Combination Therapy With Fingolimod and Neural Stem Cells Promotes Functional Myelination

Myelination, which occurs predominantly postnatally and continues throughout life, is important for proper neurologic function of the mammalian central nervous system (CNS). We have previously demonstrated that the combination therapy of fingolimod (FTY720) and transplanted neural stem cells (NSCs) had a significantly enhanced therapeutic effect on the chronic stage of experimental autoimmune encephalomyelitis, an animal model of CNS autoimmunity, compared to using either one of them alone. However, reduced disease severity may be secondary to the immunomodulatory effects of FTY720 and NSCs, while whether this therapy directly affects myelinogenesis remains unknown. To investigate this important question, we used three myelination models under minimal or non-inflammatory microenvironments. Our results showed that FTY720 drives NSCs to differentiate into oligodendrocytes and promotes myelination in an ex vivo brain slice culture model, and in the developing CNS of healthy postnatal mice in vivo. Elevated levels of neurotrophic factors, e.g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, were observed in the CNS of the treated infant mice. Further, FTY720 and NSCs efficiently prolonged the survival and improved sensorimotor function of shiverer mice. Together, these data demonstrate a direct effect of FTY720, beyond its known immunomodulatory capacity, in NSC differentiation and myelin development as a novel mechanism underlying its therapeutic effect in demyelinating diseases

Mdivi-1, a mitochondrial fission inhibitor, modulates T helper cells and suppresses the development of experimental autoimmune encephalomyelitis.

BACKGROUND: Unrestrained activation of Th1 and Th17 cells is associated with the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). While inactivation of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, can reduce EAE severity by protecting myelin from demyelination, its effect on immune responses in EAE has not yet been studied. METHODS: We investigated the effect of Mdivi-1, a small molecule inhibitor of Drp1, on EAE. Clinical scores, inflammation, demyelination and Drp1 activation in the central nervous system (CNS), and T cell responses in both CNS and periphery were determined. RESULTS: Mdivi-1 effectively suppressed EAE severity by reducing demyelination and cellular infiltration in the CNS. Mdivi-1 treatment decreased the phosphorylation of Drp1 (ser616) on CD4+ T cells, reduced the numbers of Th1 and Th17 cells, and increased Foxp3+ regulatory T cells in the CNS. Moreover, Mdivi-1 treatment effectively inhibited IFN-γ+, IL-17+, and GM-CSF+ CD4+ T cells, while it induced CD4+ Foxp3+ regulatory T cells in splenocytes by flow cytometry. CONCLUSIONS: Together, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells

Using finite volume method for simulating the natural convective heat transfer of nano-fluid flow inside an inclined enclosure with conductive walls in the presence of a constant temperature heat source

In the present work, natural convective heat transfer of water/Al2O3 nano-fluid in an inclined square enclosure is investigated. The side walls of the cavity are cold and the upper and lower ones are insulated. A wall with a thermal-conductivity of 100 and a thickness of 0.5 is located on the cold walls. Moreover, there is a constant temperature heat source in the center of the enclosure. The enclosure is located under the influence of an inclined magnetic field (MF). The governing equations were solved using the finite volume method (FVM) and solved using the SIMPLE algorithm. The results show that the heat transfer rate intensifies up to 3.11 times with intensifying the Rayleigh number (Ra). The maximum heat transfer occurred at weak magnetic fields. By augmenting the angle of the enclosure, the heat transfer rate on the right and left walls intensifies by 33% and declines by 55%, respectively. The heat transfer rate on the right wall intensifies by 14% by augmenting the angle of the MF. The addition of nano-additives also results in intensification in the heat transfer rate

Progressive Preference Articulation for Decision Making in Multi-Objective Optimisation Problems

This paper proposes a novel algorithm for addressing multi-objective optimisation problems, by employing a progressive preference articu- lation approach to decision making. This enables the interactive incorporation of problem knowledge and decision maker preferences during the optimisation process. A novel progressive preference articulation mechanism, derived from a statistical technique, is herein proposed and implemented within a multi-objective framework based on evolution strategy search and hypervolume indicator selection. The proposed algo- rithm is named the Weighted Z-score Covariance Matrix Adaptation Pareto Archived Evolution Strategy with Hypervolume-sorted Adaptive Grid Algorithm (WZ-HAGA). WZ-HAGA is based on a framework that makes use of evolution strategy logic with covariance matrix adaptation to perturb the solutions, and a hypervolume indicator driven algorithm to select successful solutions for the subsequent generation. In order to guide the search towards interesting regions, a preference articulation procedure composed of four phases and based on the weighted z-score approach is employed. The latter procedure cascades into the hypervolume driven algorithm to perform the selection of the solutions at each generation. Numerical results against five modern algorithms representing the state-of-the-art in multi-objective optimisation demonstrate that the pro- posed WZ-HAGA outperforms its competitors in terms of both the hypervolume indicator and pertinence to the regions of interest

Ionic Liquid 3-Methyl-1-sulphonic Acid Imidazolium Chloride {[Msim]Cl}: A Highly Efficient, Mild and Green Catalyst for the Synthesis of β-Acetamido Ketones

Brønstedacidic ionic liquid 3-methyl-1-sulphonic acid imidazolium chloride {[Msim]Cl} is utilized as a highly efficient, inexpensive, mild and green catalyst for the synthesis of β-acetamido ketones by the one-pot multi-component coupling between acetophenones, arylaldehydes, acetonitrile and acetyl chloride at room temperature. Under these conditions, the title compounds are produced in high to excellent yields and in relatively short reaction times. In addition, this method is superior to reported methods, for the synthesis of β-acetamido ketones and is applicable for the synthesis of tris(β-acetamido ketone).Keyword: 3-Methyl-1-sulphonic acid imidazolium chloride {[Msim]Cl}, β-acetamido ketone, Brønsted acidic catalyst, ionic liquid, one-pot multi-component reaction, acetophenon

Therapeutic effect of baicalin on experimental autoimmune encephalomyelitis is mediated by SOCS3 regulatory pathway

Natural compounds derived from medicinal plants have long been considered a rich source of novel therapeutic agents. Baicalin (Ba) is a bioactive flavonoid compound derived from the root of Scutellaria baicalensis, an herb widely used in traditional medicine for the treatment of various inflammatory diseases. In this study, we investigate the effects and mechanism of action of Ba in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Ba treatment effectively ameliorated clinical disease severity in myelin oligodendrocyte glycoprotein (MOG)35-55 peptide-induced EAE, and reduced inflammation and demyelination of the central nervous system (CNS). Ba reduced infiltration of immune cells into the CNS, inhibited expression of proinflammatory molecules and chemokines, and prevented Th1 and Th17 cell differentiation via STAT/NF B signaling pathways. Further, we showed that SOCS3 induction is essential to the effects of Ba, given that the inhibitory effect of Ba on pathogenic Th17 responses was largely abolished when SOCS3 signaling was knocked down. Taken together, our findings demonstrate that Ba has significant potential as a novel anti-inflammatory agent for therapy of autoimmune diseases such as MS

Modeling of single mode optical fiber having a complicated refractive index profile by using modified scalar finite element method

A numerical method based on modified scalar finite element method (SC-FEM) is presented and programmed on MATLAB platform for optical fiber modeling purpose. We have estimated the dispersion graph, mode cut off condition, and group delay and waveguide dispersion for highly complicated chirped type refractive index profile fiber. The convergence study of our FEM formulation is carried out with respect to the number of division in core. It has been found that the numerical error becomes less than 2 % when the number of divisions in the core is more then 30. To predict the accurate waveguide dispersion characteristics, we need to compute expression (d^2 (Vb))/(dV^2 ) numerically by the FEM method. For that the normalized propagation constant b (in terms of β) should be an accurate enough up to around 6 decimal points. To achieve this target, we have used 1 million sampling points in our FEM simulations. Further to validate our results we have derived the higher order polynomial expression for each case. Comparison with other methods in calculation of normalized propagation constant is found to be satisfactory. In traditional FEM analysis a spurious solution is generated because the functional does not satisfy the boundary conditions in the original waveguide problem, However in our analysis a new term that compensate the missing boundary condition has been added in the functional to eliminate the spurious solutions. Our study will be useful for the analysis of optical fiber having varying refractive index profile

Combination Therapy With Fingolimod and Neural Stem Cells Promotes Functional Myelination in vivo Through a Non-immunomodulatory Mechanism

Myelination, which occurs predominantly postnatally and continues throughout life, is important for proper neurologic function of the mammalian central nervous system (CNS). We have previously demonstrated that the combination therapy of fingolimod (FTY720) and transplanted neural stem cells (NSCs) had a significantly enhanced therapeutic effect on the chronic stage of experimental autoimmune encephalomyelitis, an animal model of CNS autoimmunity, compared to using either one of them alone. However, reduced disease severity may be secondary to the immunomodulatory effects of FTY720 and NSCs, while whether this therapy directly affects myelinogenesis remains unknown. To investigate this important question, we used three myelination models under minimal or non-inflammatory microenvironments. Our results showed that FTY720 drives NSCs to differentiate into oligodendrocytes and promotes myelination in an ex vivo brain slice culture model, and in the developing CNS of healthy postnatal mice in vivo. Elevated levels of neurotrophic factors, e.g., brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor, were observed in the CNS of the treated infant mice. Further, FTY720 and NSCs efficiently prolonged the survival and improved sensorimotor function of shiverer mice. Together, these data demonstrate a direct effect of FTY720, beyond its known immunomodulatory capacity, in NSC differentiation and myelin development as a novel mechanism underlying its therapeutic effect in demyelinating diseases

Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity

© The American Society of Gene and Cell Therapy. Treatment of chronic neurodegenerative diseases such as multiple sclerosis (MS) remains a major challenge. Here we genetically engineer neural stem cells (NSCs) to produce a triply therapeutic cocktail comprising IL-10, NT-3, and LINGO-1-Fc, thus simultaneously targeting all mechanisms underlie chronicity of MS in the central nervous system (CNS): persistent inflammation, loss of trophic support for oligodendrocytes and neurons, and accumulation of neuroregeneration inhibitors. After transplantation, NSCs migrated into the CNS inflamed foci and delivered these therapeutic molecules in situ. NSCs transduced with one, two, or none of these molecules had no or limited effect when injected at the chronic stage of experimental autoimmune encephalomyelitis; cocktail-producing NSCs, in contrast, mediated the most effective recovery through inducing M2 macrophages/microglia, reducing astrogliosis, and promoting axonal integrity and endogenous oligodendrocyte/neuron differentiation. These engineered NSCs simultaneously target major mechanisms underlying chronicity of multiple sclerosis (MS) and encephalomyelitis (EAE), thus representing a novel and potentially effective therapy for the chronic stage of MS, for which there is currently no treatment available