Huntington disease (HD) is fatal in humans within
Figure 2 and its legend should appear as follows: Figure 2. Spatial distribution of characteristic m/z values for the traumatized, trauma adjacent, and healthy muscle regions. (A) Average peak MALDI mass spectra intensity of primary trauma (tm, red) and trauma adjacent muscle/healthy (hm, tam, blue) region. (B) HE staining of the healthy and the injured soleus muscle in the region of interest are indicated by the red (tm), black (tam), and green (hm) frame. Ion density distributions to the corresponding spectra peak intensity by using (C) supervised approach (ClinProTools) and (D) unsupervised approach (SCiLS Lab). The m/z values 976 and 1488 show significantly lower intensities (p < 0.05) in the primary trauma region (tm) compared to the trauma adjacent (tam) or healthy (hm) muscle regions. In contrast, the m/z values 985 and 1255 exhibited significantly higher intensities (p < 0.05) in the primary trauma region (tm) compared to tam and hm regions. C
Hypoxia is a pro-fibrotic stimulus, which is associated with enhanced collagen synthesis, as well as with augmented collagen prolyl 4-hydroxylase (C-P4H) activity. C-P4H activity is controlled mainly by regulated expression of the ␣ C-P4H subunit.In this study we demonstrate that the increased synthesis of C-P4H-␣(I) protein in human HT1080 fibroblasts under long term hypoxia (36 h, 1% oxygen) is controlled at the translational level. This is mediated by an interaction of RNA-binding protein nucleolin (ϳ64 kDa form) at the 5-and 3-untranslated regions (UTR) of the mRNA. The 5/3-UTR-dependent mechanism elevates the C-P4H-␣(I) expression rate 2.3-fold, and participates in a 5.3-fold increased protein level under long term hypoxia. The interaction of nucleolin at the 5-UTR occurs directly and depends on the existence of an AU-rich element. Statistical evaluation of the ϳ64-kDa nucleolin/RNA interaction studies revealed a core binding sequence, corresponding to UAAAUC or AAAUCU. At the 3-UTR, nucleolin assembles indirectly via protein/protein interaction, with the help of another 3-UTRbinding protein, presumably annexin A2. The increased protein level of the ϳ64-kDa nucleolin under hypoxia can be attributed to an autocatalytic cleavage of a high molecular weight nucleolin form, without alterations in nucleolin mRNA concentration. Thus, the alteration of translational efficiency by nucleolin, which occurs through a hypoxia inducible factor independent pathway, is an important step in C-P4H-␣(I) regulation under hypoxia.
Wound contraction is an ancient survival mechanism of vertebrates that results from tensile forces supporting wound closure. So far, tissue tension was attributed to cellular forces produced by tissue‐resident (myo‐)fibroblasts alone. However, difficulties in explaining pathological deviations from a successful healing path motivate the exploration of additional modulatory factors. Here, it is shown in a biomaterial‐based in vitro wound healing model that the storage of tensile forces in the extracellular matrix has a significant, so‐far neglected contribution to macroscopic tissue tension. In situ monitoring of tissue forces together with second harmonic imaging reveal that the appearance of collagen fibrils correlates with tissue contraction, indicating a mechanical contribution of tensioned collagen fibrils in the contraction process. As the re‐establishment of tissue tension is key to successful wound healing, the findings are expected to advance the understanding of tissue healing but also underlying principles of misregulation and impaired functionality in scars and tissue contractures.
The developing mammalian brain experiences a period of rapid growth during which various otherwise innocuous environmental factors cause widespread apoptotic neuronal death. To gain insight into developmental events influenced by a premature exposure to high oxygen levels and identify proteins engaged in neurodegenerative and reparative processes, we analyzed mouse brain proteome changes at P7, P14 and P35 caused by an exposure to hyperoxia at P6. Changes detected in the brain proteome suggested that hyperoxia leads to oxidative stress and apoptotic neuronal death. These changes were consistent with results of histological and biochemical evaluation of the brains, which revealed widespread apoptotic neuronal death and increased levels of protein carbonyls. Furthermore, we detected changes in proteins involved in synaptic function, cell proliferation and formation of neuronal connections, suggesting interference of oxidative stress with these developmental events. These effects are age-dependent, as they did not occur in mice subjected to hyperoxia in adolescence.
Purpose Precise histological classification of epithelial ovarian cancer (EOC) has immanent diagnostic and therapeutic consequences, but remains challenging in histological routine. The aim of this pilot study is to examine the potential of matrix‐assisted laser desorption/ionization (MALDI) imaging mass spectrometry in combination with machine learning methods to classify EOC histological subtypes from tissue microarray. Experimental design Formalin‐fixed‐paraffin‐embedded tissue of 20 patients with ovarian clear‐cell, 14 low‐grade serous, 19 high‐grade serous ovarian carcinomas, and 14 serous borderline tumors are analyzed using MALDI‐Imaging. Classifications are computed by linear discriminant analysis (LDA), support vector machines with linear (SVM‐lin) and radial basis function kernels (SVM‐rbf), a neural network (NN), and a convolutional neural network (CNN). Results MALDI‐Imaging and machine learning methods result in classification of EOC histotypes with mean accuracy of 80% for LDA, 80% SVM‐lin, 74% SVM‐rbf, 83% NN, and 85% CNN. Based on sensitivity (69–100%) and specificity (90–99%), CCN and NN are most suited to EOC classification. Conclusion and clinical relevance The pilot study demonstrates the potential of MALDI‐Imaging derived proteomic classifiers in combination with machine learning algorithms to discriminate EOC histotypes. Applications may support the development of new prognostic parameters in the assessment of EOC.
Neurotransmitter signaling is essential for physiologic brain development. Sedative and anticonvulsant agents that reduce neuronal excitability via antagonism at Nmethyl-D-aspartate receptors (NMDARs) and/or agonism at ␥-aminobutyric acid subtype A receptors (GABA A Rs) are applied frequently in obstetric and pediatric medicine. We demonstrated that a 1-day treatment of infant mice at postnatal day 6 (P6) with the NMDAR antagonist dizocilpine or the GABA A R agonist phenobarbital not only has acute but also long term effects on the cerebral cortex. Changes of the cerebral cortex proteome 1 day (P7), 1 week (P14), and 4 weeks (P35) following treatment at P6 suggest that a suppression of synaptic neurotransmission during brain development dysregulates proteins associated with apoptosis, oxidative stress, inflammation, cell proliferation, and neuronal circuit formation. These effects appear to be age-dependent as most protein changes did not occur in mice subjected to such pharmacological treatment in adulthood. Previously performed histological evaluations of the brains revealed widespread apoptosis and decreased cell proliferation following such a drug treatment in infancy and are thus consistent with brain protein changes reported in this study. Our results point toward several pathways modulated by a reduction of neuronal excitability that might interfere with critical developmental events and thus affirm concerns about the impact of NMDAR-and/or GABA A
Treatment of mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridene hydrochloride (MPTP) is a well established animal model for Parkinson's disease (PD), while overexpression of L1 cell adhesion molecule (L1cam) has been proposed to attenuate the degeneration of dopaminergic neurons induced by MPTP. To gain insight into the role of L1cam in the pathomechanism of PD, we investigated protein expression patterns after MPTP-treatment in both C57BL/6 (wild-type) and transgenic mice overexpressing L1cam in astrocytes. Our results showed that during the acute phase, proteins in functional complexes responsible for mitochondrial, glycolysis, and cytoskeletal function were down-regulated in MPTP-treated wild-type mice. After a recovery phase, proteins that were down-regulated in the acute phase reverted to normal levels. In L1cam transgenic mice, a much higher number of proteins was altered during the acute phase and this number even increased after the recovery phase. Many proteins involved in oxidative phosphorylation were still down-regulated and glycolysis related protein were still up-regulated. This pattern indicates a lasting severely impaired energy production in L1cam mice after MPTP treatment.
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