (in 2007 and 2008) included 2012 community-dwelling men (aged 65–93 years) in Nara prefecture, Japan. Clinical follow-up surveys were conducted 5 and 10 years after the baseline survey, and 1539 and 906 men completed them, respectively. Supplemental mail, telephone, and visit surveys were conducted with non-participants to obtain outcome information. Survival and fracture outcomes were determined for 2006 men, with 566 deaths identified and 1233 men remaining in the cohort at 10-year follow-up. Comments The baseline survey covered a wide range of bone health-related indices including bone mineral density, trabecular microarchitecture assessment, vertebral imaging for detecting vertebral fractures, and biochemical markers of bone turnover, as well as comprehensive geriatric assessment items. Follow-up surveys were conducted to obtain outcomes including osteoporotic fracture, cardiovascular diseases, initiation of long-term care, and mortality. A complete list of publications relating to the FORMEN study can be found at https://www.med.kindai.ac.jp/pubheal/FORMEN/Publications.html .

Abstract Background Body mass-independent parameters might be more appropriate for assessing cardiometabolic abnormalities than weight-dependent indices in Asians who have relatively high visceral adiposity but low body fat. Dual-energy X-ray absorptiometry (DXA)-measured trunk-to-peripheral fat ratio is one such body mass-independent index. However, there are no reports on relationships between DXA-measured regional fat ratio and cardiometabolic risk factors targeting elderly Asian men. Methods We analyzed cross-sectional data of 597 elderly men who participated in the baseline survey of the Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) study, a community-based single-center prospective cohort study conducted in Japan. Whole-body fat and regional fat were measured with a DXA scanner. Trunk-to-appendicular fat ratio (TAR) was calculated as trunk fat divided by appendicular fat (sum of arm and leg fat), and trunk-to-leg fat ratio (TLR) as trunk fat divided by leg fat. Results Both TAR and TLR in the group of men who used ≥ 1 medication for hypertension, dyslipidemia, or diabetes (“user group”; N = 347) were significantly larger than those who did not use such medication (“non-user group”; N = 250) (P < 0.05). After adjusting for potential confounding factors including whole-body fat, both TAR and TLR were significantly associated with low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, fasting serum insulin, and the insulin resistance index in the non-user group and non-overweight men in the non-user group (N = 199). Conclusion The trunk-to-peripheral fat ratio was associated with cardiometabolic risk factors independently of whole-body fat mass. Parameters of the fat ratio may be useful for assessing cardiometabolic risk factors, particularly in underweight to normal-weight populations.

Background: Central obesity as measured by waist-to-hip circumference ratio (WHR) has been reported to be associated with renal hemodynamics and function. However, the adipose component of WHR, which is a composite measure of fat mass and fat-free mass, is small, particularly in nonobese subjects. Trunk-to-peripheral fat ratio as measured using dual-energy absorptiometry (DXA) is a more precise method for evaluating central fat distribution than WHR. The present study investigated the cross-sectional association between DXA-measured trunk-to-peripheral fat ratio and estimated glomerular filtration rate (eGFR) in community-dwelling elderly Japanese men. Methods: Participants were 575 men aged ≥65 years at the time of the baseline survey of the second Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) cohort study. Trunk-to-appendicular fat ratio (TAR) was calculated as trunk fat divided by appendicular fat (sum of arm and leg fat), and trunk-to-leg fat ratio (TLR) as trunk fat divided by leg fat. Results: eGFR values significantly decreased from the lowest to the highest quintile of TAR/TLR. After adjusting for potential confounding factors including whole-body fat, the highest quintile of both TAR and TLR showed statistically significant odds ratios for the risk of eGFR

Abstract Repulsive guidance molecule-a (RGMa), a glycosylphosphatidylinositol-anchored membrane protein, has diverse functions in axon guidance, cell patterning, and cell survival. Inhibition of RGMa attenuates pathological dysfunction in animal models of central nervous system (CNS) diseases including spinal cord injury, multiple sclerosis, and neuromyelitis optica. Here, we examined whether antibody-based inhibition of RGMa had therapeutic effects in a mouse model of Parkinson’s disease (PD). We treated mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and found increased RGMa expression in the substantia nigra (SN). Intraventricular, as well as intravenous, administration of anti-RGMa antibodies reduced the loss of tyrosine hydroxylase (TH)-positive neurons and accumulation of Iba1-positive microglia/macrophages in the SN of MPTP-treated mice. Selective expression of RGMa in TH-positive neurons in the SN-induced neuronal loss/degeneration and inflammation, resulting in a progressive movement disorder. The pathogenic effects of RGMa overexpression were attenuated by treatment with minocycline, which inhibits microglia and macrophage activation. Increased RGMa expression upregulated pro-inflammatory cytokine expression in microglia. Our observations suggest that the upregulation of RGMa is associated with the PD pathology; furthermore, inhibitory RGMa antibodies are a potential therapeutic option.

Abstract Surface inactivation of human microbial pathogens has a long history. The Smith Papyrus (2600 ~ 2200 B.C.) described the use of copper surfaces to sterilize chest wounds and drinking water. Brass and bronze on doorknobs can discourage microbial spread in hospitals, and metal-base surface coatings are used in hygiene-sensitive environments, both as inactivators and modulators of cellular immunity. A limitation of these approaches is that the reactive oxygen radicals (ROS) generated at metal surfaces also damage human cells by oxidizing their proteins and lipids. Silicon nitride (Si3N4) is a non-oxide ceramic compound with known surface bacterial resistance. We show here that off-stoichiometric reactions at Si3N4 surfaces are also capable of inactivating different types of single-stranded RNA (ssRNA) viruses independent of whether their structure presents an envelop or not. The antiviral property of Si3N4 derives from a hydrolysis reaction at its surface and the subsequent formation of reactive nitrogen species (RNS) in doses that could be metabolized by mammalian cells but are lethal to pathogens. Real-time reverse transcription (RT)-polymerase chain reaction (PCR) tests of viral RNA and in situ Raman spectroscopy suggested that the products of Si3N4 hydrolysis directly react with viral proteins and RNA. Si3N4 may have a role in controlling human epidemics related to ssRNA mutant viruses.

Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes mellitus characterised by early onset and dominant inheritance. Delayed diagnosis or misdiagnosis as type 1 or type 2 diabetes mellitus is common. Definitive genetic diagnosis is essential for appropriate treatment of patients with MODY. The hepatocyte nuclear factor 1-beta (HNF1B) gene is responsible for MODY type 5 (MODY5), which has distinctive clinical features including renal disease. MODY5 should always be considered by clinicians in patients with early onset diabetes and renal anomalies. We report a case of a 30-year-old Japanese male with early-onset diabetes mellitus, renal anomalies and family history of diabetes that was suggestive of MODY5. Renal histology showed no evidence of diabetic nephropathy. Genetic testing revealed a novel heterozygous splice-site mutation of the HNF1B gene in the family members. It was strongly suggested that the mutation could underlie our patient’s MODY5.

Abstract Background Limited evidence exists regarding the relationship between central-to-peripheral fat ratio measured by dual-energy X-ray absorptiometry (DXA) and subsequent cardiometabolic risk in both pediatric and adult populations. Methods The present cohort study investigated the relationship between DXA-measured body fat distribution and cardiometabolic parameters. The source population was 275 4th–6th graders (aged 9.6–12.6 years) in the northeast region of Japan (Shiokawa area in Kitakata). A 3-year follow-up was conducted to obtain complete information from 155 normal-weight children (87 boys and 68 girls). Normal-weight children were identified using sex- and age-specific international cut-offs for body mass index (BMI) based on adult BMI values of 25 kg/m2 and 18.5 kg/m2, respectively. Body fat distribution was assessed using the trunk-to-appendicular fat ratio (TAR) and trunk-to-leg fat ratio (TLR) measured by DXA. Results In boys, systolic blood pressure (SBP) at follow-up showed a significant relationship with TAR at baseline after adjusting for age, height, pubic hair appearance, SBP, and whole body fat at baseline (β = 0.24, P < 0.05), and SBP also showed a significant relationship with TLR after adjusting for confounding factors including whole body fat (β = 0.25, P < 0.05). In girls, there were no significant relationships between blood pressure and TAR/TLR. Conclusion Body fat distribution in normal-weight boys predicted subsequent blood pressure levels in adolescence. The relationship between fat distribution and blood pressure was independent of fat volume.

Abstract The carbonophosphate Na3FePO4CO3 was synthesized by the mechanical ball milling method for the first time. The composition of the obtained sample with a higher amount of Fe2+ was Na2.66Fe2+ 0.66Fe3+ 0.34PO4CO3 as confirmed by Mössbauer analysis, owing to the good airtight properties of this method. The obtained samples in an organic electrolyte delivered an initial discharge capacity of 124 mAh/g at room temperature, and a larger discharge capacity of 159 mAh/g (1.66 Na+/mole) at 60 °C. With 17 m NaClO4 aqueous electrolyte, a discharge capacity of 161 mAh/g (1.69 Na+/mole) was delivered because of the high ionic conductivity of the concentrated aqueous electrolyte. During the charge-discharge process, the formation of Fe4+ after charging up to 4.5 V and the return of Fe2+ after discharging down to 1.5 V were detected by ex-situ X-ray absorption near edge structure (XANES) analysis.

Background: Current trends in serum lipid levels among children are likely to be important predictors of future cardiovascular disease prevalence. However, no studies have examined trends in low-density lipoprotein cholesterol (LDL-C) levels in Japanese children. Methods: We investigated trends in LDL-C levels from 2008 through 2017 and HDL-C levels from 2007 through 2017 in a population of 10- and 13-year-old children in Fukuroi City, Japan. We analyzed 17,838 children, accounting for 93.8% of all fifth and eighth graders in the entire city. Adverse lipid levels were defined as follows: 130 mg/dL or higher for LDL-C, and lower than 40 mg/dL for HDL-C. The Jonckheere-Terpstra and Cochran-Armitage tests were used to evaluate secular trends in mean serum lipid levels and prevalence of dyslipidemia, respectively. Results: There were no significant trends in BMI during the study period. In children aged 10 years, serum levels of LDL-C and HDL-C showed significant positive associations with calendar year during the study period for both sexes. A significant increase in HDL-C levels was observed in girls aged 13 years. On the other hand, no significant trends were observed in the prevalence of high LDL-C or low HDL-C regardless of sex or age, while the prevalence of high non-HDL-C showed a significant increase in boys. Conclusions: In the Fukuroi population, serum levels of LDL-C and HDL-C slightly increased in both boys and girls aged 10 years, and HDL-C levels slightly increased in girls aged 13 years, during the past decade.

Previous studies have suggested that change-related cortical responses are phenomena similar to the onset response and could be applied to the loudness dependence of auditory evoked potential (LDAEP) paradigm. In the present study, we examined the relationship between LDAEP and the change-related response using electroencephalography findings in 50 healthy subjects. There were five conditions (55, 65, 75, 85, and 95 dB) for LDAEP and five similar conditions (abrupt sound pressure increase from 70 to 75, 80, 85, 90, and 95 dB) for the change-related response. Both the onset and abrupt sound pressure increase evoked a triphasic response with peaks at approximately 50 (P50), 100 (N100), and 200 (P200) ms. We calculated the peak-to-peak amplitudes for P50/N100 and N100/P200. Medians and slopes for P50/N100 and N100/P200 amplitudes were calculated and compared between the two measures. Results revealed a significant correlation for both the slope and median for P50/N100 (r = 0.36, 0.37, p = 1.0 × 10-2, 7.9 × 10-3), N100/P200 (r = 0.40, 0.34, p = 4.0 × 10-3, 1.6 × 10-2), and P50/N100/P200 (r = 0.36, 0.35, p = 1.0 × 10-2, 1.3 × 10-2). These results suggested that the change-related response and LDAEP shared generation mechanisms at least partially.

Abstract The multiple mutations of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus have created variants with structural differences in both their spike and nucleocapsid proteins. While the functional relevance of these mutations is under continuous scrutiny, current findings have documented their detrimental impact in terms of affinity with host receptors, antibody resistance, and diagnostic sensitivity. Raman spectra collected on two British variant sub‐types found in Japan (QK002 and QHN001) are compared with that of the original Japanese isolate (JPN/TY/WK‐521), and found bold vibrational differences. These included: i) fractions of sulfur‐containing amino acid rotamers, ii) hydrophobic interactions of tyrosine phenol ring, iii) apparent fractions of RNA purines and pyrimidines, and iv) protein secondary structures. Building upon molecular scale results and their statistical validations, the authors propose to represent virus variants with a barcode specially tailored on Raman spectrum. Raman spectroscopy enables fast identification of virus variants, while the Raman barcode facilitates electronic recordkeeping and translates molecular characteristics into information rapidly accessible by users.

Abstract Background Epidemiological data regarding the association between serum levels of IGF-I and bone mineral acquisition during childhood are scarce. Here, we investigated the association between serum levels of IGF-I and bone status during puberty. Methods We analyzed prospective 3-year follow-up data of 254 community-dwelling children who completed both baselines (at age 11.2 years) and follow-up (at age 14.2 years) surveys in Hamamatsu, Japan. Total body (TB) bone area and bone mineral parameters were assessed using dual-energy X-ray absorptiometry. Results During the 3-year follow-up period, there were significant (P < 0.05) increases in total body less head (TBLH) areal bone mineral density (aBMD), TBLH bone mineral content (BMC), and TB bone area, and a significant decrease in TB bone mineral apparent density (BMAD, volumetric bone mineral density, vBMD). IGF-I levels showed significant positive relationships with TBLH BMC and TBLH aBMD at both baseline and follow-up. TBLH aBMD in boys and TB BMAD in girls at follow-up showed significant increases from the lowest to highest quartiles of baseline IGF-I levels after adjusting for confounding factors. Similarly, changes in TBLH aBMD in boys and TB BMAD in girls during the 3-year follow-up period showed significant increases from the lowest to highest quartiles of baseline IGF-I levels after adjusting for confounding factors. Conclusions These results suggest that pubertal children with high levels of serum IGF-I tended to have high bone mineral acquisition later on.

Background: Maternal pre-pregnancy weight has been reported to be positively associated with offspring weight. The association between maternal weight and offspring weight might be explained by maternal lifestyle. We investigated the strength of the relationship between maternal body mass index (BMI) at the beginning of pregnancy and offspring BMI at several growth stages. Methods: The source population was all eighth graders registered in all public schools in the city of Fukuroi, Japan, in 2012. Records of maternal anthropometry at the beginning of pregnancy were obtained from the Maternal and Child Health (MCH) Handbook. The height and body weight of each student were measured. A regression model was used to assess the association between maternal BMI z-score at the beginning of pregnancy and offspring BMI z-score at various ages. Results: Of the source population, data from the MCH Handbook were obtained for 480 students. Among males, maternal BMI z-score was not associated with offspring BMI z-score at birth and at age 3 years but was associated with offspring BMI z-score at age 13 years (standardized regression coefficient (β) = 0.19; P < 0.01). Among females, maternal BMI z-score was associated with offspring BMI z-score at birth (β = 0.11; P < 0.05), at age 3 years (β = 0.22; P < 0.01) and at age 13 years (β = 0.51; P < 0.01). Conclusions: Our results suggest that the positive association between maternal weight at the beginning of pregnancy and offspring weight around puberty is stronger than that between maternal weight and offspring weight at birth. Maternal lifestyle may influence offspring weight in adolescence.

Microglia are resident immune cells in the central nervous system (CNS). Microglia exhibit diversity in their morphology, density, electrophysiological properties, and gene expression profiles, and play various roles in neural development and adulthood in both physiological and pathological conditions. Recent transcriptomic analysis using bulk and single-cell RNA-seq has revealed that microglia can shift their gene expression profiles in various contexts, such as developmental stages, aging, and disease progression in the CNS, suggesting that the heterogeneity of microglia may be associated with their distinct functions. Epigenetic changes, including histone modifications and DNA methylation, coordinate gene expression, thereby contributing to the regulation of cellular state. In this review, we summarize the current knowledge regarding the epigenetic mechanisms underlying spatiotemporal and functional diversity of microglia that are altered in response to developmental stages and disease conditions. We also discuss how this knowledge may lead to advances in therapeutic approaches for diseases.

Neuropathic pain refers to pain caused by lesions or diseases of the somatosensory nervous system that is characteristically different from nociceptive pain. Moreover, neuropathic pain occurs in the maxillofacial region due to various factors and is treated using tricyclic antidepressants and nerve block therapy; however, some cases do not fully recover. Netrin is a secreted protein crucially involved in neural circuit formation during development, including cell migration, cell death, neurite formation, and synapse formation. Recent studies show Netrin-4 expressed in the dorsal horn of the spinal cord is associated with chronic pain. Here we found involvement of Netrin-4 in neuropathic pain in the maxillofacial region. Netrin-4, along with one of its receptors, Unc5B, are expressed in the caudal subnucleus of the trigeminal spinal tract nucleus. Inhibition of its binding by anti-Netrin-4 antibodies not only shows a behavioral analgesic effect but also neuronal activity suppression. There was increased Netrin-4 expression at 14 days after infraorbital nerve injury. Our findings suggest that Netrin-4 induced by peripheral nerve injury causes neuropathic pain via Unc5B.

Downy mildew of grapevine, caused by Plasmopara viticola (Berk. and Curt.) Berl. and de Toni, is one of the most devastating diseases of grapevine, severely affecting grape and wine production and quality worldwide. Infections are usually controlled by the intensive application of synthetic fungicides or by copper-based products in organic farming, rising problems for soil contamination and adverse impacts on environment and human health. While strict regulations attempt to minimize their harmful consequences, the situation calls for the development of alternative fungicidal strategies. This study presents the unprecedented case of a bioceramic, silicon nitride, with antimicrobial properties against P. viticola, but without adverse effects on human cells and environment, opening the way to the possible extension of silicon nitride applications in agriculture. Raman spectroscopic assessments of treated sporangia in conjunction with microscopic observations mechanistically showed that the nitrogen-chemistry of the bioceramic surface affects pathogen’s biochemical components and cell viability, thus presenting a high potential for host protection from P. viticola infections.

Summary: Microglia, the resident immune cells of the central nervous system, accumulate along axons and support neuronal survival during the early postnatal period. Although methods have been developed to isolate microglia or neurons, the procedures for co-culture of these cells can inadvertently affect the interactions between them. Here, we describe a protocol to investigate the accumulation of microglia toward neuronal axons using axon isolation culture devices. This approach is useful for modeling neuron-glia associations.For complete details on the use and execution of this protocol, please refer to Ueno et al. (2013) and Fujita et al. (2020).

Summary: Microglia, the resident immune cells of the central nervous system, accumulate along subcerebral projection axons and support neuronal survival during the early postnatal period. It remains unknown how microglia follow an axon-specific distribution pattern to maintain neural circuits. Here, we investigated the mechanisms of microglial accumulation along subcerebral projection axons that were necessary for microglial accumulation in the internal capsule. Screening of molecules involved in this accumulation of microglia to axons of layer V cortical neurons identified netrin-G1, a member of the netrin family of axon guidance molecules with a glycosyl-phosphatidylinositol anchor. Deletion or knockdown of the netrin-G1 gene Ntng1 reduced microglial accumulation and caused loss of cortical neurons. Netrin-G1 ligand-Ngl1 knockout-mice-derived microglia showed reduced accumulation along the axons compared with wild-type microglia. Thus, microglia accumulate around the subcerebral projection axons via NGL1-netrin-G1 signaling and support neuronal survival. Our observations unveil bidirectional neurotrophic interactions between neurons and microglia. : The mechanism underlying microglial accumulation along subcerebral projection axons to maintain neural circuits during the early postnatal period remains largely unknown. Fujita et al. demonstrate that microglial NGL1 and neuronal netrin-G1 signaling mediates microglial accumulation around the subcerebral projection axons and supports neuronal survival. Keywords: brain, microglia, neuron, axon, netrin-G1

Alzheimer's disease (AD) is a progressive neurodegenerative disease and is known to be the most common cause of dementia. We previously described the benefits of aromatherapy on the cognitive function of patients with AD utilizing various aromatic essential oils; however, its mechanism of action remains poorly understood. Consequently, in the present study, this mechanism was thoroughly evaluated employing a dementia mice model, specifically the senescence-accelerated mouse prone 8. The mice were exposed to a mixture of lemon and rosemary oil at nighttime as well as to a mixture of lavender and orange oil in the daytime for 2 months. The cognitive function of the mice was assessed before and after treatment with the aromatic essential oils using the Y-maze test. Moreover, the brain levels of amyloid beta (Aβ), abnormally phosphorylated tau, and brain-derived neurotrophic factor (BDNF) were measured following treatment. The benefits of aromatherapy on the cognitive function in mice were confirmed. It was also established that the brain levels of Aβ and abnormally phosphorylated tau were considerably lower in the aromatherapy group, while the levels of BDNF were marginally higher. These results suggest that aromatherapy employing these aromatic essential oils is beneficial for the prevention and treatment of AD.

Abstract Background Alzheimer’s disease (AD) is the most common form of dementia and the number of AD patients continues to increase worldwide. Components of the germ layer and bran of Brown rice (BR) help maintain good health and prevent AD. Because the germ layer and bran absorb little water and are very hard and difficult to cook, they are often removed during processing. To solve these problems, in this study, we tried to use a high-pressure (HP) technique. Methods We produced the highly water pressurized brown rice (HPBR) by pressurizing BR at 600 MPa, and then we fed it to an AD mouse model, senescence-accelerated mouse prone 8, to investigate the therapeutic effects of HPBR on cognitive dysfunction by Y-maze spatial memory test. Results HP treatment increased the water absorbency of BR without nutrient loss. HPBR ameliorated cognitive dysfunction and reduced the levels of amyloid-β, which is a major protein responsible for AD, in the brain. Conclusions These results suggest that HPBR is effective for preventing AD.

Abstract The E693Δ (Osaka) mutation in APP is linked to familial Alzheimer’s disease. While this mutation accelerates amyloid β (Aβ) oligomerization, only patient homozygotes suffer from dementia, implying that this mutation is recessive and causes loss-of-function of amyloid precursor protein (APP). To investigate the recessive trait, we generated a new mouse model by knocking-in the Osaka mutation into endogenous mouse APP. The produced homozygous, heterozygous, and non-knockin littermates were compared for memory, neuropathology, and synaptic plasticity. Homozygotes showed memory impairment at 4 months, whereas heterozygotes did not, even at 8 months. Immunohistochemical and biochemical analyses revealed that only homozygotes displayed intraneuronal accumulation of Aβ oligomers at 8 months, followed by abnormal tau phosphorylation, synapse loss, glial activation, and neuron loss. These pathologies were not observed at younger ages, suggesting that a certain mechanism other than Aβ accumulation underlies the memory disturbance at 4 months. For the electrophysiology studies at 4 months, high-frequency stimulation evoked long-term potentiation in all mice in the presence of picrotoxin, but in the absence of picrotoxin, such potentiation was observed only in homozygotes, suggesting their GABAergic deficit. In support of this, the levels of GABA-related proteins and the number of dentate GABAergic interneurons were decreased in 4-month-old homozygotes. Since APP has been shown to play a role in dentate GABAergic synapse formation, the observed GABAergic depletion is likely associated with an impairment of the APP function presumably caused by the Osaka mutation. Oral administration of diazepam to homozygotes from 6 months improved memory at 8 months, and furthermore, prevented Aβ oligomer accumulation, indicating that GABAergic deficiency is a cause of memory impairment and also a driving force of Aβ accumulation. Our findings suggest that the Osaka mutation causes loss of APP function, leading to GABAergic depletion and memory disorder when wild-type APP is absent, providing a mechanism of the recessive heredity.

Abstract Water purification was examined using porous ceramics prepared by sintering a powder mixture of volcanic ash, waste glass and a small amount of wood charcoal. The porous ceramics had cross-linked 3D-channels of which the diameter ranged from several nm to several μm. Three kilograms of porous ceramics placed in 90 L of circulating artificial seawater, in which several tropical fishes were actually living under aeration, caused a decrease in COD from 23.8 to 13.1 mg L−1 in a week. The number of coliform bacteria was almost constant in a range of 52–65 mL−1 despite that a lot of excrements were discharged frequently. The number of the coliform bacteria in the seawater examined “without the tropical fishes” decreased from 900 to 1 mL−1 in 2 weeks, and COD decreased from 37.9 to 7.9 mg L−1. It proved that several aerobic bacteria proliferating in the macropores inside the porous ceramics could effectively decompose several organic materials. Graphical abstract

Abstract Cortical neurogenesis is a fundamental process of brain development that is spatiotemporally regulated by both intrinsic and extrinsic cues. Although recent evidence has highlighted the significance of transcription factors in cortical neurogenesis, little is known regarding the role of RNA-binding proteins (RBPs) in the post-transcriptional regulation of cortical neurogenesis. Here, we report that meiosis arrest female 1 (MARF1) is an RBP that is expressed during neuronal differentiation. Cortical neurons expressed the somatic form of MARF1 (sMARF1) but not the oocyte form (oMARF1). sMARF1 was enriched in embryonic brains, and its expression level decreased as brain development progressed. Overexpression of sMARF1 in E12.5 neuronal progenitor cells promoted neuronal differentiation, whereas sMARF1 knockdown decreased neuronal progenitor differentiation in vitro. We also examined the function of sMARF1 in vivo using an in utero electroporation technique. Overexpression of sMARF1 increased neuronal differentiation, whereas knockdown of sMARF1 inhibited differentiation in vivo. Moreover, using an RNase domain deletion mutant of sMARF1, we showed that the RNase domain is required for the effects of sMARF1 on cortical neurogenesis in vitro. Our results further elucidate the mechanisms of post-transcriptional regulation of cortical neurogenesis by RBPs.

It is known that various endocrine modulators, including leptin and ghrelin, have neuroprotective roles in neurological diseases. Leptin is a hormone produced by adipocytes and was originally identified as a gene related to obesity in mice. The leptin receptors in the hypothalamus are the main target for the homeostatic regulation of body weight. Recent studies have demonstrated that leptin receptors are also expressed in other regions of the central nervous system (CNS), such as the hippocampus, cerebral cortex, and spinal cord. Accordingly, these studies identified the involvement of leptin in the regulation of neuronal survival and neural development. Furthermore, leptin has been shown to have neuroprotective functions in animal models of neurological diseases and demyelination. These observations also suggest that dysregulation of leptin signaling may be involved in the association between neurodegeneration and obesity. In this review, we summarize novel functions of leptin in animal models of neurodegenerative diseases. Specifically, we focus on the emerging evidence for the role of leptin in non-neuronal cells in the CNS, including astrocytes, microglia, and oligodendrocytes. Understanding leptin-mediated neuroprotective signals and molecular mechanisms underlying remyelination will be helpful to establish therapeutic strategies against neurological diseases.

Silent information regulator 1 (SIRT1) is a mammalian homolog of the nicotinamide adenine dinucleotide (NAD)-dependent deacetylase sirtuin family. Sirtuin was originally studied as the lifespan-extending gene, silent information regulator 2 (SIRT2) in budding yeast. There are seven mammalian homologs of sirtuin (SIRT1–7), and SIRT1 is the closest homolog to SIRT2. SIRT1 modulates various key targets via deacetylation. In addition to histones, these targets include transcription factors, such as forkhead box O (FOXO), Ku70, p53, NF-κB, PPAR-gamma co-activator 1-alpha (PGC-1α), and peroxisome proliferator-activated receptor γ (PPARγ). SIRT1 has many biological functions, including aging, cell survival, differentiation, and metabolism. Genetic and physiological analyses in animal models have shown beneficial roles for SIRT1 in the brain during both development and adulthood. Evidence from in vivo and in vitro studies have revealed that SIRT1 regulates the cellular fate of neural progenitors, axon elongation, dendritic branching, synaptic plasticity, and endocrine function. In addition to its importance in physiological processes, SIRT1 has also been implicated in protection of neurons from degeneration in models of neurological diseases, such as traumatic brain injury and Alzheimer’s disease. In this review, we focus on the role of SIRT1 in the neuroendocrine system and neurodegenerative diseases. We also discuss the potential therapeutic implications of targeting the sirtuin pathway.

Isocitrate dehydrogenase (IDH) mutations are a prognostic factor in diffuse glioma. However, the mechanism by which these mutations improve prognosis are not clear. In a subset of IDH-mutant glioma, remodeling of the methylome results in the glioma-CpG island methylator phenotype (G-CIMP) and transcriptional reorganization. In this study, we focus on G0/G1 switch 2 (G0S2), which is highly downregulated in G-CIMP glioma. We found that G0S2 expression tended to increase as the WHO grade increased, and G0S2 knockdown inhibited glioma invasion. Additionally, we revealed that the overexpression of the DNA demethylase Ten-eleven translocation 2 (TET2) in IDH1-plasmid transfected glioblastoma multiforme (GBM) cells restored G0S2 expression. These results indicate that G0S2 is epigenetically silenced in IDH1-mutant glioma. In addition, the stereotactic delivery of glioma cells with decreased G0S2 expression in the mouse brain resulted in prolonged survival. The Cancer Genome Atlas (TCGA) analysis also indicated that survival is longer in the lower G0S2 expression group than in the higher G0S2 expression group. Moreover, G0S2 expression was higher in recurrent tumor specimens than at the initial diagnosis in the same patient. These results provide one explanation for the improved survival in IDH1-mutant glioma as well as a new epigenetic target for glioma treatment.

Over the last decade, several studies have investigated synthetic jets. However, there are still many clarifications needed, including details of the structure and Coanda effect of synthetic jets. The present study clarifies some fundamental flow characteristics of free synthetic jets and synthetic jets near a rigid boundary by conducting an experiment and numerical simulations. As the main results, it is found that the velocity distribution of free synthetic jets depends on K = Re/S2 (the ratio of the Reynolds number to the square of the Stokes number) and can be identified by the maximum velocity at the centerline and the jet half-width. In addition, it is confirmed that the flow characteristics of the synthetic jet near a rigid boundary and the re-attachment length of the synthetic jet are determined not only by H1/b0 (normalized step height) but also K.

In vitro selection with long random RNA libraries has been used as a powerful method to generate novel functional RNAs, although it often requires laborious structural analysis of isolated RNA molecules. Rational RNA design is an attractive alternative to avoid this laborious step, but rational design of catalytic modules is still a challenging task. A hybrid strategy of in vitro selection and rational design has been proposed. With this strategy termed “design and selection,” new ribozymes can be generated through installation of catalytic modules onto RNA scaffolds with defined 3D structures. This approach, the concept of which was inspired by the modular architecture of naturally occurring ribozymes, allows prediction of the overall architectures of the resulting ribozymes, and the structural modularity of the resulting ribozymes allows modification of their structures and functions. In this review, we summarize the design, generation, properties, and engineering of four classes of ligase ribozyme generated by design and selection.

In tauopathies, a neural microtubule-associated protein tau (MAPT) is abnormally aggregated and forms neurofibrillary tangle. Therefore, inhibition of the tau aggregation is one of the key approaches for the treatment of these diseases. Here, we have identified a novel tau aggregation inhibitor, PE859. An oral administration of PE859 resulted in the significant reduction of sarkosyl-insoluble aggregated tau along with the prevention of onset and progression of the motor dysfunction in JNPL3 P301L-mutated human tau transgenic mice. These results suggest that PE859 is useful for the treatment of tauopathies.

Nucleoside diphosphate kinases (NDPK) are ubiquitous enzymes that catalyze the reversible phosphotransfer of γ-phosphates between di- and triphosphonucleosides. NDPK-D (Nm23-H4) is the only member of the NDPK family with a mitochondrial targeting sequence. Despite the high expression of NDPK-D in the developing central nervous system, its function remains to be determined. In this study, we show that NDPK-D knockdown induces apoptosis in neuroblastoma cells as well as in mouse cortex, suggesting that NDPK-D is required for neuronal survival. We identified NDPK-D as a binding partner of NAD+-dependent histone deacetylase, SIRT1, by yeast two-hybrid screening. NDPK-D co-localized with SIRT1, and the association of these molecules was confirmed by co-immunoprecipitation. Inhibition of SIRT1 increases the acetylation of NDPK-D. Overexpression of NDPK-D along with SIRT1, or mutation in the acetylated lysine residues in NDPK-D, increases its nuclear accumulation. Furthermore, the NDPK-D acetylation-mimic mutant increased apoptosis in N1E-115 cells. Our data demonstrate that acetylation regulates the shuttling of NDPK-D between nucleus and cytoplasm, and increased acetylation of NDPK-D causes apoptosis.

Jet flows have been applied in numerous fields to control flow separation. Over the last decade, several studies on the production of synthetic jets have been performed. However, little information is available about a number of aspects concerning synthetic jets, including details of the structure and the formation mechanism of such jets. The present study attempts to clarify some of the fundamental flow characteristics of free synthetic jets on the basis of experiments and numerical simulations. Experimental velocity measurements and flow visualizations are performed using the hot-wire anemometer and the smoke wire method, respectively. It is found that both the temporal change in the flow pattern and the time-averaged velocity distribution at the centerline depend on K = ReU/S2 (the ratio of the Reynolds number to the square of the Stokes number). The unsteady downstream flow characteristics are discussed in addition to the relation between the formative point of the synthetic jet and the value of K. Furthermore, the flow pattern and the unsteady flow characteristics of the synthetic jet are compared with those of a continuous jet.

Sigma-1 receptor (Sig-1R) is an integral membrane protein predominantly expressed in the endoplasmic reticulum. Sig-1R demonstrates a high affinity to various synthetic compounds including well-known psychotherapeutic drugs in the central nervous system (CNS). For that, it is considered as an alternative target for psychotherapeutic drugs. On the cellular level, when Sig-1R is activated, it is known to play a role in neuroprotection and neurite elongation. These effects are suggested to be mediated by its ligand-operated molecular chaperone activity, and/or upregulation of various Ca(2+) signaling. In addition, recent studies show that Sig-1R activation induces neurite outgrowth via neurotrophin signaling. Here, we tested the hypothesis that Sig-1R activation promotes neurite elongation through activation of tropomyosin receptor kinase (Trk), a family of neurotrophin receptors. We found that 2-(4-morpholinethyl)1-phenylcyclohexanecarboxylate (PRE-084), a selective Sig-1R agonist, significantly promoted neurite outgrowth, and K252a, a Trk inhibitor, attenuated Sig-1R-mediated neurite elongation in cerebellar granule neurons (CGNs). Moreover, we revealed that Sig-1R interacts with TrkB, and PRE-084 treatment enhances phosphorylation of Y515, but not Y706. Thus, our results indicate that Sig-1R activation promotes neurite outgrowth in CGNs through Y515 phosphorylation of TrkB.

Soil fertility and nutrient-related plant functional traits are in general only moderately related, hindering the progress in trait-based prediction models of vegetation patterns. Although the relationships may have been obscured by suboptimal choices in how soil fertility is expressed, there has never been a systematic investigation into the suitability of fertility measures. This study, therefore, examined the effect of different soil fertility measures on the strength of fertility-trait relationships in 134 natural plant communities. In particular, for eight plot-mean traits we examined (1) whether different elements (N or P) have contrasting or shared influences, (2) which timescale of fertility measures (e.g. mineralization rates for one or five years) has better predictive power, and (3) if integrated fertility measures explain trait variation better than individual fertility measures. Soil N and P had large mutual effects on leaf nutrient concentrations, whereas they had element-specific effects on traits related to species composition (e.g. Grime's CSR strategy). The timescale of fertility measures only had a minor impact on fertility-trait relationships. Two integrated fertility measures (one reflecting overall fertility, another relative availability of soil N and P) were related significantly to most plant traits, but were not better in explaining trait variation than individual fertility measures. Using all fertility measures together, between-site variations of plant traits were explained only moderately for some traits (e.g. 33% for leaf N concentrations) but largely for others (e.g. 66% for whole-canopy P concentration). The moderate relationships were probably due to complex regulation mechanisms of fertility on traits, rather than to a wrong choice of fertility measures. We identified both mutual (i.e. shared) and divergent (i.e. element-specific and stoichiometric) effects of soil N and P on traits, implying the importance of explicitly considering the roles of different elements to properly interpret fertility-trait relationships.

BACKGROUND: The cleavage of β-amyloid precursor protein (APP) generates multiple proteins: Soluble β-amyloid Precursor Protein Alpha (sAPPα), sAPPβ, and amyloid β (Aβ). Previous studies have shown that sAPPα and sAPPβ possess neurotrophic properties, whereas Aβ is neurotoxic. However, the underlying mechanism of the opposing effects of APP fragments remains poorly understood. In this study, we have investigated the mechanism of sAPPα-mediated neurotrophic effects. sAPPα and sAPPβ interact with p75 neurotrophin receptor (p75(NTR)), and sAPPα promotes neurite outgrowth. METHODS AND FINDINGS: First, we investigated whether APP fragments interact with p75(NTR), because full-length APP and Aβ have been shown to interact with p75(NTR) in vitro. Both sAPPα and sAPPβ were co-immunoprecipitated with p75(NTR) and co-localized with p75(NTR) on COS-7 cells. The binding affinity of sAPPα and sAPPβ for p75(NTR) was confirmed by enzyme-linked immunosorbent assay (ELISA). Next, we investigated the effect of sAPPα on neurite outgrowth in mouse cortical neurons. Neurite outgrowth was promoted by sAPPα, but sAPPα was uneffective in a knockdown of p75(NTR). CONCLUSION: We conclude that p75(NTR) is the receptor for sAPPα to mediate neurotrophic effects.

Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the chick retinotectal system. RGMa, one of the 3 isoforms found in mammals, is involved in laminar patterning, cephalic neural tube closure, axon guidance, and inhibition of axonal regeneration. In addition to its roles in the nervous system, RGMa plays a role in enhancing helper T-cell activation. Binding of RGM to its receptor, neogenin, is considered necessary to transduce these signals; however, information on the binding of RGM to neogenin is limited. Using co-immunoprecipitation studies, we have identified that the RGMa region required for binding to neogenin contains amino acids (aa) 259-295. Synthesized peptide consisting of aa 284-293 directly binds to the extracellular domain (ECD) of recombinant neogenin, and addition of this peptide inhibits RGMa-induced growth cone collapse in mouse cortical neurons. Thus, we propose that this peptide is a promising lead in finding reagents capable of inhibiting RGMa signaling.