Understanding the Roles of the Kynurenine Pathway in Multiple Sclerosis Progression

The kynurenine pathway (KP) is a major degradative pathway of tryptophan ultimately leading to the production of nicotinamide adenine dinucleotide (NAD+) and is also one of the major regulatory mechanisms of the immune response. The KP is known to be involved in several neuroinflammatory disorders including Alzheimer’s disease, amyotrophic lateral sclerosis, AIDS dementia complex, Parkinson’s disease, schizophrenia, Huntington’s disease and brain tumours. However, the KP remains a relatively new topic for the field of multiple sclerosis (MS). Over the last 2–3 years, some evidence has progressively emerged suggesting that the KP is likely to be involved in the pathogenesis of autoimmune diseases especially MS. Some KP modulators are already in clinical trials for other inflammatory diseases and would potentially provide a new and important therapeutic strategy for MS patients. This review summarizes the known relationships between the KP and MS

The Design of a Best Execution Market

The notion of best execution on securities markets is manifold. Best execution has different meanings to different market participants, therefore, it is difficult to find a unique market structure that meets this requirements for all the participants. Traditional market structures are either static or flexible, meaning that an individual market participant has no influence regarding the concrete market structure’s characteristics, like e. g. the price discovery mechanism, trading frequency or the market transparency. Traditional market structures are either static or flexible, meaning that an individual market participant has no influence regarding the Focussing on customer orientation, we propose a new type of market structure: the dynamic market model, where participants individually choose the characteristics of the market structure for each transaction they perform. Furthermore, this paper offers an approach to design dynamic market models from scratch. We briefly sketch the necessary steps towards a dynamic market model. Traditional market structures are either static or flexible, meaning that an individual market participant has no influence regarding the Finally, we present AMTRAS; the prototype of an electronic trading system that was conceived and implemented following the aforementioned approach. AMTRAS is an software-agent based bond trading system designed for the need of institutional investors. It implements a dynamic market model, a sophisticated product- and partner matching scheme as well as an innovative price discovery approach

Current Evidence for a Role of the Kynurenine Pathway of Tryptophan Metabolism in Multiple Sclerosis

The kynurenine pathway (KP) is the major metabolic pathway of the essential amino acid tryptophan (TRP). Stimulation by inflammatory molecules, such as interferon-γ (IFN-γ), is the trigger for induction of the KP, driving a complex cascade of production of both neuroprotective and neurotoxic metabolites, and in turn, regulation of the immune response and responses of brain cells to the KP metabolites. Consequently, substantial evidence has accumulated over the past couple of decades that dysregulation of the KP and the production of neurotoxic metabolites are associated with many neuroinflammatory and neurodegenerative diseases, including Parkinson's disease, AIDS-related dementia, motor neurone disease, schizophrenia, Huntington's disease, and brain cancers. In the past decade, evidence of the link between the KP and multiple sclerosis (MS) has rapidly grown and has implicated the KP in MS pathogenesis. KP enzymes, indoleamine 2,3-dioxygenase (IDO-1) and tryptophan dioxygenase (highest expression in hepatic cells), are the principal enzymes triggering activation of the KP to produce kynurenine from TRP. This is in preference to other routes such as serotonin and melatonin production. In neurological disease, degradation of the blood-brain barrier, even if transient, allows the entry of blood monocytes into the brain parenchyma. Similar to microglia and macrophages, these cells are highly responsive to IFN-γ, which upregulates the expression of enzymes, including IDO-1, producing neurotoxic KP metabolites such as quinolinic acid. These metabolites circulate systemically or are released locally in the brain and can contribute to the excitotoxic death of oligodendrocytes and neurons in neurological disease principally by virtue of their agonist activity at N-methyl-d-aspartic acid receptors. The latest evidence is presented and discussed. The enzymes that control the checkpoints in the KP represent an attractive therapeutic target, and consequently several KP inhibitors are currently in clinical trials for other neurological diseases, and hence may make suitable candidates for MS patients. Underpinning these drug discovery endeavors, in recent years, several advances have been made in how KP metabolites are assayed in various biological fluids, and tremendous advancements have been made in how specimens are imaged to determine disease progression and involvement of various cell types and molecules in MS.22 page(s

Haplogroup heterogeneity of LHON patients carrying the m.14484T>C mutation in India

Purpose: To investigate the clinical and mitochondrial DNA (mtDNA) haplogroup background of Indian Leber Hereditary Optic Neuropathy (LHON) patients carrying the m.14484T>C mutation. Methods: Detailed clinical investigation and complete mtDNA sequencing analysis was carried out for eight Indian LHON families with the m.14484T>C mutation. Haplogroup was constructed based on the evolutionarily important mtDNA variants. Results: In the present study, we characterized eight unrelated probands selected from 187 LHON cases. The overall penetrance of the disease was estimated to be 19.75% (16/81) in eight pedigrees with the m.14484T>C mutation and showed substantially higher sex bias (male:female = 13:3). The mtDNA haplogrouping revealed that they belong to diverse haplogroups; i.e. F1c1, M31a, U2a, M*, I1, M6, M3a1 and R30a. Interestingly, we did not find an association of the m.14484T>C mutation with any specific haplogroup within the Indian population. We also did not find any secondary mutation(s) in these pedigrees, which might affect the clinical expression of LHON. Conclusions: Contrary to earlier reports showing preferential association of the m.14484T>C mutation with western Eurasian haplogroup J and increased clinical penetrance when present in J1 subhaplogroup background, the present study shows that m.14484T>C arose independently in a different mtDNA haplogroup and ethnic background in India, which may influence the clinical expression of the disease

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Discrete wavelet transform based on EEG signal analysis for diagnosing neurological disorder

ElectroEncephaloGram (EEG) signal analysis is critical since it is a reliable approach for detecting neurological brain diseases. In this work, the artifacts in the EEG dataset are removed using the Independent Component Analysis (ICA) technique. The EEG dataset was then filtered with a band-pass filter to eliminate noise. In this work using a Discrete Wavelet Transform (DWT) to deconstruct the filtered data, the EEG signal features are recovered. The features are also supplied into four separate classifiers. Five statistical techniques are utilised to extract characteristics from EEG sub bands: Local Binary Pattern (LBP), Standard Deviation (SD), Variance, Kurtosis, and Shannon Entropy (SE). To classify the features related to their classes Linear Discriminant Analysis (LDA), Support Vector Machine (SVM), K-Nearest Neighbour (KNN), and Artificial Neural Network (ANN) are four classifiers that use the features.The overall classification accuracy approaches 90.5% using SVM, 99% using ANN, 87.5% using LDA and 97% using KNN respectively. In this work ANN gives better performance accuracy than other classifers

The involvement of Kynurenine pathway in multiple sclerosis mice model

Multiple sclerosis (MS) is a demyelinating disease of central nervous system caused by unknown multi-faceted disease inducing factors. Experimental autoimmune encephalomyelitis (EAE), an animal model for MS, manifests various forms that parallel several aspects of MS. Kynurenine pathway is the major pathway for tryptophan metabolism producing number of catabolites along its route having neurotoxic [quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA) and picolinic acid (PIC)] properties. Kynurenine pathway is thought to be involved in multiple sclerosis but its precise role and the mechanism involved is yet to be established. Hence, the main aim of this research was to characterize and analyze this pathway in MS mice model focusing therapeutic aspects. The major findings of this project are: (1) Kynurenine pathway enzyme expression was observed in oligodendroglial cell lines (N19 and N20.1) (2) QUIN toxicity on oligodendroglial cell lines may be neutralized by treatment with QUIN monoclonal antibody. (3) Kynurenine pathway is activated upon EAE induction and it is dependent on disease severity index, (4) Reduced KYNA neuroprotection and increased QUIN neurotoxicity was also observed upon EAE induction (5) Kynurenine pathway modulators effectively alleviate the EAE disease progression. The findings revealed in this thesis present a huge opportunity to pursue a new possibility of research for the therapeutic approach for MS. In conclusion, this study provides the complete evidence of involvement of kynurenine pathway in MS

Quinolinic acid toxicity on oligodendroglial cells : relevance for multiple sclerosis and therapeutic strategies

The excitotoxin quinolinic acid, a by-product of the kynurenine pathway, is known to be involved in several neurological diseases including multiple sclerosis (MS). Quinolinic acid levels are elevated in experimental autoimmune encephalomyelitis rodents, the widely used animal model of MS. Our group has also found pathophysiological concentrations of quinolinic acid in MS patients. This led us to investigate the effect of quinolinic acid on oligodendrocytes; the main cell type targeted by the autoimmune response in MS. We have examined the kynurenine pathway (KP) profile of two oligodendrocyte cell lines and show that these cells have a limited threshold to catabolize exogenous quinolinic acid. We further propose and demonstrate two strategies to limit quinolinic acid gliotoxicity: 1) by neutralizing quinolinic acid's effects with anti-quinolinic acid monoclonal antibodies and 2) directly inhibiting quinolinic acid production from activated monocytic cells using specific KP enzyme inhibitors. The outcome of this study provides a new insight into therapeutic strategies for limiting quinolinic acid-induced neurodegeneration, especially in neurological disorders that target oligodendrocytes, such as MS.11 page(s