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Insulin/IGF Signaling in Early Brain Development
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Selma Yagoub, Rachel N. Lippert
After the closure of the neural chord, the proliferation of neuronal cells occurs. This neurogenesis is mediated in part by insulin but has primarily been studied in the context of IGF signaling. Seminal studies have concentrated on the role of these peptides in neurogenesis in the chick embryonic retina. Further studies using in vitro models have confirmed the role of insulin, IGF-1 and IGF-2 as trophic factors for neurons in culture. Using cultured sympathetic neurons from 7-day-old chick embryos, insulin, IGF-1 and IGF-2 induced a significant increase in proliferation of this neuronal cell type (29). The specific action of IGF1 and IGF2 on this process was via the Insulin-like Growth Factor Binding Proteins (IGFBPs) rather than directly via receptor-mediated signaling. In primary fetal rat neuronal cells, IGF-1 increases the survival and expansion of neuronal and non-neuronal cell populations (30). Further, stimulation of growth of neural stem cells (NSCs) by other growth factors, such as EGF and FGF-2 requires the presence of IGF-1 (31). This effect is mediated by the phosphorylation of Akt/Bad/Bcl-2 signaling and the phosphorylation of Akt at Thr308 and Ser473 and is inhibited in the presence of excess PTEN, a protein phosphatase, as shown in Figure 2.1 (32, 33). The derivation of neural tissues from embryonic stem cells necessitates IGF-2 signaling via the IGF1-R and subsequent modulation of neural markers, SOX1, IRX3, and SIX3, further indicating a role of the IGF axis in neurogenesis and differentiation (34).
Neuromuscular Junction Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Diana Mnatsakanova, Qin Li Jiang
Studies showed that anti-SOX1 antibody is found in 64–67% of patients with LEMS and SCLC, and only 0–5% LEMS patients without tumor. It is used as a marker for early tumor detection in patients diagnosed with LEMS and is highly specific in distinguishing between LEMS with or without tumor.21,22
Multi-omics Analysis
Published in Altuna Akalin, Computational Genomics with R, 2020
Inspection of the factor coefficients in the heatmap above reveals that Joint NMF has found two nearly orthogonal non-negative factors. One is associated with high expression of the HOXC11, ZIC5, and XIRP1 genes, frequent mutations in the BRAF, PCDHGA6, and DNAH5 genes, as well as losses in the 18q12.2 and gains in 8p21.1 cytobands. The other factor is associated with high expression of the SOX1 gene, more frequent mutations in the APC, KRAS, and TP53 genes, and a weak association with some CNVs.
Developmental neurotoxicity of silver nanoparticles: the current state of knowledge and future directions
Published in Nanotoxicology, 2022
Lidia Strużyńska, Beata Dąbrowska-Bouta, Grzegorz Sulkowski
In vitro models that use embryonic neural stem cells (NSCs) from mouse (Yin et al. 2018), human, and rat fetuses (Liu et al. 2015), and primary organotypic mouse midbrain cultures (Weldon et al. 2018) have been developed to determine whether AgNPs are capable of causing developmental neurotoxicity. The data from in vitro studies demonstrate that AgNPs perturb cell-specific differentiation processes in neural progenitors and induce abnormal expression of neural ectoderm marker genes, such as Sox1, Sox3, Map2, NeuroD, Nestin, and Pax6, at concentrations below 0.1 μg/mL (Yin et al. 2018). However, as the complexity of the CNS is extremely high and its proper functioning depends on the multidirectional interactions of brain cells which are impossible to reproduce in culture, we believe that in vitro models of AgNPs neurotoxicity are not as useful as animal models, particularly the rodent models which are frequently used for this purpose. According to the reported data, despite different time scales, the sequence of key events in brain development and maturation is largely consistent between humans and rodents and similarities in regional vulnerability to brain injuries can be observed (Semple et al. 2013).
What human blood-brain barrier models can tell us about BBB function and drug discovery?
Published in Expert Opinion on Drug Discovery, 2019
Human astrocytes have been derived either from hiPSC-derived neural stem cells (NSCs) [32] or cell aggregates (EZ spheres) [26]. The NSCs were characterized by the expression of markers including transcription factors SOX1 and SOX2 as well as the intermediate filament protein NESTIN and the absence of pluripotency and astroglial markers [32]. The NSCs were then differentiated into astrocytes expressing the protein glial fibrillary acidic protein (GFAP). For the differentiation protocol comprising a cell aggregate step, iPSCs were initially differentiated as cell aggregates (EZ spheres) and subsequently, using astrocyte induction medium supplemented with RA, differentiated into astrospheres, a neural progenitor population [26]. Astrospheres were differentiated into astrocytes in culture medium supplemented with N2 ultimately yielding cells with glial morphology, expression of GFAP and S100 calcium-binding protein (S100B), and absence of the expression of PAX-6 or βIII tubulin.
Amifampridine for the treatment of Lambert-Eaton myasthenic syndrome
Published in Expert Review of Clinical Immunology, 2019
Because of the high prevalence of SCLC in LEMS, it is mandatory to perform a careful tumor screening, especially in patients with a history of smoking. SCLC is usually identified within 2 years of the diagnosis of LEMS using modern diagnostic tests [9]. The best diagnostic test for SCLC is a high-resolution chest CT scans and possibly also a bronchoscopy and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scan if the CT scan is negative. Screening detected 96% of SCLC within 1 year of diagnosis of LEMS according to Titulaer’s study [9] Follow-up should be continued with a CT scan every 6 months for at least 2 years. Sixty-four percent of LEMS with SCLC also were found to have antibodies against SOX1, an immunogenic tumor antigen in SCLC [17]. Reports suggest that SOX1 may play a role as an early marker of the future predisposition to paraneoplastic LEMS. The presence of SOX1 antibodies has a specificity of 95% for SCLC-LEMS but sensitivity is only 65%.