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To improve the isolation ability of the existing equipment for low-frequency line spectrum, this paper presents an electromagnetic double-layer vibration isolation system (ED-VIS) for the first time. The negative and positive stiffness values of the ED-VIS are provided by the electromagnet and the linear spring, respectively. To better analyze the vibration isolation system designed in this paper, the dynamic model of the ED-VIS is established, and the effects of damping ratio, excitation force amplitude, and mass ratio on the force transmissibility feature of the isolator are analyzed. Then, the ED-VIS test bench is built, and the low-frequency vibration isolation capability of the ED-VIS is measured by a frequency sweep test. According to the sweep test results, a method to improve the low-frequency vibration isolation capability of the isolator is proposed. Finally, the reliability of the system in isolating low-frequency vibration is verified. The results show that compared with the equivalent linear vibration isolation system, ED-VIS is more sensitive to low-frequency vibration and has a lower initial vibration isolation frequency. Therefore, this paper designs the ED-VIS has better low-frequency vibration isolation performance. [ABSTRACT FROM AUTHOR]

Background: The resolution or aggravation of dengue infection depends on the patient's immune response during the critical phase. Cytokines released by immune cells increase with the worsening severity of dengue infections. Cytokines activate the kynurenine pathway (KP) and the extent of KP activation then influences disease severity.Methods: KP metabolites and cytokines in plasma samples of patients with dengue infection (dengue without warning signs [DWS-], dengue with warning signs [DWS+], or severe dengue) were analyzed. Cytokines (interferon gamma [IFN-ɣ], tumor necrosis factor, interleukin 6, CXCL10/interferon-inducile protein 10 [IP-10], interleukin 18 [IL-18], CCL2/monocyte chemoattractant protein-1 [MCP-1], and CCL4/macrophage inflammatory protein-1beta [MIP-1β] were assessed by a Human Luminex Screening Assay, while KP metabolites (tryptophan, kynurenine, anthranilic acid [AA], picolinic acid, and quinolinic acid) were assessed by ultra-high-performance liquid chromatography and Gas Chromatography Mass Spectrophotometry [GCMS] assays.Results: Patients with DWS+ had increased activation of the KP where kynurenine-tryptophan ratio, anthranilic acid, and picolinic acid were elevated. These patients also had higher levels of the cytokines IFN-ɣ, CXCL10, CCL4, and IL-18 than those with DWS-. Further receiver operating characteristic analysis identified 3 prognostic biomarker candidates, CXCL10, CCL2, and AA, which predicted patients with higher risks of developing DWS+ with an accuracy of 97%.Conclusions: The data suggest a unique biochemical signature in patients with DWS+. CXCL10 and CCL2 together with AA are potential prognostic biomarkers that discern patients with higher risk of developing DWS+ at earlier stages of infection. [ABSTRACT FROM AUTHOR]

Jatropha oil-based polyurethane acylate gel polymer electrolyte was mixed with different concentrations of tetrabutylammonium iodide salt (TBAI). The temperature dependences of ionic conductivity, dielectric modulus and relaxation time were studied in the range of 298 to 393 K. The highest ionic conductivity of (1.88 ± 0.020) × 10–4 Scm−1 at 298 K was achieved when the gel contained 30 wt% of TBAI and 2.06 wt% of I2. Furthermore, the study found that conductivity-temperature dependence followed the Vogel-Tammann Fulcher equation. From that, it could be clearly observed that 30 wt% TBAI indicated the lowest activation energy of 6.947 kJ mol−1. By using the fitting method on the Nyquist plot, the number density, mobility and diffusion coefficient of the charge carrier were determined. The charge properties were analysed using the dielectric permittivity, modulus and dissipation factor. Apart from this, the stoke drag and capacitance were determined. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a chronic immune-mediated disorder of the central nervous system characterized by demyelination, neuroinflammation, and neurodegeneration. Activation of the kynurenine pathway (KP) results from acute and chronic neuroinflammation leading to both immune suppression and neurotoxicity. However, the exact effects of KP metabolites and changes in neurodegenerative diseases over time are not fully understood. Studies, including those in MS models, have reported that short-term KP activation is beneficial through immune tolerance. However, the effects of long-term KP activation are poorly understood. We hypothesized that such chronic activation is responsible for the neurodegeneration in MS, and further, modulating the KP in EAE-induced mice could significantly decrease the EAE disease severity.Methods: We biochemically altered the KP at different stages of the disease in experimental allergic encephalomyelitis (EAE) mouse model of MS and at two different enzymatic levels of the KP (IDO-1 (indoleamine 2,3 dioxygenase)) and KMO (kynurenine monooxygenase). CNS tissue and blood samples were analyzed longitudinally using GCMS, HPLC, IHC, and RT-PCR.Results: We showed that the KP was steadily upregulated correlating with disease severity and associated with a shift towards increasing concentrations of the KP metabolite quinolinic acid, a neuro- and gliotoxin. KP modulation by inhibition of IDO-1 with 1-methyl tryptophan (1-MT) was dependent on the timing of treatment at various stages of EAE. IDO-1 inhibition at EAE score 2 led to significantly higher numbers of FoxP3 cells (p < 0.001) in the spleen than earlier IDO-1 inhibition (prophylactic 1-MT treatment group (p < 0.001)), 1-MT treatment after EAE induction (EAE score 0; p < 0.001), and 1-MT treatment at EAE score of 1 (p < 0.05). Significant improvement of disease severity was observed in EAE mice treated with 1-MT at EAE score 2 compared to the untreated group (p < 0.05). KP modulation by KMO inhibition with Ro 61-8048 led to significantly greater numbers of Foxp3 cells (p < 0.05) in Ro 61-8048 treated mice and even more significant amelioration of EAE disease compared to the 1-MT treatment groups.Conclusions: These results provide a new mechanistic link between neuroinflammation and neurodegeneration and point to KP modulation at the KMO level to preserve immune tolerance and limit neurodegeneration in EAE. They provide the foundation for new clinical trials for MS. [ABSTRACT FROM AUTHOR]

Various countries throughout the world have started their efforts in designing and implementing smart cities. China alone has over 300 smart city projects, with strong participation by industries and government offices. India too have allocated trillions in budget to build over 100 smart cities. An essential part of a smart city is transport. In this paper, we will discuss the current state, developments, and some of the emerging advances in transportation technologies and how these advances in smart roads will prepare the society towards the realization of future smart cities. [ABSTRACT FROM AUTHOR]

Chronic kynurenine pathway (KP) activation is implicated in Alzheimer's disease (AD) pathophysiology and results in quinolinic acid–induced excitotoxic stimulation of the N-methyl-D-aspartate receptor. However, most studies focus on plasma and it is unclear if peripheral concentrations reflect brain concentrations and how these may correlate to the AD biomarkers amyloid-β, total-tau (t-tau), or phosphorylated-tau (p-tau). We characterized the KP in matched plasma and cerebrospinal fluid (CSF) samples from 20 AD patients and 18 age-matched control subjects. Plasma concentrations of kynurenine (KYN), 3-hydroxykynurenine, anthranilic acid, picolinic acid, and neopterin significantly correlated with their respective CSF levels. In patients with AD, plasma KYN (r = −0.48, p = 0.033) and picolinic acid (r = −0.57, p = 0.009) inversely correlated with CSF p-tau and t-tau, respectively. Furthermore, in AD CSF, increased 3-hydroxykynurenine/KYN ratio correlated with t-tau (r = 0.58, p = 0.009) and p-tau (r = 0.52, p = 0.020). These data support KP involvement in AD pathogenesis and add to the case for the therapeutic modulation of the KP in AD. • CSF KP metabolites correlate with AD biomarkers, t-tau and p-tau. • Kynurenine pathway (KP) metabolites correlate in matched plasma and CSF samples. • KP correlation with t-tau and p-tau may suggest mechanistic links. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify biomarkers of zoledronate-induced nephrotoxicity and to further characterize the mechanisms underlying this process by analyzing urinary metabolites. Twenty-four rats were randomly divided into four groups containing four (two control groups) or eight rats (two zoledronate groups) per group. The rats were injected intravenously with saline or zoledronate (3 mg/kg) singly (single, 3 weeks) or repeatedly eight times (3 weeks/time, 24 weeks). Serum blood urea nitrogen, serum creatinine, creatinine clearance, and kidney injury observed by hematoxylin and eosin and immunohistochemical staining were changed only in the repeated zoledronate group (3 mg/kg, 3 weeks/time, 24 weeks). Urinary levels of S -adenosylmethionine, S -adenosylhomocysteine, l -cystathionine, l -γ-glutamylcysteine, and glutathione related to glutathione metabolism and fumaric acid and succinic acid related to the tricarboxylic acid cycle in the zoledronate-treated group (3 mg/kg, 3 weeks/time, 24 weeks) were significantly lower than those in the control group, suggesting that zoledronate may cause cellular oxidative stress. Besides, urinary levels of uracil and uridine related to pyrimidine metabolism also decreased after zoledronate treatment (3 mg/kg, 3 weeks/time, 24 weeks), while the levels of hypoxanthine related to purine metabolism, histamine related to histamine metabolism, and several amino acids were significantly increased. Moreover, zoledronate-induced enhanced oxidative stress and histamine overproduction were confirmed by reactive oxygen species (ROS) and histamine measurement in a human proximal tubular cell line. Taken together, zoledronate-induced nephrotoxicity may be attributed to it inducing perturbations in glutathione biosynthesis and the tricarboxylic acid cycle, further causing ROS overproduction, oxidative stress, and cellular inflammation, thereby leading to nephrotoxicity. [ABSTRACT FROM AUTHOR]

Even in thin-gauged 3% Si-Fe strips with the same final thickness reduction, the strong {110}〈001〉 Goss component at the cold-rolled strip surfaces becomes the {110}〈001〉 texture after final annealing, which results in a magnetic induction (B[SUB10], Tesla) higher than 1.9 T. On the other hand, the strips with the {110}〈uvw〉 component deviating from the Goss component show a low magnetic induction (B[SUB10], Tesla) of about 1.60 T which results from the final {110}〈uvw〉 texture. The strong dependence of final texture and magnetic induction on the cold-rolling texture at the surfaces of the strip is due to the intrinsic characteristic of diffusionless nucleation that is followed by the surface-energy-induced selective grain growth. [ABSTRACT FROM AUTHOR]

During final annealing, microalloyed sulfur in thin-gauged silicon steel segregates to the strip surface and on grain boundaries and thus affects the texture development. With increasing flow rate of hydrogen, the profile of magnetic induction was shifted to a shorter annealing time, and the time range of lower magnetic induction was drastically shortened. This is ascribed to the faster depletion of surface-segregated sulfur that accelerates surface-energy-induced selective growth of (110)[001] Goss grains. After final annealing for 14.4 ks, the strips showed a high magnetic induction of about 1.9 T. By controlling the surface segregation behavior of sulfur, it is possible to achieve the surface-energy-induced selective growth of grains favorable for magnetic induction in thin-gauged silicon steel. [ABSTRACT FROM AUTHOR]

The effects of heating rate and surface oxidation on magnetic induction of thin-gauged 3% Si–Fe strips have been investigated. Magnetic induction increased with increasing final annealing temperature. Before and after 1150 °C, the planar orientation of grains shifted from (100)[011] to (110)[001], resulting in magnetic induction higher than 1.90 T. Magnetic induction after final annealing was higher in case of a faster heating rate. This is because enough time for growth of (110) grains is given in the case. Irrespective of transient annealing temperature, magnetic induction after final annealing was mostly higher than 1.90 T. A maximum, 1.97 T, was obtained at a transient annealing temperature of 800 °C. This is because iron oxide formed at 800 °C inhibited the surface-energy-induced selective growth of (100)[011] grains during heating up to 1200 °C. © 2000 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Surface-energy-induced secondary or tertiary recrystallization by grains with a specific surface plane can be freely governed in thin-gauged 3% Si–Fe strips by controlling the bulk content of sulfur and annealing atmosphere. During a vacuum or hydrogen annealing process, a convex profile in segregated-sulfur concentration is formed due to evaporation or desorption of segregated sulfur as a hydrogen sulfide, corresponding to a trough in magnetic induction. High magnetic induction is obtained after the annealing treatments. Final annealing under an argon atmosphere caused a saturation in segregated-sulfur concentration with annealing time. Under this extremely high segregated sulfur, grains of high index crystal plane including {111} continued to grow, resulting in low magnetic induction. © 2000 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Neuroinflammation leads to microglia activation and release of a large number of proinflammatory mediators. The kynurenine pathway (KP) of tryptophan catabolism is one of the major regulators of the immune response and is also likely to be implicated in the inflammatory and neurotoxic events in Parkinsonism. Several neuroactive compounds are produced through the KP that can be either a neurotoxic, neuroprotective or immunomodulator. Among these metabolites kynurenic acid (KYNA), produced by astrocytes, is considered as neuroprotective whereas quinolinic acid (QUIN), released by activated microglia, can activate the N-methyl- d -aspartate (NMDA) receptor-signalling pathway, leading to excitotoxicity and amplify the inflammatory response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD both in vivo and in vitro . There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that some of the KP metabolites could be used as prognostic biomarkers and that pharmacological modulators of the KP enzymes could represent a new therapeutic strategy for PD. [ABSTRACT FROM AUTHOR]

Infections during pregnancy and subsequent maternal immune activation (MIA) increase risk for schizophrenia in offspring. The progeny of rodents injected with the viral infection mimic polyI:C during gestation display brain and behavioural abnormalities but the underlying mechanisms are unknown. Since the blood kynurenine pathway (KP) of tryptophan degradation impacts brain function and is strongly regulated by the immune system, we tested if KP changes occur in polyI:C offspring at preadolescence. We also tested whether MK801-induced hyperlocomotion, a behaviour characteristic of adult polyI:C offspring, is prevented by adolescent treatment with celecoxib, a COX-2 inhibitor that impacts the KP. Pregnant rats were treated with polyI:C (4 mg/kg, i.v.) or vehicle on gestational day 19. Serum levels of KP metabolites were measured in offspring of polyI:C or vehicle treated dams at postnatal day (PND) 31–33 using HPLC/GCMS. Additional polyI:C or vehicle exposed offspring were given celecoxib or vehicle between PND 35 and 46 and tested with MK801 (0.3 mg/kg) in adulthood (PND > 90). Prenatal polyI:C resulted in increases in the serum KP neurotoxic metabolite quinolinic acid at PND 31–33 (105%, p = 0.014). In contrast, the neuroprotective kynurenic acid and its precursor kynurenine were significantly decreased (28% p = 0.027, and 31% p = 0.033, respectively). Picolinic acid, another neuroprotective KP metabolite, was increased (31%, p = 0.014). Adolescent treatment with celecoxib (2.5 and 5 mg/kg/day, i.p.) prevented the development of MK801-induced hyperlocomotion in adult polyI:C offspring. Our study reveals the blood KP as a potential mechanism by which MIA interferes with postnatal brain maturation and associated behavioural disturbances and emphasises the preventative potential of inflammation targeting drugs. [ABSTRACT FROM AUTHOR]

The levels of the essential pyridine nucleotide, NAD+ and its reduced form NADH have not been documented in MS patients. We aimed to investigate NAD+ and NADH levels in serum in patients with different disease stages and forms of MS. NAD+ and NADH levels were measured in the serum from 209 patients with relapsing remitting MS (RRMS), 136 with secondary progressive MS (SPMS), 51 with primary progressive MS (PPMS), and 99 healthy controls. All patients were in a clinically stable phase. Serum NAD+ levels declined by at least 50% in patients with MS compared to controls (17.9±3.2μg/ml; p=0.0012). Within the MS sub-groups NAD+ levels were higher in RRMS (9.9±2.9μg/ml; p=0.001) compared to PPMS (6.3±2.1μg/ml; p=0.003) and SPMS (7.8±2.0μg/ml; p=0.005). A two-fold increase in NADH levels (p=0.002) and at least three-fold reduction in the NAD+/NADH ratio (p=0.009) were observed in MS patients compared to controls. Serum NAD+ and NADH levels are may be associated with disease progression in MS. Given the importance of NAD+ in the maintenance of normal cellular function, it is likely that this molecule is of therapeutic relevance in MS. [ABSTRACT FROM AUTHOR]

The NMDA-receptor antagonist ketamine has proven efficient in reducing symptoms of suicidality, although the mechanisms explaining this effect have not been detailed in psychiatric patients. Recent evidence points towards a low-grade inflammation in brains of suicide victims. Inflammation leads to production of quinolinic acid (QUIN) and kynurenic acid (KYNA), an agonist and antagonist of the glutamatergic N-methyl-D-aspartate (NMDA) receptor, respectively. We here measured QUIN and KYNA in the cerebrospinal fluid (CSF) of 64 medication-free suicide attempters and 36 controls, using gas chromatography mass spectrometry and high-performance liquid chromatography. We assessed the patients clinically using the Suicide Intent Scale and the Montgomery-Asberg Depression Rating Scale (MADRS). We found that QUIN, but not KYNA, was significantly elevated in the CSF of suicide attempters (P<0.001). As predicted, the increase in QUIN was associated with higher levels of CSF interleukin-6. Moreover, QUIN levels correlated with the total scores on Suicide Intent Scale. There was a significant decrease of QUIN in patients who came for follow-up lumbar punctures within 6 months after the suicide attempt. In summary, we here present clinical evidence of increased QUIN in the CSF of suicide attempters. An increased QUIN/KYNA quotient speaks in favor of an overall NMDA-receptor stimulation. The correlation between QUIN and the Suicide Intent Scale indicates that changes in glutamatergic neurotransmission could be specifically linked to suicidality. Our findings have important implications for the detection and specific treatment of suicidal patients, and might explain the observed remedial effects of ketamine. [ABSTRACT FROM AUTHOR]

The kynurenine pathway (KP) and one of its end-products, the excitotoxin quinolinic acid (QUIN), are involved in the pathogenesis of several major neuroinflammatory brain diseases. A relevant animal model to study KP metabolism is now needed to assess whether intervention in this pathway may improve the outcome of such diseases. Humans and macaques share a very similar genetic makeup. In this study, we characterized the KP metabolism in macaque primary macrophages of three different species in comparison to human cells. We found that the KP profiles in simian macrophages were very similar to those in humans when challenged with inflammatory cytokines. Further, we found that macaque macrophages are capable of producing a pathophysiological concentration of QUIN. Our data validate the simian model as a relevant model to study the human cellular KP metabolism in the context of inflammation. [ABSTRACT FROM AUTHOR]

Pathfinder Normalized Difference Vegetation Index (NDVI) derived from Channel 1 (Red) and Channel 2 (near-infrared) of Advanced Very High Resolution Radiometer (AVHRR) onboard NOAA 14 became abnormally high for the 10-day composite from February 11 to 20 in 1999 for Western Australia. There was a solar eclipse in the satellite path on February 16 about the same time when NOAA 14 was above the eclipse location, causing the Channel 1 value to be 0 in many cells. The NDVI composite updating rule was to capture the greenest condition of each composite period. There seems to have been a possible lack of quality control during the NDVI composite generation, which could have caused the abnormally high NDVI values. However, there were some cells within the affected area that had values close to normal for NDVI as well as Channel 1 and Channel 2. The abnormal NDVI data values could have been avoided by not using the data obtained during the eclipse in the generation of the composite. Further investigation on those cells which were not affected by the eclipse is suggested for a better quality control of remote sensing data obtained during eclipse occurrences. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: It is important to understand the involvement of oligodendrocytes in the kynurenine pathway (KP) and more particularly, their potential ability to produce neuroprotective metabolites such as kynurenic acid (KYNA) or picolinic acid (PIC), and the possibility of taking up and catabolizing the excitotoxin quinolinic acid (QUIN). These mechanisms may play a crucial role in the pathophysiology of neuroinflammatory diseases, especially multiple sclerosis. We used RT-PCR and HPLC to delineate KP enzyme expression and KP metabolite production. We characterized the KP in oligodendrocytes and showed that they lack IDO expression and are unable to catabolize tryptophan. However, the other enzymes in the pathway are present. These results indicate that human oligodendrocytes are more likely to produce neuroprotective KP metabolites such as KYNA and PIC rather than QUIN. However, because of the lack of IDO they are not able to down-regulate the immune response and as such may be more vulnerable to autoimmune phenomena. [Copyright &y& Elsevier]

The temporal behavior of naturally produced dust parameters (radius and density) and plasma parameters (electron temperature and ion flux) was investigated in radio frequency SiH4/H2/Ar plasmas. As a result, the electron temperature and ion flux were shown to be strongly correlated with the three-step dust growth pattern. In addition, the generation of dust particles was suppressed by mixing more hydrogen gas due to the plasma chemistry, and consequently, the dust growth rate in the molecular accretion growth, which is known to be proportional to the growth rate of thin film deposition, increased. [ABSTRACT FROM AUTHOR]

Impact craters on solar system bodies are used to determine the relative ages of surfaces. The smaller the limiting primary crater size, the higher the spatial resolution in surface/resurfacing age dating. A manually counted database (Robbins & Hynek, 2012, https://doi.org/10.1029/2011JE003966) of >384,000 craters on Mars >1 km in diameter exists. But because crater size scales as a power law, the number of impact craters in the size range 10 m to 1 km is in the tens of millions, a number making precise analysis of local variations of age, over an entire surface, impossible to perform by manual counting. To decode this crater size population at a planetary scale, we developed an automated Crater Detection Algorithm based on the You Only Look Once v3 object detection system. The algorithm was trained by annotating images of the controlled Thermal Emission Imaging System daytime infrared data set. This training data set contains 7,048 craters that the algorithm used as a learning benchmark. The results were validated against the manually counted database as the ground truth data set. We applied our algorithm to the Thermal Emission Imaging System global mosaic between ±65° of latitude, returning a true positive detection rate of 91% and a diameter estimation error (~15%) consistent with typical manual count variation. Importantly, although a number of automated crater counting algorithms have been published, for the first time we demonstrate that automatic counting can be routinely used to derive robust surface ages. Plain Language Summary: Crater counting is the traditional method of determining the surface ages of planets throughout the solar system. This method, up to now, has used data that have been painstakingly counted by hand. The current published database for Mars contains hundreds of thousands of craters for diameters larger than 1 km. If we can count craters smaller than this, we will be able to target specific areas of interest to date. But the rate of impacts on planetary surfaces follows a power law such that the number of small (less than 1 km) craters is exponentially higher than the number of large craters. To count these requires an automated tool. Here we show that we have developed such a tool. We have validated the results against current manual databases. Importantly, and for the first time, we demonstrate that an automated crater counting tool can deliver geologically meaningful ages. Key Points: We built a library of 7,048 craters to train a Crater Detection Algorithm (CDA) that we developed based on a neural network architectureWe applied our algorithm to the Mars global THEMIS mosaic, generating results comparable to manual countingWe applied the CDA to higher‐resolution images generating model ages indistinguishable (within error) from literature ages [ABSTRACT FROM AUTHOR]

Activation of the kynurenine pathway (KP) of tryptophan metabolism results from chronic inflammation and is known to exacerbate progression of neurodegenerative disease. To gain insights into the links between inflammation, the KP and multiple sclerosis (MS) pathogenesis, we investigated the KP metabolomics profile of MS patients. Most significantly, we found aberrant levels of two key KP metabolites, kynurenic acid (KA) and quinolinic acid (QA). The balance between these metabolites is important as it determines overall excitotoxic activity at the N-methyl-D-Aspartate (NMDA) receptor. We also identified that serum KP metabolic signatures in patients can discriminate clinical MS subtypes with high sensitivity and specificity. A C5.0 Decision Tree classification model discriminated the clinical subtypes of MS with a sensitivity of 91%. After validation in another independent cohort, sensitivity was maintained at 85%. Collectively, our studies suggest that abnormalities in the KP may be associated with the switch from early-mild stage MS to debilitating progressive forms of MS and that analysis of KP metabolites in MS patient serum may have application as MS disease biomarkers. [ABSTRACT FROM AUTHOR]

Neopterin, a well-established biomarker for immune system activation, is found at increased levels in the cerebrospinal fluid of individuals affected by neurological/neurodegenerative diseases. Here, neopterin synthesis was investigated in different nerve cells (rodent and human) and in the mouse hippocampus under inflammatory stimuli. We also aimed to investigate whether neopterin preconditioning could modulate the inflammasome activation, a component of the innate immune system. Increased neopterin was detected in human nerve cells supernatants (highest secretion in astrocytes) exposed to lipopolysaccharide (LPS) and interferon-gamma (INF-γ) and in the hippocampus of mice receiving LPS (0.33 mg/kg; intraperitoneal). In parallel to the hippocampal-increased neopterin, it was observed a significant increase in the expression of the rate-limiting enzyme of its biosynthetic pathway, and both phenomena occurred before the inflammasome activation. Moreover, a significant inhibition of the inflammasome activation was observed in neopterin pre-conditioned human astrocytes, when challenged with LPS, by reducing IL-1β, caspase-1 and ASC expression or content, components of the NLRP3 inflammasome. Mechanistically, neopterin might induce eletrophilic stress and consequently the nuclear translocation of the transcription factor Nrf-2, and the anti-inflammatory cytokines IL-10 and IL-1ra release, which would induce the inhibition of the inflammasome activation. Altogether, this strongly suggests an essential role of neopterin during inflammatory processes. [ABSTRACT FROM AUTHOR]

β-Methylamino- l-alanine (BMAA) is implicated in neurodegeneration and neurotoxicity, particularly in ALS-Parkinson Dementia Complex. Neurotoxic properties of BMAA have been partly elucidated, while its transcellular spreading capacity has not been examined. Using reconstructed neuronal networks in microfluidic chips, separating neuronal cells into two subcompartments-(1) the proximal, containing first-order neuronal soma and dendrites, and (2) a distal compartment, containing either only axons originating from first-order neurons or second-order striatal neurons-creates a cortico-striatal network. Using this system, we investigated the toxicity and spreading of BMAA in murine primary neurons. We used a newly developed antibody to detect BMAA in cells. After treatment with 10 μM BMAA, the cyanotoxin was incorporated in first-degree neurons. We also observed a rapid trans-neuronal spread of BMAA to unexposed second-degree neurons in 48 h, followed by axonal degeneration, with limited somatic death. This in vitro study demonstrates BMAA axonal toxicity at sublethal concentrations and, for the first time, the transcellular spreading abilities of BMAA. This neuronal dying forward spread that could possibly be associated with progression of some neurodegenerative diseases especially amyotrophic lateral sclerosis. [ABSTRACT FROM AUTHOR]

During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery. Methods: Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9-10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry. Results: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores. Conclusion: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI. [ABSTRACT FROM AUTHOR]

Background Patients with depression and suicidality suffer from low-grade neuroinflammation. Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N -methyl- d -aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF). Methods We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over 2 years (total patient samples n = 143, individuals n = 30) and healthy controls ( n = 36). The association between the markers and psychiatric symptoms was assessed using the Montgomery Åsberg Depression Rating Scale and the Suicide Assessment Scale. Results Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms. Conclusions We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression. [ABSTRACT FROM AUTHOR]

The kynurenine pathway is a major route of L-tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the kynurenine pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the kynurenine pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of kynurenine pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the kynurenine pathway in neurons and the first description of the involvement of the kynurenine pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence. [ABSTRACT FROM AUTHOR]

Purpose: This study evaluated the bioequivalence of China-manufactured biosimilar, HLX02, to reference China (CN)- and European Union (EU)-sourced trastuzumab.Methods: This was a two-part Phase 1 study conducted in healthy Chinese males. Part 1 evaluated the safety of different doses of HLX02 (2, 4, 6 or 8 mg/kg; intravenous infusion over 90 min, n = 3 per group). Part 2, a randomized, double-blind study, investigated the pharmacokinetics (PK), safety and immunogenicity of study drugs (HLX02 [n = 37], CN-trastuzumab [n = 35] or EU-trastuzumab [n = 37] at the dose suggested by Part 1 results). The primary PK endpoint was the area under the serum concentration-time curve from time 0 to infinity (AUCinf). Equivalence was concluded if the 90% confidence interval (CI) for the geometric least squares mean ratio (GLSMR) fell in the equivalence criteria of 0.80-1.25.Results: In Part 1, all doses of HLX02 were well tolerated and 6 mg/kg was suggested for Part 2. The GLSMRs and 90% CIs for AUCinf were: 0.950 (0.891-1.013), 0.914 (0.858-0.973) and 0.962 (0.902-1.025) for HLX02 versus CN-trastuzumab, HLX02 versus EU-trastuzumab and CN-trastuzumab versus EU-trastuzumab, respectively. Secondary endpoints comparisons also fell in the equivalence criteria. Treatment-emergent adverse events were reported in 75.7, 86.5 and 70.3% of the subjects in HLX02, CN-trastuzumab, and EU-trastuzumab groups, respectively. No serious adverse events or deaths occurred. No treatment-related anti-drug antibodies were detected.Conclusion: This study demonstrated comparable safety profiles and PK bioequivalence among HLX02, CN-trastuzumab and EU-trastuzumab in healthy Chinese male subjects.Clinical Trial Registration: ClinicalTrials.gov, NCT02581748, registered at October 19, 2015. [ABSTRACT FROM AUTHOR]

This paper describes a direct calculation method for medium fields in perpendicular recording systems. The method accounts for the effect of the zig-zag transition in the written medium pattern which can be obtained using micromagnetic simulations. The described method is useful for studying the cross-track characteristics of read sensors. The method is able to deal with a recording medium layer with nonunity relative permeability. The computed medium field in the gap region under the read head is compared with that obtained using the finite-element method. The purpose of this study is to develop a fast and effective tool for producing read-back signals based on computer modeling and simulation. [ABSTRACT FROM AUTHOR]

• Severe peripartum depression (PPD) with suicidality is an understudied disorder. • Severe depression in the post-partum involves dysregulation of the immune response. • Tryptophan is shunted towards the kynurenine pathway instead of serotonin production. • Women with reduced plasma serotonin are at an increased risk for suicidal behavior. • Inflammation and the kynurenine pathway may be treatment targets in severe PPD. Depression during pregnancy and the post-partum is common, with severe cases resulting in suicidal behavior. Despite the urgent and unmet medical need, the biological underpinnings of peri-partum depression remain unclear. It has been suggested that it is triggered by dynamic changes of the immune system during pregnancy and at delivery. Therefore, we investigated whether a pro-inflammatory status in plasma, together with changes in the kynurenine pathway activity, is associated with the development of severe depression and suicidal behavior in the post-partum. Our cross-sectional study targets a unique, understudied population in which the pronounced severity of symptoms required hospitalization. We analyzed plasma IL-1β, IL-2, IL-6, IL-8, TNF-α, tryptophan, serotonin, kynurenine, nicotinamide, quinolinic- and kynurenic acids in post-partum women diagnosed with peripartum onset depression (PPD) and healthy controls (n = 165). We assessed depression severity using the Edinburgh Postnatal Depression Scale and suicidality using the Columbia-Suicide Severity Rating Scale. We found that increased plasma IL-6 and IL-8 and reductions of serotonin, IL-2 and quinolinic acid were associated with the severity of depressive symptoms and increased the risk for PPD. Moreover, women with lower serotonin levels were at an increased risk for suicidal behavior, even when adjusting for depression severity, psychosocial factors, age BMI, and medication. Our results indicate that severe depression in the post-partum involves dysregulation of the immune response and the kynurenine pathway, with a concomitant reduction in serotonin levels. We propose that inflammatory cytokines and the kynurenine pathway are potential treatment targets in PPD, opening up the possibility of novel therapeutic strategies targeting the peripartum. [ABSTRACT FROM AUTHOR]

There is strong epidemiological evidence that poor diet is associated with depression. The reverse has also been shown, namely that eating a healthy diet rich in fruit, vegetables, fish and lean meat, is associated with reduced risk of depression. To date, only one randomised controlled trial (RCT) has been conducted with elevated depression symptoms being an inclusion criterion, with results showing that a diet intervention can reduce clinical levels of depression. No such RCTs have been performed in young adults. Young adults with elevated levels of depression symptoms and who habitually consume a poor diet were randomly allocated to a brief 3-week diet intervention (Diet Group) or a habitual diet control group (Control Group). The primary and secondary outcome measures assessed at baseline and after the intervention included symptoms of depression (Centre for Epidemiological Studies Depression Scale; CESD-R; and Depression Anxiety and Stress Scale– 21 depression subscale; DASS-21-D), current mood (Profile of Mood States), self-efficacy (New General Self-Efficacy Scale) and memory (Hopkins Verbal Learning Test). Diet compliance was measured via self-report questionnaires and spectrophotometry. One-hundred-and-one individuals were enrolled in the study and randomly assigned to the Diet Group or the Control Group. Upon completion of the study, there was complete data for 38 individuals in each group. There was good compliance with the diet intervention recommendations assessed using self-report and spectrophotometry. The Diet group had significantly lower self-reported depression symptoms than the Control Group on the CESD-R (p = 0.007, Cohen’s d = 0.65) and DASS-21 depression subscale (p = 0.002, Cohen’s d = 0.75) controlling for baseline scores on these scales. Reduced DASS-21 depression subscale scores were maintained on follow up phone call 3 months later (p = .009). These results are the first to show that young adults with elevated depression symptoms can engage in and adhere to a diet intervention, and that this can reduce symptoms of depression. The findings provide justification for future research into the duration of these benefits, the impacts of varying diet composition, and their biological basis. [ABSTRACT FROM AUTHOR]

Upregulation of the kynurenine pathway (KP) of tryptophan metabolism is commonly observed in neurodegenerative disease. When activated, L-kynurenine (KYN) increases in the periphery and central nervous system where it is further metabolised to other neuroactive metabolites including 3-hydroxykynurenine (3-HK), kynurenic acid (KYNA) and quinolinic acid (QUIN). Particularly biologically relevant metabolites are 3-HK and QUIN, formed downstream of the enzyme kynurenine 3-monooxygenase (KMO) which plays a pivotal role in maintaining KP homeostasis. Indeed, excessive production of 3-HK and QUIN has been described in neurodegenerative disease including Alzheimer's disease and Huntington's disease. In this study, we characterise KMO activity in human primary neurons and identified new mechanisms by which KMO activation mediates neurotoxicity. We show that while transient activation of the KP promotes synthesis of the essential co-enzyme nicotinamide adenine dinucleotide (NAD+), allowing cells to meet short-term increased energy demands, chronic KMO activation induces production of reactive oxygen species (ROS), mitochondrial damage and decreases spare-respiratory capacity (SRC). We further found that these events generate a vicious-cycle, as mitochondrial dysfunction further shunts the KP towards the KMO branch of the KP to presumably enhance QUIN production. These mechanisms may be especially relevant in neurodegenerative disease as neurons are highly sensitive to oxidative stress and mitochondrial impairment. [ABSTRACT FROM AUTHOR]

ABSTRACT: Amphiphilic cationic poly(ethylene oxide)‐S(polylysine)‐poly( d, l‐lactide) (mPEO‐S(CKn)‐PLA) tri‐arm star copolymers were synthesized by a combination of ring opening polymerization (ROP) and a thiol–disulfide exchange. The mPEO‐S(CKn)‐PLA copolymers were found to be non‐cytotoxic and could effectively condense GFP plasmid DNA into nanometer‐sized complexes, as characterized by dynamic light scattering (DLS), suitable for endocytotic cellular uptake. In vitro DNA transfection studies showed that the amphiphilic structure is capable of DNA transfection and GFP expression. Addition of chloroquine into the medium further enhanced the DNA transfection efficiency. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 635–644 [ABSTRACT FROM AUTHOR]

In the manganese-free 3% silicon steel, the trough in magnetic induction corresponded to the convex profile in segregation concentration of sulfur. This is due to the surface-energy induced selective growth of grains from (110) to (111) or higher index plane in the increasing order of segregated sulfur. The manganese-added steel showed a minimum in segregation concentration at the initial stage of final annealing, and a maximum with further annealing. Such a segregation behavior in the manganese-added strip may result from the precipitation and subsequent dissolution of MnS with final annealing time. A lower maximum of segregation concentration in the manganese-added strip is due to the faster H[sub 2]S reaction rate under hydrogen atmosphere than the evaporation rate of sulfur under vacuum. Final magnetic induction of 1.9 T was obtained from the manganese-free strip through the selective growth of {110}〈001... Goss grains, while the other strip showed a much lower value of 1.71 T due to the main texture component close to {100}〈011.... [ABSTRACT FROM AUTHOR]

Background For xenotransplantation to truly succeed, we must develop immunomodulatory strategies to suppress the xenoimmune response but by minimizing immunosuppression over the long term. Regulatory macrophages (Mreg) have been shown to suppress polyclonal T-cell proliferation in vitro and prolong allograft survival in vivo. However, the question of whether they are capable of suppressing xenoimmune responses remains unknown. This study assessed the potential of human Mreg to be used as an effective immunomodulatory method in xenotransplantation. Methods CD14+ monocytes selected from human peripheral blood mononuclear cells ( PBMC) were cultured with macrophage colony-stimulating factor (M- CSF) for 7 days with IFN-γ added at day 6 for Mreg induction. Mreg phenotyping was performed by flow cytometric analysis, and the in vitro suppressive function was assessed by mixed lymphocyte reaction ( MLR) using irradiated pig PBMC as the xenogeneic stimulator cells, human PBMC as responder cells, and autologous Mreg as suppressor cells. To assess mRNA expression of Mreg functional molecules indoleamine-2,3-dioxygenase ( IDO), IL-10, inducible nitric oxide synthase ( iNOS) and TGF-β were measured by real-time PCR. Supernatants were collected from the MLR cultures for IDO activity assay by high-performance liquid chromatography ( HPLC). The effects of the IDO inhibitor 1-D/L-methyl-tryptophan (1- MT), iNOS inhibitor NG-monomethyl-l-arginine (L- NMMA), and anti- IFN-γ or anti- TGF-β monoclonal antibody ( mAb) treatment on Mreg suppressive capacity were tested from the supernatants of the MLR assays. Results We demonstrated that induced Mreg with a phenotype of CD14low CD16−/low CD80low CD83−/low CD86+/hi HLA- DR+/hi were capable of suppressing proliferating human PBMC, CD4+, and CD8+ T cells, even at a higher responder:Mreg ratio of 32:1 in a pig-human xenogeneic MLR. The strong suppressive potency of Mreg was further correlated with their upregulated IDO expression and activity. The IDO upregulation of Mreg was associated with an increased production of IFN-γ, an IDO stimulator, by xenoreactive responder cells in the xenogeneic MLR. While no effect on Mreg suppressive potency was detected by addition of the iNOS inhibitor L- NMMA or anti- TGF-β mAb into the MLR assays, inhibition of IDO activity by neutralizing IFN-γ or by IDO inhibitor 1- MT substantially impaired the capacity of Mreg to suppress the xenogeneic response, indicating the importance of upregulated IDO activity in Mreg-mediated suppression of the xenogeneic response in vitro. Conclusion This study demonstrates that human Mreg are capable of suppressing the xenoimmune response in vitro via IDO-involved mechanism(s), suggesting their potential role as an effective immunomodulatory tool in xenotransplantation. [ABSTRACT FROM AUTHOR]

Background: Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients.Methods: We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system.Results: Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects.Conclusions: Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice. (Funded by the National Health and Medical Research Council of Australia and others.). [ABSTRACT FROM AUTHOR]

The kynurenine pathway (KP) of tryptophan metabolism has emerged in recent years as a key regulator of the production of both neuroprotective (e.g. kynurenic and picolinic acid, and the essential cofactor NAD+) and neurotoxic metabolites (e.g. quinolinic acid, 3-hydroxykynurenine). The balance between the production of the two types of metabolites is controlled by key rate-limiting enzymes such as indoleamine-2,3-dioxygenase (IDO-1), and in turn, molecular signals such as interferon-γ (IFN-γ), which activate the KP metabolism of tryptophan by this enzyme, as opposed to alternative pathways for serotonin and melatonin production. Dysregulated KP metabolism has been strongly associated with neurological diseases in recent years, and is the subject of increasing efforts to understand how the metabolites are causative of disease pathology. Concurrent with these endeavours are drug development initiatives to use inhibitors to block certain enzymes in the pathway, resulting in reduced levels of neurotoxic metabolites (e.g. quinolinic acid, an excitotoxin and N -Methyl- d -Aspartate (NMDA) receptor agonist), while in turn enhancing the bioavailability of the neuroprotective metabolites such as kynurenic acid. Neurodegenerative diseases often have a substantial autoimmune or inflammatory component; hence a greater understanding of how KP metabolites influence the inflammatory cascade is required. Additionally, challenges exist in diseases like multiple sclerosis (MS) and motor neurone disease (MND), which do not have reliable biomarkers. Clinical diagnosis can often be prolonged in order to exclude other diseases, and often diagnosis occurs at an advanced state of disease pathology, which does not allow a lengthy time for patient assessment and intervention therapies. This review considers the current evidence for involvement of the KP in several neurological diseases, in biomarkers of disease and also the parallels that exist in KP metabolism with what is known in other diseases such as HIV, Alzheimer's disease/dementia, infection, immune privilege and cardiovascular disease. This article is part of the Special Issue entitled ‘The Kynurenine Pathway in Health and Disease’. [ABSTRACT FROM AUTHOR]

High-quality Tin doped Cadmium Sulfide (CdS) comb-like nanostructures have been synthesized by a simple in situ seeding chemical vapor deposition process. The color-tunable dual emission of these comb-like nanostructures is demonstrated by changing the excitation power intensity. In fact, the color-tunable emission is in principal due to the variation of the dual emission intensity, which is proven by photoluminescence spectra and real color photoluminescence charge-coupled device images. Especially for different parts in the nano comb, the emission color can be varied even under the same pumping power. This is mainly due to the difference in local structure. By comparison, the color variation was not observed in pure CdS multi-branched nanostructures. The lifetime results demonstrate that the green emission originate from the recombination of free excitons. The origin of red emission is from the recombination of the dopant-induced intrinsic or extrinsic defect states. These findings provide potential applications of laser assisted anti-counterfeit label and micro-size monitors. [ABSTRACT FROM AUTHOR]

Inhibitory proteins, particularly Nogo 66, a highly conserved 66-amino-acid loop of Nogo A (an isoform of RTN4), play key roles in limiting the intrinsic capacity of the central nervous system (CNS) to regenerate after injury. Ligation of surface Nogo receptors (NgRs) and/or leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue the paired immunoglobulin-like receptor B (PIRB) by Nogo 66 transduces inhibitory signals that potently inhibit neurite outgrowth. Here, we show that soluble leukocyte immunoglobulin-like receptor A3 (LILRA3) is a high-affinity receptor for Nogo 66, suggesting that LILRA3 might be a competitive antagonist to these cell surface inhibitory receptors. Consistent with this, LILRA3 significantly reversed Nogo-66-mediated inhibition of neurite outgrowth and promoted synapse formation in primary cortical neurons through regulation of the ERK/MEK pathway. LILRA3 represents a new antagonist to Nogo-66-mediated inhibition of neurite outgrowth in the CNS, a function distinct from its immune-regulatory role in leukocytes. This report is also the first to demonstrate that a member of LILR family normally not expressed in rodents exerts functions on mouse neurons through the highly homologous Nogo 66 ligand. [ABSTRACT FROM AUTHOR]

Type 2 diabetes is associated with an inflammatory phenotype in the pancreatic islets. We previously demonstrated that proinflammatory cytokines potently activate the tryptophan/kynurenine pathway (TKP) in INS-1 cells and in normal rat islets. Here we examined: (1) the TKP enzymes expression in the diabetic GK islets; (2) the TKP enzymes expression profiles in the GK islets before and after the onset of diabetes; (3) The glucose-stimulated insulin secretion (GSIS) in vitro in GK islets after KMO knockdown using specific morpholino-oligonucleotides against KMO or KMO blockade using the specific inhibitor Ro618048; (4) The glucose tolerance and GSIS after acute in vivo exposure to Ro618048 in GK rats. We report a remarkable induction of the kmo gene in GK islets and in human islets exposed to proinflammatory conditions. It occurred prominently in beta cells. The increased expression and activity of KMO reflected an acquired adaptation. Both KMO knockdown and specific inhibitor Ro618048 enhanced GSIS in vitro in GK islets. Moreover, acute administration of Ro618048 in vivo improved glucose tolerance, GSIS and basal blood glucose levels in GK rats. These results demonstrate that targeting islet TKP is able to correct defective GSIS. KMO inhibition could represent a potential therapeutic strategy for type 2 diabetes. [Display omitted] • The tryptophan/kynurenine pathway (TKP) is activated in pancreatic islets of diabetic GK rats. • TKP is also activated in human islets exposed to proinflammatory conditions. • Increased KMO expression in GK rat pancreas occurs prominently in the endocrine cells. • KMO inhibition allows the reactivation of GSIS of diabetic islet in vitro and in vivo. [ABSTRACT FROM AUTHOR]

Recent results of three astrophysically relevant experiments at Caltech are summarized. In the first experiment magnetohydrodynamically driven plasma jets simulate astrophysical jets that undergo a kink instability. Lateral acceleration of the kinking jet spawns a Rayleigh–Taylor instability, which in turn spawns a magnetic reconnection. Particle heating and a burst of waves are observed in association with the reconnection. The second experiment uses a slightly different setup to produce an expanding arched plasma loop which is similar to a solar corona loop. It is shown that the plasma in this loop results from jets originating from the electrodes. The possibility of a transition from slow to fast expansion as a result of the expanding loop breaking free of an externally imposed strapping magnetic field is investigated. The third and completely different experiment creates a weakly ionized plasma with liquid nitrogen cooled electrodes. Water vapour injected into this plasma forms water ice grains that in general are ellipsoidal and not spheroidal. The water ice grains can become quite long (up to several hundred microns) and self-organize so that they are evenly spaced and vertically aligned. [ABSTRACT FROM PUBLISHER]

Unlabelled: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery.Methods: Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9-10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry.Results: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores.Conclusion: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI. [ABSTRACT FROM AUTHOR]