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A derivatization and validation strategy for determining the spatial localization of endogenous amine metabolites in tissues using MALDI imaging mass spectrometry.
Manier ML, Spraggins JM, Reyzer ML, Norris JL, Caprioli RM
(2014) J Mass Spectrom 49: 665-73
MeSH Terms: Acrolein, Adrenal Glands, Amino Acids, Animals, Catecholamines, Cerebellum, Chromatography, High Pressure Liquid, Histocytochemistry, Molecular Imaging, Rats, Reproducibility of Results, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Swine
Show Abstract · Added February 12, 2015
Imaging mass spectrometry (IMS) studies increasingly focus on endogenous small molecular weight metabolites and consequently bring special analytical challenges. Since analytical tissue blanks do not exist for endogenous metabolites, careful consideration must be given to confirm molecular identity. Here, we present approaches for the improvement in detection of endogenous amine metabolites such as amino acids and neurotransmitters in tissues through chemical derivatization and matrix-assisted laser desorption/ionization (MALDI) IMS. Chemical derivatization with 4-hydroxy-3-methoxycinnamaldehyde (CA) was used to improve sensitivity and specificity. CA was applied to the tissue via MALDI sample targets precoated with a mixture of derivatization reagent and ferulic acid as a MALDI matrix. Spatial distributions of chemically derivatized endogenous metabolites in tissue were determined by high-mass resolution and MS(n) IMS. We highlight an analytical strategy for metabolite validation whereby tissue extracts are analyzed by high-performance liquid chromatography (HPLC)-MS/MS to unambiguously identify metabolites and distinguish them from isobaric compounds.
Copyright © 2014 John Wiley & Sons, Ltd.
1 Communities
3 Members
0 Resources
13 MeSH Terms
Implementation of a Gaussian beam laser and aspheric optics for high spatial resolution MALDI imaging MS.
Zavalin A, Yang J, Haase A, Holle A, Caprioli R
(2014) J Am Soc Mass Spectrom 25: 1079-82
MeSH Terms: Animals, Cerebellum, Lasers, Mice, Molecular Imaging, Optics and Photonics, Proteins, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Show Abstract · Added May 20, 2014
We have investigated the use of a Gaussian beam laser for MALDI Imaging Mass Spectrometry to provide a precisely defined laser spot of 5 μm diameter on target using a commercial MALDI TOF instrument originally designed to produce a 20 μm diameter laser beam spot at its smallest setting. A Gaussian beam laser was installed in the instrument in combination with an aspheric focusing lens. This ion source produced sharp ion images at 5 μm spatial resolution with signals of high intensity as shown for images from thin tissue sections of mouse brain.
1 Communities
1 Members
0 Resources
8 MeSH Terms
Temporal identity transition from Purkinje cell progenitors to GABAergic interneuron progenitors in the cerebellum.
Seto Y, Nakatani T, Masuyama N, Taya S, Kumai M, Minaki Y, Hamaguchi A, Inoue YU, Inoue T, Miyashita S, Fujiyama T, Yamada M, Chapman H, Campbell K, Magnuson MA, Wright CV, Kawaguchi Y, Ikenaka K, Takebayashi H, Ishiwata S, Ono Y, Hoshino M
(2014) Nat Commun 5: 3337
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Cells, Cultured, Cerebellum, GABAergic Neurons, Immunohistochemistry, Interneurons, Mice, Nerve Tissue Proteins, Oligodendrocyte Transcription Factor 2, Purkinje Cells, Stem Cells, Transcription Factors
Show Abstract · Added March 14, 2014
In the cerebellum, all GABAergic neurons are generated from the Ptf1a-expressing ventricular zone (Ptf1a domain). However, the machinery to produce different types of GABAergic neurons remains elusive. Here we show temporal regulation of distinct GABAergic neuron progenitors in the cerebellum. Within the Ptf1a domain at early stages, we find two subpopulations; dorsally and ventrally located progenitors that express Olig2 and Gsx1, respectively. Lineage tracing reveals the former are exclusively Purkinje cell progenitors (PCPs) and the latter Pax2-positive interneuron progenitors (PIPs). As development proceeds, PCPs gradually become PIPs starting from ventral to dorsal. In gain- and loss-of-function mutants for Gsx1 and Olig1/2, we observe abnormal transitioning from PCPs to PIPs at inappropriate developmental stages. Our findings suggest that the temporal identity transition of cerebellar GABAergic neuron progenitors from PCPs to PIPs is negatively regulated by Olig2 and positively by Gsx1, and contributes to understanding temporal control of neuronal progenitor identities.
3 Communities
2 Members
1 Resources
13 MeSH Terms
The Purkinje neuron acts as a central regulator of spatially and functionally distinct cerebellar precursors.
Fleming JT, He W, Hao C, Ketova T, Pan FC, Wright CC, Litingtung Y, Chiang C
(2013) Dev Cell 27: 278-92
MeSH Terms: Animals, Astrocytes, Cell Differentiation, Cell Proliferation, Cells, Cultured, Cerebellum, Flow Cytometry, Hedgehog Proteins, Immunoenzyme Techniques, Mice, Mice, Knockout, Neural Stem Cells, Neurons, Purkinje Cells, RNA, Messenger, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, gamma-Aminobutyric Acid
Show Abstract · Added December 2, 2013
The prospective white matter (PWM) in the nascent cerebellum contains a transient germinal compartment that produces all postnatally born GABAergic inhibitory interneurons and astrocytes. However, little is known about the molecular identity and developmental potential of resident progenitors or key regulatory niche signals. Here, we show that neural stem-cell-like primary progenitors (Tnc(YFP-low) CD133(+)) generate intermediate astrocyte (Tnc(YFP-low) CD15(+)) precursors and GABAergic transient amplifying (Ptf1a(+)) cells. Interestingly, these lineally related but functionally divergent progenitors commonly respond to Sonic hedgehog (Shh), and blockade of reception in TNC(YFP-low) cells attenuates proliferation in the PWM, reducing both intermediate progenitor classes. Furthermore, we show that Shh produced from distant Purkinje neurons maintains the PWM niche independently of its classical role in regulating granule cell precursor proliferation. Our results indicate that Purkinje neurons maintain a bidirectional signaling axis, driving the production of spatially and functionally opposed inhibitory and excitatory interneurons important for motor learning and cognition.
Copyright © 2013 Elsevier Inc. All rights reserved.
2 Communities
3 Members
0 Resources
18 MeSH Terms
Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1.
Cologna SM, Cluzeau CV, Yanjanin NM, Blank PS, Dail MK, Siebel S, Toth CL, Wassif CA, Lieberman AP, Porter FD
(2014) J Inherit Metab Dis 37: 83-92
MeSH Terms: 1-Deoxynojirimycin, Adolescent, Alleles, Animals, Biomarkers, Brain, Cerebellum, Cerebral Cortex, Chemokine CCL3, Chemokine CXCL5, Child, Child, Preschool, Complement C3, Disease Models, Animal, Female, Gene Expression Regulation, Humans, Infant, Infant, Newborn, Inflammation, Interleukins, Male, Mice, Mice, Inbred BALB C, Mice, Transgenic, Niemann-Pick Disease, Type C, Young Adult
Show Abstract · Added March 13, 2014
Niemann-Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post-mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C-X-C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL-3, IL-10 and IL-13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.
0 Communities
1 Members
0 Resources
27 MeSH Terms
Quantitative proteomic analysis of Niemann-Pick disease, type C1 cerebellum identifies protein biomarkers and provides pathological insight.
Cologna SM, Jiang XS, Backlund PS, Cluzeau CV, Dail MK, Yanjanin NM, Siebel S, Toth CL, Jun HS, Wassif CA, Yergey AL, Porter FD
(2012) PLoS One 7: e47845
MeSH Terms: Alzheimer Disease, Animals, Biomarkers, Blotting, Western, Cerebellum, Child, Electrophoresis, Gel, Two-Dimensional, Female, Gene Expression Profiling, Humans, Intracellular Signaling Peptides and Proteins, Mass Spectrometry, Mice, Mice, Inbred BALB C, Mice, Knockout, Middle Aged, Niemann-Pick Disease, Type C, Oligonucleotide Array Sequence Analysis, Prefrontal Cortex, Proteins, Proteome, Proteomics, Reverse Transcriptase Polymerase Chain Reaction
Show Abstract · Added March 13, 2014
Niemann-Pick disease, type C1 (NPC1) is a fatal, neurodegenerative disorder for which there is no definitive therapy. In NPC1, a pathological cascade including neuroinflammation, oxidative stress and neuronal apoptosis likely contribute to the clinical phenotype. While the genetic cause of NPC1 is known, we sought to gain a further understanding into the pathophysiology by identifying differentially expressed proteins in Npc1 mutant mouse cerebella. Using two-dimensional gel electrophoresis and mass spectrometry, 77 differentially expressed proteins were identified in Npc1 mutant mice cerebella compared to controls. These include proteins involved in glucose metabolism, detoxification/oxidative stress and Alzheimer disease-related proteins. Furthermore, members of the fatty acid binding protein family, including FABP3, FABP5 and FABP7, were found to have altered expression in the Npc1 mutant cerebellum relative to control. Translating our findings from the murine model to patients, we confirm altered expression of glutathione s-transferase α, superoxide dismutase, and FABP3 in cerebrospinal fluid of NPC1 patients relative to pediatric controls. A subset of NPC1 patients on miglustat, a glycosphingolipid synthesis inhibitor, showed significantly decreased levels of FABP3 compared to patients not on miglustat therapy. This study provides an initial report of dysregulated proteins in NPC1 which will assist with further investigation of NPC1 pathology and facilitate implementation of therapeutic trials.
0 Communities
1 Members
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23 MeSH Terms
The index case for the fungal meningitis outbreak in the United States.
Pettit AC, Kropski JA, Castilho JL, Schmitz JE, Rauch CA, Mobley BC, Wang XJ, Spires SS, Pugh ME
(2012) N Engl J Med 367: 2119-25
MeSH Terms: Aspergillosis, Aspergillus fumigatus, Brain, Cerebellum, Cerebral Infarction, Cerebrospinal Fluid, Diagnosis, Differential, Disease Outbreaks, Drug Contamination, Fatal Outcome, Glucocorticoids, Headache, Humans, Injections, Epidural, Intracranial Hemorrhages, Low Back Pain, Male, Meningitis, Fungal, Middle Aged, Tomography, X-Ray Computed, United States
Show Abstract · Added August 14, 2014
Persistent neutrophilic meningitis presents a diagnostic challenge, because the differential diagnosis is broad and includes atypical infectious causes. We describe a case of persistent neutrophilic meningitis due to Aspergillus fumigatus in an immunocompetent man who had no evidence of sinopulmonary or cutaneous disease. An epidural glucocorticoid injection was identified as a potential route of entry for this organism into the central nervous system, and the case was reported to the state health department.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Fractional anisotropy distributions in 2- to 6-year-old children with autism.
Cascio C, Gribbin M, Gouttard S, Smith RG, Jomier M, Field S, Graves M, Hazlett HC, Muller K, Gerig G, Piven J
(2013) J Intellect Disabil Res 57: 1037-49
MeSH Terms: Anisotropy, Autistic Disorder, Brain, Cerebellum, Cerebral Cortex, Child, Child, Preschool, Cross-Sectional Studies, Diffusion Tensor Imaging, Female, Humans, Longitudinal Studies, Male, Nerve Fibers, Myelinated
Show Abstract · Added March 14, 2018
BACKGROUND - Increasing evidence suggests that autism is a disorder of distributed neural networks that may exhibit abnormal developmental trajectories. Characterisation of white matter early in the developmental course of the disorder is critical to understanding these aberrant trajectories.
METHODS - A cross-sectional study of 2- to 6-year-old children with autism was conducted using diffusion tensor imaging combined with a novel statistical approach employing fractional anisotropy distributions. Fifty-eight children aged 18-79 months were imaged: 33 were diagnosed with autism, 8 with general developmental delay, and 17 were typically developing. Fractional anisotropy values within global white matter, cortical lobes and the cerebellum were measured and transformed to random F distributions for each subject. Each distribution of values for a region was summarised by estimating δ, the estimated mean and standard deviation of the approximating F for each distribution.
RESULTS - The estimated δ parameter, , was significantly decreased in individuals with autism compared to the combined control group. This was true in all cortical lobes, as well as in the cerebellum, but differences were most robust in the temporal lobe. Predicted developmental trajectories of across the age range in the sample showed patterns that partially distinguished the groups. Exploratory analyses suggested that the variability, rather than the central tendency, component of was the driving force behind these results.
CONCLUSIONS - While preliminary, our results suggest white matter in young children with autism may be abnormally homogeneous, which may reflect poorly organised or differentiated pathways, particularly in the temporal lobe, which is important for social and emotional cognition.
© 2012 The Authors. Journal of Intellectual Disability Research © 2012 John Wiley & Sons Ltd, MENCAP & IASSID.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Approaching expert results using a hierarchical cerebellum parcellation protocol for multiple inexpert human raters.
Bogovic JA, Jedynak B, Rigg R, Du A, Landman BA, Prince JL, Ying SH
(2013) Neuroimage 64: 616-29
MeSH Terms: Algorithms, Atrophy, Cerebellum, Humans, Image Enhancement, Image Interpretation, Computer-Assisted, Observer Variation, Pattern Recognition, Automated, Professional Competence, Reproducibility of Results, Sensitivity and Specificity
Show Abstract · Added March 26, 2014
Volumetric measurements obtained from image parcellation have been instrumental in uncovering structure-function relationships. However, anatomical study of the cerebellum is a challenging task. Because of its complex structure, expert human raters have been necessary for reliable and accurate segmentation and parcellation. Such delineations are time-consuming and prohibitively expensive for large studies. Therefore, we present a three-part cerebellar parcellation system that utilizes multiple inexpert human raters that can efficiently and expediently produce results nearly on par with those of experts. This system includes a hierarchical delineation protocol, a rapid verification and evaluation process, and statistical fusion of the inexpert rater parcellations. The quality of the raters' and fused parcellations was established by examining their Dice similarity coefficient, region of interest (ROI) volumes, and the intraclass correlation coefficient of region volume. The intra-rater ICC was found to be 0.93 at the finest level of parcellation.
Copyright © 2012 Elsevier Inc. All rights reserved.
0 Communities
1 Members
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11 MeSH Terms
Bax deficiency prolongs cerebellar neurogenesis, accelerates medulloblastoma formation and paradoxically increases both malignancy and differentiation.
Garcia I, Crowther AJ, Gama V, Miller CR, Miller CR, Deshmukh M, Gershon TR
(2013) Oncogene 32: 2304-14
MeSH Terms: Animals, Apoptosis, Cell Differentiation, Cell Movement, Cerebellar Neoplasms, Cerebellum, Down-Regulation, Medulloblastoma, Mice, Mice, Transgenic, Neurogenesis, Proto-Oncogene Proteins c-bcl-2, Receptors, G-Protein-Coupled, Smoothened Receptor, Stem Cells, bcl-2-Associated X Protein
Show Abstract · Added October 26, 2015
Neurogenesis requires negative regulation through differentiation of progenitors or their programmed cell death (PCD). Growth regulation is particularly important in the postnatal cerebellum, where excessive progenitor proliferation promotes medulloblastoma, the most common malignant brain tumor in children. We present evidence that PCD operates alongside differentiation to regulate cerebellar granule neuron progenitors (CGNPs) and to prevent medulloblastoma. Here, we show that genetic deletion of pro-apoptotic Bax disrupts regulation of cerebellar neurogenesis and promotes medulloblastoma formation. In Bax(-/-) mice, the period of neurogenesis was extended into the third week of postnatal life, and ectopic neurons and progenitors collected in the molecular layer of the cerebellum and adjacent tectum. Importantly, genetic deletion of Bax in medulloblastoma-prone ND2:SmoA1 transgenic mice greatly accelerated tumorigenesis. Bax-deficient medulloblastomas exhibited strikingly distinct pathology, with reduced apoptosis, increased neural differentiation and tectal migration. Comparing Bax(+/+) and Bax(-/-) medulloblastomas, we were able to identify upregulation of Bcl-2 and nuclear exclusion of p27 as tumorigenic changes that are required to mitigate the tumor suppressive effect of Bax. Studies on human tumors confirmed the importance of modulating Bax in medulloblastoma pathogenesis. Our results demonstrate that Bax-dependent apoptosis regulates postnatal cerebellar neurogenesis, suppresses medulloblastoma formation and imposes selective pressure on tumors that form. Functional resistance to Bax-mediated apoptosis, required for medulloblastoma tumorigenesis, may be a tumor-specific vulnerability to be exploited for therapeutic benefit.
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16 MeSH Terms