Gender effect on the accumulation of hyperphosphorylated tau in the brain of locus-ceruleus-injured APP-transgenic mouse

Locus ceruleus (LC) neurons are preferentially and initially affected in Alzheimer disease (AD); however, the impact of the loss of LC neurons on the pathological sequence of AD, including amyloid β-protein (Aβ) deposition and neurofibrillary tangle formation, has not been elucidated. In this study, we chemically injured LC neurons of the brains of familial AD-related amyloid precursor protein (APP)-transgenic mice using the LC-noradrenergic neuron-selective neurotoxin, N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP4). The levels of noradrenaline significantly decreased in the cerebral cortices of DSP4-treated mice. The deposition of amyloid fibrils was biochemically observed in the APP-transgenic mouse brains; however, those levels were not significantly altered following DSP4 treatment. In contrast, the levels of accumulated hyperphosphorylated tau markedly increased in the cerebral cortices of DSP4-treated female but not male APP-transgenic mice. Our results suggest that innervation from LC neurons and testosterone secretion are potent and mutually independent suppressors of amyloid-related accumulation of hyperphosphorylated tau in the brain.     

VHL-box and SOCS-box domains determine binding specificity for Cul2-Rbx1 and Cul5-Rbx2 modules of ubiquitin ligases

The ECS (Elongin B/C-Cul2/Cul5-SOCS-box protein) complex is a member of a family of ubiquitin ligases that share a Cullin-Rbx module. SOCS-box proteins recruit substrates to the ECS complex and are linked to Cullin-Rbx via Elongin B/C. VHL has been implicated as a SOCS-box protein, but lacks a C-terminal sequence (downstream of the BC box) of the SOCS box. We now show that VHL specifically interacts with endogenous Cul2-Rbx1 in mammalian cells, whereas SOCS-box proteins associate with Cul5-Rbx2. We also identify LRR-1 and FEM1B as proteins that share a region of homology with VHL (the VHL box, including the BC box and downstream residues) and associate with Cul2-Rbx1. ECS complexes can thus be classified into two distinct protein assemblies, that is, those that contain a subunit with a VHL box (composed of the BC box and a downstream Cul2 box) that interacts with Cul2-Rbx1, and those that contain a subunit with a SOCS box (BC box and downstream Cul5 box) that interacts with Cul5-Rbx2. Domain-swapping analyses showed that the specificity of interaction of VHL-box and SOCS-box proteins with Cullin-Rbx modules is determined by the Cul2 and Cul5 boxes, respectively. Finally, RNAi-mediated knockdown of the Cul2-Rbx1 inhibited the VHL-mediated degradation of HIF-2alpha, whereas knockdown of Cul5-Rbx2 did not affect it. These data suggest that the functions of the Cul2-Rbx1 and Cul5-Rbx2 modules are distinct.     

Inhibition of protein kinases A and C demonstrates dual modes of response in human eosinophils stimulated with platelet-activating factor

BACKGROUND: Platelet-activating factor (PAF) is a potent stimulator of human eosinophils involved in the pathogenesis of allergic diseases. However, intracellular signaling mechanisms in eosinophils involving the PAF receptor are incompletely understood. OBJECTIVE: We sought to determine the roles of protein kinase C (PKC) and cyclic AMP-dependent protein kinase (protein kinase A [PKA]) in signaling pathways of human eosinophils stimulated with PAF. METHODS: After pretreatment with a PKC inhibitor, bisindolylmaleimide I, or a PKA inhibitor, H89, we investigated PAF-evoked functions, such as CD11b expression, cellular adhesion, superoxide anion generation, and degranulation in human eosinophils. RESULTS: Preincubation of eosinophils with bisindolylmaleimide I resulted in enhancement of upregulated CD11b expression and adhesion induced by PAF. H89 pretreatment also enhanced PAF-induced cellular adhesion. Superoxide anion generation and degranulation were suppressed by means of inhibition of either PKC or PKA. CONCLUSION: PKC and PKA negatively regulate PAF-induced CD11b upregulation and cellular adhesion but promote eosinophil effector functions, such as superoxide anion generation and degranulation. PKC and PKA modulate PAF-evoked intracellular signaling of the eosinophil function in distinct ways.     

Pregnancy-induced hypertension is associated with maternal history and a risk of cardiovascular disease in later life: A Japanese cross-sectional study

Objective

To clarify the associations between pregnancy-induced hypertension (PIH) with heritability of PIH from mother to daughter and the risk of cardiovascular disease in later life in Japanese women.

Study design

The Japan Nurses’ Health Study (JNHS) is a cohort study of Japanese women's health. Data from the JNHS baseline survey between 2001 and 2007 were used to conduct a cross-sectional analysis. Of the 49,927 respondents in the baseline survey, 10,456 parous women who were ≥45 years old at baseline were included in the analysis.

Main outcome measures

The age-adjusted odds ratio (OR) of PIH in women whose mother had a history of PIH, and the age-adjusted OR of PIH in participants for hypertension, hypercholesterolemia and diabetes mellitus (DM).

Results

The age-adjusted OR of PIH was 2.72 (95% confidence interval [CI]: 2.14–3.46) in women whose mother had a history of PIH compared with those whose mother did not have PIH. PIH was a risk factor for hypertension (age adjusted OR: 2.85, 95% CI: 2.45–3.11), hypercholesterolemia (age-adjusted OR: 1.49, 95% CI: 1.29–1.72) and DM (age-adjusted OR: 1.53, 95% CI: 1.11–2.11), as determined by logistic regression analysis.

Conclusions

In Japanese women, the risk of PIH is approximately 2.7-fold greater in those whose mothers also had PIH compared with those whose mothers did not. PIH is a risk factor for hypertension, hypercholesterolemia, and diabetes mellitus in later life.     

Iliotibial band irritation caused by the EndoButton after anatomic double-bundle anterior cruciate ligament reconstruction: Report of two cases

Two patients underwent arthroscopic anatomic double-bundle anterior cruciate ligament (ACL) reconstruction using the EndoButton for femoral fixation. The femoral tunnels were created by the inside-out technique through a far anteromedial portal. The patients postoperatively developed moderate lateral knee pain without instability. At the second-look arthroscopic evaluation, the two EndoButtons were removed. Both patients were completely asymptomatic several months after implant removal, implying that the EndoButtons caused the mechanical irritation in the iliotibial band. This is the first report describing removal of EndoButtons because of pain caused by friction with the iliotibial band. In anatomic ACL reconstruction, if the femoral tunnel exit is positioned near the lateral femoral epicondyle, care should be taken to prevent iliotibial band friction syndrome that could result because of the EndoButton.     

Lower respiratory tract infections and gastrointestinal infections among mature babies in Japan

Background: Epidemiologic evidence regarding the background factors of childhood infections in Japan is scarce. The aim of the present study was therefore to investigate the rates and associated factors of hospitalization for lower respiratory tract infections (LRTI) and gastrointestinal infections (GII) among children with birthweight ≥2500 g and ≥37 weeks of gestational age. Method: The data for the study were collected at 18‐month health checkups in one city in Japan. The community database included information on the main outcome (past hospitalization) and 16 host, environmental, and parenting factors. The Kaplan–Meier method and log–rank test were used to determine sex differences in hospital admission for infection, and the Cox regression model to analyze sex‐specific factors associated with the hospitalization. Results: The proportion of children who were admitted to hospital before their 18‐month checkup was 7.1% for LRTI and 2.2% for GII. Hospital admission for LRTI among boys was higher than girls. Multivariate analysis indicated the following LRTI‐associated factors: child‐care attendance (hazard ratio [HR]= 1.97) and three or more adults living together (HR = 2.63) for boys; and child‐care attendance (HR = 4.30) and two or more children living together (HR = 4.57) for girls. GII‐associated factors were maternal age <25 years (HR = 3.45) for boys, and hand washing by caregivers after lavatory use and diaper changing (HR = 6.93) for girls. Conclusions: One out of 11 children was hospitalized because of LRTI or GII during their first 18 months, which was associated with a biologic factor (sex), environmental factors (child‐care attendance and family size), and parenting practices (shorter duration of exclusive breast‐feeding and caregivers' unfavorable hygiene practices).     

Elevated CO2 promotes satellite stomata production in young cotyledons of Arabidopsis thaliana

Stomata are tiny pores on plant leaves and stems surrounded by a pair of differentiated epidermal cells known as guard cells. Plants undergo guard cell differentiation in response to environmental cues, including atmospheric CO₂. To quantitatively evaluate stomatal development in response to elevated CO₂, imaging analysis of stomata was conducted using young cotyledons of Arabidopsis thaliana grown under ambient (380 ppm) and elevated (1,000 ppm) CO₂ conditions. Our analysis revealed that treatment with 1,000 ppm CO₂ did not affect stomatal numbers on abaxial sides of cotyledons but increased cotyledon area, resulting in decreased stomatal density, 7 days after germination. Interestingly, this treatment also perturbed the uniform distribution of stomata via excess satellite stomata and stomatal precursor cells. We used overexpression lines of the DNA replication licensing factor gene CDC6, a reported positive regulator of satellite stomata production. CDC6 overexpression decreased the speed of cotyledon expansion, even under treatment with 1,000 ppm CO₂, possibly by suppressing pavement cell maturation. In contrast, treatment with 1,000 ppm CO₂ induced stomatal distribution changes in the overexpressor. These results suggest that treatment with 1,000 ppm CO₂ enhances both cotyledon expansion and satellite stomata production via independent pathways, at least in young cotyledons of A. thaliana.