Neuromodulated synaptic plasticity on the SpiNNaker neuromorphic system

SpiNNaker is a digital neuromorphic architecture, designed specifically for the low power simulation of large-scale spiking neural networks at speeds close to biological real-time. Unlike other neuromorphic systems, SpiNNaker allows users to develop their own neuron and synapse models as well as specify arbitrary connectivity. As a result SpiNNaker has proved to be a powerful tool for studying different neuron models as well as synaptic plasticity—believed to be one of the main mechanisms behind learning and memory in the brain. A number of Spike-Timing-Dependent-Plasticity(STDP) rules have already been implemented on SpiNNaker and have been shown to be capable of solving various learning tasks in real-time. However, while STDP is an important biological theory of learning, it is a form of Hebbian or unsupervised learning and therefore does not explain behaviors that depend on feedback from the environment. Instead, learning rules based on neuromodulated STDP (three-factor learning rules) have been shown to be capable of solving reinforcement learning tasks in a biologically plausible manner. In this paper we demonstrate for the first time how a model of three-factor STDP, with the third-factor representing spikes from dopaminergic neurons, can be implemented on the SpiNNaker neuromorphic system. Using this learning rule we first show how reward and punishment signals can be delivered to a single synapse before going on to demonstrate it in a larger network which solves the credit assignment problem in a Pavlovian conditioning experiment. Because of its extra complexity, we find that our three-factor learning rule requires approximately 2× as much processing time as the existing SpiNNaker STDP learning rules. However, we show that it is still possible to run our Pavlovian conditioning model with up to 1 × 104 neurons in real-time, opening up new research opportunities for modeling behavioral learning on SpiNNaker

Transient 23–30 Hz oscillations in mouse hippocampus during exploration of novel environments

The hippocampus is a key brain structure for the encoding of new experiences and environments. Hippocampal activity shows distinct oscillatory patterns, but the relationships between oscillations and memory are not well understood. Here we describe bursts of hippocampal ∼23–30 Hz (beta2) oscillations in mice exploring novel, but not familiar, environments. In marked contrast to the relatively invariant ∼8 Hz theta rhythm, beta2 power was weak during the very first lap of the novel environment, increased sharply as the mice reencountered their start point, then persisted for only a few minutes. Novelty-evoked oscillations reflected precise synchronization of individual neurons, and participating pyramidal cells showed a selective enhancement of spatial specificity. Through focal viral manipulations, we found that novelty-evoked oscillations required functional NMDA receptors in CA3, a subregion critical for fast oscillations in vitro. These findings suggest that beta2 oscillations indicate a hippocampal dynamic state that facilitates the formation of unique contextual representations. © 2008 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/58576/1/20435_ftp.pd

InForm software: A semi-Automated research tool to identify presumptive human hepatic progenitor cells, and other histological features of pathological significance

Hepatic progenitor cells (HPCs) play an important regenerative role in acute and chronic liver pathologies. Liver disease research often necessitates the grading of disease severity, and pathologists' reports are the current gold-standard for assessment. However, it is often impractical to recruit pathologists in large cohort studies. In this study we utilise PerkinElmer's "InForm" software package to semi-Automate the scoring of patient liver biopsies, and compare outputs to a pathologist's assessment. We examined a cohort of eleven acute hepatitis samples and three non-Alcoholic fatty liver disease (NAFLD) samples, stained with HPC markers (GCTM-5 and Pan Cytokeratin), an inflammatory marker (CD45), Sirius Red to detect collagen and haematoxylin/eosin for general histology. InForm was configured to identify presumptive HPCs, CD45 +ve inflammatory cells, areas of necrosis, fat and collagen deposition (p < 0.0001). Hepatitis samples were then evaluated both by a pathologist using the Ishak-Knodell scoring system, and by InForm through customised algorithms. Necroinflammation as evaluated by a pathologist, correlated with InForm outputs (r 2 = 0.8192, p < 0.05). This study demonstrates that the InForm software package provides a useful tool for liver disease research, allowing rapid, and objective quantification of the presumptive HPCs and identifies histological features that assist with assessing liver disease severity, and potentially can facilitate diagnosis

A structural determinant required for RNA editing

RNA editing by adenosine deaminases acting on RNAs (ADARs) can be both specific and non-specific, depending on the substrate. Specific editing of particular adenosines may depend on the overall sequence and structural context. However, the detailed mechanisms underlying these preferences are not fully understood. Here, we show that duplex structures mimicking an editing site in the Gabra3 pre-mRNA unexpectedly fail to support RNA editing at the Gabra3 I/M site, although phylogenetic analysis suggest an evolutionarily conserved duplex structure essential for efficient RNA editing. These unusual results led us to revisit the structural requirement for this editing by mutagenesis analysis. In vivo nuclear injection experiments of mutated editing substrates demonstrate that a non-conserved structure is a determinant for editing. This structure contains bulges either on the same or the strand opposing the edited adenosine. The position of these bulges and the distance to the edited base regulate editing. Moreover, elevated folding temperature can lead to a switch in RNA editing suggesting an RNA structural change. Our results indicate the importance of RNA tertiary structure in determining RNA editing

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

The ITGB6 gene: its role in experimental and clinical biology.

Integrin αvβ6 is a membrane-spanning heterodimeric glycoprotein involved in wound healing and the pathogenesis of diseases including fibrosis and cancer. Therefore, it is of great clinical interest for us to understand the molecular mechanisms of its biology. As the limiting binding partner in the heterodimer, the β6 subunit controls αvβ6 expression and availability. Here we describe our understanding of the ITGB6 gene encoding the β6 subunit, including its structure, transcriptional and post-transcriptional regulation, the biological effects observed in ITGB6 deficient mice and clinical cases of ITGB6 mutations

The key DNA-binding residues in the C-terminal domain of Mycobacterium tuberculosis DNA gyrase A subunit (GyrA)

As only the type II topoisomerase is capable of introducing negative supercoiling, DNA gyrase is involved in crucial cellular processes. Although the other domains of DNA gyrase are better understood, the mechanism of DNA binding by the C-terminal domain of the DNA gyrase A subunit (GyrA-CTD) is less clear. Here, we investigated the DNA-binding sites in the GyrA-CTD of Mycobacterium tuberculosis gyrase through site-directed mutagenesis. The results show that Y577, R691 and R745 are among the key DNA-binding residues in M.tuberculosis GyrA-CTD, and that the third blade of the GyrA-CTD is the main DNA-binding region in M.tuberculosis DNA gyrase. The substitutions of Y577A, D669A, R691A, R745A and G729W led to the loss of supercoiling and relaxation activities, although they had a little effect on the drug-dependent DNA cleavage and decatenation activities, and had no effect on the ATPase activity. Taken together, these results showed that the GyrA-CTD is essential to DNA gyrase of M.tuberculosis, and promote the idea that the M.tuberculosis GyrA-CTD is a new potential target for drug design. It is the first time that the DNA-binding sites in GyrA-CTD have been identified

Polarimetric Plasmonic Sensing with Bowtie Nanoantenna Arrays

We propose a polarimetric plasmonic biosensor based on bowtie nanoantenna array transducers. Through numerical simulations, based on the finite element method (FEM), we study the phase retardation between the components of light polarized parallel and perpendicular to the major axis of the bowties within the arrays. From a design for high volumetric sensitivity at a wavelength of 780 nm, sensitivities ∼5 rad/RIU is obtained, corresponding to a detection limit of ∼10−7 when using a polarimetric readout platform. Similarly, surface sensitivity of the same array is evaluated by simulating the phase retardation changes induced by the coverage of bioreceptors and analytes of the metallic nanostructures

The endoplasmic reticulum stress marker CHOP predicts survival in malignant mesothelioma.

BACKGROUND: Mesothelioma is an incurable cancer originating from the mesothelial cells that line the pleural, peritoneal and pericardial cavities. These cells synthesise large quantities of surface glycoproteins, rendering them dependent upon efficient endoplasmic reticulum (ER) function. When faced with elevated levels of secretory protein load, cells are said to experience ER stress, which has been implicated in the pathogenesis of many human diseases including cancer. METHOD: We set out to measure markers of ER stress in malignant mesothelioma and to determine whether ER stress signalling correlates with clinical parameters. RESULTS: We observed that expression of the ER stress-responsive transcription factor C/EBP homologous protein (CHOP) correlated with patient survival and remained an independent prognostic variable in pairwise comparisons with all clinical variables tested. The most parsimonious multivariate model in our study comprised only performance status and CHOP staining. In contrast, expression of the ER stress-responsive phosphatase growth arrest and DNA damage 34 (GADD34) correlated with the degree of mesothelial differentiation, being lost progressively in biphasic and sarcomatoid mesotheliomas. CONCLUSION: Our findings suggest that staining for CHOP provides prognostic information that may be useful in the stratification of patients with mesothelioma. Staining for GADD34 may prove useful in classification of mesothelioma histopathology

Phase II evaluation of MGBG in non-small cell carcinoma of the lung

One hundred and eight patients with non-small cell lung cancer were treated in a Phase II trial with MGBG at a dose of 600 mg/m 2 i.v. weekly. Partial responses were noted in 3/43 patients with adenocarcinoma and 1/40 with squamous cell carcinoma. No responses were noted in 24 patients with large cell carcinoma. Overall, the drug was reasonably well-tolerated. At this dosage and schedule, MGBG has no substantial antitumor activity for patients with non-small cell lung cancer.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45128/1/10637_2004_Article_BF00180196.pd