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RNA Aptamer Probes as Optical Imaging Agents for the Detection of Amyloid Plaques
Optical imaging using multiphoton microscopy and whole body near infrared imaging has become a routine part of biomedical research. However, optical imaging methods rely on the availability of either small molecule reporters or genetically encoded fluorescent proteins, which are challenging and time consuming to develop. While directly labeled antibodies can also be used as imaging agents, antibodies are species specific, can typically not be tagged with multiple fluorescent reporters without interfering with target binding, and are bioactive, almost always eliciting a biological response and thereby influencing the process that is being studied. We examined the possibility of developing highly specific and sensitive optical imaging agents using aptamer technology. We developed a fluorescently tagged anti-Aβ RNA aptamer, β55, which binds amyloid plaques in both ex vivo human Alzheimer’s disease brain tissue and in vivo APP/PS1 transgenic mice. Diffuse β55 positive halos, attributed to oligomeric Aβ, were observed surrounding the methoxy-XO4 positive plaque cores. Dot blots of synthetic Aβ aggregates provide further evidence that β55 binds both fibrillar and non-fibrillar Aβ. The high binding affinity, the ease of probe development, and the ability to incorporate multiple and multimodal imaging reporters suggest that RNA aptamers may have complementary and perhaps advantageous properties compared to conventional optical imaging probes and reporters
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Metabolic correlates of prevalent mild cognitive impairment and Alzheimer's disease in adults with Down syndrome.
IntroductionDisruption of metabolic function is a recognized feature of late onset Alzheimer's disease (LOAD). We sought to determine whether similar metabolic pathways are implicated in adults with Down syndrome (DS) who have increased risk for Alzheimer's disease (AD).MethodsWe examined peripheral blood from 292 participants with DS who completed baseline assessments in the Alzheimer's Biomarkers Consortium-Down Syndrome (ABC-DS) using untargeted mass spectrometry (MS). Our sample included 38 individuals who met consensus criteria for AD (DS-AD), 43 who met criteria for mild cognitive impairment (DS-MCI), and 211 who were cognitively unaffected and stable (CS).ResultsWe measured relative abundance of 8,805 features using MS and 180 putative metabolites were differentially expressed (DE) among the groups at false discovery rate-corrected q< 0.05. From the DE features, a nine-feature classifier model classified the CS and DS-AD groups with receiver operating characteristic area under the curve (ROC AUC) of 0.86 and a two-feature model classified the DS-MCI and DS-AD groups with ROC AUC of 0.88. Metabolite set enrichment analysis across the three groups suggested alterations in fatty acid and carbohydrate metabolism.DiscussionOur results reveal metabolic alterations in DS-AD that are similar to those seen in LOAD. The pattern of results in this cross-sectional DS cohort suggests a dynamic time course of metabolic dysregulation which evolves with clinical progression from non-demented, to MCI, to AD. Metabolomic markers may be useful for staging progression of DS-AD
Presence of 5-hydroxyguaiacyl units as native lignin constituents in plants as seen by Py-GC/MS
Instituto de Recursos Naturales y Agrobiología de Sevilla, CSIC, P.O. Box 1052, 41080-Seville, Spain
2Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, E-28040 Madrid, Spain
E-mail address: [email protected] (J.C. del Río)The presence of 5-hydroxyguaiacyl moieties in the lignin from several plants has been assessed by Py-GC/MS. Different woody (eucalypt) and nonwoody (flax, hemp, kenaf, jute, sisal and abaca) angiosperms were selected for this study. The pyrolysis of whole fibers released lignin-derived products with p-hydroxyphenyl, guaiacyl and syringyl structures. Indeed, a series of compounds having a 5-hydroxyguaiacyl nuclei, including 3-methoxycatechol, 5-vinyl-3-methoxycatechol and 5-propenyl-3-methoxycatechol, were detected and identified in all samples, although in lower amounts than the normal guaiacyl and syringyl compounds. The analysis of the lignins isolated from the same plants also indicated the presence of 5-hydroxyguaiacyl moieties in the isolated lignins. These compounds are supposed to arise from the pyrolysis of 5-hydroxyguaiacyl moieties, which are supposed to be native constituents of lignin in plants forming benzodioxane substructures.This study has been supported by the Spanish Ministerio de Ciencia y Tecnología (MCyT) and FEDER funds (project AGL2005-01748) and the EU project BIORENEW (NMP2-CT-2006-026456). We thank CELESA S.A. (Tortosa, Spain) for providing the nonwoody plant samples, and ENCE for providing the eucalypt wood sample.Peer reviewe
Differential dopamine function in fibromyalgia
Approximately 30% of Americans suffer from chronic pain disorders, such as fibromyalgia (FM), which can cause debilitating pain. Many pain-killing drugs prescribed for chronic pain disorders are highly addictive, have limited clinical efficacy, and do not treat the cognitive symptoms reported by many patients. The neurobiological substrates of chronic pain are largely unknown, but evidence points to altered dopaminergic transmission in aberrant pain perception. We sought to characterize the dopamine (DA) system in individuals with FM. Positron emission tomography (PET) with [18F]fallypride (FAL) was used to assess changes in DA during a working memory challenge relative to a baseline task, and to test for associations between baseline D2/D3 availability and experimental pain measures. Twelve female subjects with FM and eleven female controls completed study procedures. Subjects received one FAL PET scan while performing a “2-back” task, and one while performing a “0-back” (attentional control, “baseline”) task. FM subjects had lower baseline FAL binding potential (BP) in several cortical regions relative to controls, including anterior cingulate cortex. In FM subjects, self-reported spontaneous pain negatively correlated with FAL BP in the left orbitofrontal cortex and parahippocampal gyrus. Baseline BP was significantly negatively correlated with experimental pain sensitivity and tolerance in both FM and CON subjects, although spatial patterns of these associations differed between groups. The data suggest that abnormal DA function may be associated with differential processing of pain perception in FM. Further studies are needed to explore the functional significance of DA in nociception and cognitive processing in chronic pain
Effect of environmental conditions on the relationship between solar induced fluorescence and gross primary productivity at an OzFlux grassland site
Recent studies have utilized coarse spatial and temporal resolution remotely sensed solar induced fluorescence (SIF) for modeling terrestrial gross primary productivity (GPP) at regional scales. Although these studies have demonstrated the potential of SIF, there have been concerns about the ecophysiological basis of the relationship between SIF and GPP in different environmental conditions. Launched in 2014, the Orbiting Carbon Observatory-2 (OCO-2) has enabled fine scale (1.3-by-2.5 km) retrievals of SIF that are comparable with measurements recorded at eddy covariance towers. In this study, we examine the effect of environmental conditions on the relationship of OCO-2 SIF with tower GPP over the course of a growing season at a well-characterized natural grassland site. Combining OCO-2 SIF and eddy covariance tower data with a canopy radiative transfer and an ecosystem model, we also assess the potential of OCO-2 SIF to constrain the estimates of V_(cmax), one of the most important parameters in ecosystem models. Based on the results, we suggest that although environmental conditions play a role in determining the nature of relationship between SIF and GPP, overall the linear relationship is more robust at ecosystem scale than the theory based on leaf-level processes might suggest. Our study also shows that the ability of SIF to constrain V_(cmax) is weak at the selected site
D2/D3 dopamine receptor binding with [F-18]fallypride correlates of executive function in medication-naïve patients with schizophrenia
Converging evidence indicates that the prefrontal cortex is critically involved in executive control and that executive dysfunction is implicated in schizophrenia. Reduced dopamine D2/D3 receptor binding potential has been reported in schizophrenia, and the correlations with neuropsychological test scores have been positive and negative for different tasks. The aim of this study was to examine the relation between dopamine D2/D3 receptor levels with frontal and temporal neurocognitive performance in schizophrenia. Resting-state 18F-fallypride positron emission tomography was performed on 20 medication-naïve and 5 previously medicated for brief earlier periods patients with schizophrenia and 19 age- and sex-matched healthy volunteers. Striatal and extra-striatal dopamine D2/D3 receptor levels were quantified as binding potential using fallypride imaging. Magnetic resonance images in standard Talairach position and segmented into gray and white matter were co-registered to the fallypride images, and the AFNI stereotaxic atlas was applied. Two neuropsychological tasks known to activate frontal and temporal lobe function were chosen, specifically the Wisconsin Card Sorting Test (WCST) and the California Verbal Learning Test (CVLT). Images of the correlation coefficient between fallypride binding and WCST and CVLT performance showed a negative correlation in contrast to positive correlations in healthy volunteers. The results of this study demonstrate that lower fallypride binding potential in patients with schizophrenia may be associated with better performance. Our findings are consistent with previous studies that failed to find cognitive improvements with typical dopamine-blocking medications
Drift Macroalgal Distribution In Northern Gulf of Mexico Seagrass Meadows
Drift macroalgae, often found in clumps or mats adjacent to or within seagrass beds, can increase the value of seagrass beds as habitat for nekton via added food resources and structural complexity. But, as algal biomass increases, it can also decrease light availability, inhibit faunal movements, smother benthic communities, and contribute to hypoxia, all of which can reduce nekton abundance. We quantified the abundance and distribution of drift macroalgae within seagrass meadows dominated by turtle grass Thalassia testudinum across the northern Gulf of Mexico and compared seagrass characteristics to macroalgal biomass and distribution. Drift macroalgae were most abundant in areas with higher seagrass shoot densities and intermediate canopy heights. We did not find significant relationships between algal biomass and point measures of salinity, temperature, or depth. The macroalgal genera Laurencia and Gracilaria were present across the study region, Agardhiella and Digenia were collected in the western Gulf of Mexico, and Acanthophora was collected in the eastern Gulf of Mexico. Our survey revealed drift algae to be abundant and widespread throughout seagrass meadows in the northern Gulf of Mexico, which likely influences the habitat value of seagrass ecosystems
Cerebrospinal fluid biomarkers of Alzheimer\u27s disease in a cohort of adults with Down syndrome
Introduction: Virtually all individuals with Down syndrome (DS) will develop Alzheimer\u27s disease (AD) pathology by age 40. Cerebrospinal fluid (CSF) biomarkers have characterized AD pathology in cohorts of late-onset AD (LOAD) and autosomal-dominant AD (ADAD). Few studies have evaluated such biomarkers in adults with DS.
Methods: CSF concentrations of amyloid beta (Aβ)40, Aβ42, tau, phospho-tau181 (p-tau), neurofilament light chain (NfL), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase-3-like protein 1 (YKL-40), alpha synuclein (αSyn), neurogranin (Ng), synaptosomal-associated protein 25 (SNAP-25), and visinin-like protein 1 (VILIP-1) were assessed in CSF from 44 adults with DS from the Alzheimer\u27s Biomarker Consortium-Down Syndrome study. Biomarker levels were evaluated by cognitive status, age, and apolipoprotein E gene (
Results: Biomarker abnormalities indicative of amyloid deposition, tauopathy, neurodegeneration, synaptic dysfunction, and neuroinflammation were associated with increased cognitive impairment. Age and
Discussion: The profile of many established and emerging CSF biomarkers of AD in a cohort of adults with DS was similar to that reported in LOAD and ADAD, while some differences were observed
Relationship Between Rate and Composition of Mass Gain During Overfeeding Plus Resistance Training
A common goal among athletes is to gain additional body mass (BM), particularly fat-free mass (FFM), in order to improve muscle strength, power, and overall performance. Athletes typically undergo BM accretion over a specific period of time in conjunction with high-volume resistance training (RT) in order to preferentially gain FFM and promote concomitant muscular performance improvements. PURPOSE: The purpose of this study was to examine the relationship between the rate of BM gain and the proportion of BM gained as FFM versus fat mass (FM) during a 6-week period of overfeeding and resistance training. METHODS: 21 resistance-trained males (mean ± SD: age = 22.6 ± 2.5 years; height = 177.8 ± 6.8 cm; BM = 73.3 ± 12.3 kg, body fat % = 14.8 ± 5.1%, bench press [BP] 1-repetition maximum [1RM] = 1.3 ± 0.3, leg press [LP] 1RM = 3.3 ± 0.9) were recruited and assigned to 6 weeks of RT for 3-days/week and instructed to consume a high-calorie protein/carbohydrate supplement daily. Prior to the intervention, participants performed 1RM tests for the BP and LP exercises to assess training status, with the minimum requirement for study participation being BP 1RM ≥ 1.0xBM and LP 1RM ≥ 2.0xBM. At baseline and post-intervention, body composition assessments were performed using dual-energy x-ray absorptiometry (DXA), air displacement plethysmography (ADP), and bioimpedance spectroscopy (BIS) in order to produce a criterion 4-compartment model. Simple linear regression was performed to determine if the relative rate of mass gain predicted the composition of mass gain (calculated as the change in fat-free mass divided by the change in body mass). Assumptions of normality, outliers, homogeneity, and independence were examined and addressed as needed. RESULTS: The change in BM, FM, and FFM were (mean ± SD) 5.6 ± 2.3%, 1.3 ± 14.8%, and 6.0 ± 2.1%, respectively. In the regression model, the relative rate of mass gain significantly predicted the composition of mass gain (β: -0.81 [-1.11, -0.50], mean [95% confidence interval]). Based on these data, for every 1% increase in the rate of relative mass gain, the percent of mass gained as FFM decreased by approximately 10% (with a 95% confidence interval of -6 to -13%). A rate of mass gain of 0.93%/week corresponded to 100% of mass being gained as FFM, with slower rates allowing for simultaneous FFM gain and FM loss. CONCLUSION: For individuals who are moderately well-trained with respect to resistance training, a rate of BM gain of ~1%/week may allow for nearly all mass to be gained as FFM while slower rates may allow for simultaneous increases in FFM and decreases in FM
Legacy extragalactic UV survey (LEGUS) with the hubble space telescope. I. Survey description
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