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Ramji R.,National University of Singapore | Bhagat A.A.S.,Clearbridge Biomeidics Pte Ltd. | Lim C.T.,National University of Singapore | Chen C.-H.,National University of Singapore | Chen C.-H.,Singapore Institute for Neurotechnology SINAPSE
17th International Conference on Miniaturized Systems for Chemistry and Life Sciences, MicroTAS 2013 | Year: 2013

Single cell intracellular protein studies have gained importance over the recent years due to their ability to differentiate data obtained from ensemble measurements. We demonstrated for the first time, the ability to compartmentalize cells inside droplets and study a dynamic kinase signaling process which is triggered by activation of a tyrosine kinase receptor upon ligand binding at the cell surface. In addition, we also reported spatial ordering of cells using inertial focusing through pinched microchannel structures. This design allows us to encapsulate single cells inside the droplets by breaking cell aggregates during their passage through the pinch structure.


Ong W.-Y.,National University of Singapore | Tanaka K.,National University of Singapore | Dawe G.S.,National University of Singapore | Dawe G.S.,Singapore Institute for Neurotechnology SINAPSE | And 2 more authors.
Journal of Alzheimer's Disease | Year: 2013

Progress is being made in identifying possible pathogenic factors and novel genes in the development of Alzheimer's disease (AD). Many of these could contribute to 'slow excitotoxicity', defined as neuronal loss due to overexcitation as a consequence of decreased energy production due, for instance, to changes in insulin receptor signaling; or receptor abnormalities, such as tau-induced alterations the N-methyl-D-aspartate (NMDA) receptor phosphorylation. As a result, glutamate becomes neurotoxic at concentrations that normally show no toxicity. In AD, NMDA receptors are overexcited by glutamate in a tonic, rather than a phasic manner. Moreover, in prodromal AD subjects, functional MRI reveals an increase in neural network activities relative to baseline, rather than loss of activity. This may be an attempt to compensate for reduced number of neurons, or reflect ongoing slow excitotoxicity. This article reviews possible links between AD pathogenic factors such as AβPP/Aβ and tau; novel risk genes including clusterin, phosphatidylinositol-binding clathrin assembly protein, complement receptor 1, bridging integrator 1, ATP-binding cassette transporter 7, membrane-spanning 4-domains subfamily A, CD2-associated protein, sialic acid-binding immunoglobulin-like lectin, and ephrin receptor A1; metabolic changes including insulin resistance and hypercholesterolemia; lipid changes including alterations in brain phospholipids, cholesterol and ceramides; glial changes affecting microglia and astrocytes; alterations in brain iron metallome and oxidative stress; and slow excitotoxicity. Better understanding of the possible molecular links between pathogenic factors and slow excitotoxicity could inform our understanding of the disease, and pave the way towards new therapeutic strategies for AD. © 2013 - IOS Press and the authors. All rights reserved.


Lee L.C.,National University of Singapore | Lee L.C.,Singapore Institute for Neurotechnology SINAPSE | Rajkumar R.,National University of Singapore | Rajkumar R.,Singapore Institute for Neurotechnology SINAPSE | And 2 more authors.
Brain Research | Year: 2014

The nucleus incertus (NI), a brainstem nucleus found in the pontine periventricular grey, is the primary source of the neuropeptide relaxin-3 in the mammalian brain. The NI neurons have also been previously reported to express several receptors and neurotransmitters, including corticotropin releasing hormone receptor 1 (CRF1) and gamma-aminobutyric acid (GABA). The NI projects widely to putative neural correlates of stress, anxiety, depression, feeding behaviour, arousal and cognition leading to speculation that it might be involved in several neuropsychiatric conditions. On the premise that relaxin-3 expressing neurons in the NI predominantly co-express CRF1 receptors, a novel method for selective ablation of the rat brain NI neurons using corticotropin releasing factor (CRF)-saporin conjugate is described. In addition to a behavioural deficit in the fear conditioning paradigm, reverse transcriptase polymerase chain reaction (RT-PCR), western blotting (WB) and immunofluorescence labelling (IF) techniques were used to confirm the NI lesion. We observed a selective and significant loss of CRF1 expressing cells, together with a consistent decrease in relaxin-3 and GAD65 expression. The significant ablation of relaxin-3 positive neurons of the NI achieved by this lesioning approach is a promising model to explore the neuropsychopharmacological implications of NI/relaxin-3 in behavioural neuroscience. © 2013 The Authors.


Rajkumar R.,National University of Singapore | Rajkumar R.,Singapore Institute for Neurotechnology SINAPSE | Fam J.,National University of Singapore | Yeo E.Y.M.,National University of Singapore | And 3 more authors.
Pharmacological Research | Year: 2015

Abstract Depression and suicide are known to be intricately entwined but the neurobiological basis underlying this association is yet to be understood. Ketamine is an N-methyl d-aspartate (NMDA) receptor antagonist used for induction and maintenance of general anaesthesia but paradoxically its euphoric effects lead to its classification under drugs of abuse. The serendipitous finding of rapid-onset antidepressant action of subanaesthetic dosing with ketamine by intravenous infusion has sparked many preclinical and clinical investigations. A remarkable suppression of suicidal ideation was also reported in depressed patients. This review focuses on the clinical trials on ketamine that reported remedial effects in suicidal ideation in depression and addresses also the molecular mechanisms underlying the antidepressant and psychotomimetic actions of ketamine. The neuropsychiatric profile of subanaesthetic doses of ketamine encourages its use in the management of suicidal ideation that could avert emergent self-harm or suicide. Finally, the need for neuroimaging studies in suicidal patients to identify the brain region specific and temporal effects of ketamine, and the possibility of employing ketamine as an experimental tool in rodent-based studies to study the mechanisms underlying suicidal behaviour are highlighted. © 2015 Elsevier Ltd.


Jing T.,National University of Singapore | Jing T.,Singapore Alliance for Research and Technology Center | Ramji R.,National University of Singapore | Warkiani M.E.,Singapore Alliance for Research and Technology Center | And 8 more authors.
Biosensors and Bioelectronics | Year: 2015

Activated proteases such as matrix metalloproteinases (MMPs) secreted from cancer cells can degrade the extracellular matrix (ECM) and contribute to tumour formation and metastasis. Measuring MMP activity in individual cancer cells can provide important insights on cancer cell heterogeneity and disease progression. Here, we present a microfluidic platform combining a droplet jetting generator and a deterministic lateral displacement (DLD) size-sorting channel that is capable of encapsulating individual cancer cells inside picoliter droplets effectively. Droplet jetting with cell-triggered Rayleigh-Plateau instability was employed which produced large droplets capable of cell encapsulation (diameter, ~25. μm) and small empty droplets (diameter, ~14. μm), which were then size-separated using a DLD size-sorting channel to enrich the single-cell encapsulated droplets (~78%), regardless of the cell density of input sample solutions. The droplets containing encapsulated cancer cells were collected in an observation chamber to determine the kinetic profiles of MMP secretion and the inhibitory response in the presence of the drug doxycycline at the single-cell level to reveal their heterogeneous MMPs secretion activities. © 2014 Elsevier B.V.


Kumar J.R.,National University of Singapore | Kumar J.R.,Singapore Institute for Neurotechnology SINAPSE | Rajkumar R.,National University of Singapore | Rajkumar R.,Singapore Institute for Neurotechnology SINAPSE | And 9 more authors.
Physiology and Behavior | Year: 2015

The nucleus incertus (NI), located in the caudal brainstem, mainly consists of GABAergic neurons with widespread projections across the brain. It is the chief source of relaxin-3 in the mammalian brain and densely expresses corticotropin-releasing factor type 1 (CRF1) receptors. Several other neurotransmitters, peptides and receptors are reportedly expressed in the NI. In the present investigation, we show the expression of dopamine type-2 (D2) receptors in the NI by reverse transcriptase-polymerase chain reaction (RT-PCR), western blotting (WB) and immunofluorescence (IF). RT-PCR did not show expression of D3 receptors. D2 receptor short isoform (D2S)-like, relaxin-3, CRF1/2 receptor and NeuN immunoreactivity were co-expressed in the cells of the NI. Behavioural effects of D2 receptor activation by intra-NI infusion of quinpirole (a D2/D3 agonist) were evaluated. Hypolocomotion was observed in home cage monitoring system (LABORAS) and novel environment-induced suppression of feeding behavioural paradigms. Thus the D2 receptors expressed in the NI are likely to play a role in locomotion. Based on its strong bidirectional connections to the median raphe and interpeduncular nuclei, the NI was predicted to play a role in modulating behavioural activity and the present results lend support to this hypothesis. This is the first evidence of expression of a catecholamine receptor, D2-like immunoreactivity, in the NI. © 2015 The Authors. Published by Elsevier Inc.


Zeming K.K.,Singapore Institute for Neurotechnology SINAPSE | Thakor N.V.,Singapore Institute for Neurotechnology SINAPSE | Thakor N.V.,Johns Hopkins University | Zhang Y.,National University of Singapore | And 2 more authors.
Lab on a Chip - Miniaturisation for Chemistry and Biology | Year: 2016

Nanoparticles exhibit size-dependent properties which make size-selective purification of proteins, DNA or synthetic nanoparticles essential for bio-analytics, clinical medicine, nano-plasmonics and nano-material sciences. Current purification methods of centrifugation, column chromatography and continuous-flow techniques suffer from particle aggregation, multi-stage process, complex setups and necessary nanofabrication. These increase process costs and time, reduce efficiency and limit dynamic range. Here, we achieve an unprecedented real-time nanoparticle separation (51-1500 nm) using a large-pore (2 μm) deterministic lateral displacement (DLD) device. No external force fields or nanofabrication are required. Instead, we investigated innate long-range electrostatic influences on nanoparticles within a fluid medium at different NaCl ionic concentrations. In this study we account for the electrostatic forces beyond Debye length and showed that they cannot be assumed as negligible especially for precise nanoparticle separation methods such as DLD. Our findings have enabled us to develop a model to simultaneously quantify and modulate the electrostatic force interactions between nanoparticle and micropore. By simply controlling buffer solutions, we achieve dynamic nanoparticle size separation on a single device with a rapid response time (<20 s) and an enlarged dynamic range (>1200%), outperforming standard benchtop centrifuge systems. This novel method and model combines device simplicity, isolation precision and dynamic flexibility, opening opportunities for high-throughput applications in nano-separation for industrial and biological applications. © The Royal Society of Chemistry 2016.


Delbruck T.,ETH Zurich | Pfeiffer M.,ETH Zurich | Juston R.,Aix - Marseille University | Orchard G.,Singapore Institute for Neurotechnology SINAPSE | And 3 more authors.
Proceedings - IEEE International Symposium on Circuits and Systems | Year: 2015

This paper describes an open-source implementation of an event-based dynamic and active pixel vision sensor (DAVIS) for racing human vs. computer on a slot car track. The DAVIS is mounted in 'eye-of-god' view. The DAVIS image frames are only used for setup and are subsequently turned off because they are not needed. The dynamic vision sensor (DVS) events are then used to track both the human and computer controlled cars. The precise control of throttle and braking afforded by the low latency of the sensor output enables consistent outperformance of human drivers at a laptop CPU load of <3% and update rate of 666Hz. The sparse output of the DVS event stream results in a data rate that is about 1000 times smaller than from a frame-based camera with the same resolution and update rate. The scaled average lap speed of the 1/64 scale cars is about 450km/h which is twice as fast as the fastest Formula 1 lap speed. A feedbackcontroller mode allows competitive racing by slowing the computer controlled car when it is ahead of the human. In tests of human vs. computer racing the computer still won more than 80% of the races. © 2015 IEEE.


Lee W.W.,National University of Singapore | Yeow C.H.,National University of Singapore | Ren H.,National University of Singapore | Kukreja S.L.,National University of Singapore | Thakor N.V.,Singapore Institute for Neurotechnology SINAPSE
Proceedings of the IEEE RAS and EMBS International Conference on Biomedical Robotics and Biomechatronics | Year: 2016

Spatiotemporal spike patterns from a population of mechanoreceptors provide a concise representation of tactile stimuli that facilitates rapid sensory processing in the brain. Efficient models of mechanoreceptors are needed for the adoption of spike-based processing for robotic tactile sensing applications. This paper presents a biomimetic model of the fast-Adapting type 1 (FA-1) mechanoreceptor, implemented on a field-programmable-gate-Array (FPGA). The simplicity of this model enables its realization on large arrays of sensing elements while operating with sub-millisecond temporal precision required to capture deformation patterns. We illustrate this capability by interfacing with a 4096 element tactile sensor array with a 5.2 kHz sampling rate. Through physical experiments, we demonstrate the discrimination of force magnitude and local curvature during transient mechanical contact, using spike patterns obtained from the model. The approach has the potential to deliver responsive full-body tactile sensing in robotic and prosthetic applications. © 2016 IEEE.


PubMed | Johns Hopkins University, Singapore Institute for Neurotechnology SINAPSE and National University of Singapore
Type: Journal Article | Journal: Lab on a chip | Year: 2015

Nanoparticles exhibit size-dependent properties which make size-selective purification of proteins, DNA or synthetic nanoparticles essential for bio-analytics, clinical medicine, nano-plasmonics and nano-material sciences. Current purification methods of centrifugation, column chromatography and continuous-flow techniques suffer from particle aggregation, multi-stage process, complex setups and necessary nanofabrication. These increase process costs and time, reduce efficiency and limit dynamic range. Here, we achieve an unprecedented real-time nanoparticle separation (51-1500 nm) using a large-pore (2 m) deterministic lateral displacement (DLD) device. No external force fields or nanofabrication are required. Instead, we investigated innate long-range electrostatic influences on nanoparticles within a fluid medium at different NaCl ionic concentrations. In this study we account for the electrostatic forces beyond Debye length and showed that they cannot be assumed as negligible especially for precise nanoparticle separation methods such as DLD. Our findings have enabled us to develop a model to simultaneously quantify and modulate the electrostatic force interactions between nanoparticle and micropore. By simply controlling buffer solutions, we achieve dynamic nanoparticle size separation on a single device with a rapid response time (<20 s) and an enlarged dynamic range (>1200%), outperforming standard benchtop centrifuge systems. This novel method and model combines device simplicity, isolation precision and dynamic flexibility, opening opportunities for high-throughput applications in nano-separation for industrial and biological applications.

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