TrkB Receptor Signalling: Implications in Neurodegenerative, Psychiatric and Proliferative Disorders

The Trk family of receptors play a wide variety of roles in physiological and disease processes in both neuronal and non-neuronal tissues. Amongst these the TrkB receptor in particular has attracted major attention due to its critical role in signalling for brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3) and neurotrophin-4 (NT4). TrkB signalling is indispensable for the survival, development and synaptic plasticity of several subtypes of neurons in the nervous system. Substantial evidence has emerged over the last decade about the involvement of aberrant TrkB signalling and its compromise in various neuropsychiatric and degenerative conditions. Unusual changes in TrkB signalling pathway have also been observed and implicated in a range of cancers. Variations in TrkB pathway have been observed in obesity and hyperphagia related disorders as well. Both BDNF and TrkB have been shown to play critical roles in the survival of retinal ganglion cells in the retina. The ability to specifically modulate TrkB signalling can be critical in various pathological scenarios associated with this pathway. In this review, we discuss the mechanisms underlying TrkB signalling, disease implications and explore plausible ameliorative or preventive approaches

Multidisciplinary Ophthalmic Imaging Progressive Loss of Retinal Ganglion Cells and Axons in Nonoptic Neuritis Eyes in Multiple Sclerosis: A Longitudinal Optical Coherence Tomography Study

Citation: Graham EC, You Y, Yiannikas C, et al. Progressive loss of retinal ganglion cells and axons in non-optic neuritis eyes in multiple sclerosis: a longitudinal optical coherence tomography study. Invest Ophthalmol Vis Sci. 2016;57:231157: -231757: . DOI:10.1167 PURPOSE. To examine the rate of retinal ganglion cell (RGC) layer and retinal nerve fiber layer (RNFL) changes in nonoptic neuritis (NON) eyes of relapsing remitting multiple sclerosis (RRMS) patients, and to find a specific imaging parameter useful for identifying disease progression. METHODS. Forty-five consecutive RRMS patients and 20 age-and sex-matched healthy subjects were enrolled. All patients were followed up for 3 years with annual optical coherence tomography (OCT) scans, which included a peripapillary ring scan protocol for RNFL analysis and a macular radial star-like scan to obtain RGC/inner plexiform layer (IPL) thickness measures. Healthy controls were scanned twice, 3 years apart. RESULTS. Retinal ganglion cell/inner plexiform layer and temporal RNFL (tRNFL) demonstrated highly significant thinning (P < 0.01), but all nasal segments and global RNFL (gRNFL) were not significantly different from normal controls. While receiver operating characteristics (ROC) analysis showed no advantage of RGC/IPL over tRNFL in cross-sectional detection of thinning, cut-off point based of fifth percentile in healthy controls demonstrated higher rate of abnormality for RGC/IPL. There was a significant progressive loss of RGC/IPL and tRNFL during the follow-up period. The largest thickness reduction was observed in tRNFL. ROC analysis demonstrated that tRNFL provided better sensitivity/specificity for detecting change over time than RGC/IPL (area under the curve [AUC] 0.78 vs. 0.52), which was confirmed by higher detection rate when 95 th percentile of progression in healthy controls was used as a cut-off. CONCLUSIONS. This study confirmed significant thinning of RGC/IPL and tRNFL in NON eyes of RRMS patients. Progressive losses were more apparent on tRNFL, while RGC/IPL showed less change over the follow-up period

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Visual evoked potential recording in rodents

The visual evoked potential (VEP) is an electronic potential recorded from the visual cortex in response to a visual stimulus. It provides a means to examine the function of the visual pathway from the retina to the occipital cortex. The most common animals employed in VEP laboratory studies are rats. In this chapter, we describe the basic 'flash VEP' recording protocol in rodents and discuss the practical aspects of the preparation including anaesthesia methods, electrode configuration, stimulus design, dark adaptation, filter settings and signal sampling with the authors' personal experience. We also review the recent use of the VEP in laboratory researches in several optic nerve disease models, including glaucoma, ischemic optic neuropathy and optic neuritis.11 page(s

Nighttime physician staffing in an intensive care unit

1 page(s

Regulation of Brain-Derived Neurotrophic Factor and Growth Factor Signaling Pathways by Tyrosine Phosphatase Shp2 in the Retina: A Brief Review

SH2 domain-containing tyrosine phosphatase-2 (PTPN11 or Shp2) is a ubiquitously expressed protein that plays a key regulatory role in cell proliferation, differentiation and growth factor (GF) signaling. This enzyme is well expressed in various retinal neurons and has emerged as an important player in regulating survival signaling networks in the neuronal tissues. The non-receptor phosphatase can translocate to lipid rafts in the membrane and has been implicated to regulate several signaling modules including PI3K/Akt, JAK-STAT and Mitogen Activated Protein Kinase (MAPK) pathways in a wide range of biochemical processes in healthy and diseased states. This review focuses on the roles of Shp2 phosphatase in regulating brain-derived neurotrophic factor (BDNF) neurotrophin signaling pathways and discusses its cross-talk with various GF and downstream signaling pathways in the retina

Improving reproducibility of VEP recording in rats : electrodes, stimulus source and peak analysis

The aims of this study were to evaluate and improve the reproducibility of visual evoked potential (VEP) measurement in rats and to develop a mini-Ganzfeld stimulator for rat VEP recording. VEPs of Sprague-Dawley rats were recorded on one randomly selected eye on three separate days within a week, and the recordings were repeated three times on the first day to evaluate the intrasession repeatability and intersession reproducibility. The VEPs were recorded with subdermal needle and implanted skull screw electrodes, respectively, to evaluate the effect of electrode configuration on VEP reproducibility. We also designed a mini-Ganzfeld stimulator for rats, which provided better eye isolation than the conventional visual stimuli such as flash strobes and large Ganzfeld systems. The VEP responses from mini-Ganzfeld were compared with PS33-PLUS photic strobe and single light-emitting diode (LED). The latencies of P1, N1, P2, N2, and P3 and the amplitude of each component were measured and analysed. Intrasession and intersession within-subject standard deviations (Sw), coefficient of variation, repeatability (R95) and intraclass correlatio n coefficient (ICC) were calculated. The VEPs recorded using the implanted skull electrodes showed significantly larger amplitude and higher reproducibility compared to the needle electrodes (P < 0.05). The mini-Ganzfeld stimulator showed superior repeatability and reproducibility in VEP recording. The intra/intersession ICCs of latency were 0.85/0.70 for mini-Ganzfeld, 0.72/0.62 for PS33-PLUS and only 0.59/0.42 for single LED. The latencies of the early peaks (N1 and P2) demonstrated better reproducibility than the later waves. The mean intrasession and intersession ICCs were 0.96 and 0.86 for the early peaks. Using a combination of skull screw electrodes, mini-Ganzfeld stimulator and early peak analysis, we achieved a high reproducibility in the rat VEP measurement. The latencies of the early peaks of rat VEPs were more consistent, which may be due to their generation in the primary visual cortex via the retino-geniculate fibres.11 page(s

Latency delay of visual evoked potential is a real measurement of demyelination in a rat model of optic neuritis

To investigate the relationship between size of demyelinated lesion, extent of axonal loss, and degree of latency delay of visual evoked potentials (VEPs) in a rat model of experimental demyelination. Lysolecithin 1% (0.4 or 0.8 μL) was microinjected into an optic nerve of each of 14 rats 2 mm posterior to the globe. Standard flash VEPs were recorded with skull-implanted electrodes before and 2, 4, and 6 days after the microinjection. The optic nerves were stained with Luxol-fast blue and Bielschowsky's silver to assess demyelination and axonal pathology, respectively. Demyelinated areas were measured on serial sections, and lesion volumes were deduced by three-dimensional reconstruction. Focal lesions of demyelination and variable axonal loss were observed. The mean volume of the lesion was 3.2 ± 1.1 × 102 mm3. The injected eye showed a significant latency delay and amplitude decrease. Regression analysis demonstrated a strong correlation between N1 latency delay and lesion volume (r = 0.863, P < 0.0001), which remained significant after adjustment for axonal loss (r = 0.829, P < 0.001). N1 latency delay also showed a correlation with axonal loss (r = 0.552, P = 0.041), but the correlation became nonsignificant when controlling for demyelination (r = 0.387, P = 0.191). A linear association between N1-P2 amplitude decrease and axonal loss (r = 0.681, P = 0.007) was also observed. The latency of the VEP accurately reflected the amount of demyelination in the visual pathway, whereas the amplitude correlated with axonal damage. This study supports the concept that the VEP provides a highly sensitive tool with which to measure demyelination in optic neuritis.8 page(s

Shp-2 regulates the TrkB receptor activity in the retinal ganglion cells under glaucomatous stress

AbstractTropomyosin‐receptor‐kinase B (TrkB receptor) activation plays an important role in the survival of retinal ganglion cells (RGCs). This study reports a novel finding that, SH2 domain-containing phosphatase-2 (Shp-2) binds to the TrkB receptor in RGCs and negatively regulates its activity under glaucomatous stress. This enhanced binding of TrkB and Shp2 is mediated through caveolin. Caveolin 1 and 3 undergo hyper-phosphorylation in RGCs under stress and bind to the Shp2 phosphatase. Shp2 undergoes activation under glaucomatous stress conditions in RGCs in vivo with a concurrent loss of TrkB activity. Inhibiting the Shp2 phosphatase restored TrkB activity in cells exposed to excitotoxic and oxidative stress. Collectively, these findings implicate a molecular basis of Shp2 mediated TrkB deactivation leading to RGC degeneration observed in glaucoma