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Crystal structure and domains of CaMK1D (PMID: 2JC6). The AID is shown in purple, CaM binding domain in red, activation loop in yellow, and the kinase domain in teal. Elements that do not fall into these categories are shown in grey. The termini are indicated by “N” and “C”.
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Alzheimer’s disease (AD) is the most common cause of dementia worldwide. Despite extensive research and targeting of the main molecular components of the disease, beta-amyloid (Aβ) and tau, there are currently no treatments that alter the progression of the disease. Here, we examine the effects of two specific kinase inhibitors for calcium/calmodul...
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... Genes such as plexin A4 (PLXNA4), neuropilin 2 (NRP2), and members of the nerve growth factor family, including semaphorin 3A (SEMA3A) and semaphorin 3C (SEMA3C), may play roles in neural development and synaptic plasticity [34][35][36][37]. Additionally, calcium/calmodulin dependent protein kinase ID (CAMK1D), glutaredoxin and cysteine rich domain containing 1 (GRXCR1), and FBXO protein 45 (FBXO45) are implicated in cellular stress responses, signaling, cell cycle regulation, and stress responses [38][39][40]. Gammaaminobutyric acid type a receptor subunit alpha2 (GABRA2) and gamma-aminobutyric acid type a receptor subunit beta2 (GABRB2)-which encode GABA receptor subunits-along with adhesion G protein-coupled receptor B1 (ADGRB1) are involved in stress response and emotion regulation [41,42]. Ankyrin repeat domain 1 (ANKRD1) is associated with stress and cardiovascular health [43]. ...
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The duck industry is an important pillar of China’s livestock industry; however, the development of China’s duck industry has been constrained by the low productivity of local domestic duck breeds due to unsystematic selection and breeding. Matahu duck, Weishan partridge duck, and Wendeng black duck are endemic breeds in Shandong with complex genetic backgrounds, which are natural material pools for duck selection and improvement, but the structural variation data at the genomic level have not yet been resolved and are still to be mined. In this study, we synthesized the SV datasets of three breeds using two software programs, LUMPY and DELLY, and counted the distribution of SVs. On this basis, we analyzed their population genetic structure and preliminarily inferred the kinship relationship of the three breeds. This is consistent with the results of our previous research based on single nucleotide polymorphism loci. We used a selection signal analysis method (Fst) for any two of the three breeds among the varieties. We found a significant enrichment of GO entries and KEGG pathways regarding nervous system development in the different breeds. In addition, some genes related to spindle assembly and energy metabolism were also mined. This study identified and annotated the structural variation of three local domestic duck breeds, preliminarily deduced the affinities of the local domestic duck breeds, and divided the genetic differences among different breeds, which provides an important reference for the conservation of duck breed resources and the cultivation of new breeds in China.
... However, adverse effects of environmental chemicals mediated by the CaMKK-CaMKI signaling pathway on developmental processes have been reported recently, such as molt dysfunction, nausea, and vomiting reactions during gestation and lactation Krull et al. 2022). The study has shown that inhibition of calcium/calmodulin-dependent protein kinase ID (CaM-KID) blocks beta-amyloid-induced tau protein aggregation in adult neurons, thereby slowing the progression of Alzheimer's disease (AD) lesions (Grant et al. 2021). Similar to the mechanism of CaMKII regulation of synaptic structure, Ca 2+ located in the synaptic gap enters the postsynaptic membrane via ryanodine receptor (RyR) channels to phosphorylate the CaMKK-CaMKI signaling pathway. ...
Calcium/calmodulin-dependent protein kinases (CaMKs) are important proteins in the calcium signaling cascade response pathway, which can broadly regulate biological functions in vivo. Multifunctional CaMKs play key roles in neural development, including neuronal circuit building, synaptic plasticity establishment, and neurotrophic factor secretion. Currently, four familial proteins, calcium/calmodulin-dependent protein kinase I (CaMKI), calcium/calmodulin-dependent protein kinase II (CaMKII), eukaryotic elongation factor 2 kinase (eEF2K, popularly known as CaMKIII) and calcium/calmodulin-dependent protein kinase IV (CaMKIV), are thought to have been the most extensively studied during neurodevelopment. Although their spatial structures are extremely similar, as well as the initial starting point of activation, both require the activation of calcium and calmodulin (CaM) complexes to be involved in the process, and the phosphorylation sites and modes of each member are different. Furthermore, due to the high structural similarity of CaMKs, their members may play synergistic roles in the regulation of neural development, but different CaMKs also have their own means of regulating neural development. In this review, we first describe the visualized protein structural forms of CaMKI, CaMKII, eEF2K and CaMKIV, and then describe the functions of each kinase in neurodevelopment. After that, we focus on four main mechanisms of neurodevelopmental damage caused by CaMKs: CaMKI/ERK/CREB pathway inhibition leading to dendritic spine structural damage; Ca²⁺/CaM/CaMKII through induction of mitochondrial kinetic disorders leading to neurodevelopmental damage; CaMKIII/eEF2 hyperphosphorylation affects the establishment of synaptic plasticity; and CaMKIV/JNK/NF-κB through induction of an inflammatory response leading to neurodevelopmental damage. In conclusion, we briefly discuss the pathophysiological significance of aberrant CaMK family expression in neurodevelopmental disorders, as well as the protective effects of conventional CaMKII and CaMKIII antagonists against neurodevelopmental injury.
... Alzheimer's disease (AD) is a neurodegenerative disease that is considered the most common cause of dementia. The key pathological hallmarks of AD are plaque and tangle formation arising due to amyloid beta deposition and hyper phosphorylation of tau in brain tissues, respectively (Basaly et al., 2021;Grant et al., 2021). The main clinical symptoms of Alzheimer's disease include cognitive dysfunction and progressive loss of memory. ...
Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease and is associated with dementia. Presently, various chemical and environmental agents are used to induce in-vitro models of Alzheimer disease to investigate the efficacy of different therapeutic drugs. We screened literature from databases such as PubMed, ScienceDirect, and Google scholar, emphasizing the diverse targeting mechanisms of neuro degeneration explored in in-vitro models. The results revealed studies in which different types of chemicals and environmental agents were used for in-vitro development of Alzheimer-targeting mechanisms of neurodegeneration. Studies using chemically induced in-vitro AD models included in this systematic review will contribute to a deeper understanding of AD. However, none of these models can reproduce all the characteristics of disease progression seen in the majority of Alzheimer’s disease subtypes. Additional modifications would be required to replicate the complex conditions of human AD in an exact manner. In-vitro models of Alzheimer’s disease developed using chemicals and environmental agents are instrumental in providing insights into the disease’s pathophysiology; therefore, chemical-induced in-vitro AD models will continue to play vital role in future AD research. This systematic screening revealed the pivotal role of chemical-induced in-vitro AD models in advancing our understanding of AD pathophysiology and is therefore important to understand the potential of these chemicals in AD pathogenesis.
... [9][10][11] Cortical neurons can be cultured through enzyme digestion, which enables separation of neurological tissues. 12 Currently, both trypsin and papain have wide applications in culturing primary neurons. 13 Both enzymes can be used for digesting neurons, but few studies have compared their efficiency. ...
The objective of this study was to compare the efficiency of trypsin and papain in neuronal digestion and determine which enzyme is more efficient. Cortical tissues were obtained from Sprague–Dawley (SD) rats. According to the different digestive enzymes, the samples were divided into the trypsin group and the papain group. After being digested by each of the two enzymes, cortical neurons were collected from the samples. Then, the morphology of the cortical neurons was determined. Moreover, the cortical neurons were transfected with the negative control (NC) lentivirus. The transfection efficiency and morphology were determined and compared. Compared with the papain group, cortical neurons in the trypsin group were more in number, had larger cell size, had longer axonal length, and had fewer impurities. The transfection efficiency of the trypsin group (57.77%) was higher than that of the papain group (53.83%). The morphology of neurons that was displayed showed that the cell body of most neurons shrank and became smaller, and the axis mutation became shorter and less in the papain group 6 days after transfection with the NC lentivirus. Trypsin is more efficient in digesting neurons because the neurons digested by this enzyme are more in number, have a larger cell body, longer axons, and greater transfection efficiency. In the present study, a comparative study of trypsin and papain digestion for primary cortical neurons was conducted. Cortical neurons digested by trypsin were more in number, had larger in cell body size, longer in axonal length, and had fewer impurities. Meanwhile, the transfection efficiency of the lentivirus in the trypsin group was higher than that in the papain group. The morphology of neurons that was displayed showed that the cell body of most neurons shrank and became smaller, and the axis mutation became shorter and less in the papain group 6 days after transfection with the NC lentivirus.
Epilepsy is a complex genetic disorder that affects about 2% of the global population. Although the frequency and severity of epileptic seizures can be reduced by a range of pharmacological interventions, there are no disease-modifying treatments for epilepsy. The development of new and more effective drugs is hindered by a lack of suitable animal models. Available rodent models may not recapitulate all key aspects of the disease. Spontaneous epileptic convulsions were observed in few Göttingen Minipigs (GMPs), which may provide a valuable alternative animal model for the characterisation of epilepsy-type diseases and for testing new treatments. We have characterised affected GMPs at the genome level and have taken advantage of primary fibroblast cultures to validate the functional impact of fixed genetic variants on the transcriptome level. We found numerous genes connected to calcium metabolism that have not been associated with epilepsy before, such as ADORA2B, CAMK1D, ITPKB, MCOLN2, MYLK, NFATC3, PDGFD, and PHKB. Our results have identified two transcription factor genes, EGR3 and HOXB6, as potential key regulators of CACNA1H, which was previously linked to epilepsy-type disorders in humans. Our findings provide the first set of conclusive results to support the use of affected subsets of GMPs as an alternative and more reliable model system to study human epilepsy. Further neurological and pharmacological validation of the suitability of GMPs as an epilepsy model is therefore warranted.
Spatially resolved transcriptomics technologies provide high-throughput measurements of gene expression in a tissue slice, but the sparsity of this data complicates the analysis of spatial gene expression patterns such as gene expression gradients. We address these issues by deriving a topographic map of a tissue slice—analogous to a map of elevation in a landscape—using a novel quantity called the isodepth . Contours of constant isodepth enclose spatial domains with distinct cell type composition, while gradients of the isodepth indicate spatial directions of maximum change in gene expression. We develop GASTON, an unsupervised and interpretable deep learning algorithm that simultaneously learns the isodepth, spatial gene expression gradients, and piecewise linear functions of the isodepth that model both continuous gradients and discontinuous spatial variation in the expression of individual genes. We validate GASTON by showing that it accurately identifies spatial domains and marker genes across several biological systems. In SRT data from the brain, GASTON reveals gradients of neuronal differentiation and firing, and in SRT data from a tumor sample, GASTON infers gradients of metabolic activity and epithelial-mesenchymal transition (EMT)-related gene expression in the tumor microenvironment.
