RNA interference (RNAi) is a mechanism for interfering with gene expression through the action of small, non-coding RNAs. We previously constructed a short-hairpin-loop RNA (shRNA) encoding library that is random at the nucleotide level . In this library, the stems of the hairpin are completely complementary. To improve the potency of initial hits, and therefore signal-to-noise ratios in library screening, as well as to simplify hit-sequence retrieval by PCR, we constructed a second-generation library in which we introduced random mismatches between the two halves of the stem of each hairpin, on a random template background. In a screen for shRNAs that protect an interleukin-3 (IL3) dependent cell line from IL3 withdrawal, our second-generation library yielded hit sequences with significantly higher potencies than those from the first-generation library in the same screen. Our method of random mutagenesis was effective for a random template and is likely suitable, therefore, for any DNA template of interest. The improved potency of our second-generation library expands the range of possible unbiased screens for small-RNA therapeutics and biologic tools.
Nearly all aptamers identified so far for any given target molecule have been specific for the same binding site (epitope). The most notable exception to the 1 aptamer per target molecule rule is the pair of DNA aptamers that bind to different epitopes of thrombin. This communication refutes the suggestion that these aptamers exist because different partitioning methods were used when they were selected. The possibility that selection of these aptamers was biased by conflicting secondary structures was also investigated and found not to contribute. The preparation of protein-coated magnetic beads for systematic evolution of ligands by exponential enrichment (SELEX) and the different specificities of the thrombin aptamers for the α and β forms of thrombin are also reported.
The European protected-area network will cease to be efficient for biodiversity conservation, particularly in the Mediterranean region, if species are driven out of protected areas by climate warming. Yet, no empirical evidence of how climate change influences ecological communities in Mediterranean nature reserves really exists. Here, we examine long-term (1998–2011/2012) and short-term (2011–2012) changes in the butterfly fauna of Dadia National Park (Greece) by revisiting 21 and 18 transects in 2011 and 2012 respectively, that were initially surveyed in 1998. We evaluate the temperature trend for the study area for a 22-year-period (1990–2012) in which all three butterfly surveys are included. We also assess changes in community composition and species richness in butterfly communities using information on (a) species’ elevational distributions in Greece and (b) Community Temperature Index (calculated from the average temperature of species' geographical ranges in Europe, weighted by species' abundance per transect and year). Despite the protected status of Dadia NP and the subsequent stability of land use regimes, we found a marked change in butterfly community composition over a 13 year period, concomitant with an increase of annual average temperature of 0.95°C. Our analysis gave no evidence of significant year-to-year (2011–2012) variability in butterfly community composition, suggesting that the community composition change we recorded is likely the consequence of long-term environmental change, such as climate warming. We observe an increased abundance of low-elevation species whereas species mainly occurring at higher elevations in the region declined. The Community Temperature Index was found to increase in all habitats except agricultural areas. If equivalent changes occur in other protected areas and taxonomic groups across Mediterranean Europe, new conservation options and approaches for increasing species’ resilience may have to be devised.
Decision making is thought to be an important determinant of health and well-being across the lifespan, but little is known about the association of decision making with mortality.
Participants were 675 older persons without dementia from the Rush Memory and Aging Project, a longitudinal cohort study of aging. Baseline assessments of decision making were used to predict the risk of mortality during up to 4 years of follow-up.
The mean score on the decision making measure at baseline was 7.1 (SD=2.9, range: 0-12), with lower scores indicating poorer decision making. During up to 4 years of follow-up (mean=1.7 years), 40 (6% of 675) persons died. In a proportional hazards model adjusted for age, sex, and education, the risk of mortality increased by about 20% for each additional decision making error (HR=1.19, 95% CI 1.07, 1.32, p=0.002). Thus, a person who performed poorly on the measure of decision making (score=3, 10th percentile) was about four times more likely to die compared to a person who performed well (score=11, 90th percentile). Further, the association of decision making with mortality persisted after adjustment for the level of cognitive function.
Poor decision making is associated with an increased risk of mortality in old age even after accounting for cognitive function.
Background and Aims
The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle-aged cohorts.
This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age ≥53 years), the Kungsholmen Project (KP) (n = 905, age ≥75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age ≥65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C-statistics were computed for individual participants for the ANU-ADRI and the CAIDE index.
For the ANU-ADRI using available data, the MAP study c-statistic was 0·637 (95% CI 0·596–0·678), for the KP study it was 0·740 (0·712–0·768) and for the CVHS it was 0·733 (0·691–0·776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650–0.727), 0.666 (0.628–0.704) and 0.734 (0.707–0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427–0.554) to 0.595 (0.565–0.625).
A composite risk score derived from the ANU-ADRI weights including 8–10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long-term follow-up.
To provide objective measures which characterize mobility in older adults assessed in the community setting and to examine the extent to which these measures are associated with parkinsonian gait.
During conventional mobility testing in the community-setting, 351 ambulatory non-demented Memory and Aging Project participants wore a belt with a whole body sensor that recorded both acceleration and angular velocity in 3 directions. We used measures derived from these recordings to quantify 5 subtasks including a) walking, b) transition from sit to stand, c) transition from stand to sit, d) turning and e) standing posture. Parkinsonian gait and other mild parkinsonian signs were assessed with a modified version of the original Unified Parkinson’s Disease Rating Scale (mUPDRS).
In a series of separate regression models which adjusted for age and sex, all 5 mobility subtask measures were associated with parkinsonian gait and accounted for 2% to 32% of its variance. When all 5 subtask measures were considered in a single model, backward elimination showed that measures of walking sit to stand and turning showed independent associations with parkinsonian gait and together accounted for more than 35% of its variance. Cross-validation using data from a 2nd group of 258 older adults showed similar results. In similar analyses, only walking was associated with bradykinesia and sway with tremor.
Quantitative mobility subtask measures vary in their associations with parkinsonian gait scores and other parkinsonian signs in older adults. Quantifying the different facets of mobility has the potential to facilitate the clinical characterization and understanding the biologic basis for impaired mobility in older adults.
The Religious Orders Study and the Rush Memory and Aging Project are both cohort studies of aging and dementia that include organ donation at death. Together, more than 2,700 persons have agreed to annual clinical evaluation and brain donation at death. A subset of participants also participated in a substudy that included ante-mortem imaging. We highlight recent findings that have been highly cited over the past five years. The findings fall into three general categories. The first relates to the neuropathology of probable Alzheimer’s disease, mild cognitive impairment, and those without dementia or mild cognitive impairment. The second relates to risk factors for Alzheimer’s disease and neuropathology. The third are clinical and imaging studies of mild cognitive impairment. The findings illustrate the range of insights that can be gained into cognitive aging by incorporating neuropathologic indices into well designed, prospective cohort studies.
clinical-pathology; mild cognitive impairment; risk factors
While neuritic plaques and neurofibrillary tangles in older adults are correlated with cognitive impairment and severity of dementia, it has long been recognized that the relationship is imperfect as some people exhibit normal cognition despite high levels of AD pathology. We compared the cellular, synaptic and biochemical composition of midfrontal cortices in female subjects from the Religious Orders Study who were stratified into three subgroups: 1) pathological AD with normal cognition (“AD-Resilient”), 2) pathological AD with AD-typical dementia (“AD-Dementia)” and 3) pathologically normal with normal cognition (“Normal Comparison”). The AD-Resilient group exhibited preserved densities of synaptophysin-labeled presynaptic terminals and synaptopodin-labeled dendritic spines compared to the AD-Dementia group, and increased densities of GFAP astrocytes compared to both the AD-Dementia and Normal Comparison group. Further, in a discovery antibody microarray protein analysis we identified a number of candidate protein abnormalities that were associated with diagnostic group. These data characterize cellular and synaptic features and identify novel biochemical targets that may be associated with resilient cognitive brain aging in the setting of pathological AD.
cognitive reserve; synapse; synaptophysin; synaptopodin; glial fibrillary acidic protein; antibody microarray
Hybridization is common between species of animals, particularly in waterfowl (Anatidae). One factor shown to promote hybridization is restricted mate choice, which can occur when 2 species occur in sympatry but one is rare. According to the Hubbs principle, or "desperation hypothesis," the rarer species is more likely to mate with heterospecifics. We report the second of 2 independent examples of hybridization between 2 species of ducks inhabiting island ecosystems in the Subantarctic and South Atlantic Ocean. Yellow-billed pintails (Anas georgica) and speckled teal (Anas flavirostris) are abundant in continental South America, where they are sympatric and coexist in mixed flocks. But on South Georgia, an isolated island in the Subantarctic, the pintail population of approximately 6000 pairs outnumbers a small breeding population of speckled teal 300∶1. Using 6 genetic loci (mtDNA and 5 nuclear introns) and Bayesian assignment tests coupled with coalescent analyses, we identified hybrid-origin speckled teal alleles in 2 pintails on South Georgia. While it is unclear whether introgression has also occurred into the speckled teal population, our data suggest that this hybridization was not a recent event, but occurred some time ago. We also failed to identify unequivocal evidence of introgression in a much larger sample of pintails and speckled teal from Argentina using a 3-population "Isolation-with-Migration" coalescent analysis. Combined with parallel findings of hybridization between these same 2 duck species in the Falkland Islands, where population ratios are reversed and pintails are outnumbered by speckled teal 1:10, our results provide further support for the desperation hypothesis, which predicts that scarcity in one population and abundance of another will often lead to hybridization. While the South Georgia pintail population appears to be thriving, it's possible that low density of conspecific mates and inverse density dependence (Allee effect) may be one factor limiting the reproductive output of the speckled teal population, and this situation may persist unless speckled teal increase in abundance on South Georgia.
Early-life adversity is related to adult health in old age but little is known about its relation with cognitive decline.
Participants included more than 6,100 older residents (mean age = 74.9 [7.1] years; 61.8% African American) enrolled in the Chicago Health and Aging Project, a geographically defined, population-based study of risk factors for Alzheimer disease. Participants were interviewed at approximately 3-year intervals for up to 16 years. The interview included a baseline evaluation of early-life adversity, and administration of 4 brief cognitive function tests to assess change in cognitive function. We estimated the relation of early-life adversity to rate of cognitive decline in a series of mixed-effects models.
In models stratified by race, and adjusted for age and sex, early-life adversity was differentially related to decline in African Americans and whites. Whereas no measure of early-life adversity related to cognitive decline in whites, both food deprivation and being thinner than average in early life were associated with a slower rate of cognitive decline in African Americans. The relations were not mediated by years of education and persisted after adjustment for cardiovascular factors.
Markers of early-life adversity had an unexpected protective effect on cognitive decline in African Americans.
Pancreatic adenocarcinoma has a five-year survival rate of less than 6%. This low survival rate is attributed to the lack of accurate detection methods, which limits diagnosis to late-stage disease. Here, an in vivo pilot study assesses the feasibility of optical spectroscopy to improve clinical detection of pancreatic adenocarcinoma. During surgery on 6 patients, we collected spectrally-resolved reflectance and fluorescence in vivo. Site-matched in vivo and ex vivo data agreed qualitatively and quantitatively. Quantified differences between adenocarcinoma and normal tissues in vivo were consistent with previous results from a large ex vivo data set. Thus, optical spectroscopy is a promising method for the improved diagnosis of pancreatic cancer in vivo.
(170.6510) Spectroscopy, tissue diagnostics; (170.4580) Optical diagnostics for medicine; (170.3660) Light propagation in tissues
The study aim was to test the hypothesis that motor function undergoes accelerated decline proximate to death. As part of a longitudinal clinical-pathologic study, 124 older Catholic nuns, priests, and monks completed at least 7 annual clinical evaluations, died, and underwent brain autopsy and uniform neuropathologic examination. Each evaluation included administration of 11 motor tests and 19 cognitive tests from which global measures of motor and cognitive function were derived. The global motor measure (baseline mean = 0.82, SD=0.21) declined a mean 0.024-unit per year (95% confidence interval [CI]: −0.032, −0.016) until a mean of 2.46 years (95% CI: −2,870, −2.108) before death when rate of decline increased nearly 5-fold to −0.117-unit per year (95% CI: −0.140, −097). The global cognitive measure (baseline mean =0.07, SD =0.45) declined a mean of 0.027-unit per year (95% CI: −0.041, −0.014) until a mean of 2.76 years (95% CI: −3.157, −2.372) before death when rate of decline increased more than 13-fold to −0.371-unit per year (95% CI: −0.443, −0.306). Onset of terminal motor decline was highly correlated with onset of terminal cognitive decline (r=0.94, 95% CI: 0.81, 0.99), but rates of motor and cognitive change were not strongly correlated (preterminal r = 0.20, 95% CI: −0.05, 0.38; terminal r = 0.34, 95% CI: 0.03, 0.62). Higher level of plaques and tangles was associated with earlier onset of terminal decline in motor function, but no pathologic measures were associated with rate of preterminal or terminal motor decline. The results demonstrate that motor and cognitive function both undergo a period of accelerated decline in the last few years of life.
motor decline; cognitive decline; mortality; neuritic plaques; neurofibrillary tangles
This study examined the association of cognitive and physical functions with age-related transition and progression of activities of daily living (ADL) disability in a population-based longitudinal cohort of nondisabled older adults.
A longitudinal population-based cohort study of 5,317 initially nondisabled older adults with an average age of 73.6 years of an urban Chicago community were interviewed annually for up to 8 years from 2000 through 2008. Cognitive function was assessed using a standardized global cognitive score and physical function using a combination of measured walk, tandem stand, and chair stand. A novel two-part model was used to access the relationship between cognitive and physical functions and age at onset and progression of ADL disability.
The sample consisted of 5,317 participants, 65% blacks, and 61% females. Twenty-five percent reported an onset of ADL disability during follow-up. After adjusting for confounders, lower cognitive and physical functions were associated with an increased risk for lower age at onset. Lower cognitive function was longitudinally associated with increased rate of progression of disability after onset. However, lower physical function did not alter the rate of progression of ADL disability.
Cognitive and physical functions were associated with age at onset. However, only cognitive function was associated with the rate of progression of ADL disability.
Physical disability; Age at onset; Progression; Cognitive function; Physical function
The study aim was to describe the temporal course of cognitive decline in Alzheimer‘s disease (AD). We selected 226 persons from 2 longitudinal clinical-pathological studies who were cognitively healthy at baseline, followed at least 4 years (mean = 10.2, SD = 3.5), and clinically diagnosed with AD at some point during follow-up. Each evaluation included a battery of 17 cognitive tests from which a previously established composite measure of global cognition was derived. In those who died, a uniform neuropathologic examination established the pathological diagnoses of Alzheimer's disease and other common conditions that impair cognition. Mixed-effects models with 2 change points were used to assess trajectories of cognitive decline. In the main analysis, there was no change in cognitive function until a mean of 7.5 years before dementia was diagnosed (95% confidence interval [CI]: -8.3, -6.7). The global cognitive measure declined a mean of 0.087-unit per year (95% CI: -0.099, -0.073) until a mean of 2.0 years before the diagnosis (95% CI: -2.2, -1.7) when it increased more than fourfold to a mean loss of 0.370-unit per year (95% CI: -0.417, -0.334). Of 126 individuals who died and underwent autopsy, 101 (80%) met pathologic criteria for AD of whom 67 had at least one other pathologic condition. Pathologic measures of AD and cerebral infarction were not strongly related to cognitive trajectories. The results indicate that cognitive decline in AD begins many years before dementia is diagnosed and accelerates during the course of the disease.
longitudinal study; cognitive decline; Alzheimer's disease; mild cognitive impairment; neuropathologic examination
In a pilot study, multimodal optical spectroscopy coupled with quantitative tissue-optics models distinguished intraductal papillary mucinous neoplasm (IPMN), a common precursor to pancreatic cancer, from normal tissues in freshly excised human pancreas. A photon-tissue interaction (PTI) model extracted parameters associated with cellular nuclear size and refractive index (from reflectance spectra) and extracellular collagen content (from fluorescence spectra). The results suggest that tissue optical spectroscopy has the potential to characterize pre-cancerous neoplasms in human pancreatic tissues.
(170.6510) Spectroscopy, tissue diagnostics; (170.4580) Optical diagnostics for medicine
Zinc (Zn) homeostasis is required for a functional immune system. Critically ill patients often exhibit decreased Zn serum concentrations and could potentially benefit from Zn supplementation as a therapeutic strategy. However, the conventional approaches to monitoring Zn are time consuming and costly. This work reports on detection of Zn by anodic stripping voltammetry (ASV) on bismuth electrodes in a microfabricated electrochemical cell. The working potential window of the electrodeposited bismuth film electrode was investigated by cyclic voltammetry, while square wave ASV was used for measuring Zn in acetate buffer and blood serum. Conditions critical to sensing, such as preconcentration potential, preconcentration time, and buffer pH, were optimized for Zn detection. The sensor was successfully calibrated with pH 6 acetate buffer in the physiologically-relevant range of 5 μM to 50μM Zn and exhibited well-defined and highly repeatable peaks. The sensor was used to demonstrate measurement of Zn in blood serum digested in HCl. The results of this work show that Zn detection in serum is possible with smaller sample volumes (μL vs. μL) and faster turnaround time (hours vs. days) as compared with the conventional spectroscopic methods.
Anodic stripping voltammetry; Bismuth electrode; Microfabricated electrochemical cell; Zinc in serum
This work describes development of a lab-on-a-chip sensor for electrochemical detection of highly electro-negative heavy metals such as manganese and zinc by anodic stripping voltammetry. The sensor consists of a three-electrode system, with a bismuth working electrode, a Ag/AgCl reference electrode, and a Au auxiliary electrode. Hydrolysis at the auxiliary electrode is a critical challenge in such electrochemical sensors as its onset severely limits the ability to detect electronegative metals. The bismuth working electrode is used due to its comparable negative detection window and reduced toxicity with respect to a conventional mercury electrode. Through optimization of the sensor layout and the working electrode surface, effects of hydrolysis were substantially reduced and the potential window was extended to the −0.3 to −1.9 V range (vs. Ag/AgCl reference electrode), which is far more negative than what is possible with conventional Au, Pt, or carbon electrodes. The described lab-on-a-chip sensor for the first time permits reliable and sensitive detection of the highly electronegative manganese. The favorable performance of the bismuth electrode coupled with its environmentally-friendly nature make the described sensor attractive for applications where disposable chips are desirable. With further development and integrated sample preparation, the lab-on-a-chip may be converted into a point-of-care platform for monitoring heavy metals in blood (e.g., assessment of manganese exposure).
Electrochemical sensor; Bismuth electrodes; Anodic stripping voltammetry; Heavy metal detection; Lab-on-a-chip
The purpose of the study was to test the hypothesis that a higher level of childhood adversity is associated with increased risk of cerebral infarction in old age.
Older participants in a longitudinal clinical–pathologic study rated adverse childhood experiences (e.g., emotional neglect, parental intimidation and violence) on a previously established 16-item scale. During a mean of 3.5 years of follow-up, there were 257 deaths, with 206 brain autopsies (80.2). Number of chronic cerebral infarcts (gross plus microscopic; expressed as 0, 1, or >1) was determined in a uniform neuropathologic examination, which had been completed in 192 individuals at the time of these analyses.
Childhood adversity scores ranged from 0 to 31 (mean = 8.3, SD = 6.4). In an ordinal logistic regression model adjusted for age, sex, and education, higher adversity was associated with higher likelihood of chronic cerebral infarction. In analyses of childhood adversity subscales, only emotional neglect was associated with infarction (odds ratio [OR] = 1.097; 95% confidence interval [CI] 1.048–1.148). The likelihood of infarction was 2.8 times higher (95% CI 2.0–4.1) in those reporting a moderately high level of childhood emotional neglect (score = 6, 75th percentile) vs a moderately low level of neglect (score = 1, 25th percentile). Results were comparable in subsequent analyses that controlled for lifetime socioeconomic status, cardiovascular risk factors, and an anxiety-related trait.
Emotional neglect in childhood may be a risk factor for cerebral infarction in old age.
Examine the relation of Alzheimer's disease (AD) pathology, cerebral infarcts, and Lewy body (LB) pathology to cognition in persons without cognitive impairment.
Persons without dementia from two cohort studies of aging, the Religious Orders Study and the Memory and Aging Project, agreed to annual clinical evaluation and brain donation. The studies had 19 neuropsychological performance tests in common that assessed five cognitive domains. Of 296 persons without cognitive impairment who died and underwent post-mortem assessment, we quantified AD pathology as a global pathology score, and as amyloid load and PHFtau tangle density, cerebral infarcts and LB pathology. Linear regression was used to examine the relation of neuropathology to cognitive abilities controlling for demographics.
Nearly all persons had AD pathology with more than three quarters exhibiting amyloid; 22% macroscopic and 24% microscopic infarctions, and 13% had LB pathology. The global measure of AD pathology was related to global cognition (p=0.008) whereas infarcts and Lewy bodies were not. Amyloid load was related to global cognition (p<0.05) with only a trend for tangles (p=0.08). In analyses of cognitive domains, AD pathology (p=0.006), PHFtau tangles (p=0.03), and macroscopic infarctions (p=0.02) were related to episodic memory with a trend for amyloid load (p=0.06); and AD pathology (p=0.02) and amyloid load (p=0.03) were related to working memory. Findings for global cognition and episodic memory were stronger in additional analyses with neocortical amyloid and mesial temporal tangles.
AD pathology and macroscopic infarctions are common in older persons without cognitive impairment and related to episodic and working memory.
clinical-pathology; no cognitive impairment
A comparative evaluation of the immunity stimulated with a vaccine regimen that includes simian immunodeficiency virus (SIV), interleukin 2 (IL-2), and IL-15 DNAs, recombinant modified vaccinia virus Ankara (rMVA), and inactivated SIVmac239 particles administered into the oral and nasal cavities, small intestine, and vagina was carried out in female rhesus macaques to determine the best route to induce diverse anti-SIV immunity that may be critical to protection from SIV infection and disease. All four immunizations generated mucosal SIV-specific IgA. Oral immunization was as effective as vaginal immunization in inducing SIV-specific IgA in vaginal secretions and generated greater IgA responses in rectal secretions and saliva samples compared to the other immunization routes. All four immunizations stimulated systemic T-cell responses against Gag and Env, albeit to a different extent, with oral immunization providing greater magnitude and nasal immunization providing wider functional heterogeneity. SIV-specific T cells producing gamma interferon (IFN-γ) dominated these responses. Limited levels of SIV-specific IgG antibodies were detected in plasma samples, and no SIV-specific IgG antibodies were detected in secretions. Vaccination also induced CD4+ and CD8+ T-cell responses in the rectal and vaginal mucosa with greater functional heterogeneity than in blood samples. Rectal T-cell responses were significantly greater in the orally vaccinated animals than in the other animals. The most balanced, diverse, and higher-magnitude vaginal T-cell responses were observed after intestinal vaccination. Significantly higher CD8+ granzyme B-positive T-cell responses were observed systemically after intestinal vaccination and in rectal cells after oral immunization. The majority of SIV-specific T cells that produced granzyme B did not produce cytokines. Of the immunization routes tested, oral vaccination provided the most diverse and significant response to the vaccine.
Friedreich ataxia is an inherited, severe, progressive neuro- and cardiodegenerative disorder for which there currently is no approved therapy. Friedreich ataxia is caused by the decreased expression and/or function of frataxin, a mitochondrial matrix protein that binds iron and is involved in the formation of iron-sulfur clusters. Decreased frataxin function leads to decreased iron-sulfur cluster formation, mitochondrial iron accumulation, cytosolic iron depletion, oxidative stress, and mitochondrial dysfunction. Cloning of the disease gene for Friedreich ataxia and elucidation of many aspects of the biochemical defects underlying the disorder have led to several major therapeutic initiatives aimed at increasing frataxin expression, reversing mitochondrial iron accumulation, and alleviating oxidative stress. These initiatives are in preclinical and clinical development, and are reviewed herein.
Friedreich ataxia; mitochondria; iron; experimental therapeutics; trinucleotide repeat disorders
During the past 15 years, the pace of research advancement in Friedreich ataxia has been rapid. The abnormal gene has been discovered and its gene product characterized, leading to the development of new evidence-based therapies. Still, various unsettled issues remain that affect clinical trials. These include the level of frataxin deficiency needed to cause disease, the mechanism by which frataxin-deficient mitochondrial dysfunction leads to symptomatology, and the reason selected cells are most affected in Friedreich ataxia. In this review, we summarize these questions and propose testable hypotheses for their resolution.
antioxidant; cerebellum; dorsal root ganglion; mitochondrion
Early detection and targeted therapy are two major challenges in the battle against cancer. Novel imaging contrast agents and targeting approaches are greatly needed to improve the sensitivity and specificity of cancer theranostic agents. Here, we implemented a novel approach using a magnetic micromesh and biocompatible fluorescent magnetic nanoparticles (FMN) to magnetically enhance cancer targeting in living subjects. This approach enables magnetic targeting of systemically administered individual FMN, containing a single 8 nm superparamagnetic iron oxide (SPIO) core. Using a human glioblastoma mouse model, we show that nanoparticles can be magnetically retained in both the tumor neovasculature and surrounding tumor tissues. Magnetic accumulation of nanoparticles within the neovasculature was observable by fluorescence intravital microscopy in real time. Finally, we demonstrate that such magnetically enhanced cancer targeting augments the biological functions of molecules linked to the nanoparticle surface.
To assess the association between lifestyle practices (cognitive and physical activity) and β-amyloid deposition, measured with positron emission tomography using carbon 11–labeled Pittsburgh Compound B ([11C]PiB), in healthy older individuals.
Cross-sectional clinical study.
Volunteer sample of 65 healthy older individuals (mean age, 76.1 years), 10 patients with Alzheimer disease (AD) (mean age, 74.8 years), and 11 young controls (mean age, 24.5 years) were studied from October 31, 2005, to February 22, 2011.
Main Outcome Measures
Cortical [11C]PiB average (frontal, parietal, lateral temporal, and cingulate regions) and retrospective, self-report scales assessing participation in cognitive activities (eg, reading, writing, and playing games) and physical exercise.
Greater participation in cognitively stimulating activities across the lifespan, but particularly in early and middle life, was associated with reduced [11C]PiB uptake (P <.001, accounting for age, sex, and years of education). Older participants in the highest cognitive activity tertile had [11C]PiB uptake comparable to young controls, whereas those in the lowest cognitive activity tertile had [11C]PiB uptake comparable to patients with AD. Although greater cognitive activity was associated with greater physical exercise, exercise was not associated with [11C]PiB uptake.
Individuals with greater early- and middle-life cognitive activity had lower [11C]PiB uptake. The tendency to participate in cognitively stimulating activities is likely related to engagement in a variety of lifestyle practices that have been implicated in other studies showing reduced risk of AD-related pathology. We report a direct association between cognitive activity and [11C]PiB uptake, suggesting that lifestyle factors found in individuals with high cognitive engagement may prevent or slow deposition of β-amyloid, perhaps influencing the onset and progression of AD.
Error-driven learning rules have received considerable attention because of their close relationships to both optimal theory and neurobiological mechanisms. However, basic forms of these rules are effective under only a restricted set of conditions in which the environment is stable. Recent studies have defined optimal solutions to learning problems in more general, potentially unstable, environments, but the relevance of these complex mathematical solutions to how the brain solves these problems remains unclear. Here, we show that one such Bayesian solution can be approximated by a computationally straightforward mixture of simple error-driven ‘Delta’ rules. This simpler model can make effective inferences in a dynamic environment and matches human performance on a predictive-inference task using a mixture of a small number of Delta rules. This model represents an important conceptual advance in our understanding of how the brain can use relatively simple computations to make nearly optimal inferences in a dynamic world.
The ability to make accurate predictions is important to thrive in a dynamic world. Many predictions, like those made by a stock picker, are based, at least in part, on historical data thought also to reflect future trends. However, when unexpected changes occur, like an abrupt change in the value of a company that affects its stock price, the past can become irrelevant and we must rapidly update our beliefs. Previous research has shown that, under certain conditions, human predictions are similar to those of mathematical, ideal-observer models that make accurate predictions in the presence of change-points. Despite this progress, these models require superhuman feats of memory and computation and thus are unlikely to be implemented directly in the brain. In this work, we address this conundrum by developing an approximation to the ideal-observer model that drastically reduces the computational load with only a minimal cost in performance. We show that this model better explains human behavior than other models, including the optimal model, and suggest it as a biologically plausible model for learning and prediction.