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

Solving Linear Coupled Fractional Differential Equations by Direct Operational Method and Some Applications

A new direct operational inversion method is introduced for solving coupled linear systems of ordinary fractional differential equations. The solutions so-obtained can be expressed explicitly in terms of multivariate Mittag-Leffler functions. In the case where the multiorders are multiples of a common real positive number, the solutions can be reduced to linear combinations of Mittag-Leffler functions of a single variable. The solutions can be shown to be asymptotically oscillatory under certain conditions. This technique is illustrated in detail by two concrete examples, namely, the coupled harmonic oscillator and the fractional Wien bridge circuit. Stability conditions and simulations of the corresponding solutions are given

Detention Properties of Subsurface Stormwater Modules Under Tropical Climate

Subsurface stormwater module is one of the components of a sustainable drainage system. However, the performance of subsurface stormwater module as on-site detention under tropical climate like Malaysia has not been extensively studied in the literature. The current study involves on-site installation of pilot scale subsurface stormwater modules exposed to tropical climate to simulate real conditions to evaluate the detention performance. Rainfall together with the changes in water level and volume of water detained in the installation were observed for six months between April 2021 to October 2021. The subsurface stormwater module used in the current study has a porosity of 94%. It was found that the subsurface stormwater module setup was able to detain between 35.2% to 95.6% of the rainfall volume generated from total rainfall between 11.1 mm to 56.8 mm. The findings can be used as design consideration for using subsurface stormwater module under tropical climate

Detention Properties of Subsurface Stormwater Modules Under Tropical Climate

Subsurface stormwater module is one of the components of a sustainable drainage system. However, the performance of subsurface stormwater module as on-site detention under tropical climate like Malaysia has not been extensively studied in the literature. The current study involves on-site installation of pilot scale subsurface stormwater modules exposed to tropical climate to simulate real conditions to evaluate the detention performance. Rainfall together with the changes in water level and volume of water detained in the installation were observed for six months between April 2021 to October 2021. The subsurface stormwater module used in the current study has a porosity of 94%. It was found that the subsurface stormwater module setup was able to detain between 35.2% to 95.6% of the rainfall volume generated from total rainfall between 11.1 mm to 56.8 mm. The findings can be used as design consideration for using subsurface stormwater module under tropical climate

Kynurenic acid as a biochemical factor underlying the association between Western-style diet and depression : a cross-sectional study

Consumption of a Western-style diet (WS-diet), high in saturated fat and added sugar, is associated with increased depression risk. However, the physiological mechanisms underlying the relationship requires elucidation. Diet can alter tryptophan metabolism along the kynurenine pathway (KP), potentially linking inflammation and depression. This study aimed to examine whether urinary inflammatory markers and KP metabolites differed according to WS-diet consumption and depression severity. Depression symptoms and habitual WS-diet consumption were assessed in 169 healthy adults aged 17–35 recruited from two experimental studies. Targeted metabolomics profiling of seven KP metabolites, ELISA-based assays of interleukin-6 (IL-6) and C-reactive protein (CRP) were performed using urine samples collected from the participants. Parametric tests were performed for group comparison and associations analysis. Multilevel mixed-effect modelling was applied to control for biases. Higher intake of WS-diet was associated with lower levels of neuroprotective kynurenic acid (KA; R = −0.17, p = 0.0236). There were no differences in IL-6 or CRP across diet groups (p > 0.05). Physical activity had negative associations with most KP metabolites. Mixed-effects regression analysis showed the glutamatergic inhibitor, KA, was the only biomarker to have a significant association with depression symptoms in a model adjusted for demographic and lifestyle variables: a unit increase in KA was associated with 0.21 unit decrease in Depression Anxiety and Stress Scale-21 depression score (p = 0.009). These findings suggest that urinary KA is associated with both habitual WS-diet intake, and levels of depression symptoms, independent of inflammation. Findings support the role of neuroprotection and glutamatergic modulation in depression. We propose that KA may act as endogenous glutamatergic inhibition in regulating depression severity in the absence of inflammation. Further comparison with blood-based markers will assist in validating the utility of non-invasive urine samples for measuring KP metabolites

Method for distortion correction of multi-layered surface reconstruction using time-gated wavefront sensing approach

In order to estimate the multi-layer surface profile and to detect the inter-layer surfaces defects, gated wavefront sensing approach has been proposed in the previous works [1, 2]. However, the proposed methodology measures the wavefront that has been distorted by its prior surfaces (reflected wavefront) or post surfaces (transmitted wavefront). Analysis has to be performed to estimate the multi-layer wavefront sensing by taking into consideration the multi-layer surfaces condition. For reflected wavefront, the bottom layer(s) wavefront is (are) being distorted twice via separate interface points while traveling back to the lenslet arrays through our observation for the slope and phase measurement. The subsequent reconstructed surfaces are not accurate and corrected. Thus, a discrete layer correction technique for the surface reconstruction has been proposed to enhance the reconstruction accuracy by using the upper/top layer’s wavefront information. This paper discusses on the case of 2-layer system, where the reflected wavefront from the bottom layer has been distorted and its surface reconstruction has been corrected. The results show that the distortion is significant and the correction is deemed necessary for industrial application such as in wafer warpage inter-layer profile estimation

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

Electrophysiological correlates of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism

The brain-derived neurotrophic factor (BDNF) protein is essential for neuronal development. Val66Met (rs6265) is a functional polymorphism at codon 66 of the BDNF gene that affects neuroplasticity and has been associated with cognition, brain structure and function. The aim of this study was to clarify the relationship between BDNF Val66Met polymorphism and neuronal oscillatory activity, using the electroencephalogram (EEG), in a normative cohort. Neurotypical (N = 92) young adults were genotyped for the BDNF Val66Met polymorphism and had eyes open resting-state EEG recorded for four minutes. Focal increases in right fronto-parietal delta, and decreases in alpha-1 and right hemispheric alpha-2 amplitudes were observed for the Met/Met genotype group compared to Val/Val and Val/Met groups. Stronger frontal topographies were demonstrated for beta-1 and beta-2 in the Val/Met group versus the Val/Val group. Findings highlight BDNF Val66Met genotypic differences in EEG spectral amplitudes, with increased cortical excitability implications for Met allele carriers

Alterations in serum kynurenine pathway metabolites in individuals with high neocortical amyloid-β load: A pilot study

The kynurenine pathway (KP) is dysregulated in neuroinflammatory diseases including Alzheimer\u27s disease (AD), however has not been investigated in preclinical AD characterized by high neocortical amyloid-β load (NAL), prior to cognitive impairment. Serum KP metabolites were measured in the cognitively normal KARVIAH cohort. Participants, aged 65-90 y, were categorised into NAL+ (n = 35) and NAL- (n = 65) using a standard uptake value ratio cut-off = 1.35. Employing linear models adjusting for age and APOEϵ4, higher kynurenine and anthranilic acid (AA) in NAL+ versus NAL- participants were observed in females (kynurenine, p = 0.004; AA, p = 0.001) but not males (NALxGender, p = 0.001, 0.038, respectively). To evaluate the predictive potential of kynurenine or/and AA for NAL+ in females, logistic regressions with NAL+/- as outcome were carried out. After age and APOEϵ4 adjustment, kynurenine and AA were individually and jointly significant predictors (p = 0.007, 0.005, 0.0004, respectively). Areas under the receiver operating characteristic curves were 0.794 using age and APOEϵ4 as predictors, and 0.844, 0.866 and 0.871 when kynurenine, AA and both were added. Findings from the current study exhibit increased KP activation in NAL+ females and highlight the predictive potential of KP metabolites, AA and kynurenine, for NAL+. Additionally, the current study also provides insight into he influence of gender in AD pathogenesi