Dynamics of active systems with nonlinear excitation of the phase

Many physical and chemical systems exhibit self-oscillatory dynamics, for example systems involving the Belousov-Zhabotinsky reaction and systems used for material synthesis by solid-phase combustion, known as self-propagating high-temperature synthesis. Phase of oscillators crucially depend on diffusion (or thermal conductivity), which is reflected in the partial differential equation governing the phase of oscillations. At first sight, the role of diffusion is to equalise the phase in space. However, more complex situations are possible; for example the phase equation may involve self-excitation such as anti-diffusion in the (Kuramoto-Sivashinsky equation). In this research we investigate a version of the phase equation based on a nonlinear self-excitation. Previously it was shown that nonlinear self-excitation can arise in chemical systems with non-local interaction. In the present research, we analyse this kind of system in order to determine the validity range of the nonlinearly excited phase equation in the parametric space. Specifically, we numerically evaluate the values of the parameters that guarantee the assumptions of slow variations of the phase in space and time and, simultaneously, the key role of the nonlinear self-excitation. We also numerically solve the phase equation with nonlinear self-excitation in two spatial dimensions by finite-difference discretization in space and subsequent numerical integration of a system of ordinary differential equation in time. Irregular dynamics intermitting with periods of slow evolution are revealed and discussed. As a separate task, we derive a forced variant of the phase equation and present selected exact solutions - stationary and oscillatory. They are also used to verify the numerical code. In the numerical experiments, we use a range of sizes of spatial domain. Lastly, different forms of the nonlinearly excited phase equation are investigated based on different types of dynamical balance

DISTINCT PHENOTYPIC CHANGES BY PACAP AND VIP IN LIPOPOLYSACCHARIDE STIMULATED BV2 MICROGLIAL CELLS

Background: Aberrant microglial activation plays a key role in the progressive neuronal loss seen in many neurodegenerative diseases. PACAP and VIP are two neuropeptides that elicit robust immunosuppressive functions within the CNS. However, the underlying mechanisms through which these peptides regulate microglia activities are not clear. Aim & Objectives: Using lipopolysaccharide (LPS) to induce BV2 microglial cell polarisation, we aimed at testing whether and how administration of either PACAP or VIP could differentially affect microglial pro-inflammatory profile, polarisation state and morphological appearance to elicit immunosuppressive effects. Methods: Quantitative real-time PCR, Western blot, Griess reactions, immunofluorescence and morphological analyses were conducted in order to determine the effects of PACAP and VIP in BV2 microglial cells exposed or not to 1µg/ml LPS. Results: Our data demonstrated that both PACAP and VIP reduce the expression of pro-inflammatory mediators in LPS-stimulated BV2 cells. We also found that exogenous administration of PACAP and VIP rescued the dysregulations of the endogenous PACAP/VIP levels and attenuated the expression of microglial activation markers caused by LPS. Interestingly, despite the similar anti-inflammatory activities of PACAP and VIP, PACAP mainly reduced the number of M1 polarised cells, whereas VIP acted by increasing the subpopulation of cells exhibiting an ‘intermediate’ phenotype/bipolar-shaped (p<0.001 vs. control), at the expenses of resting/rounded cells. Conclusion: PACAP and VIP both possess immunosuppressive effects in activated BV2 microglial cells, but these effects seem to involve the differential shift of certain cell subpopulations towards distinctive phenotypes

Identification of dysregulated microRNA networks in schwann cell-like cultures exposed to immune challenge: Potential crosstalk with the protective VIP/PACAP neuropeptide system

© 2018 by the authors. Licensee MDPI, Basel, Switzerland. Following peripheral nerve injury, dysregulations of certain non-coding microRNAs (miRNAs) occur in Schwann cells. Whether these alterations are the result of local inflammation and/or correlate with perturbations in the expression profile of the protective vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP) system is currently unknown. To address these issues, we aimed at profiling the expression of selected miRNAs in the rat RT4 Schwann cell line. Cells exposed to lipopolysaccharide (LPS), to mimic the local inflammatory milieu, were appraised by real-time qPCR, Western blot and ELISAs. We found that upon LPS treatment, levels of pro-inflammatory cytokines (IL-1β, -6, -18, -17A, MCP-1 and TNFα) increased in a time-dependent manner. Unexpectedly, the expression levels of VIP and PACAP were also increased. Conversely, levels of VPAC1 and VPAC2 receptors were reduced. Downregulated miRNAs included miR-181b, -145, -27a, -340 and -132 whereas upregulated ones were miR-21, -206, -146a, -34a, -155, -204 and -29a, respectively. Regression analyses revealed that a subset of the identified miRNAs inversely correlated with the expression of VPAC1 and VPAC2 receptors. In conclusion, these findings identified a novel subset of miRNAs that are dysregulated by immune challenge whose activities might elicit a regulatory function on the VIP/PACAP system

Tackling dipeptidyl peptidase IV in neurological disorders

© 2018, Medknow Publications. All rights reserved. Dipeptidyl peptidase IV (DPP-IV) is a serine protease best known for its role in inactivating glucagon-like peptide-1 (GLP-1), pituitary adenylate cyclase-activating polypeptide (PACAP) and glucose-dependent insulinotropic peptide (GIP), three stimulators of pancreatic insulin secretion with beneficial effects on glucose disposal. Owing to the relationship between DPP-IV and these peptides, inhibition of DPP-IV enzyme activity is considered as an attractive treatment option for diabetic patients. Nonetheless, increasing studies support the idea that DPP-IV might also be involved in the development of neurological disorders with a neuroinflammatory component, potentially through its non-incretin activities on immune cells. In this review article, we aim at highlighting recent literature describing the therapeutic value of DPP-IV inhibitors for the treatment of such neurological conditions. Finally, we will illustrate some of the promising results obtained using berberine, a plant extract with potent inhibitory activity on DPP-IV

Assessing the Anti-Inflammatory Activity of the Anxiolytic Drug Buspirone Using CRISPR-Cas9 Gene Editing in LPS-Stimulated BV-2 Microglial Cells

Buspirone is an anxiolytic drug with robust serotonin receptor 1A (Htr1a) agonist activities. However, evidence has demonstrated that this drug also targets the dopamine D3 receptor (Drd3), where it acts as a potent antagonist. In vivo, Drd3 blockade is neuroprotective and reduces inflammation in models of Parkinson's disease. To test if buspirone also elicited anti-inflammatory activities in vitro, we generated stable Drd3-/- and Htr1a-/- BV2 microglial cell lines using CRISPR-Cas9 technology and then tested the effects of buspirone after lipopolysaccharide (LPS) challenge. We found that LPS exposure had no effect on cell viability, except in Htr1a-/- cells, where viability was reduced (p -/- cells, but not in WT or Htr1a-/- cells. Buspirone counteracted LPS-induced NO release, NOS2, IL-1β and TNF-α gene expression in WT cells, whereas it exerted limited effects in Drd3-/- or Htr1a-/- microglia. In summary, our findings indicate that buspirone attenuates microglial polarization after LPS challenge. These results also highlight some major effects of Drd3 or Htr1a genetic ablation on microglial biology, raising important questions on the complex role of neurotransmitters in regulating microglia functions

Metformin Treatment Attenuates Brain Inflammation and Rescues PACAP/VIP Neuropeptide Alterations in Mice Fed a High-Fat Diet.

High-fat diet (HFD)-induced comorbid cognitive and behavioural impairments are thought to be the result of persistent low-grade neuroinflammation. Metformin, a first-line medication for the treatment of type-2 diabetes, seems to ameliorate these comorbidities, but the underlying mechanism(s) are not clear. Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) are neuroprotective peptides endowed with anti-inflammatory properties. Alterations to the PACAP/VIP system could be pivotal during the development of HFD-induced neuroinflammation. To unveil the pathogenic mechanisms underlying HFD-induced neuroinflammation and assess metformin's therapeutic activities, (1) we determined if HFD-induced proinflammatory activity was present in vulnerable brain regions associated with the development of comorbid behaviors, (2) investigated if the PACAP/VIP system is altered by HFD, and (3) assessed if metformin rescues such diet-induced neurochemical alterations. C57BL/6J male mice were divided into two groups to receive either standard chow (SC) or HFD for 16 weeks. A further HFD group received metformin (HFD + M) (300 mg/kg BW daily for 5 weeks) via oral gavage. Body weight, fasting glucose, and insulin levels were measured. After 16 weeks, the proinflammatory profile, glial activation markers, and changes within the PI3K/AKT intracellular pathway and the PACAP/VIP system were evaluated by real-time qPCR and/or Western blot in the hypothalamus, hippocampus, prefrontal cortex, and amygdala. Our data showed that HFD causes widespread low-grade neuroinflammation and gliosis, with regional-specific differences across brain regions. HFD also diminished phospho-AKT(Ser473) expression and caused significant disruptions to the PACAP/VIP system. Treatment with metformin attenuated these neuroinflammatory signatures and reversed PI3K/AKT and PACAP/VIP alterations caused by HFD. Altogether, our findings demonstrate that metformin treatment rescues HFD-induced neuroinflammation in vulnerable brain regions, most likely by a mechanism involving the reinstatement of PACAP/VIP system homeostasis. Data also suggests that the PI3K/AKT pathway, at least in part, mediates some of metformin's beneficial effects

Macroscopic study of syrinx in the common bulbul (Pycnontus barbatus) and indigenous pigeon (Columba domestica)

In this study, syrinx of five male common bulbuls (Pycnontus barbatus) weighing (25.93 ±0.89 g) and five male indigenous pigeons (Columba domestica) weighing (286±0.73 g) were examined for macroscopic structure. The results showed the anatomical positions of the syrinx. The syrinx was observed ventral to the esophagus exactly on the base of heart in the common bulbul, whilst in pigeon; the syrinx was hidden by the heart. The morphological structure of the syrinx in both species could be classified as tracheobronchial type. The number of tracheo-syringeal rings could not be determined certainly in common bulbul, while in the pigeon, tracheo-syringeal part was composed of the two cartilaginous rings (T1 and T2). These two cartilaginous rings were different in diameters and joined each other at the middle. In the common bulbul, tympanum which is the middle part of syrinx has the bilateral bulla; while tympanum of pigeon does not have bulla. Furthermore, the broncho-syringeal cartilages from the caudal part of a syrinx, which is composed of five C-shaped rings in both species. The caudal syringeal part of common bulbul has intrabronchial foramen, which absents in a pigeon

Rapid GFAP and Iba1 Expression Changes in the Female Rat Brain following Spinal Cord Injury

Spinal cord injury (SCI) is a devastating condition often associated with sleep disorders, mood change and depression. Evidence suggests that rapid changes to supporting glia may predispose individuals with SCI to such comorbidities. Here, we interrogated the expression of astrocyte- and microglial-specific markers glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (Iba1) in the rat brain in the first 24 hours following spinal cord injury (SCI). Female Sprague Dawley rats underwent thoracic laminectomy; half of the rats received a mild contusion injury at the level of the T10 vertebral body (SCI group), the other half did not (Sham group). Twenty-four hours post-surgery the rats were sacrificed, and the amygdala, periaqueductal grey, prefrontal cortex, hypothalamus, lateral thalamus, hippocampus (dorsal and ventral) were collected. GFAP and Iba1 mRNA and protein levels were measured by real-time qPCR and Western blot. In SCI rats, GFAP mRNA and protein expression increased in the amygdala and hypothalamus (*p<0.05). In contrast, gene and protein expression decreased in the thalamus (**p<0.01) and dorsal hippocampus (*p<0.05 and **p<0.01, respectively). Interestingly, Iba1 transcripts and proteins were significantly diminished only in the dorsal (*p<0.05 and **p<0.01, respectively) and ventral hippocampus, where gene expression diminished (*p<0.05 for both mRNA and protein). Considered together, these findings demonstrate that as early as 24 hours post-SCI there are region-specific disruptions of GFAP and Iba1 transcript and protein levels in higher brain regions

Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead.

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology

Ammonia-Nitrogen Recovery from Synthetic Solution using Agricultural Waste Fibers

In this study, modification of Empty Fruit Bunch (EFB) fibers as a means to recover ammonianitrogen from a synthetic solution was investigated. Methods: The EFB fiber was modified using sodium hydroxide.Adsorption-desorption studies of ammonia nitrogen into the modified EFB fiber were investigated Findings: Theincrease in adsorption capacity was found to be proportional with the increase of pH up to 7, temperature and ammoniaconcentration. The maximum adsorption capacity is 0.53-10.89 mg/g. The attachment of ammonia nitrogen involves ionexchange-chemisorption. The maximum desorption capacity of 0.0999 mg/g. Applications: This study can be used as abaseline for designing a low cost adsorbent system for ammonia nitrogen recovery drainage and industrial wastewater aswell as EFBs-palm oil mill effluent composting