No correlation between time-linked plasma and CSF Aβ levels

Plasma β-amyloid protein (Aβ) isoforms are considered potential biomarkers for Alzheimer's disease (AD) and dementia. The relation between plasma and cerebrospinal fluid (CSF) levels of Aβ isoforms remains unclear. In order to identify possible correlations between Aβ levels in plasma and CSF we determined Aβ levels in time-linked plasma and CSF samples. Aβ concentrations in plasma (Aβ_1–42 and Aβ_N–42) and CSF (Aβ_1–42) samples from 49 AD patients, 47 non-Alzheimer's disease dementia (NONAD) patients, 39 MCI patients and 29 controls were determined using a multi-parameter fluorimetric bead-based immunoassay using xMAP^® technology (for plasma) and a conventional single-parameter ELISA (for CSF). Plasma Aβ_1–42 concentrations did not correlate with CSF Aβ_1–42 concentrations in the total study population, or in the different diagnostic groups. No correlations between plasma Aβ_N–42 and CSF Aβ_1–42 levels were found either. The CSF/serum albumin index did not show any significant differences between AD, NONAD, MCI and controls.These results suggest that the Aβ levels in plasma are independent of the Aβ levels in CSF both in dementia and controls. The fact that CSF and plasma Aβ do not correlate in patients as well as controls and no significant differences in plasma Aβ_1–42 or Aβ_N–42 between patients and controls can be detected hampers the diagnostic utility of the plasma Aβ levels as biomarkers for dementia.     

The Mind-Writing Pupil: A Human-Computer Interface Based on Decoding of Covert Attention through Pupillometry

We present a new human-computer interface that is based on decoding of attention through pupillometry. Our method builds on the recent finding that covert visual attention affects the pupillary light response: Your pupil constricts when you covertly (without looking at it) attend to a bright, compared to a dark, stimulus. In our method, participants covertly attend to one of several letters with oscillating brightness. Pupil size reflects the brightness of the selected letter, which allows us–with high accuracy and in real time–to determine which letter the participant intends to select. The performance of our method is comparable to the best covert-attention brain-computer interfaces to date, and has several advantages: no movement other than pupil-size change is required; no physical contact is required (i.e. no electrodes); it is easy to use; and it is reliable. Potential applications include: communication with totally locked-in patients, training of sustained attention, and ultra-secure password input.     

Genome-wide association study identifies single nucleotide polymorphism in DYRK1A associated with replication of HIV-1 in monocyte-derived macrophages

Background

HIV-1 infected macrophages play an important role in rendering resting T cells permissive for infection, in spreading HIV-1 to T cells, and in the pathogenesis of AIDS dementia. During highly active anti-retroviral treatment (HAART), macrophages keep producing virus because tissue penetration of antiretrovirals is suboptimal and the efficacy of some is reduced. Thus, to cure HIV-1 infection with antiretrovirals we will also need to efficiently inhibit viral replication in macrophages. The majority of the current drugs block the action of viral enzymes, whereas there is an abundance of yet unidentified host factors that could be targeted. We here present results from a genome-wide association study identifying novel genetic polymorphisms that affect in vitro HIV-1 replication in macrophages.

Methodology/Principal Findings

Monocyte-derived macrophages from 393 blood donors were infected with HIV-1 and viral replication was determined using Gag p24 antigen levels. Genomic DNA from individuals with macrophages that had relatively low (n = 96) or high (n = 96) p24 production was used for SNP genotyping with the Illumina 610 Quad beadchip. A total of 494,656 SNPs that passed quality control were tested for association with HIV-1 replication in macrophages, using linear regression. We found a strong association between in vitro HIV-1 replication in monocyte-derived macrophages and SNP rs12483205 in DYRK1A (p = 2.16×10⁻⁵). While the association was not genome-wide significant (p<1×10⁻⁷), we could replicate this association using monocyte-derived macrophages from an independent group of 31 individuals (p = 0.0034). Combined analysis of the initial and replication cohort increased the strength of the association (p = 4.84×10⁻⁶). In addition, we found this SNP to be associated with HIV-1 disease progression in vivo in two independent cohort studies (p = 0.035 and p = 0.0048).

Conclusions/Significance

These findings suggest that the kinase DYRK1A is involved in the replication of HIV-1, in vitro in macrophages as well as in vivo.     

The trade-off between maturation and growth during accelerated development in frogs

Developmental energetics are crucial to a species' life history and ecology but are poorly understood from a mechanistic perspective. Traditional energy and mass budgeting does not distinguish between costs of growth and maturation, making it difficult to account for accelerated development. We apply a metabolic theory that uniquely considers maturation costs (Dynamic Energy Budget theory, DEB) to interpret empirical data on the energetics of accelerated development in amphibians. We measured energy use until metamorphosis in two related frogs, Crinia georgiana and Pseudophryne bibronii. Mass and energy content of fresh ova were comparable between the species. However, development to metamorphosis was 1.7 times faster in C. georgiana while P. bibronii produced nine times the dry biomass at metamorphosis and had lower mass-specific oxygen requirements. DEB theory explained these patterns through differences in ontogenetic energy allocation to maturation. P. bibronii partitioned energy in the same (constant) way throughout development whereas C. georgiana increased the fraction of energy allocated to maturation over growth between hatching and the onset of feeding. DEB parameter estimation for additional, direct-developing taxa suggests that a change in energy allocation during development may result from a selective pressure to increase development rate, and not as a result of development mode.     

The Pupillary Light Response Reveals the Focus of Covert Visual Attention

The pupillary light response is often assumed to be a reflex that is not susceptible to cognitive influences. In line with recent converging evidence, we show that this reflexive view is incomplete, and that the pupillary light response is modulated by covert visual attention: Covertly attending to a bright area causes a pupillary constriction, relative to attending to a dark area under identical visual input. This attention-related modulation of the pupillary light response predicts cuing effects in behavior, and can be used as an index of how strongly participants attend to a particular location. Therefore, we suggest that pupil size may offer a new way to continuously track the focus of covert visual attention, without requiring a manual response from the participant. The theoretical implication of this finding is that the pupillary light response is neither fully reflexive, nor under complete voluntary control, but is instead best characterized as a stereotyped response to a voluntarily selected target. In this sense, the pupillary light response is similar to saccadic and smooth pursuit eye movements. Together, eye movements and the pupillary light response maximize visual acuity, stabilize visual input, and selectively filter visual information as it enters the eye.     

Interactions between Bdellovibrio and its host cell.

The bdellovibrios are extremely small bacteria with the unique property of being parasites of other (gram-negative) bacteria. In the presence of viable and susceptible bacteria a Bdellovibrio cell physically 'attacks' an individual host cell, attaches to its surface, penetrates the cell wall, and multiples within the periplasmic (intramural) space of its prey. The invading Bdellovibrio and its progeny degrade and consume the cellular constituents of the invaded host bacterium. This process finally results in complete lysis of the host cell and release of the Bdellovibrio progeny. From a population of parasitic bdellovibrios, derivatives can be selected that grow on complex nutrient media. Currently, none of the different nutritional types can be propagated in a fully defined synthetic medium. By degradation of the cellular constituents of the host the Bdellovibrio cell in its periplasmic space has available all the monomeric subunits needed to synthesis of the macromolecules. Peculiarities of Bdellovibrio metabolism with respect to uptake of preformed molecules and energy efficiency are discussed.     

A kinetic inhibition mechanism for maintenance

To fulfil their maintenance costs, most species use mobile pools of metabolites (reserve) in favourable conditions, but can also use less mobile pools (structure) under food-limiting conditions. While some empirical models always pay maintenance costs from structure, the presence of reserve inhibits the use of structure for maintenance purposes. The standard dynamic energy budgets (DEB) model captures this by simply supplementing all costs that could not be paid from reserve with structure. This is less realistic at the biochemical level, and involves a sudden use of structure that can complicate the analysis of the model properties. We here propose a new inhibition formulation for the preferential use of reserve above structure in maintenance that avoids sudden changes in the metabolites use. It is based on the application of the theory for synthesizing units, which can easily become rather complex for demand processes, such as the maintenance. We found, however, a simple explicit expression for the use of reserve and structure for maintenance purposes and compared the numerical behaviour with that of a classical model in oscillating conditions, by using parameters values from a fit of the models to data on yeasts in a batch culture. We conclude that our model can better handle variable environments. This new inhibition formulation has a wide applicability in modelling metabolic processes.     

Improving Executive Functioning in Children with ADHD: Training Multiple Executive Functions within the Context of a Computer Game. A Randomized Double-Blind Placebo Controlled Trial

Introduction

Executive functions (EFs) training interventions aimed at ADHD-symptom reduction have yielded mixed results. Generally, these interventions focus on training a single cognitive domain (e.g., working memory [WM], inhibition, or cognitive-flexibility). However, evidence suggests that most children with ADHD show deficits on multiple EFs, and that these EFs are largely related to different brain regions. Therefore, training multiple EFs might be a potentially more effective strategy to reduce EF-related ADHD symptoms.

Methods

Eighty-nine children with a clinical diagnosis of ADHD (aged 8–12) were randomized to either a full-active-condition where visuospatial WM, inhibition and cognitive-flexibility were trained, a partially-active-condition where inhibition and cognitive-flexibility were trained and the WM-training task was presented in placebo-mode, or to a full placebo-condition. Short-term and long-term (3-months) effects of this gamified, 25-session, home-based computer-training were evaluated on multiple outcome domains.

Results

During training compliance was high (only 3% failed to meet compliance criteria). After training, only children in the full-active condition showed improvement on measures of visuospatial short-term-memory (STM) and WM. Inhibitory performance and interference control only improved in the full-active- and the partially-active condition. No Treatment-condition x Time interactions were found for cognitive-flexibility, verbal WM, complex-reasoning, nor for any parent-, teacher-, or child-rated ADHD behaviors, EF-behaviors, motivational behaviors, or general problem behaviors. Nonetheless, almost all measures showed main Time-effects, including the teacher-ratings.

Conclusions

Improvements on inhibition and visuospatial STM and WM were specifically related to the type of treatment received. However, transfer to untrained EFs and behaviors was mostly nonspecific (i.e., only interference control improved exclusively in the two EF training conditions). As such, in this multiple EF-training, mainly nonspecific treatment factors – as opposed to the specific effects of training EFs—seem related to far transfer effects found on EF and behavior.

Trial Registration

trialregister.nl NTR2728. Registry name: improving executive functioning in children with ADHD: training executive functions within the context of a computer game; registry number: NTR2728.