221 research outputs found
Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer's disease.
Autosomal dominant Alzheimer's disease (ADAD) is a small subset of Alzheimer's disease that is genetically determined with 100% penetrance. It provides a valuable window into studying the course of pathologic processes that leads to dementia. Arterial spin labeling (ASL) MRI is a potential AD imaging marker that non-invasively measures cerebral perfusion. In this study, we investigated the relationship of cerebral blood flow measured by pseudo-continuous ASL (pCASL) MRI with measures of cerebral metabolism (FDG PET) and amyloid deposition (Pittsburgh Compound B (PiB) PET). Thirty-one participants at risk for ADAD (age 39 ± 13 years, 19 females) were recruited into this study, and 21 of them received both MRI and FDG and PiB PET scans. Considerable variability was observed in regional correlations between ASL-CBF and FDG across subjects. Both regional hypo-perfusion and hypo-metabolism were associated with amyloid deposition. Cross-sectional analyses of each biomarker as a function of the estimated years to expected dementia diagnosis indicated an inverse relationship of both perfusion and glucose metabolism with amyloid deposition during AD development. These findings indicate that neurovascular dysfunction is associated with amyloid pathology, and also indicate that ASL CBF may serve as a sensitive early biomarker for AD. The direct comparison among the three biomarkers provides complementary information for understanding the pathophysiological process of AD
CemOrange2 fusions facilitate multifluorophore subcellular imaging in C. elegans
Due to its ease of genetic manipulation and transparency, Caenorhabditis elegans (C. elegans) has become a preferred model system to study gene function by microscopy. The use of Aequorea victoria green fluorescent protein (GFP) fused to proteins or targeting sequences of interest, further expanded upon the utility of C. elegans by labeling subcellular structures, which enables following their disposition during development or in the presence of genetic mutations. Fluorescent proteins with excitation and emission spectra different from that of GFP accelerated the use of multifluorophore imaging in real time. We have expanded the repertoire of fluorescent proteins for use in C. elegans by developing a codon-optimized version of Orange2 (CemOrange2). Proteins or targeting motifs fused to CemOrange2 were distinguishable from the more common fluorophores used in the nematode; such as GFP, YFP, and mKate2. We generated a panel of CemOrange2 fusion constructs, and confirmed they were targeted to their correct subcellular addresses by colocalization with independent markers. To demonstrate the potential usefulness of this new panel of fluorescent protein markers, we showed that CemOrange2 fusion proteins could be used to: 1) monitor biological pathways, 2) multiplex with other fluorescent proteins to determine colocalization and 3) gain phenotypic knowledge of a human ABCA3 orthologue, ABT-4, trafficking variant in the C. elegans model organism
Recent secular trends in child and adolescent physical activity and sedentary behavior internationally : analyses of active healthy kids global alliance global matrices 1.0 to 4.0
We examined recent global secular trends in 5 indicators of child and adolescent physical activity and sedentary behavior (Overall Physical Activity, Organized Sport and Physical Activity, Active Play, Active Transportation, and Sedentary Behavior) and 4 influences on these (Family and Peers, School, Community and Environment, and Government). Active Healthy Kids Global Alliance letter grades (A+ to F) were assigned numbers from 15 to 2, with 0 assigned for missing/incomplete grades. Trends from Active Healthy Kids Global Alliance Global Matrices 1.0 (2014) to 4.0 (2022) were analyzed using linear mixed-effects models with level of economic development and gender inequity considered as potential moderators. Report card grades were generally relatively stable. Trends generally did not differ significantly by level of economic development (except for Active Transportation and Active Play), but gender inequality did significantly moderate trends for most of the indicators, with higher gender inequality associated with more adverse changes in grades. The number of "incomplete" grades decreased over time, but this did not reach statistical significance. While trends varied within and between countries, physical activity and sedentary behaviors, and the influences on these behaviors globally, were relatively stable over the past decade or so, albeit at undesirable levels
Triggers of acute attacks of gout, does age of gout onset matter?: a primary care based cross-sectional study
Objectives
To determine the proportion of people with gout who self-report triggers of acute attacks; identify the commonly reported triggers, and examine the disease and demographic features associated with self-reporting any trigger(s) of acute attacks of gout.
Methods
Individuals with gout were asked to fill a questionnaire enquiring about triggers that precipitated their acute gout attacks. Binary logistic regression was used to compute odds ratio (OR) and 95% confidence intervals (CI) to examine the association between having ≥1 self-reported trigger of acute gout and disease and demographic risk factors and to adjust for covariates. All statistical analyses were performed using STATA.
Results
550 participants returned completed questionnaires. 206 (37.5%) reported at least one trigger of acute attacks, and less than 5% reported >2 triggers. Only 28.73% participants reported that their most recent gout attack was triggered by dietary or lifestyle risk factors. The most frequently self-reported triggers were alcohol intake (14.18%), red-meat or sea-food consumption (6%), dehydration (4.91%), injury or excess activity (4.91%), and excessively warm or cold weather (4.36% and 5.45%). Patients who had onset of gout before the age of 50 years were significantly more likely to identify a trigger for precipitating their acute gout attacks (aOR (95%CI) 1.73 (1.12–2.68) after adjusting for covariates.
Conclusion
Most people with gout do not identify any triggers for acute attacks, and identifiable triggers are more common in those with young onset gout. Less than 20% people self-reported acute gout attacks from conventionally accepted triggers of gout e.g. alcohol, red-meat intake, while c.5% reported novel triggers such as dehydration, injury or physical activity, and weather extremes
Prorenin anno 2008
For many years, prorenin has been considered to be nothing more than the inactive precursor of renin. Yet, its elevated levels in diabetic subjects with microvascular complications and its extrarenal production at various sites in the body suggest otherwise. This review discusses the origin, regulation, and enzymatic activity of prorenin, its role during renin inhibition, and the angiotensin-dependent and angiotensin-independent consequences of its binding to the recently discovered (pro)renin receptor. The review ends with the concept that prorenin rather than renin determines tissue angiotensin generation
Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition
The effect of compressive strain on the Raman modes of the dry and hydrated BaCe0.8Y0.2O3 proton conductor
The BaCe0.8Y0.2O3-{\delta} proton conductor under hydration and under
compressive strain has been analyzed with high pressure Raman spectroscopy and
high pressure x-ray diffraction. The pressure dependent variation of the Ag and
B2g bending modes from the O-Ce-O unit is suppressed when the proton conductor
is hydrated, affecting directly the proton transfer by locally changing the
electron density of the oxygen ions. Compressive strain causes a hardening of
the Ce-O stretching bond. The activation barrier for proton conductivity is
raised, in line with recent findings using high pressure and high temperature
impedance spectroscopy. The increasing Raman frequency of the B1g and B3g modes
thus implies that the phonons become hardened and increase the vibration energy
in the a-c crystal plane upon compressive strain, whereas phonons are relaxed
in the b-axis, and thus reveal softening of the Ag and B2g modes. Lattice
toughening in the a-c crystal plane raises therefore a higher activation
barrier for proton transfer and thus anisotropic conductivity. The experimental
findings of the interaction of protons with the ceramic host lattice under
external strain may provide a general guideline for yet to develop epitaxial
strained proton conducting thin film systems with high proton mobility and low
activation energy
Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.
The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD
Phosphorylation Regulates SIRT1 Function
BACKGROUND: SIR2 is an NAD(+)-dependent deacetylase [1]-[3] implicated in the regulation of lifespan in species as diverse as yeast [4], worms [5], and flies [6]. We previously reported that the level of SIRT1, the mammalian homologue of SIR2 [7], [8], is coupled to the level of mitotic activity in cells both in vitro and in vivo[9]. Cells from long-lived mice maintained SIRT1 levels of young mice in tissues that undergo continuous cell replacement by proliferating stem cells. Changes in SIRT1 protein level were not associated with changes in mRNA level, suggesting that SIRT1 could be regulated post-transcriptionally. However, other than a recent report on sumoylation [10] and identification of SIRT1 as a nuclear phospho-protein by mass spectrometry [11], post-translational modifications of this important protein have not been reported. METHODOLOGY/PRINCIPAL FINDINGS: We identified 13 residues in SIRT1 that are phosphorylated in vivo using mass spectrometry. Dephosphorylation by phosphatases in vitro resulted in decreased NAD(+)-dependent deacetylase activity. We identified cyclinB/Cdk1 as a cell cycle-dependent kinase that forms a complex with and phosphorylates SIRT1. Mutation of two residues phosphorylated by Cyclin B/Cdk1 (threonine 530 and serine 540) disturbs normal cell cycle progression and fails to rescue proliferation defects in SIRT1-deficient cells [12], [13]. CONCLUSIONS/SIGNIFICANCE: Pharmacological manipulation of SIRT1 activity is currently being tested as a means of extending lifespan in mammals. Treatment of obese mice with resveratrol, a pharmacological activator of SIRT1, modestly but significantly improved longevity and, perhaps more importantly, offered some protection against the development of type 2 diabetes mellitus and metabolic syndrome [14]-[16]. Understanding the endogenous mechanisms that regulate the level and activity of SIRT1, therefore, has obvious relevance to human health and disease. Our results identify phosphorylation by cell cycle dependent kinases as a major mechanism controlling the level and function of this sirtuin and complement recent reports of factors that inhibit [17], [18] and activate [19] SIRT1 by protein-protein interactions
Resistance of Trichoplusia ni to Bacillus thuringiensis Toxin Cry1Ac Is Independent of Alteration of the Cadherin-Like Receptor for Cry Toxins
Alteration of binding sites for Bacillus thuringiensis (Bt) toxins in insect midgut is the major mechanism of high-level resistance to Bt toxins in insects. The midgut cadherin is known to be a major binding protein for Bt Cry1A toxins and linkage of Bt-resistance to cadherin gene mutations has been identified in lepidopterans. The resistance to Bt toxin Cry1Ac evolved in greenhouse populations of Trichoplusia ni has been identified to be associated with the down-regulation of an aminopeptidase N (APN1) gene by a trans-regulatory mechanism and the resistance gene has been mapped to the locus of an ABC transporter (ABCC2) gene. However, whether cadherin is also involved with Cry1Ac-resistance in T. ni requires to be understood. Here we report that the Cry1Ac-resistance in T. ni is independent of alteration of the cadherin. The T. ni cadherin cDNA was cloned and the cadherin sequence showed characteristic features known to cadherins from Lepidoptera. Various T. ni cadherin gene alleles were identified and genetic linkage analysis of the cadherin alleles with Cry1Ac-resistance showed no association of the cadherin gene with the Cry1Ac-resistance in T. ni. Analysis of cadherin transcripts showed no quantitative difference between the susceptible and Cry1Ac-resistant T. ni larvae. Quantitative proteomic analysis of midgut BBMV proteins by iTRAQ-2D-LC-MS/MS determined that there was no quantitative difference in cadherin content between the susceptible and the resistant larvae and the cadherin only accounted for 0.0014% (mol%) of the midgut BBMV proteins, which is 1/300 of APN1 in molar ratio. The cadherin from both the susceptible and resistant larvae showed as a 200-kDa Cry1Ac-binding protein by toxin overlay binding analysis, and nano-LC-MS/MS analysis of the 200-kDa cadherin determined that there is no quantitative difference between the susceptible and resistant larvae. Results from this study indicate that the Cry1Ac-resistance in T. ni is independent of cadherin alteration
- …