The New Inhibitor of Monoamine Oxidase, M30, has a Neuroprotective Effect Against Dexamethasone-Induced Brain Cell Apoptosis

Stress detrimentally affects the brain and body and can lead to or be accompanied by depression. Although stress and depression may contribute to each other, the exact molecular mechanism underlying the effects is unclear. However, there is a correlation between stress and an increase in glucocorticoid secretion which causes a subsequent increase in monoamine oxidase (MAO) activity during stress. Consequently, MAO inhibitors have been used as traditional antidepressant drugs. Cellular treatment with the synthetic glucocorticoid, dexamethasone (a cellular stressor), has been reported to markedly increase both MAO A and MAO B catalytic activities, as well as apoptosis. This study compares the neuroprotective abilities of M30 (a new generation inhibitor of both MAO A and MAO B) with rasagiline (Azilect®, another new MAO B inhibitor) and selegiline (Deprenyl®, a traditional MAO B inhibitor) in the prevention of dexamethasone-induced brain cell death and MAO activity in human neuroblastoma cells, SH-SY5Y. M30 demonstrated the highest inhibitory effect on MAO A; however, M30 showed the lowest inhibitory effect on MAO B enzymatic activity in comparison to rasagiline and selegiline. Although, M30 exhibited the greatest neuroprotective effect by decreasing cell death rates and apoptotic DNA damage compared to rasagiline and selegiline, these neuroprotective effects of M30 were, overall, similar to rasagiline. Summarily, M30 has a generally greater impact on neuroprotection than the MAO B inhibitors, selegiline and rasagiline. Our results suggest that M30 may have great potential in alleviating disorders involving increases in both MAO A and MAO B, such as stress-induced disorders

Differential Expression of Genes Related to Innate Immune Responses in Ex Vivo Spinal Cord and Cerebellar Slice Cultures Infected With West Nile Virus

West Nile virus (WNV) infection results in a spectrum of neurological symptoms, ranging from a benign fever to severe WNV neuroinvasive disease with high mortality. Many who recover from WNV neuroinvasive infection present with long-term deficits, including weakness, fatigue, and cognitive problems. While neurons are a main target of WNV, other cell types, especially astrocytes, play an important role in promoting WNV-mediated central nervous system (CNS) damage. Conversely, it has been shown that cultured primary astrocytes secrete high levels of interferons (IFNs) immediately after WNV exposure to protect neighboring astrocytes, as well as neurons. However, how intrinsic responses to WNV in specific cell types and different regions of the brain modify immune protection is not fully understood. Here, we used a mouse ex vivo spinal cord slice culture (SCSC) and cerebellar slice culture (CSC) models to determine the innate immune responses specific to the CNS during WNV infection. Slices were prepared from the spinal cord and cerebellar tissue of 7⁻9-day-old mouse pups. Four-day-old SCSC or CSC were infected with 1 × 10³ or 1 × 10⁵ PFU of WNV, respectively. After 12 h exposure to WNV and 3 days post-infection in normal growth media, the pooled slice cultures were processed for total RNA extraction and for gene expression patterns using mouse Affymetrix arrays. The expression patterns of a number of genes were significantly altered between the mock- and WNV-treated groups, both in the CSCs and SCSCs. However, distinct differences were observed when CSC data were compared with SCSC. CSCs showed robust induction of interferons (IFNs), IFN-stimulated genes (ISGs), and regulatory factors. Some of the antiviral genes related to IFN were upregulated more than 25-fold in CSCs as compared to mock or SCSC. Though SCSCs had twice the number of dysregulated genes, as compared CSCs, they exhibited a much subdued IFN response. In addition, SCSCs showed astrogliosis and upregulation of astrocytic marker genes. In sum, our results suggest that early anti-inflammatory response to WNV infection in CSCs may be due to large population of distinct astrocytic cell types, and lack of those specialized astrocytes in SCSC may make spinal cord cells more susceptible to WNV damage. Further, the understanding of early intrinsic immune response events in WNV-infected ex vivo culture models could help develop potential therapies against WNV

Genome-Wide Analysis of Protein-Protein Interactions and Involvement of Viral Proteins in SARS-CoV Replication

Analyses of viral protein-protein interactions are an important step to understand viral protein functions and their underlying molecular mechanisms. In this study, we adopted a mammalian two-hybrid system to screen the genome-wide intraviral protein-protein interactions of SARS coronavirus (SARS-CoV) and therefrom revealed a number of novel interactions which could be partly confirmed by in vitro biochemical assays. Three pairs of the interactions identified were detected in both directions: non-structural protein (nsp) 10 and nsp14, nsp10 and nsp16, and nsp7 and nsp8. The interactions between the multifunctional nsp10 and nsp14 or nsp16, which are the unique proteins found in the members of Nidovirales with large RNA genomes including coronaviruses and toroviruses, may have important implication for the mechanisms of replication/transcription complex assembly and functions of these viruses. Using a SARS-CoV replicon expressing a luciferase reporter under the control of a transcription regulating sequence, it has been shown that several viral proteins (N, X and SUD domains of nsp3, and nsp12) provided in trans stimulated the replicon reporter activity, indicating that these proteins may regulate coronavirus replication and transcription. Collectively, our findings provide a basis and platform for further characterization of the functions and mechanisms of coronavirus proteins

Robust Model Predictive Control of Networked Control Systems under Input Constraints and Packet Dropouts

This paper deals with the problem of robust model predictive control (RMPC) for a class of linear time-varying systems with constraints and data losses. We take the polytopic uncertainties into account to describe the uncertain systems. First, we design a robust state observer by using the linear matrix inequality (LMI) constraints so that the original system state can be tracked. Second, the MPC gain is calculated by minimizing the upper bound of infinite horizon robust performance objective in terms of linear matrix inequality conditions. The method of robust MPC and state observer design is illustrated by a numerical example

Abnormal Glucose Homeostasis and Pancreatic Islet Function in Mice with Inactivation of the Fem1b Gene

Type 2 diabetes mellitus is a disorder of glucose homeostasis involving complex gene and environmental interactions that are incompletely understood. Mammalian homologs of nematode sex determination genes have recently been implicated in glucose homeostasis and type 2 diabetes mellitus. These are the Hedgehog receptor Patched and Calpain-10, which have homology to the nematode tra-2 and tra-3 sex determination genes, respectively. Here, we have developed Fem1b knockout (Fem1b-KO) mice, with targeted inactivation of Fem1b, a homolog of the nematode fem-1 sex determination gene. We show that the Fem1b-KO mice display abnormal glucose tolerance and that this is due predominantly to defective glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion is also affected. The Fem1b gene is expressed in pancreatic islets, within both β cells and non-β cells, and is highly expressed in INS-1E cells, a pancreatic β-cell line. In conclusion, these data implicate Fem1b in pancreatic islet function and insulin secretion, strengthening evidence that a genetic pathway homologous to nematode sex determination may be involved in glucose homeostasis and suggesting novel genes and processes as potential candidates in the pathogenesis of diabetes mellitus

Glyceraldehyde-3-Phosphate Dehydrogenase–Monoamine Oxidase B-Mediated Cell Death-Induced by Ethanol is Prevented by Rasagiline and 1-R-Aminoindan

KlimafolgenSturmfluten in den Ästuaren von Elbe, Jade-Weser und Ems können bereits heute sowohl große Schäden verursachen als auch das Leben der Bewohner dieser Küstengebiete gefährden. Zur Entwicklung geeigneter Anpassungsstrategien an die Folgen des Klimawandels ist es nötig, sowohl die heutige Situation zu verstehen, als auch mögliche Zukünfte unter Klimaänderungsbedingungen zu analysieren. Sturmfluten in den Ästuaren werden sowohl durch die Gezeitendynamik und den Windstau in der Deutschen Bucht als auch durch die Topographie des Ästuares, den Oberwasserzufluss in das Ästuar oder den Wind über dem Ästuar geprägt. In einer vorausgehenden Sensitivitätsstudie werden Szenarien untersucht, die zentrale Elemente einer möglichen Zukunft wie z. B. ein Meeresspiegelanstieg in der Nordsee oder eine Zunahme des Oberwasserzuflusses in die Ästuare berücksichtigen und deren Einfluss auf den Sturmflutscheitelwasserstand analysieren. Der Einsatz hydrodynamisch - numerischer Modelle ermöglicht es, den Einfluss der genannten Prozesse auf den Wasserstandsverlauf bei Sturmflut jeweils einzeln zu untersuchen. Auf der Grundlage dieser Sensitivitätsstudie können durch Sturmfluten gefährdete Gebiete entlang der Ästuare identifiziert und Anpassungsoptionen entwickelt werden. In der vorliegenden Studie wird die Wirksamkeit von Anpassungsoptionen betrachtet. So wird z. B. die Schutzfunktion von Einengungsmaßnahmen oder Sturmflutsperrwerken in den Mündungsgebieten der Ästuare bei durch den Klimawandel veränderten Wasserständen der Nordsee oder den veränderten Abflüssen aus dem Binnenbereich untersucht. Die Ergebnisse dieser Untersuchung ermöglichen es, die Vor- und Nachteile der Anpassungsoptionen für z. B. die Metropolregion Hamburg oder die Wasserstraßen in den Ästuaren von Elbe, Jade-Weser und Ems abzuwägen und Anpassungsstrategien zu entwickeln, die den durch einen Klimawandel entstehenden Problemen entgegenwirken