Adult onset cardiac dilatation in a transgenic mouse line with Galβ1,3GalNAc α2,3-sialyltransferase II (ST3Gal-II) transgenes: a new model for dilated cardiomyopathy

Sugar chain abnormalities in glycolipids and glycoproteins are associated with various diseases. Here, we report an adult onset cardiac dilatation in a transgenic mouse line with Galβ1,3GalNAc α2,3-sialyltransferase II (ST3Gal-II) transgenes. The transgenic hearts at the end-stage, at around 7 months old, were enlarged, with enlarged cavities and thin, low-tensile walls, typical of dilated cardiomyopathy. Although no apparent change was found in heart gangliosides, glycosylation of heart proteins was altered. Interestingly, sugar moieties not directly related to the ST3Gal-II catalytic reaction were also changed. Significant increases in calreticulin and calnexin were observed in hearts of the transgenic mice. These results suggest that expression of ST3Gal-II transgenes induces abnormal protein glycosylation, which disorganizes the endoplasmic/sarcoplasmic reticulum quality control system and elevates the calreticulin/calnexin level, resulting in suppression of cardiac function. The transgenic mice showed 100% incidence of adult onset cardiac dilatation, suggesting great potential as a new model for dilated cardiomyopathy

Canola and hydrogenated soybean oils accelerate ectopic bone formation induced by implantation of bone morphogenetic protein in mice

AbstractCanola oil (Can) and hydrogenated soybean oil (H2-Soy) are commonly used edible oils. However, in contrast to soybean oil (Soy), they shorten the survival of stroke-prone spontaneously hypertensive (SHRSP) rats. It has been proposed that the adverse effects of these oils on the kidney and testis are caused at least in part by dihydro-vitamin K (VK) 1 in H2-Soy and unidentified component(s) in Can. Increased intake of dihydro-VK1 is associated with decreased tissue VK2 levels and bone mineral density in rats and humans, respectively. The aim of the present study was to determine the effects of these oils on bone morphogenetic protein (BMP)-induced ectopic bone formation, which is promoted by VK2 deficiency, in relation to the role of VK in the γ-carboxylation of osteocalcin and matrix Gla protein. A crude extract of BMPs was implanted into a gap in the fascia of the femoral muscle in 5-week-old mice maintained on a Soy, Can, or H2-Soy diet. Newly formed bone volume, assessed by three-dimensional X-ray micro-computed tomography and three-dimensional reconstruction imaging for bone, was 4-fold greater in the Can and H2-Soy groups than in the Soy group. The plasma carboxylated osteocalcin (Gla-OC) and total OC (Gla-OC plus undercarboxylated osteocalcin [Glu-OC]) levels were significantly lower in the Can group than in the Soy group (p < 0.05). However, these levels did not significantly differ between the H2-Soy and Soy groups. The plasma Gla-OC/Glu-OC ratio in the Can and H2-Soy groups was significantly lower (in Can; p = 0.044) or was almost significantly lower (in H2-Soy; p = 0.053) than that in the Soy group. In conclusion, Can and H2-Soy accelerated BMP-induced bone formation in mice to a greater extent than Soy. Further research is required to evaluate whether the difference in accelerated ectopic bone formation is associated with altered levels of VK2 and VK-dependent protein(s) among the three dietary groups

Comparison of six antibody assays and two combination assays for COVID-19

[Introduction] In this work, six SARS-CoV-2-specific antibody assays were evaluated, namely, two pan-immunoglobulin (pan-Ig) assays [Roche Elecsys Anti-SARS-CoV-2 (named "Elecsys" in this study) and the PerkinElmer SuperFlex™ Anti-SARS-CoV-2 Ab Assay (SuperFlex_Ab)], two IgM assays [SuperFlex™ Anti-SARS-CoV-2 IgM Assay (SuperFlex_IgM) and YHLO iFlash-SARS-CoV-2 IgM (iFlash_IgM)], and two IgG assays [SuperFlex™ Anti-SARS-CoV-2 IgG Assay (SuperFlex_IgG) and iFlash-SARS-CoV-2 IgG (iFlash_IgG)]. Combination assays of SuperFlex™ (SuperFlex_any) and iFlash (iFlash_any) were also evaluated. [Methods] A total of 438 residual serum samples from 54 COVID-19 patients in the COVID-19 group and 100 samples from individuals without evidence of SARS-CoV-2 infection in the negative control group were evaluated. [Results] In the early stage of COVID-19 infection, within 14 days of symptom onset, the seropositive rate was lower than that of the late stage 15 days after onset (65.4% vs 99.6%). In the total period, the pan-Ig and IgG assays had higher sensitivity (90.8–95.3%) than the IgM assays (36.5–40.7%). SuperFlex_Ab and SuperFlex_any had higher sensitivity than Elecsys and SuperFlex_IgG (p < 0.05). The specificity of all the assays was 100%, except for SuperFlex_IgM (99.0%). The concordance rate between each assay was higher (96.4–100%) in the late stage than in the early stage (77.4–98.1%). [Conclusion] For the purpose of COVID-19 diagnosis, antibody testing should be performed 15 days after onset. For the purpose of epidemiological surveillance, highly sensitive assays should be used as much as possible, such as SuperFlex_Ab, iFlash_IgG and their combination. IgM assays were not suitable for these purposes

Effect of short-stay service use on stay-at-home duration for elderly with certified care needs: Analysis of long-term care insurance claims data in Japan

ObjectiveHome independence is an important issue for the elderly in many countries and cultures. The aim of this study was to examine the effect of short-stay service use on stay-at-home duration for elderly people by level of care need under the Japanese long-term care insurance system.MethodsWe analyzed anonymous, Ministry of Health, Labour and Welfare of Japan Long-Term Care Insurance claims data from Ibaraki Prefecture. All participants were certified as eligible for long-term care insurance and had moved into a facility under long-term care insurance after certification between April 2006 and March 2012. Data was analyzed for 2,454 participants aged 65 years or older who entered residential care at least 1 month after initial use of care services. The participants were divided into 2 groups (low- and high-care need), depending on their required level of care. Cox proportional hazard modeling was used to calculate the adjusted hazard ratio (HR) of residential care admission after initial use of care services.ResultsUse of short-stay services was positively correlated to delay of residential care admission compared to non-use in the low-care need group (HR; 0.834, 95% confidence interval (CI); 0.740–0.939). In the high-care need group, however, use of short-stay services was somewhat correlated with earlier admission (HR; 1.254, 95% CI; 1.084–1.451).ConclusionsThe results of this study show that appropriate timing short-stay service use is necessary for the elderly to stay at home longer

Explaining the decline in coronary heart disease mortality rates in Japan: Contributions of changes in risk factors and evidence-based treatments between 1980 and 2012

Background We aimed to quantify contributions of changes in risks and uptake of evidence-based treatment to coronary heart disease (CHD) mortality trends in Japan between 1980 and 2012. Methods We conducted a modelling study for the general population of Japan aged 35 to 84 years using the validated IMPACT model incorporating data sources like Vital Statistics. The main outcome was difference in the number of observed and expected CHD deaths in 2012. Results From 1980 to 2012, age-adjusted CHD mortality rates in Japan fell by 61%, resulting in 75,700 fewer CHD deaths in 2012 than if the age and sex-specific mortality rates had remained unchanged. Approximately 56% (95% uncertainty interval [UI]: 54–59%) of the CHD mortality decrease, corresponding to 42,300 (40,900–44,700) fewer CHD deaths, was attributable to medical and surgical treatments. Approximately 35% (28–41%) of the mortality fall corresponding to 26,300 (21,200–31,000) fewer CHD deaths, was attributable to risk factor changes in the population, 24% (20–29%) corresponding to 18,400 (15,100–21,900) fewer and 11% (8–14%) corresponding to 8400 (60,500–10,600) fewer from decreased systolic blood pressure (8.87 mm Hg) and smoking prevalence (14.0%). However, increased levels of cholesterol (0.28 mmol/L), body mass index (BMI) (0.68 kg/m2), and diabetes prevalence (1.6%) attenuated the decrease in mortality by 2% (1–3%), 3% (2–3%), and 4% (1–6%), respectively. Conclusions Japan should continue their control policies for blood pressure and tobacco, and build a strategy to control BMI, diabetes, and cholesterol levels to prevent further CHD deaths

Enhanced stability of hippocampal place representation caused by reduced magnesium block of NMDA receptors in the dentate gyrus

BACKGROUND: Voltage-dependent block of the NMDA receptor by Mg(2+) is thought to be central to the unique involvement of this receptor in higher brain functions. However, the in vivo role of the Mg(2+) block in the mammalian brain has not yet been investigated, because brain-wide loss of the Mg(2+) block causes perinatal lethality. In this study, we used a brain-region specific knock-in mouse expressing an NMDA receptor that is defective for the Mg(2+) block in order to test its role in neural information processing. RESULTS: We devised a method to induce a single amino acid substitution (N595Q) in the GluN2A subunit of the NMDA receptor, specifically in the hippocampal dentate gyrus in mice. This mutation reduced the Mg(2+) block at the medial perforant path–granule cell synapse and facilitated synaptic potentiation induced by high-frequency stimulation. The mutants had more stable hippocampal place fields in the CA1 than the controls did, and place representation showed lower sensitivity to visual differences. In addition, behavioral tests revealed that the mutants had a spatial working memory deficit. CONCLUSIONS: These results suggest that the Mg(2+) block in the dentate gyrus regulates hippocampal spatial information processing by attenuating activity-dependent synaptic potentiation in the dentate gyrus

Reconstruction of Insulin Signal Flow from Phosphoproteome and Metabolome Data

SummaryCellular homeostasis is regulated by signals through multiple molecular networks that include protein phosphorylation and metabolites. However, where and when the signal flows through a network and regulates homeostasis has not been explored. We have developed a reconstruction method for the signal flow based on time-course phosphoproteome and metabolome data, using multiple databases, and have applied it to acute action of insulin, an important hormone for metabolic homeostasis. An insulin signal flows through a network, through signaling pathways that involve 13 protein kinases, 26 phosphorylated metabolic enzymes, and 35 allosteric effectors, resulting in quantitative changes in 44 metabolites. Analysis of the network reveals that insulin induces phosphorylation and activation of liver-type phosphofructokinase 1, thereby controlling a key reaction in glycolysis. We thus provide a versatile method of reconstruction of signal flow through the network using phosphoproteome and metabolome data

Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms

Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.ArticleeNeuro.4(2):e0250(2017)journal articl