Positive almost periodicity on SICNNs incorporating mixed delays and D operator

This article involves a kind of shunting inhibitory cellular neural networks incorporating D operator and mixed delays. First of all, we demonstrate that, under appropriate external input conditions, some positive solutions of the addressed system exist globally. Secondly, with the help of the differential inequality techniques and exploiting Lyapunov functional approach, some criteria are established to evidence the globally exponential stability on the positive almost periodic solutions. Eventually, a numerical case is provided to test and verify the correctness and reliability of the proposed findings

Demystifying Digital Twin Buzzword: A Novel Generic Evaluation Model

Despite the growing popularity of digital twin (DT) developments, there is a lack of common understanding and definition for important concepts of DT. It is needed to address this gap by building a shared understanding of DT before it becomes an obstacle for future work. With this challenge in view, the objective of our study is to assess the existing DT from various domains on a common basis and to unify the knowledge and understanding of DT developers and stakeholders before practice. To achieve this goal, we conducted a systematic literature review and analyzed 25 selected papers to identify and discuss the characteristics of existing DT's. The review shows an inconsistency and case-specific choices of dimensions in assessing DT. Therefore, this article proposes a four-dimensional evaluation framework to assess the maturity of digital twins across different domains, focusing on the characteristics of digital models. The four identified dimensions in this model are Capability, Cooperability, Coverage, and Lifecycle. Additionally, a weight mechanism is implemented inside the model to adapt the importance of each dimension for different application requirements. Several case studies are devised to validate the proposed model in general, industrial and scientific cases.Comment: This is a draft of the article that subject to future change and correctio

Cerebellar granule neuron progenitors are the source of Hk2 in the postnatal cerebellum

A response to Leprince: The role of Bergmann glial cells in cerebellar development. Cancer & Metabolism 2013, 1:14 We recently demonstrated that developmentally regulated aerobic glycolysis is integral to the normal process of postnatal neurogenesis and becomes co-opted in medulloblastoma. In our work, we concluded that Hexokinase 2 (Hk2), which we found to be required for Shh-induced aerobic glycolysis, was expressed specifically by cerebellar granule neuron progenitors (CGNPs). We observed altered migration of CGNPs in hGFAP-cre;Hk2f/f mice and attributed this aspect of the phenotype to premature differentiation of CGNPs caused by loss of aerobic glycolysis. In response to our work, LePrince draws attention to the role of Bergmann glia in cerebellar development

Histone deacetylase 11 regulates oligodendrocyte-specific gene expression and cell development in OL-1 oligodendroglia cells

Both in vivo and in vitro studies indicate a correlation between reduced acetylation of histone core proteins and oligodendrocyte development. The nature of these histone modifications and the mechanisms mediating them remain undefined. To address these issues we utilized OL-1 cells, a rat non-transformed oligodendrocyte cell line, and primary oligodendrocyte cultures. We found that the acetylated histone H3 at lysine 9 and lysine 14 (H3K9/K14ac) is reduced in both the myelin basic protein (MBP) and proteolipid protein (PLP) genes of maturing oligodendroglial OL-1 cells, and furthermore, this temporally correlates with increases in MBP, PLP, and histone deacetylase (HDAC) 11 expression. Disruption of developmentally-regulated histone H3 deacetylation within the MBP and PLP genes by the HDAC inhibitor trichostatin A blunts MBP and PLP expression. With its increased expression, interaction of HDAC 11 with acetylated histone H3 and recruitment of HDAC 11 to the MBP and PLP genes markedly increases in maturing OL-1 cells. Moreover, suppressing HDAC 11 expression with small interfering RNA significantly: 1) increases H3K9/K14ac globally and within the MBP and PLP genes, 2) decreases MBP and PLP mRNA expression, and 3) blunts the morphological changes associated with oligodendrocyte development. Our data strongly support a specific role for HDAC 11 in histone deacetylation and in turn the regulation of oligodendrocyte-specific protein gene expression and oligodendrocyte development

Developmental expression of histone deacetylase 11 in the murine brain

Recent studies indicate that neural cell development in the central nervous system (CNS) correlates with a reduction in acetylation of histone core proteins. Moreover, histone hypoacetylation is thought to be important to oligodendrocyte lineage development. The mechanisms mediating the reduction in acetylation during postnatal neural development remain to be defined. To begin to understand these mechanisms, we investigated the expression of histone deacetylase 11 (HDAC11), a newly identified HDAC, in mouse brain during postnatal development. We show that HDAC11 was widely expressed in the brain and that this expression gradually increased in a region-specific pattern between birth and 4 weeks of age. At the cellular level HDAC11 protein was predominately localized in the nuclei of mature oligodendrocytes but only minimally in astrocytes. Although dentate gyrus granule neurons abundantly expressed HDAC11, granule neuron precursors in the subgranule layer exhibited little HDAC11 immunoreactivity. Double-immunostaining of the corpus callosum and dentate gyrus demonstrated that HDAC11 and Ki67, a cell-proliferating marker, are rarely colocalized in same cells. Our data show that HDAC11 was expressed in the developing brain in a temporal and spatial pattern that correlates with the maturation of neural cells, including cells of the oligodendrocyte lineage. These findings support a role for HDAC11 in CNS histone deacetylation and the development of oligodendrocytes and neurons during postnatal development

β-catenin mediates insulin-like growth factor-I actions to promote cyclin D1 mRNA expression, cell proliferation and survival in oligodendroglial cultures

By promoting cell proliferation, survival and maturation insulin-like growth factor (IGF)-I is essential to the normal growth and development of the central nervous system. It is clear that IGF-I actions are primarily mediated by the type I IGF receptor (IGF1R), and that phosphoinositide 3 (PI3)-Akt kinases and MAP kinases signal many of IGF-I-IGF1R actions in neural cells, including oligodendrocyte lineage cells. The precise downstream targets of these signaling pathways, however, remain to be defined. We studied oligodendroglial cells to determine whether β-catenin, a molecule that is a downstream target of glycogen synthase kinase-3β (GSK3β) and plays a key role in the Wnt canonical signaling pathway, mediates IGF-I actions. We found that IGF-I increases β-catenin protein abundance within an hour after IGF-I-induced phosphorylation of Akt and GSK3β. Inhibiting the PI3-Akt pathway suppressed IGF-I-induced increases in β-catenin and cyclin D1 mRNA, while suppression of GSK3β activity simulated IGF-I actions. Knocking-down β-catenin mRNA by RNA interference suppressed IGF-I-stimulated increases in the abundance of cyclin D1 mRNA, cell proliferation, and cell survival. Our data suggest that β-catenin is an important downstream molecule in the PI3-Akt-GSK3β pathway, and as such it mediates IGF-I upregulation of cyclin D1 mRNA and promotion of cell proliferation and survival in oligodendroglial cells

Spontaneous combustion characteristics of hydrothermal eroded coal in deep mining

In the process of deep mining, the temperature of mine water is significantly higher than that of shallow coal seams. The erosion of high-temperature hydrothermal fluids affects the physical and chemical characteristics of coal, which in turn affects its spontaneous combustion process. To study the spontaneous combustion characteristics and influencing mechanisms of coal under the influence of hydrothermal erosion in deep mining, through low-field nuclear magnetic resonance, molecular dynamics simulation, mechanical test and C600 trace heat experiment, the influence of hydrothermal erosion on coal porosity, pore size distribution, mechanical strength and oxidation heat characteristic parameters was analyzed. Combined with correlation analysis, the correlation between various parameters was quantitatively described. The study results show that under the dual influence of thermal stress and swelling, the internal pore structure of hydrothermal eroded coal changes significantly. There is a significant positive correlation between hydrothermal temperature and total porosity of coal, and the correlation coefficient is 0.97. With the increase of hydrothermal temperature, the total porosity of coal increases from 0.24% to 1.35%, the proportion of micropores decreases from more than 69% to less than 60%, and the proportion of mesopores and macropores increases. Coal body pore size significantly affects the oxygen diffusion coefficient, which increases exponentially with a linear increase in coal body pore size. Under the influence of hydrothermal erosion, the development of coal pores and the dissolution of some organic matter significantly reduce the mechanical strength of coal. From raw coal to 80 ℃ hydrothermal eroded coal, the average compressive strength decreases from 23 MPa to 11.6 MPa, which is reduced by 50%. Compared with raw coal, the heat release intensity of hydrothermal erosion coal is higher and the heat release is greater. The heat release of TH40, TH50, TH60, TH70 and TH80 increase by 12.61%, 16.63%, 17.32%, 19.36% and 25.02%, respectively. The correlation coefficient between hydrothermal temperature and coal oxidation heat release is 0.92. Hydrothermal erosion significantly affects the porosity and oxidation process of coal. As the hydrothermal temperature increases, the porosity of the coal body increases, the mechanical strength weakens, the oxygen consumption and oxidation rate of the oxidation process accelerate, and the heat release increases. Hydrothermal erosion coal has a higher risk of spontaneous combustion, and the higher the hydrothermal temperature is, the greater the risk is

A Novel ENU-Induced

The fission and fusion of mitochondria are important processes for maintaining mitochondrial health. One of the proteins responsible for mediating mitochondrial fusion, mitofusin 2 (MFN2), has over 100 known mutations that cause Charcot–Marie–Tooth disease type 2A (CMT2A). This disease causes the nerves that control your muscles to degenerate, leading to muscle atrophy and weakness, problems walking, and other related symptoms. In this paper, we describe a mouse line with a recessive mutation in the Mfn2 gene (Leu643Pro) that causes a similar set of symptoms, including abnormal gait, weight loss, and decreased muscular endurance. However, further analysis of these mice revealed signs of skeletal muscle dysfunction (including smaller mitochondria) and bone abnormalities, with little evidence of axon degeneration typical of CMT2A. While this makes these mice a poor model for CMT2A, they are the first reported mouse line with a mutation in the transmembrane domain, a region critical for MFN2′s role in mitochondrial fusion. For this reason, we believe these mice will be a valuable tool for scientists interested in studying the biological functions of MFN2

Pyruvate Kinase Inhibits Proliferation during Postnatal Cerebellar Neurogenesis and Suppresses Medulloblastoma Formation

Aerobic glycolysis supports proliferation through unresolved mechanisms. We have previously shown that aerobic glycolysis is required for the regulated proliferation of cerebellar granule neuron progenitors (CGNP) and for the growth of CGNP-derived medulloblastoma. Blocking the initiation of glycolysis via deletion of hexokinase-2 (Hk2) disrupts CGNP proliferation and restricts medulloblastoma growth. Here, we assessed whether disrupting pyruvate kinase-M (Pkm), an enzyme that acts in the terminal steps of glycolysis, would alter CGNP metabolism, proliferation, and tumorigenesis. We observed a dichotomous pattern of PKM expression, in which postmitotic neurons throughout the brain expressed the constitutively active PKM1 isoform, while neural progenitors and medulloblastomas exclusively expressed the less active PKM2. Isoform-specific Pkm2 deletion in CGNPs blocked all Pkm expression. Pkm2-deleted CGNPs showed reduced lactate production and increased SHH-driven proliferation.13C-flux analysis showed that Pkm2 deletion reduced the flow of glucose carbons into lactate and glutamate without markedly increasing glucose-to-ribose flux. Pkm2 deletion accelerated tumor formation in medulloblastoma- prone ND2:SmoA1 mice, indicating the disrupting PKM releases CGNPs from a tumor-suppressive effect. These findings show that distal and proximal disruptions of glycolysis have opposite effects on proliferation, and that efforts to block the oncogenic effect of aerobic glycolysis must target reactions upstream of PKM

Verification of alternative splicing variants based on domain integrity, truncation length and intrinsic protein disorder

According to current estimations ∼95% of multi-exonic human protein-coding genes undergo alternative splicing (AS). However, for 4000 human proteins in PDB, only 14 human proteins have structures of at least two alternative isoforms. Surveying these structural isoforms revealed that the maximum insertion accommodated by an isoform of a fully ordered protein domain was 5 amino acids, other instances of domain changes involved intrinsic structural disorder. After collecting 505 minor isoforms of human proteins with evidence for their existence we analyzed their length, protein disorder and exposed hydrophobic surface. We found that strict rules govern the selection of alternative splice variants aimed to preserve the integrity of globular domains: alternative splice sites (i) tend to avoid globular domains or (ii) affect them only marginally or (iii) tend to coincide with a location where the exposed hydrophobic surface is minimal or (iv) the protein is disordered. We also observed an inverse correlation between the domain fraction lost and the full length of the minor isoform containing the domain, possibly indicating a buffering effect for the isoform protein counteracting the domain truncation effect. These observations provide the basis for a prediction method (currently under development) to predict the viability of splice variants