Common dysregulation network in the human prefrontal cortex underlies two neurodegenerative diseases.

Using expression profiles from postmortem prefrontal cortex samples of 624 dementia patients and non-demented controls, we investigated global disruptions in the co-regulation of genes in two neurodegenerative diseases, late-onset Alzheimer's disease (AD) and Huntington's disease (HD). We identified networks of differentially co-expressed (DC) gene pairs that either gained or lost correlation in disease cases relative to the control group, with the former dominant for both AD and HD and both patterns replicating in independent human cohorts of AD and aging. When aligning networks of DC patterns and physical interactions, we identified a 242-gene subnetwork enriched for independent AD/HD signatures. This subnetwork revealed a surprising dichotomy of gained/lost correlations among two inter-connected processes, chromatin organization and neural differentiation, and included DNA methyltransferases, DNMT1 and DNMT3A, of which we predicted the former but not latter as a key regulator. To validate the inter-connection of these two processes and our key regulator prediction, we generated two brain-specific knockout (KO) mice and show that Dnmt1 KO signature significantly overlaps with the subnetwork (P = 3.1 × 10(-12)), while Dnmt3a KO signature does not (P = 0.017)

The analysis of European lacquer : optimization of thermochemolysis temperature of natural resins

In order to optimize chromatographic analysis of European lacquer, thermochemolysis temperature was evaluated for the analysis of natural resins. Five main ingredients of lacquer were studied: sandarac, mastic, colophony, Manila copal and Congo copal. For each, five temperature programs were tested: four fixed temperatures (350, 480, 550, 650 degrees C) and one ultrafast thermal desorption (UFD), in which the temperature rises from 350 to 660 degrees C in 1 min. In total, the integrated signals of 27 molecules, partially characterizing the five resins, were monitored to compare the different methods. A compromise between detection of compounds released at low temperatures and compounds formed at high temperatures was searched. 650 degrees C is too high for both groups, 350 degrees C is best for the first, and 550 degrees C for the second. Fixed temperatures of 480 degrees C or UFD proved to be a consensus in order to detect most marker molecules. UFD was slightly better for the molecules released at low temperatures, while 480 degrees C showed best compounds formed at high temperatures

Systemic AAV vectors for widespread and targeted gene delivery in rodents

We recently developed adeno-associated virus (AAV) capsids to facilitate efficient and noninvasive gene transfer to the central and peripheral nervous systems. However, a detailed protocol for generating and systemically delivering novel AAV variants was not previously available. In this protocol, we describe how to produce and intravenously administer AAVs to adult mice to specifically label and/or genetically manipulate cells in the nervous system and organs, including the heart. The procedure comprises three separate stages: AAV production, intravenous delivery, and evaluation of transgene expression. The protocol spans 8 d, excluding the time required to assess gene expression, and can be readily adopted by researchers with basic molecular biology, cell culture, and animal work experience. We provide guidelines for experimental design and choice of the capsid, cargo, and viral dose appropriate for the experimental aims. The procedures outlined here are adaptable to diverse biomedical applications, from anatomical and functional mapping to gene expression, silencing, and editing

Taxonomy based on science is necessary for global conservation

Peer reviewe

Integration of epitaxial colossal magnetoresistive films onto Si(100) using SrTiO\u3csub\u3e3\u3c/sub\u3e as a template layer

We report on the integration of epitaxial colossal magnetoresistive La0.67Ba0.33MnO films on Si(100) semiconductor using SrTiO3 template layer by pulsed-laser deposition. X-ray diffraction reveals the superior quality of the manganite film that grows epitaxially on heteroepitaxially grown SrTiO3 template layer on Si substrate. The epitaxial films demonstrate remarkable surface morphology, magnetic transition and hysteresis, magnetoresistance, and ferromagnetic resonance, illustrating the ferromagnetic nature of the film and possible device applications at room temperature

Visible light-induced switching of soft matter materials properties based on thioindigo photoswitches

Thioindigos are visible light responsive photoswitches with excellent spatial control over the conformational change between their trans- and cis- isomers. However, they possess limited solubility in all conventional organic solvents and polymers, hindering their application in soft matter materials. Herein, we introduce a strategy for the covalent insertion of thioindigo units into polymer main chains, enabling thioindigos to function within crosslinked polymeric hydrogels. We overcome their solubility issue by developing a thioindigo bismethacrylate linker able to undergo radical initiated thiol-ene reaction for step-growth polymerization, generating indigo-containing polymers. The optimal wavelength for the reversible trans-/cis- isomerisation of thioindigo was elucidated by constructing a detailed photochemical action plot of their switching efficiencies at a wide range of monochromatic wavelengths. Critically, indigo-containing polymers display significant photoswitching of the materials’ optical and physical properties in organic solvents and water. Furthermore, the photoswitching of thioindigo within crosslinked structures enables visible light induced modulation of the hydrogel stiffness. Both the thioindigo-containing hydrogels and photoswitching processes are non-toxic to cells, thus offering opportunities for advanced applications in soft matter materials and biology-related research

Improved imputation quality of low-frequency and rare variants in European samples using the ‘Genome of The Netherlands'

Although genome-wide association studies (GWAS) have identified many common variants associated with complex traits, low-frequency and rare variants have not been interrogated in a comprehensive manner. Imputation from dense reference panels, such as the 1000 Genomes Project (1000G), enables testing of ungenotyped variants for association. Here we present the results of imputation using a large, new population-specific panel: the Genome of The Netherlands (GoNL). We benchmarked the performance of the 1000G and GoNL reference sets by comparing imputation genotypes with ‘true' genotypes typed on ImmunoChip in three European populations (Dutch, British, and Italian). GoNL showed significant improvement in the imputation quality for rare variants (MAF 0.05–0.5%) compared with 1000G. In Dutch samples, the mean observed Pearson correlation, r2, increased from 0.61 to 0.71. We also saw improved imputation accuracy for other European populations (in the British samples, r2 improved from 0.58 to 0.65, and in the Italians from 0.43 to 0.47). A combined reference set comprising 1000G and GoNL improved the imputation of rare variants even further. The Italian samples benefitted the most from this combined reference (the mean r2 increased from 0.47 to 0.50). We conclude that the creation of a large population-specific reference is advantageous for imputing rare variants and that a combined reference panel across multiple populations yields the best imputation results

Activation and Monitoring of mtDNA Damage in Cancer Cells via the "proton-Triggered" Decomposition of an Ultrathin Nanosheet

Mitochondrial DNA (mtDNA) damage is a very important molecular event, which has significant effects on living organisms. Therefore, a particularly important challenge for biomaterials research is to develop functionalized nanoparticles that can activate and monitor mtDNA damage and instigate cancer cell apoptosis, and as such eliminate the negative effects on living organisms. Toward that goal, with this research, we have developed a hydroxyapatite ultrathin nanosheet (HAP-PDCns) - a high Ca2+ content biomaterial. HAP-PDCns undergoes proton-triggered decomposition after entering cancer cells via clathrin-mediated endocytosis, and then, it selectively concentrates in the charged mitochondrial membrane. This kind of proton-triggered decomposition phenomenon facilitates mtDNA damage by causing instantaneous local calcium overload in the mitochondria of cancer cells, and inhibits tumor growth. Importantly, at the same time, a real-time green-red-green fluorescence change occurs that correlates with the degree of mtDNA deterioration because of the changes in the highest occupied molecular orbital-lowest unoccupied molecular orbital energy gaps during this process. Significantly, the decomposition and the fluorescence changes cannot be triggered in normal cells. Thus, HAP-PDCns can selectively induce apoptosis and the death of a cancer cell by facilitating mtDNA damage, but does not affect normal cells. In addition, HAP-PDCns can simultaneously monitor the degree of mtDNA damage. We anticipate that this design strategy can be generalized to develop other functionalized biomaterials that can be used to instigate the positive effects of mtDNA damage on living organisms while eliminating any negative effects. </p