New insights into the mechanism and DNA-sequence specificity of INO80 chromatin remodeling.

The INO80 complex stood out in a large family of ATP-dependent chromatin remodelers because of its ATPase domain binding and translocating on DNA at the edge of nucleosomes, rather than at two helical turns from the center of DNA that is wrapped around nucleosomes. This unique property of INO80 was thought to account for its singular role in nucleosome placement at gene promoters in a DNA-sequence dependent manner that is crucial for transcription regulation. Now, we uncover INO80 functions differently than previously thought with its ATPase domain translocating on DNA close to the center of nucleosomes, like other remodelers. Our discovery also reveals the physical properties of the first ~36 bp of DNA on the entry side of nucleosomes is the main determinant for the DNA specificity of INO80 rather than the properties of the extranucleosomal DNA. The DNA sequence sensitive step of INO80 is after DNA is displaced from the histone octamer on the entry side of nucleosomes and 20 bp of DNA are moved out the exit side. We find the ATPase domain and Arp5 subunit of INO80 are likely involved in INO80's DNA specificity and the mechanism of INO80 remodeling is substantially different than originally proposed.

Uracil-DNA glycosylase of murine gammaherpesvirus 68 binds cognate viral replication factors independently of its catalytic residues.

Herpesviruses are large double-stranded DNA viruses that encode core replication proteins and accessory factors involved in nucleotide metabolism and DNA repair. Mammalian uracil-DNA glycosylases (UNG) excise deleterious uracil residues from their genomic DNA. Each herpesvirus UNG studied to date has demonstrated conservation of the enzymatic function to excise uracil residues from DNA. We previously reported that a murine gammaherpesvirus (MHV68) with a stop codon in ORF46 (ORF46.stop) that encodes for vUNG was defective in lytic replication and latency in vivo. However, a mutant virus that expressed a catalytically inactive vUNG (ORF46.CM) had no replication defect unless coupled with additional mutations in the catalytic motif of the viral dUTPase (ORF54.CM). The disparate phenotypes observed in the vUNG mutants led us to explore the non-enzymatic properties of vUNG. Immunoprecipitation of vUNG followed by mass spectrometry in MHV68-infected fibroblasts identified a complex comprising the cognate viral DNA polymerase, vPOL, encoded by ORF9, and the viral DNA polymerase processivity factor, vPPF, encoded by ORF59. MHV68 vUNG co-localized with vPOL and vPPF in subnuclear structures consistent with viral replication compartments. In reciprocal co-immunoprecipitations, the vUNG formed a complex with the vPOL and vPPF upon transfection with either factor alone or in combination. Lastly, we determined that key catalytic residues of vUNG are not required for interactions with vPOL and vPPF upon transfection or in the context of infection. We conclude that the vUNG of MHV68 associates with vPOL and vPPF independently of its catalytic activity. IMPORTANCE Gammaherpesviruses encode a uracil-DNA glycosylase (vUNG) that is presumed to excise uracil residues from viral genomes. We previously identified the vUNG enzymatic activity, but not the protein itself, as dispensable for gammaherpesvirus replication in vivo. In this study, we report a non-enzymatic role for the viral UNG of a murine gammaherpesvirus in forming a complex with two key components of the viral DNA replication machinery. Understanding the role of the vUNG in this viral DNA replication complex may inform the development of antiviral drugs that combat gammaherpesvirus-associated cancers.

Uracil-DNA Glycosylase of Murine Gammaherpesvirus 68 Binds Cognate Viral Replication Factors Independently of its Catalytic Residues.

Herpesviruses are large double-stranded DNA viruses that encode core replication proteins and accessory factors involved in nucleotide metabolism and DNA repair. Mammalian Uracil-DNA glycosylases (UNG) excise deleterious uracil residues from their genomic DNA. Each herpesvirus UNG studied to date has demonstrated conservation of the enzymatic function to excise uracil residues from DNA. We previously reported that a murine gammaherpesvirus (MHV68) with a stop codon in ORF46 (ORF46.stop) that encodes for vUNG was defective in lytic replication and latency in vivo. However, a mutant virus that expressed a catalytically inactive vUNG (ORF46.CM) had no replication defect, unless coupled with additional mutations in the catalytic motif of the viral dUTPase (ORF54.CM). The disparate phenotypes observed in the vUNG mutants led us to explore the non-enzymatic properties of vUNG. Immunoprecipitation of vUNG followed by mass spectrometry in MHV68-infected fibroblasts identified a complex comprised of the cognate viral DNA polymerase, vPOL encoded by ORF9 , and the viral DNA polymerase processivity factor, vPPF encoded by ORF59 . MHV68 vUNG colocalized with vPOL and vPPF in subnuclear structures consistent with viral replication compartments. In reciprocal co-immunoprecipitations, the vUNG formed a complex with the vPOL and vPPF upon transfection with either factor alone, or in combination. Last, we determined that key catalytic residues of vUNG are not required for interactions with vPOL and vPPF upon transfection or in the context of infection. We conclude that the vUNG of MHV68 associates with vPOL and vPPF independently of its catalytic activity. IMPORTANCE: Gammaherpesviruses encode a uracil-DNA glycosylase (vUNG) that is presumed to excise uracil residues from viral genomes. We previously identified the vUNG enzymatic activity, but not the protein itself, as dispensable for gammaherpesvirus replication in vivo . In this study, we report a non-enzymatic role for the viral UNG of a murine gammaherpesvirus to form a complex with two key components of the viral DNA replication machinery. Understanding the role of the vUNG in this viral DNA replication complex may inform the development of antiviral drugs that combat gammaherpesvirus associated cancers.

A Recombinant Antibody For Tracking Murine Gammaherpesvirus 68 Uracil DNA Glycosylase Expression.

Antibodies are powerful tools to detect expressed proteins. However off-target recognition can confound their use. Therefore, careful characterization is needed to validate specificity in distinct applications. Here we report the sequence and characterization of a mouse recombinant antibody that specifically detects ORF46 of murine gammaherpesvirus 68 (MHV68). This ORF encodes the viral uracil DNA glycosylase (vUNG). The antibody does not recognize murine uracil DNA glycosylase and is useful in detecting vUNG expressed in virally infected cells. It can detect expressed vUNG in cells via immunostaining and microscopy or flow cytometry analysis. The antibody can detect vUNG from lysates of expressing cells via immunoblot under native conditions but not denaturing conditions. This suggests it recognizes a confirmational based epitope. Altogether this manuscript describes the utility of the anti-vUNG antibody and suitability for use in studies of MHV68 infected cells.

Contrasting spectroscopic response of human hemoglobin in presence of graphene oxides and its reduced form: Comparative approach with carbon quantum dots.

Recently, a considerable amount of research is being directed towards study of graphene oxide (GO) and its reduced form (RGO) since their exposed functional groups make them better candidates in nanobiotechnolgy. In order to assess their biocompatibility, the nature of interactions between Human Hemoglobin (HHb) and GO/RGO are monitored since a comparative spectroscopic approach towards understanding their nature of interactions has not been investigated previously. UV-vis spectroscopy reveals hyperchromicity for HHb-GO system and hypochromicity for HHb-RGO system in the region of absorption of tryptophan/tyrosine residues. Notably, although steady-state fluorescence static quenching of HHb for GO and enhancement of fluorescence for RGO is noticed, but average fluorescence-lifetime is remaining unchanged in presence of GO/RGO. Calorimetric data illustrates three-site and five-site binding model to be the best-fit model for GO and RGO respectively. Also, synchronous fluorescence quenching corresponding to alterations in microenvironment of tryptophan/ tyrosine residues is observed only in presence of GO. Likewise FTIR spectroscopy elucidates involvement of both amide I and amide II bond of HHb backbone through H-bonding interaction only for GO. Furthermore RLS spectra demonstrate an increase and a decrease in signal for GO and RGO respectively. Surprisingly, secondary structure of HHb is maintained upon interaction with both GO/RGO, as revealed by CD spectroscopy, thus supporting their potential application in biological microenvironment. Thus it appears that the spectroscopic properties of HHb upon interaction with GO is altered upon its reduction to RGO. Furthermore the role of HHb as good candidate for bimolecular interaction has been highlighted.

Recent Advances in Arsenic Research: Significance of Differential Susceptibility and Sustainable Strategies for Mitigation.

Arsenic contamination in drinking water and associated adverse outcomes are one of the major health issues in more than 50 countries worldwide. The scenario is getting even more detrimental with increasing number of affected people and newer sites reported from all over the world. Apart from drinking water, the presence of arsenic has been found in various other dietary sources. Chronic arsenic toxicity affects multiple physiological systems and may cause malignancies leading to death. Exposed individuals, residing in the same area, developed differential dermatological lesion phenotypes and varied susceptibility toward various other arsenic-induced disease risk, even after consuming equivalent amount of arsenic from the similar source, over the same duration of time. Researches so far indicate that differential susceptibility plays an important role in arsenic-induced disease manifestation. In this comprehensive review, we have identified major population-based studies of the last 20 years, indicating possible causes of differential susceptibility emphasizing arsenic methylation capacity, variation in host genome (single nucleotide polymorphism), and individual epigenetic pattern (DNA methylation, histone modification, and miRNA expression). Holistic multidisciplinary strategies need to be implemented with few sustainable yet cost-effective solutions like alternative water source, treatment of arsenic-contaminated water, new adaptations in irrigation system, simple modifications in cooking strategy, and dietary supplementations to combat this menace. Our review focuses on the present perspectives of arsenic research with special emphasis on the probable causes of differential susceptibility toward chronic arsenic toxicity and sustainable remediation strategies.

Understanding the mechanistic insight of arsenic exposure and decoding the histone cipher.

BACKGROUND: The study of heritable epigenetic changes in arsenic exposure has intensified over the last decade. Groundwater arsenic contamination causes a great threat to humans and, to date, no accurate measure has been formulated for remediation. The fascinating possibilities of epi-therapeutics identify the need for an in-depth mechanistic understanding of the epigenetic landscape. OBJECTIVE: In this comprehensive review, we have set to analyze major studies pertaining to histone post-translational modifications in arsenic-mediated disease development and carcinogenesis during last ten years (2008-2018). RESULTS: The role of the specific histone marks in arsenic toxicity has been detailed. A comprehensive list that includes major arsenic-induced histone modifications identified for the last 10 years has been documented and details of different states of arsenic, organisms, exposure type, study platform, and findings were provided. An arsenic signature panel was suggested to help in early prognosis. An attempt has been made to identify the grey areas of research. PROSPECTS: Future prospective multi-target analyses of the inter-molecular crosstalk among different histone marks are needed to be explored further in order to understand the mechanism of arsenic toxicity and carcinogenicity and to confirm the suitability of these epi-marks as prognostic markers.

Memory-Efficient Synaptic Connectivity for Spike-Timing- Dependent Plasticity.

Spike-Timing-Dependent Plasticity (STDP) is a bio-inspired local incremental weight update rule commonly used for online learning in spike-based neuromorphic systems. In STDP, the intensity of long-term potentiation and depression in synaptic efficacy (weight) between neurons is expressed as a function of the relative timing between pre- and post-synaptic action potentials (spikes), while the polarity of change is dependent on the order (causality) of the spikes. Online STDP weight updates for causal and acausal relative spike times are activated at the onset of post- and pre-synaptic spike events, respectively, implying access to synaptic connectivity both in forward (pre-to-post) and reverse (post-to-pre) directions. Here we study the impact of different arrangements of synaptic connectivity tables on weight storage and STDP updates for large-scale neuromorphic systems. We analyze the memory efficiency for varying degrees of density in synaptic connectivity, ranging from crossbar arrays for full connectivity to pointer-based lookup for sparse connectivity. The study includes comparison of storage and access costs and efficiencies for each memory arrangement, along with a trade-off analysis of the benefits of each data structure depending on application requirements and budget. Finally, we present an alternative formulation of STDP via a delayed causal update mechanism that permits efficient weight access, requiring no more than forward connectivity lookup. We show functional equivalence of the delayed causal updates to the original STDP formulation, with substantial savings in storage and access costs and efficiencies for networks with sparse synaptic connectivity as typically encountered in large-scale models in computational neuroscience.

Fluorescence enhancement via aggregation effect due to microenvironmental alterations in human hemoglobin protein in presence of carbon quantum dots (CQD): Comparative spectroscopic approach.

CQDs have emerged with outstanding properties as a star member of carbon nanomaterial family and in order to reveal its wide-range of application in biological microenvironment the interactions between human hemoglobin (HHb) and CQD and also with ethylenediamine-functionalized CQD (NCQD) are assessed using several techniques. Firstly, UV-vis absorption spectra of HHb reveal hyperchromic effect in the region of absorbance of tryptophan and tyrosine residues and also hypochromicity of Soret band in presence of CQD and NCQD. Interestingly, steady-state fluorescence spectroscopy reveal distinct fluorescence enhancement of HHb with significant red shift thereby indicating exposures of tryptophan and tyrosine residues to a more hydrophilic environment. However synchronous fluorescence spectra reveal that the microenvironment of tryptophan and tyrosine residues is altered in opposite manner, i.e. exposure of tryptophan residues to a more hydrophilic environment and the tyrosine residues to a more hydrophobic environment. Moreover the fluorescence enhancement is observed to be accompanied by increase in average fluorescence-lifetime and decrease in steady-state anisotropy thus signifying a decrease in restriction of rotational motion. Furthermore tryptophan residues within HHb appear to interact more with CQD compared to NCQD. Thermodynamic parameters as revealed by Isothermal Titration Calorimetry (ITC) demonstrate that electrostatic, hydrogen bonding and hydrophobic interactions are the predominant modes of interactions in presence of CQD. Whereas hydrophobic and hydrogen bonding interactions are the major interacting forces in presence of NCQD with five-site sequential binding as best-fit model in both the cases. Such interactions also appear to be associated with an increase in aggregation of HHb as evident from the measurements by atomic force microscopy (AFM) and dynamic light scattering (DLS) study. Although FT-IR spectra display alteration of amide I band, but the overall secondary structure of HHb seems to be nearly retained even in presence of CQDs, as evident in the CD spectra. These observations thus highlight the potential biomedical application of CQDs in biological microenvironment of human especially as drug-delivery system. Also bimolecular interaction of HHb as a model protein with other nanoparticles at the nano bio-interface has been outlined.

Regulation of ATP-dependent chromatin remodelers: accelerators/brakes, anchors and sensors.

All ATP-dependent chromatin remodelers have a DNA translocase domain that moves along double-stranded DNA when hydrolyzing ATP, which is the key action leading to DNA moving through nucleosomes. Recent structural and biochemical data from a variety of different chromatin remodelers have revealed that there are three basic ways in which these remodelers self-regulate their chromatin remodeling activity. In several instances, different domains within the catalytic subunit or accessory subunits through direct protein-protein interactions can modulate the ATPase and DNA translocation properties of the DNA translocase domain. These domains or subunits can stabilize conformations that either promote or interfere with the ability of the translocase domain to bind or retain DNA during translocation or alter the ability of the enzyme to hydrolyze ATP. Second, other domains or subunits are often necessary to anchor the remodeler to nucleosomes to couple DNA translocation and ATP hydrolysis to DNA movement around the histone octamer. These anchors provide a fixed point by which remodelers can generate sufficient torque to disrupt histone-DNA interactions and mobilize nucleosomes. The third type of self-regulation is in those chromatin remodelers that space nucleosomes or stop moving nucleosomes when a particular length of linker DNA has been reached. We refer to this third class as DNA sensors that can allosterically regulate nucleosome mobilization. In this review, we will show examples of these from primarily the INO80/SWR1, SWI/SNF and ISWI/CHD families of remodelers.

Neural and Synaptic Array Transceiver: A Brain-Inspired Computing Framework for Embedded Learning.

Embedded, continual learning for autonomous and adaptive behavior is a key application of neuromorphic hardware. However, neuromorphic implementations of embedded learning at large scales that are both flexible and efficient have been hindered by a lack of a suitable algorithmic framework. As a result, most neuromorphic hardware are trained off-line on large clusters of dedicated processors or GPUs and transferred post hoc to the device. We address this by introducing the neural and synaptic array transceiver (NSAT), a neuromorphic computational framework facilitating flexible and efficient embedded learning by matching algorithmic requirements and neural and synaptic dynamics. NSAT supports event-driven supervised, unsupervised and reinforcement learning algorithms including deep learning. We demonstrate the NSAT in a wide range of tasks, including the simulation of Mihalas-Niebur neuron, dynamic neural fields, event-driven random back-propagation for event-based deep learning, event-based contrastive divergence for unsupervised learning, and voltage-based learning rules for sequence learning. We anticipate that this contribution will establish the foundation for a new generation of devices enabling adaptive mobile systems, wearable devices, and robots with data-driven autonomy.

The Arp8 and Arp4 module acts as a DNA sensor controlling INO80 chromatin remodeling.

Nuclear actin and actin-related proteins (Arps) are key components of chromatin remodeling and modifying complexes. Although Arps are essential for the functions of chromatin remodelers, their specific roles and mechanisms are unclear. Here we define the nucleosome binding interfaces and functions of the evolutionarily conserved Arps in the yeast INO80 chromatin remodeling complex. We show that the N-terminus of Arp8, C-terminus of Arp4 and the HSA domain of Ino80 bind extranucleosomal DNA 37-51 base pairs from the edge of nucleosomes and function as a DNA-length sensor that regulates nucleosome sliding by INO80. Disruption of Arp8 and Arp4 binding to DNA uncouples ATP hydrolysis from nucleosome mobilization by disengaging Arp5 from the acidic patch on histone H2A-H2B and the Ino80-ATPase domain from the Super-helical Location (SHL) -6 of nucleosomes. Our data suggest a functional interplay between INO80's Arp8-Arp4-actin and Arp5 modules in sensing the DNA length separating nucleosomes and regulating nucleosome positioning.

Multi-wavelength add-drop filter with phase-modulated shifted Bragg grating.

We present, for the first time to the best of our knowledge, a multichannel add-drop operation with a phase-modulated shifted Bragg grating based filter. The device is realized in a silicon-on-insulator waveguide platform with TiO2 as a coating material to reduce the refractive index contrast. The operation is shown for three and five wavelength channels within the telecom C-band. A line width of 0.6 nm with an extinction ratio of 20 dB is achieved. The shifted Bragg grating is modulated maintaining a modal phase-matching condition for multiple wavelengths. The phase function is calculated with an iterative Fourier transform algorithm. The experimental results are in very good agreement with the design.

A side-effect free method for identifying cancer drug targets.

Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets. Here, we put forward an integrated method of analysing a complex network of cancer and depict the importance of k-core, functional connectivity and centrality (KFC) for identifying effective drug targets. Essentially, we have extracted the proteins involved in the pathways leading to cancer from the pathway databases which enlist real experimental datasets. The interactions between these proteins were mapped to build an interactome. Integrative analyses of the interactome enabled us to unearth plausible reasons for drugs being rendered withdrawn, thereby giving future scope to pharmaceutical industries to potentially avoid them (e.g. ESR1, HDAC2, F2, PLG, PPARA, RXRA, etc). Based upon our KFC criteria, we have shortlisted ten proteins (GRB2, FYN, PIK3R1, CBL, JAK2, LCK, LYN, SYK, JAK1 and SOCS3) as effective candidates for drug development.

Interactions of Fluorescein Dye with Spherical and Star Shaped Gold Nanoparticles.

UV-vis absorption, FT-IR, steady state fluorescence and fluorescence lifetime measurements were made on Fluorescein dye (Fl dye) molecules in presence of gold nanoparticles of different morphologies: spherical gold nanoparticles (GNP) and star shaped gold nanoparticles (GNS). The experimental observations demonstrate that Fl dye molecules form dimers when adsorbed on nanosurface of spherical gold particles. On the other hand possibly due to lack of adsorption on the surface of GNS the dye molecules were unable to form dimers. The projected tips on the surface of GNS may possibly hinder the dyes to adsorb on the surface of this nanoparticle. From the spectral analysis and measurements of thermodynamic parameters it is inferred that two different types of ground state interactions occur between Fl-dye-GNP and Fl dye-GNS systems. Both the observed negative values of the thermodynamic parameters ΔH and ΔS in the case of the former system predict the possibility of occurrences of hydrogen bonding interactions between two neighboring Fl dye molecules when adsorbed on the nanosurface of GNP. On the other hand in Fl dye-GNS system electrostatic interactions appear to occur, as evidenced from negative ΔH and positive value of ΔS, between the positive charges residing on the tips of the nanoparticles and anionic form of Fl dye. It has been concluded that as the adsorption of organic dyes on solid surfaces is prerequisite for the degradation of dye pollutants, the present experimental observations demonstrate that GNP could be used as a better candidate than GNS in degradation mechanism of the xanthenes dyes.

Association of H3K79 monomethylation (an epigenetic signature) with arsenic-induced skin lesions.

Arsenic, a non mutagenic carcinogen, poses a profound health risk upon prolonged exposure. The objective of the study was to analyze the post-translational modifications of the major histone H3 and the associated molecular crosstalk to identify the epigenetic signature of arsenic susceptibility. Herein, we identified significant upregulation of H3K79me1, in individuals with arsenic-induced skin lesion (WSL), and H3K79me1 was found to be regulated by the upstream methyltransferase DOT1L. Moreover, the downstream target molecule 53BP1, a tumor suppressor protein that has a docking preference for H3K79me1 at a site of a double-strand break (DSB), was downregulated, indicating greater DNA damage in the WSL group. Western blot data confirmed higher levels of γH2AX, a known marker of DSBs, in group WSL. In vitro dose-response analysis also confirmed the association of the H3K79me1 signature with arsenic toxicity. Taken together, our findings revealed that H3K79me1 and DOT1L could be a novel epigenetic signature of the arsenic-exposed WSL group.

To reveal the nature of interactions of human hemoglobin with gold nanoparticles having two different morphologies (sphere and star-shaped) by using various spectroscopic techniques.

The nature of interactions between heme protein human hemoglobin (HHb) and gold nanoparticles of two different morphologies that is GNP (spherical) and GNS (star-shaped) have been investigated by using UV-vis absorption, steady state fluorescence, synchronous fluorescence, resonance light scattering (RLS), time resolved fluorescence, FT-IR, and circular dichroism (CD) techniques under physiological condition of pH ~7 at ambient and different temperatures. Analysis of the steady state fluorescence quenching of HHb in aqueous solution in the presence of GNP and GNS suggests that the nature of the quenching is of static type. The static nature of the quenching is also confirmed from time resolved data. The static type of quenching also indicates the possibility of formation of ground state complex for both HHb-GNP and HHb-GNS systems. From the measurements of Stern-Volmer (SV) constants KSV and binding constants, KA and number of binding sites it appears that HHb forms stronger binding with GNP relative to GNS. Analysis of the thermodynamic parameters indicates that the formation of HHb-GNP and HHb-GNS complexes are spontaneous molecular interaction processes (∆G<0). In both cases hydrogen bonding and van der Waals interactions play a dominant role (∆H<0, ∆S<0). Synchronous fluorescence spectroscopy further reveals that the ground state complex formations of HHb-GNP and HHb-GNS preferably occur by binding with the amino acid tyrosine through hydrogen bonding interactions. Moreover the α-helicity contents of the proteins as obtained from the circular dichroism (CD) spectra appears to be marginally reduced by increasing concentrations of GNP and GNS and the α-helical structures of HHb retain its identity as native secondary structure in spite of complex formations with GNP or GNS. These findings demonstrate the efficiency of biomedical applications of GNP and GNS nanoparticles as well as in elucidating their mechanisms of action as drugs or drug delivery systems in human.

Multi-wavelength filtering with a waveguide integrated phase-modulated Bragg grating.

We present a multi-wavelength band-rejection filter on a titanium dioxide-coated silicon-on-insulator platform. The concept rests on the use of a finely tuned waveguide-based Bragg grating for which the periods are slightly varied from one to another. This phase-modulated Bragg grating enables precise customization of integrated waveguide filters. The number of rejection bands and the center-to-center separation between them are tailored by dividing the grating into several super-periods and coding an optimal phase function onto each super-period. The optimal phase function is obtained by employing an iterative Fourier transform algorithm. The design is supported by an experimental demonstration.

Event-Driven Random Back-Propagation: Enabling Neuromorphic Deep Learning Machines.

An ongoing challenge in neuromorphic computing is to devise general and computationally efficient models of inference and learning which are compatible with the spatial and temporal constraints of the brain. One increasingly popular and successful approach is to take inspiration from inference and learning algorithms used in deep neural networks. However, the workhorse of deep learning, the gradient descent Gradient Back Propagation (BP) rule, often relies on the immediate availability of network-wide information stored with high-precision memory during learning, and precise operations that are difficult to realize in neuromorphic hardware. Remarkably, recent work showed that exact backpropagated gradients are not essential for learning deep representations. Building on these results, we demonstrate an event-driven random BP (eRBP) rule that uses an error-modulated synaptic plasticity for learning deep representations. Using a two-compartment Leaky Integrate & Fire (I&F) neuron, the rule requires only one addition and two comparisons for each synaptic weight, making it very suitable for implementation in digital or mixed-signal neuromorphic hardware. Our results show that using eRBP, deep representations are rapidly learned, achieving classification accuracies on permutation invariant datasets comparable to those obtained in artificial neural network simulations on GPUs, while being robust to neural and synaptic state quantizations during learning.

Arsenic toxicity and epimutagenecity: the new LINEage.

Global methylation pattern regulates the normal functioning of a cell. Research have shown arsenic alter these methylation landscapes within the genome leading to aberrant gene expression and inducts various pathophysiological outcomes. Long interspersed nuclear elements (LINE-1) normally remains inert due to heavy methylation of it's promoters, time and various environmental insults, they lose these methylation signatures and begin retro-transposition that has been associated with genomic instability and cancerous outcomes. Of the various high throughput technologies available to detect global methylation profile, development of LINE-1 methylation index shall provide a cost effect-screening tool to detect epimutagenic events in the wake of toxic exposure in a large number of individuals. In the present review, we tried to discuss the state of research and whether LINE-1 methylation can be considered as a potent epigenetic signature for arsenic toxicity.