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1.  Fiji - an Open Source platform for biological image analysis 
Nature methods  2012;9(7):10.1038/nmeth.2019.
Fiji is a distribution of the popular Open Source software ImageJ focused on biological image analysis. Fiji uses modern software engineering practices to combine powerful software libraries with a broad range of scripting languages to enable rapid prototyping of image processing algorithms. Fiji facilitates the transformation of novel algorithms into ImageJ plugins that can be shared with end users through an integrated update system. We propose Fiji as a platform for productive collaboration between computer science and biology research communities.
doi:10.1038/nmeth.2019
PMCID: PMC3855844  PMID: 22743772
3.  Derivation and Expansion Using Only Small Molecules of Human Neural Progenitors for Neurodegenerative Disease Modeling 
PLoS ONE  2013;8(3):e59252.
Phenotypic drug discovery requires billions of cells for high-throughput screening (HTS) campaigns. Because up to several million different small molecules will be tested in a single HTS campaign, even small variability within the cell populations for screening could easily invalidate an entire campaign. Neurodegenerative assays are particularly challenging because neurons are post-mitotic and cannot be expanded for implementation in HTS. Therefore, HTS for neuroprotective compounds requires a cell type that is robustly expandable and able to differentiate into all of the neuronal subtypes involved in disease pathogenesis. Here, we report the derivation and propagation using only small molecules of human neural progenitor cells (small molecule neural precursor cells; smNPCs). smNPCs are robust, exhibit immortal expansion, and do not require cumbersome manual culture and selection steps. We demonstrate that smNPCs have the potential to clonally and efficiently differentiate into neural tube lineages, including motor neurons (MNs) and midbrain dopaminergic neurons (mDANs) as well as neural crest lineages, including peripheral neurons and mesenchymal cells. These properties are so far only matched by pluripotent stem cells. Finally, to demonstrate the usefulness of smNPCs we show that mDANs differentiated from smNPCs with LRRK2 G2019S are more susceptible to apoptosis in the presence of oxidative stress compared to wild-type. Therefore, smNPCs are a powerful biological tool with properties that are optimal for large-scale disease modeling, phenotypic screening, and studies of early human development.
doi:10.1371/journal.pone.0059252
PMCID: PMC3606479  PMID: 23533608
4.  Serum and Cerebrospinal Fluid Levels of Transthyretin in Lewy Body Disorders with and without Dementia 
PLoS ONE  2012;7(10):e48042.
Parkinson’s disease (PD) without (non-demented, PDND) and with dementia (PDD), and dementia with Lewy bodies (DLB) are subsumed under the umbrella term Lewy body disorders (LBD). The main component of the underlying pathologic substrate, i.e. Lewy bodies and Lewy neurites, is misfolded alpha-synuclein (Asyn), and - in particular in demented LBD patients - co-occurring misfolded amyloid-beta (Abeta). Lowered blood and cerebrospinal fluid (CSF) levels of transthyretin (TTR) - a clearance protein mainly produced in the liver and, autonomously, in the choroid plexus - are associated with Abeta accumulation in Alzheimer’s disease. In addition, a recent study suggests that TTR is involved in Asyn clearance. We measured TTR protein levels in serum and cerebrospinal fluid of 131 LBD patients (77 PDND, 26 PDD, and 28 DLB) and 72 controls, and compared TTR levels with demographic and clinical data as well as neurodegenerative markers in the CSF. Five single nucleotide polymorphisms of the TTR gene which are considered to influence the ability of the protein to carry its ligands were also analyzed. CSF TTR levels were significantly higher in LBD patients compared to controls. Post-hoc analysis demonstrated that this effect was driven by PDND patients. In addition, CSF TTR levels correlated negatively with CSF Abeta1–42, total tau and phospho-tau levels. Serum TTR levels did not significantly differ among the studied groups. There were no relevant associations between TTR levels and genetic, demographic and clinical data, respectively. These results suggest an involvement of the clearance protein TTR in LBD pathophysiology, and should motivate to elucidate TTR-related mechanisms in LBD in more detail.
doi:10.1371/journal.pone.0048042
PMCID: PMC3485000  PMID: 23133543
5.  BoneJ: free and extensible bone image analysis in ImageJ 
Bone  2010;47(6):1076-1079.
Bone geometry is commonly measured on computed tomographic (CT) and X-ray microtomographic (μCT) images. We obtained hundreds of CT, μCT and synchrotron μCT images of bones from diverse species that needed to be analysed remote from scanning hardware, but found that available software solutions were expensive, inflexible or methodologically opaque. We implemented standard bone measurements in a novel ImageJ plugin, BoneJ, with which we analysed trabecular bone, whole bones and osteocyte lacunae. BoneJ is open source and free for anyone to download, use, modify and distribute.
doi:10.1016/j.bone.2010.08.023
PMCID: PMC3193171  PMID: 20817052
bone; tomography; image; open source; software; morphometry
6.  An Integrated Micro- and Macroarchitectural Analysis of the Drosophila Brain by Computer-Assisted Serial Section Electron Microscopy 
PLoS Biology  2010;8(10):e1000502.
A new software package allows for dense electron microscopy reconstructions of neuronal networks in the fruit fly brain, and reveals specific differences in microcircuits between insects and vertebrates.
The analysis of microcircuitry (the connectivity at the level of individual neuronal processes and synapses), which is indispensable for our understanding of brain function, is based on serial transmission electron microscopy (TEM) or one of its modern variants. Due to technical limitations, most previous studies that used serial TEM recorded relatively small stacks of individual neurons. As a result, our knowledge of microcircuitry in any nervous system is very limited. We applied the software package TrakEM2 to reconstruct neuronal microcircuitry from TEM sections of a small brain, the early larval brain of Drosophila melanogaster. TrakEM2 enables us to embed the analysis of the TEM image volumes at the microcircuit level into a light microscopically derived neuro-anatomical framework, by registering confocal stacks containing sparsely labeled neural structures with the TEM image volume. We imaged two sets of serial TEM sections of the Drosophila first instar larval brain neuropile and one ventral nerve cord segment, and here report our first results pertaining to Drosophila brain microcircuitry. Terminal neurites fall into a small number of generic classes termed globular, varicose, axiform, and dendritiform. Globular and varicose neurites have large diameter segments that carry almost exclusively presynaptic sites. Dendritiform neurites are thin, highly branched processes that are almost exclusively postsynaptic. Due to the high branching density of dendritiform fibers and the fact that synapses are polyadic, neurites are highly interconnected even within small neuropile volumes. We describe the network motifs most frequently encountered in the Drosophila neuropile. Our study introduces an approach towards a comprehensive anatomical reconstruction of neuronal microcircuitry and delivers microcircuitry comparisons between vertebrate and insect neuropile.
Author Summary
Brains contain a vast number of connections between neurons, termed synapses. The precise patterns of these synaptic contacts form the structural underpinning of electrical microcircuits responsible for animal behavior. Due to their small size, synaptic contacts can be conclusively shown using only high-resolution electron microscopy (EM). Therefore, complete series of ultrathin sections are required to reconstruct neuronal microcircuitry. The acquisition and analysis of EM sections (with 15,000 sections per millimeter of tissue) is practical only by computer-assisted means. In this article, we demonstrate the utility of the software package TrakEM2 to model interconnections of nerve fibers from consecutive EM sections and to efficiently reconstruct the neural networks encountered in different parts of a small brain, the early larval brain of the fruit fly Drosophila melanogaster. Neuronal networks are composed of patterns of axons and dendrites (neuronal extensions that transmit and receive signals, respectively), and using TrakEM2, we describe the most common motifs they form. Our study introduces an approach towards a comprehensive anatomical reconstruction of neuronal microcircuitry and delivers microcircuitry comparisons between vertebrate and insect brains.
doi:10.1371/journal.pbio.1000502
PMCID: PMC2950124  PMID: 20957184
7.  A high-level 3D visualization API for Java and ImageJ 
BMC Bioinformatics  2010;11:274.
Background
Current imaging methods such as Magnetic Resonance Imaging (MRI), Confocal microscopy, Electron Microscopy (EM) or Selective Plane Illumination Microscopy (SPIM) yield three-dimensional (3D) data sets in need of appropriate computational methods for their analysis. The reconstruction, segmentation and registration are best approached from the 3D representation of the data set.
Results
Here we present a platform-independent framework based on Java and Java 3D for accelerated rendering of biological images. Our framework is seamlessly integrated into ImageJ, a free image processing package with a vast collection of community-developed biological image analysis tools. Our framework enriches the ImageJ software libraries with methods that greatly reduce the complexity of developing image analysis tools in an interactive 3D visualization environment. In particular, we provide high-level access to volume rendering, volume editing, surface extraction, and image annotation. The ability to rely on a library that removes the low-level details enables concentrating software development efforts on the algorithm implementation parts.
Conclusions
Our framework enables biomedical image software development to be built with 3D visualization capabilities with very little effort. We offer the source code and convenient binary packages along with extensive documentation at http://3dviewer.neurofly.de.
doi:10.1186/1471-2105-11-274
PMCID: PMC2896381  PMID: 20492697
8.  High-speed panoramic light-sheet microscopy reveals global endodermal cell dynamics 
Nature Communications  2013;4:2207.
The ever-increasing speed and resolution of modern microscopes make the storage and post-processing of images challenging and prevent thorough statistical analyses in developmental biology. Here, instead of deploying massive storage and computing power, we exploit the spherical geometry of zebrafish embryos by computing a radial maximum intensity projection in real time with a 240-fold reduction in data rate. In our four-lens selective plane illumination microscope (SPIM) setup the development of multiple embryos is recorded in parallel and a map of all labelled cells is obtained for each embryo in <10 s. In these panoramic projections, cell segmentation and flow analysis reveal characteristic migration patterns and global tissue remodelling in the early endoderm. Merging data from many samples uncover stereotypic patterns that are fundamental to endoderm development in every embryo. We demonstrate that processing and compressing raw image data in real time is not only efficient but indispensable for image-based systems biology.
Systematic large-scale analysis of embryonic development requires the processing of large amounts of microscopy data. Here Schmid et al. solve this problem by developing a high-speed imaging system that projects zebrafish embryos onto a ‘world map’ in real time, revealing characteristic migration patterns in the early endoderm.
doi:10.1038/ncomms3207
PMCID: PMC3731668  PMID: 23884240

Results 1-8 (8)