Tandem catalysis with double-shelled hollow spheres.

Metal-zeolite composites with metal (oxide) and acid sites are promising catalysts for integrating multiple reactions in tandem to produce a wide variety of wanted products without separating or purifying the intermediates. However, the conventional design of such materials often leads to uncontrolled and non-ideal spatial distributions of the metal inside/on the zeolites, limiting their catalytic performance. Here we demonstrate a simple strategy for synthesizing double-shelled, contiguous metal oxide@zeolite hollow spheres (denoted as MO@ZEO DSHSs) with controllable structural parameters and chemical compositions. This involves the self-assembly of zeolite nanocrystals onto the surface of metal ion-containing carbon spheres followed by calcination and zeolite growth steps. The step-by-step formation mechanism of the material is revealed using mainly in situ Raman spectroscopy and X-ray diffraction and ex situ electron microscopy. We demonstrate that it is due to this structure that an Fe2O3@H-ZSM-5 DSHSs-showcase catalyst exhibits superior performance compared with various conventionally structured Fe2O3-H-ZSM-5 catalysts in gasoline production by the Fischer-Tropsch synthesis. This work is expected to advance the rational synthesis and research of hierarchically hollow, core-shell, multifunctional catalyst materials.

Influence of Metal-Alkyls on Early-Stage Ethylene Polymerization over a Cr/SiO2 Phillips Catalyst: A Bulk Characterization and X-ray Chemical Imaging Study.

The Cr/SiO2 Phillips catalyst has taken a central role in ethylene polymerization since its invention in 1953. The uniqueness of this catalyst is related to its ability to produce broad molecular weight distribution (MWD) PE materials as well as that no co-catalysts are required to attain activity. Nonetheless, co-catalysts in the form of metal-alkyls can be added for scavenging poisons, enhancing catalyst activity, reducing the induction period, and tailoring polymer characteristics. The activation mechanism and related polymerization mechanism remain elusive, despite extensive industrial and academic research. Here, we show that by varying the type and amount of metal-alkyl co-catalyst, we can tailor polymer properties around a single Cr/SiO2 Phillips catalyst formulation. Furthermore, we show that these different polymer properties exist in the early stages of polymerization. We have used conventional polymer characterization techniques, such as size exclusion chromatography (SEC) and 13 C NMR, for studying the metal-alkyl co-catalyst effect on short-chain branching (SCB), long-chain branching (LCB) and molecular weight distribution (MWD) at the bulk scale. In addition, scanning transmission X-ray microscopy (STXM) was used as a synchrotron technique to study the PE formation in the early stages: allowing us to investigate the produced type of early-stage PE within one particle cross-section with high energy resolution and nanometer scale spatial resolution.

Correlated X-ray Ptychography and Fluorescence Nano-Tomography on the Fragmentation Behavior of an Individual Catalyst Particle during the Early Stages of Olefin Polymerization.

A combination of X-ray ptychography and X-ray fluorescence tomography (XRF) has been used to study the fragmentation behavior of an individual Ziegler-Natta catalyst particle, ∼40 µm in diameter, in the early stages of propylene polymerization with submicron spatial resolution. The electron density signal obtained from X-ray ptychography gives the composite phases of the Ziegler-Natta catalyst particle fragments and isotactic polypropylene, while 3-D XRF visualizes multiple isolated clusters, rich in Ti, of several microns in size. The radial distribution of Ti species throughout the polymer-catalyst composite particle shows that the continuous bisection fragmentation model is the main contributor to the fragmentation pathway of the catalyst particle as a whole. Furthermore, within the largest Ti clusters the fragmentation pathway was found to occur through both the continuous bisection and layer-by-layer models. The fragmentation behavior of polyolefin catalysts was for the first time visualized in 3-D by directly imaging and correlating the distribution of the Ti species to the polymer-catalyst composite phase.

Repulsive Guidance Molecule a (RGMa) Induces Neuropathological and Behavioral Changes That Closely Resemble Parkinson's Disease.

Repulsive guidance molecule member a (RGMa) is a membrane-associated or released guidance molecule that is involved in axon guidance, cell patterning, and cell survival. In our previous work, we showed that RGMa is significantly upregulated in the substantia nigra of patients with Parkinson's disease. Here we demonstrate the expression of RGMa in midbrain human dopaminergic (DA) neurons. To investigate whether RGMa might model aspects of the neuropathology of Parkinson's disease in mouse, we targeted RGMa to adult midbrain dopaminergic neurons using adeno-associated viral vectors. Overexpression of RGMa resulted in a progressive movement disorder, including motor coordination and imbalance, which is typical for a loss of DA release in the striatum. In line with this, RGMa induced selective degeneration of dopaminergic neurons in the substantia nigra (SN) and affected the integrity of the nigrostriatal system. The degeneration of dopaminergic neurons was accompanied by a strong microglia and astrocyte activation. The behavioral, molecular, and anatomical changes induced by RGMa in mice are remarkably similar to the clinical and neuropathological hallmarks of Parkinson's disease. Our data indicate that dysregulation of RGMa plays an important role in the pathology of Parkinson's disease, and antibody-mediated functional interference with RGMa may be a disease modifying treatment option.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is a neurodegenerative disease characterized by severe motor dysfunction due to progressive degeneration of mesencephalic dopaminergic (DA) neurons in the substantia nigra. To date, there is no regenerative treatment available. We previously showed that repulsive guidance molecule member a (RGMa) is upregulated in the substantia nigra of PD patients. Adeno-associated virus-mediated targeting of RGMa to mouse DA neurons showed that overexpression of this repulsive axon guidance and cell patterning cue models the behavioral and neuropathological characteristics of PD in a remarkable way. These findings have implications for therapy development as interfering with the function of this specific axon guidance cue may be beneficial to the survival of DA neurons.

Genesis of MgCl2 -based Ziegler-Natta Catalysts as Probed with Operando Spectroscopy.

Ziegler-Natta catalysts for olefin polymerization are intrinsically complex multi-component systems. The genesis of the active sites involves several simultaneous and sequential steps, making the individual steps and interconnections difficult to be unraveled in an unambiguous manner. In this work, we combine X-ray diffraction and spectroscopy to probe each step of the birth and life of a MgCl2 -based Ziegler-Natta catalyst, namely the formation of high surface area MgCl2 by dealcoholation of an alcoholate precursor, the TiCl4 grafting, and the subsequent activation by triethylaluminum as co-catalyst. The so-prepared catalyst was tested towards ethylene polymerization, leading to the production of mainly crystalline high-density polyethylene. The use of operando characterization techniques allowed probing the transient details that are difficult to be dissected in the aftermath, but can radically affect the overall catalytic process.

Capturing the Genesis of an Active Fischer-Tropsch Synthesis Catalyst with Operando X-ray Nanospectroscopy.

A state-of-the-art operando spectroscopic technique is applied to Co/TiO2 catalysts, which account for nearly half of the world's transportation fuels produced by Fischer-Tropsch catalysis. This allows determination of, at a spatial resolution of approximately 50 nm, the interdependence of formed hydrocarbon species in the inorganic catalyst. Observed trends show intra- and interparticular heterogeneities previously believed not to occur in particles under 200 µm. These heterogeneities are strongly dependent on changes in H2 /CO ratio, but also on changes thereby induced on the Co and Ti valence states. We have captured the genesis of an active FTS particle over its propagation to steady-state operation, in which microgradients lead to the gradual saturation of the Co/TiO2 catalyst surface with long chain hydrocarbons (i.e., organic film formation).

MicroRNA-132 and early growth response-1 in nucleus basalis of Meynert during the course of Alzheimer's disease.

The cholinergic nucleus basalis of Meynert, which is important for memory functions, shows neuronal activation ('up-phase') during the early stages of Alzheimer's disease and neurodegeneration ('down-phase') in later stages of Alzheimer's disease. MicroRNA-132 (miR-132) and the transcription factor early growth response-1 (EGR1) were proposed as possible candidate molecules regulating such an up-down activity pattern of the nucleus basalis of Meynert during the course of Alzheimer's disease, as they both show this up-down pattern of expression in the prefrontal cortex during the course of Alzheimer's disease. Not only do these two molecules stimulate synaptic activity and plasticity, they are also involved in Alzheimer's disease pathology and might, in addition, affect cholinergic function. In the nucleus basalis of Meynert, we investigated the expression of miR-132 and EGR1 along the entire course of Alzheimer's disease. Forty-nine post-mortem nucleus basalis of Meynert samples were studied, ranging from non-demented controls (Braak stage = 0) to late Alzheimer's disease patients (Braak stage = VI), and from clinical Reisberg scale 1 to 7. Each Braak stage contained seven samples, that were all well matched for confounding factors, i.e. age (range 58-91), sex, post-mortem delay, cerebrospinal fluid pH (as a measure for agonal state), APOE genotype, clock time of death, tissue fixation time, and tissue storage time. The alterations of these two molecules were studied over the course of Alzheimer's disease in relation to the expression of 4G8-stained amyloid-ß, hyperphosphorylated tau stained by antibody AT8, neuronal fibrillary tangles and neuropil threads stained by silver, and in relation to alterations in choline acetyltransferase. We found that the expression of miR-132 and EGR1 in the nucleus basalis of Meynert was quite stable during the early stages of Alzheimer's disease and decreased significantly only during late Alzheimer's disease stages. In addition, miR-132 and EGR1 showed a significant positive correlation with choline acetyltransferase expression (r = 0.49, P < 0.001 and r = 0.61, P < 0.001), while choline acetyltransferase expression showed a significantly negative correlation with hyperphosphorylated tau (r = -0.33, P = 0.021) but no correlation with 4G8-stained amyloid-ß. From the functional changes of miR-132 and EGR1 along the course of Alzheimer's disease we conclude: (i) that these two molecules may play a role in keeping the cholinergic function intact in early Alzheimer's disease stages; and (ii) that these molecules may contribute to the late neurodegeneration of this cholinergic nucleus.

ONT read assembly of the black rhino genome.

OBJECTIVES: The black rhinoceros (Diceros bicornis) is an endangered mammal for which a captive breeding program is part of the conservation effort. Black rhinos in zoo's often suffer from chronic infections and heamochromatosis. Furthermore, breeding is hampered by low male fertility. To aid a research project studying these topics, we sequenced and assembled the genome of a captive male black rhino using ONT sequencing data only. DATA DESCRIPTION: This work produced over 100 Gb whole genome sequencing reads from whole blood. These were assembled into a 2.47 Gb draft genome consisting of 834 contigs with an N50 of 29.53 Mb. The genome annotation was lifted over from an available genome annotation for black rhino, which resulted in the retrieval of over 99% of gene features. This new genome assembly will be a valuable resource in for conservation genetic research in this species.

A novel peptidomics approach to detect markers of Alzheimer's disease in cerebrospinal fluid.

Sensitive and specific diagnosis and monitoring of disease progression are of prime importance to develop new therapies for Alzheimer's disease patients. Although the diagnostic accuracy, verified by pathological examination is high, it is currently not possible to diagnose Alzheimer's disease with a high degree of certainty until relatively late in the disease process. Here, we have undertaken a peptidome analysis of postmortem cerebrospinal fluid of neuropathologically confirmed Alzheimer's disease patients and non-demented controls using a combination of methods and technologies. This includes novel sample preparation based on the enrichment of endogenous, proteolytically derived peptides as well as peptides non-covalently bound to abundant proteins. We observed differences in peptide profiles associated with Alzheimer's disease in the endogenous peptide fraction and in the protein-bound peptide fraction. The discriminating peptides in the unbound peptide fraction were identified as VGF nerve growth factor inducible precursor, and complement C4 precursor, whereas the discriminating peptides in the protein-bound fraction were identified as VGF nerve growth factor inducible precursor, and alpha-2-HS-glycoprotein.

Sunlight Powered Continuous Flow Reverse Water Gas Shift Process Using a Plasmonic Au/TiO2 Nanocatalyst.

The continuous flow reverse water gas shift (rWGS) process was efficiently catalyzed by a plasmonic Au/TiO2 nanocatalyst using sunlight as sole and sustainable energy source. The influence of the catalyst bed thickness on the CO production rate was studied, and three different catalytic regimes were identified as direct plasmon catalysis (DPC), shielded plasmon catalysis (SPC) and unused plasmon catalysis (UPC). The CO2 : H2 ratio was optimized to 4 : 1 and a maximum CO production rate of 7420 mmol ⋅ m-2 ⋅ h-1 was achieved under mild reaction conditions (p=3.5 bar, no external heating, Ee =14.0 kW ⋅ m-2 ), corresponding to an aparent quantum efficiency of 4.15%. The stability of the Au/TiO2 catalyst was studied for 110 h continuous operation, maintaining more than 82% of the initial CO production rate. On/off experiments mimicking discontinuous sunlight powered processing furthermore showed that the Au/TiO2 catalyst was stable for 8 consecutive runs.

Correlated x-ray fluorescence and ptychographic nano-tomography on Rembrandt's The Night Watch reveals unknown lead "layer".

The Night Watch, one of the most famous masterpieces by Rembrandt, is the subject of a large research and conservation project. For the conservation treatment, it is of great importance to understand its current condition. Correlated nano-tomography using x-ray fluorescence and ptychography revealed a-so far unknown-lead-containing "layer", which likely acts as a protective impregnation layer applied on the canvas before the quartz-clay ground was applied. This layer might explain the presence of lead soap protrusions in areas where no other lead components are present. In addition to the three-dimensional elemental mapping, ptychography visualizes and quantifies components not detectable by hard x-ray fluorescence such as the organic fraction and quartz. The first-time use of this combination of synchrotron-based techniques on a historic paint micro-sample shows it to be an important tool to better interpret the results of noninvasive imaging techniques operating on the macroscale.

A Ziegler-type spherical cap model reveals early stage ethylene polymerization growth versus catalyst fragmentation relationships.

Polyolefin catalysts are characterized by their hierarchically complex nature, which complicates studies on the interplay between the catalyst and formed polymer phases. Here, the missing link in the morphology gap between planar model systems and industrially relevant spherical catalyst particles is introduced through the use of a spherical cap Ziegler-type catalyst model system for the polymerization of ethylene. More specifically, a moisture-stable LaOCl framework with enhanced imaging contrast has been designed to support the TiCl4 pre-active site, which could mimic the behaviour of the highly hygroscopic and industrially used MgCl2 framework. As a function of polymerization time, the fragmentation behaviour of the LaOCl framework changed from a mixture of the shrinking core (i.e., peeling off small polyethylene fragments at the surface) and continuous bisection (i.e., internal cleavage of the framework) into dominantly a continuous bisection model, which is linked to the evolution of the estimated polyethylene volume and the fraction of crystalline polyethylene formed. The combination of the spherical cap model system and the used advanced micro-spectroscopy toolbox, opens the route for high-throughput screening of catalyst functions with industrially relevant morphologies on the nano-scale.

Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer's disease.

Using the Braak staging for neurofibrillary changes as an objective indicator of the progression of Alzheimer's disease, we have performed a systematic search for global gene expression changes in the prefrontal cortex during the course of Alzheimer's disease. In the prefrontal cortex, senile plaques and neurofibrillary changes start to appear around Braak stage III, allowing for the detection of changes in gene expression before, during and after the onset of Alzheimer's disease neuropathology. Two distinct patterns of tightly co-regulated groups of genes were observed: (i) an increase in expression in early Braak stages, followed by a decline in expression in later stages (the UPDOWN clusters; containing 865 genes) and (ii) a decrease in expression in early Braak stages, followed by an increase in expression in later stages (the DOWNUP clusters; containing 983 genes). The most profound changes in gene expression were detected between Braak stages II and III, just before or at the onset of plaque pathology and neurofibrillary changes in the prefrontal cortex. We also observed an increase in intracellular beta amyloid staining from Braak stages I to III and a clear decrease in Braak stages IV to VI. These data suggest a link between specific gene expression clusters and Alzheimer's disease-associated neuropathology in the prefrontal cortex. Gene ontology over-representation and functional gene network analyses indicate an increase in synaptic activity and changes in plasticity during the very early pre-symptomatic stage of the disease. In later Braak stages, the decreased expression of these genes suggests a reduction in synaptic activity that coincides with the appearance of plaque pathology and neurofibrillary changes and the clinical diagnosis of mild cognitive impairment. The interaction of the ApoE genotype with the expression levels of the genes in the UPDOWN and DOWNUP clusters demonstrates that the accelerating role of ApoE-ε4 in the progression of Alzheimer's disease is reflected in the temporal changes in gene expression presented here. Since the UPDOWN cluster contains several genes involved in amyloid precursor protein processing and beta amyloid clearance that increase in expression in parallel with increased intracellular beta amyloid load, just before the onset of plaque pathology in the prefrontal cortex, we hypothesize that the temporally orchestrated increase in genes involved in synaptic activity represents a coping mechanism against increased soluble beta amyloid levels. As these gene expression changes occur before the appearance of Alzheimer's disease-associated neuropathology, they provide an excellent starting point for the identification of new targets for the development of therapeutic strategies aimed at the prevention of Alzheimer's disease.

Visualizing defects and pore connectivity within metal-organic frameworks by X-ray transmission tomography.

Metal-Organic Frameworks (MOFs) have the potential to change the landscape of molecular separations in chemical processes owing to their ability of selectively binding molecules. Their molecular sorting properties generally rely on the micro- and meso-pore structure, as well as on the presence of coordinatively unsaturated sites that interact with the different chemical species present in the feed. In this work, we show a first-of-its-kind tomographic imaging of the crystal morphology of a metal-organic framework by means of transmission X-ray microscopy (TXM), including a detailed data reconstruction and processing approach. Corroboration with Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM) images shows the potential of this strategy for further (non-destructively) assessing the inner architecture of MOF crystals. By doing this, we have unraveled the presence of large voids in the internal structure of a MIL-47(V) crystal, which are typically thought of as rather homogeneous lattices. This challenges the established opinion that hydrothermal syntheses yield relatively defect-free material and sheds further light on the internal morphology of crystals.

Heterogeneity in the Fragmentation of Ziegler Catalyst Particles during Ethylene Polymerization Quantified by X-ray Nanotomography.

Ziegler-type catalysts are the grand old workhorse of the polyolefin industry, yet their hierarchically complex nature complicates polymerization activity-catalyst structure relationships. In this work, the degree of catalyst framework fragmentation of a high-density polyethylene (HDPE) Ziegler-type catalyst was studied using ptychography X-ray-computed nanotomography (PXCT) in the early stages of ethylene polymerization under mild reaction conditions. An ensemble consisting of 434 fully reconstructed ethylene prepolymerized Ziegler catalyst particles prepared at a polymer yield of 3.4 g HDPE/g catalyst was imaged. This enabled a statistical route to study the heterogeneity in the degree of particle fragmentation and therefore local polymerization activity at an achieved 3-D spatial resolution of 74 nm without requiring invasive imaging tools. To study the degree of catalyst fragmentation within the ensemble, a fragmentation parameter was constructed based on a k-means clustering algorithm that relates the quantity of polyethylene formed to the average size of the spatially resolved catalyst fragments. With this classification method, we have identified particles that exhibit weak, moderate, and strong degrees of catalyst fragmentation, showing that there is a strong heterogeneity in the overall catalyst particle fragmentation and thus polymerization activity within the entire ensemble. This hints toward local mass transfer limitations or other deactivation phenomena. The methodology used here can be applied to all polyolefin catalysts, including metallocene and the Phillips catalysts to gain statistically relevant fundamental insights in the fragmentation behavior of an ensemble of catalyst particles.

Intensity-based analysis of dual-color gene expression data as an alternative to ratio-based analysis to enhance reproducibility.

BACKGROUND: Ratio-based analysis is the current standard for the analysis of dual-color microarray data. Indeed, this method provides a powerful means to account for potential technical variations such as differences in background signal, spot size and spot concentration. However, current high density dual-color array platforms are of very high quality, and inter-array variance has become much less pronounced. We therefore raised the question whether it is feasible to use an intensity-based analysis rather than ratio-based analysis of dual-color microarray datasets. Furthermore, we compared performance of both ratio- and intensity-based analyses in terms of reproducibility and sensitivity for differential gene expression. RESULTS: By analyzing three distinct and technically replicated datasets with either ratio- or intensity-based models, we determined that, when applied to the same dataset, intensity-based analysis of dual-color gene expression experiments yields 1) more reproducible results, and 2) is more sensitive in the detection of differentially expressed genes. These effects were most pronounced in experiments with large biological variation and complex hybridization designs. Furthermore, a power analysis revealed that for direct two-group comparisons above a certain sample size, ratio-based models have higher power, although the difference with intensity-based models is very small. CONCLUSIONS: Intensity-based analysis of dual-color datasets results in more reproducible results and increased sensitivity in the detection of differential gene expression than the analysis of the same dataset with ratio-based analysis. Complex dual-color setups such as interwoven loop designs benefit most from ignoring the array factor. The applicability of our approach to array platforms other than dual-color needs to be further investigated.

The Effects of Sindbis Viral Vectors on Neuronal Function.

Viral vectors are attractive tools to express genes in neurons. Transduction of neurons with a recombinant, replication-deficient Sindbis viral vector is a method of choice for studying the effects of short-term protein overexpression on neuronal function. However, to which extent Sindbis by itself may affect neurons is not fully understood. We assessed effects of neuronal transduction with a Sindbis viral vector on the transcriptome and proteome in organotypic hippocampal slice cultures, and analyzed the electrophysiological properties of individual CA1 neurons, at 24 h and 72 h after viral vector injection. Whereas Sindbis caused substantial gene expression alterations, changes at the protein level were less pronounced. Alterations in transcriptome and proteome were predominantly limited to proteins involved in mediating anti-viral innate immune responses. Sindbis transduction did not affect the intrinsic electrophysiological properties of individual neurons: the membrane potential and neuronal excitability were similar between transduced and non-transduced CA1 neurons up to 72 h after Sindbis injection. Synaptic currents also remained unchanged upon Sindbis transduction, unless slices were massively infected for 72 h. We conclude that Sindbis viral vectors at low transduction rates are suitable for studying short-term effects of a protein of interest on electrophysiological properties of neurons, but not for studies on the regulation of gene expression.

Transcriptome analysis of normal-appearing white matter reveals cortisol- and disease-associated gene expression profiles in multiple sclerosis.

Inter-individual differences in cortisol production by the hypothalamus-pituitary-adrenal (HPA) axis are thought to contribute to clinical and pathological heterogeneity of multiple sclerosis (MS). At the same time, accumulating evidence indicates that MS pathogenesis may originate in the normal-appearing white matter (NAWM). Therefore, we performed a genome-wide transcriptional analysis, by Agilent microarray, of post-mortem NAWM of 9 control subjects and 18 MS patients to investigate to what extent gene expression reflects disease heterogeneity and HPA-axis activity. Activity of the HPA axis was determined by cortisol levels in cerebrospinal fluid and by numbers of corticotropin-releasing neurons in the hypothalamus, while duration of MS and time to EDSS6 served as indicator of disease severity. Applying weighted gene co-expression network analysis led to the identification of a range of gene modules with highly similar co-expression patterns that strongly correlated with various indicators of HPA-axis activity and/or severity of MS. Interestingly, molecular profiles associated with relatively mild MS and high HPA-axis activity were characterized by increased expression of genes that actively regulate inflammation and by molecules involved in myelination, anti-oxidative mechanism, and neuroprotection. Additionally, group-wise comparisons of gene expression in white matter from control subjects and NAWM from (subpopulations of) MS patients uncovered disease-associated gene expression as well as strongly up- or downregulated genes in patients with relatively benign MS and/or high HPA-axis activity, with many differentially expressed genes being previously undescribed in the context of MS. Overall, the data suggest that HPA-axis activity strongly impacts on molecular mechanisms in NAWM of MS patients, but partly also independently of disease severity.

Gene Expression Profiling of Multiple Sclerosis Pathology Identifies Early Patterns of Demyelination Surrounding Chronic Active Lesions.

In multiple sclerosis (MS), activated microglia and infiltrating macrophages phagocytose myelin focally in (chronic) active lesions. These demyelinating sites expand in time, but at some point turn inactive into a sclerotic scar. To identify molecular mechanisms underlying lesion activity and halt, we analyzed genome-wide gene expression in rim and peri-lesional regions of chronic active and inactive MS lesions, as well as in control tissue. Gene clustering revealed patterns of gene expression specifically associated with MS and with the presumed, subsequent stages of lesion development. Next to genes involved in immune functions, we found regulation of novel genes in and around the rim of chronic active lesions, such as NPY, KANK4, NCAN, TKTL1, and ANO4. Of note, the presence of many foamy macrophages in active rims was accompanied by a congruent upregulation of genes related to lipid binding, such as MSR1, CD68, CXCL16, and OLR1, and lipid uptake, such as CHIT1, GPNMB, and CCL18. Except CCL18, these genes were already upregulated in regions around active MS lesions, showing that such lesions are indeed expanding. In vitro downregulation of the scavenger receptors MSR1 and CXCL16 reduced myelin uptake. In conclusion, this study provides the gene expression profile of different aspects of MS pathology and indicates that early demyelination, mediated by scavenger receptors, is already present in regions around active MS lesions. Genes involved in early demyelination events in regions surrounding chronic active MS lesions might be promising therapeutic targets to stop lesion expansion.

Storm before the quiet: neuronal hyperactivity and Aß in the presymptomatic stages of Alzheimer's disease.

Neuronal activity directly promotes the production and secretion of amyloid ß (Aß). Interestingly, neuronal hyperactivity can be observed in presymptomatic stages of both sporadic and familial Alzheimer's disease (AD) and in several AD mouse models. In this review, we will highlight the recent evidence for neuronal hyperactivity before or during the onset of cognitive defects in mild cognitive impairment. Furthermore, we review specific molecular mechanisms through which neuronal hyperactivity affects Aß production and degradation. With these data, we will provide more insight into the 2-faced nature of neuronal hyperactivity: does enhanced neuronal activity during the presymptomatic stages of AD provide protection against the earliest disease processes or is it a pathogenic contributor to AD?