Comparison of features between different open-source tile cache implementations: TileCache, GeoWebCache and MapProxy.
\r\n\tThorough research and analyses of most upfront neuroimaging techniques and various in vivo applications of specific mapping of normal function and under diseases are the purpose of this book. This book would hopefully capture the interests of colleagues interested in neuroimaging principles and applications, research and developments, as well as disease diagnosis and treatment, and could help convey the methodological and developmental perspectives of brain function in the medical application and research field.
\r\n\t
Web mapping has become a popular way of distributing online mapping through the Internet. Multiple services, like the popular Google Maps or Microsoft Bing Maps, allow users to visualize cartography by using a simple Web browser and an Internet connection. However, geographic information is an expensive resource, and for this reason standardization is needed to promote its availability and reuse. In order to standardize this kind of map services, the Open Geospatial Consortium (OGC) developed the Web Map Service (WMS) recommendation [1]. This standard provides a simple HTTP interface for requesting geo-referenced map images from one or more distributed geospatial databases. It was designed for custom maps rendering, enabling clients to request exactly the desired map image. This way, clients can request arbitrary sized map images to the server, superposing multiple layers, covering an arbitrary geographic bounding box, in any supported coordinate reference system or even applying specific styles and background colors.
\nHowever, this flexibility reduces the potential to cache map images, because the probability of receiving two exact map requests is very low. Therefore, it forces images to be dynamically generated on the fly each time a request is received. This involves a very time-consuming and computationally-expensive process that negatively affects service scalability and users\' Quality of Service (QoS).
\nA common approach to improve the cachability of requests is to divide the map into a discrete set of images, called tiles, and restrict user requests to that set [2]. Several specifications have been developed to address how cacheable image tiles are advertised from server-side and how a client requests cached image tiles. The Open Source Geospatial Foundation (OSGeo) developed the WMS Tile Caching (usually known as WMS-C) proposal [3]. Later, the OGC released the Web Map Tile Service Standard (WMTS) [4] inspired by the former and other similar initiatives.
\nMost popular commercial services, like Google Maps, Yahoo Maps or Microsoft Virtual Earth, have already shown that significant performance improvements can be achieved by adopting this methodology, using their custom tiling schemes.
\nThe potential of tiled map services is that map image tiles can be cached at any intermediate location between the client and the server, reducing the latency associated to the image generation process. Tile caches are usually deployed server-side, serving map image tiles concurrently to multiple users. Moreover, many mapping clients, like Google Earth or Nasa World Wind, have embedded caches, which can also reduce network congestion and network delay.
\nThis chapter deals with the algorithms that allow the optimization and management of these tile caches: population strategies (seeding), tile pre-fetching and cache replacement policies.
\nMaps have been known for a long time only as printed on paper. Those printed cartographic maps were static representations limited to a fixed visualization scale with a certain Level Of Detail (LOD). However, with the development of digital maps, users can enlarge or reduce the visualized area by zooming operations, and the LOD is expected to be updated accordingly.
\nThe adaptation of map content is strongly scale-dependent: A small-scale map contains less detailed information than a large scale map of the same area. The process of reducing the amount of data and adjusting the information to the given scale is called cartographic generalization, and it is usually carried out by the web map server [5].
\nIn order to offer a tiled web map service, the web map server renders the map across a fixed set of scales through progressive generalization. Rendered map images are then divided into tiles, describing a tile pyramid as depicted in
Tile pyramid representation.
For example, Microsoft Bing Maps uses a tiling scheme where the first level allows representing the whole world in four tiles (2x2) of 256x256 pixels. The next level represents the whole world in 16 tiles (4x4) of 256x256 pixels and so on in powers of 4. A comprehensive study on tiling schemes can be found in [2].
\nGiven the exponential nature of the scale pyramid, the resource consumption to store map tiles results often prohibitive for many providers when the cartography covers a wide geographic area for multiple scales. Consider for example that Google\'s BigTable, which contains the high-resolution satellite imagery of the world\'s surface as shown in Google Maps and Google Earth, contained approximately 70 terabytes of data in 2006 [6].
\nBesides the storage of map tiles, many caching systems also maintain metadata associated to each individual tile, such as the time when it was introduced into the cache, the last access to that object, or the number of times it has been requested. This information can then be used to improve the cache management; for example, when the cache is out of space, the LRU (Least Recently Used) replacement policy uses the last access time to discard the least recently used items first.
\nHowever, the space required to store the metadata associated to a given tile may only differ by two or three orders of magnitude to the one necessary to store the actual map image object. Therefore, it is not usually feasible to work with the statistics of individual tiles. To alleviate this problem, a simplified model has been proposed by different researchers. This model groups the statistics of adjacent tiles into a single object [7]. A grid is defined so all objects inside the same grid section are combined into a single one. The pyramidal structure of scales is therefore transformed in some way in a prism-like structure with the same number of items in all the scales.
\nIn order to deal with this complexity some cache management algorithms have been created.\nHowever, the efficiency of the designed algorithms usually depends on the service\'s workload.\nBecause of this, prior to diving into the details of the cache management policies, a workload characterization of the WMS services need to be shown.\nLets take some real-life examples for such characterization: trace files from two different tiled web map services, Cartociudad[1] - and IDEE-Base[1] -, provided by the National Geographic Institute (IGN)[1] - of Spain, are presented in this chapter.
\nCartociudad is the official cartographic database of the Spanish cities and villages with their streets and roads networks topologically structured, while IDEE-Base allows viewing the Numeric Cartographic Base 1:25,000 and 1:200,000 of the IGN.
\nPercentile of requests for the analyzed services.
Available trace files were filtered to contain only valid web map requests according to the WMS-C recommendation. Traces from Cartociudad comprise a total of 2.369.555 requests received from the 9th December of 2009 to 13th May in 2010. IDEE-Base logs reflect a total of 16.891.616 requests received between 15th March and 17th June in 2010.
\nIt must be noted that the performance gain achieved by the use of a tile cache will vary depending on how the tile requests are distributed over the tiling space. If those were uniformly distributed, the cache gain would be proportional to the cache size. However, lucky for us, it has been found that tile requests usually follow a heavy-tailed Pareto distribution, as shown in
Distribution of requests along the different resolution levels for Cartociudad service.
Distribution of requests along the different resolution levels for IDEE-Base service.
▭ and
With the standardization of tiled web map services, multiple tile cache implementations have appeared. Between them, the main existent implementations are: TileCache, GeoWebCache and MapProxy. A comparison between these implementations is summarized in Table ▭.
\n\n | TileCache | \nGeoWebCache | \nMapProxy | \n
Company | \nMetacarta Labs | \nOSGeo | \nOmniscale | \n
Implementation | \nPython | \nJava | \nPython | \n
Supported services | \nWMS-C, TMS, KML | \nWMS, WMS-C, TMS WMTS, KML, Google Maps, Bing Maps | \nWMS, WMS-C, TMS WMTS, KML | \n
Tile storage | \nDisk, GoogleDisk, Memcached, Amazon S3, MBTiles | \nDisk | \nDisk, MBTiles | \n
Tile metadata storage | \nNo | \nYes | \nYes | \n
Replacement policies | \nLRU | \nLRU, LFU | \nNone | \n
Seeding regions | \nbounding box | \nbounding box | \nbounding box | \n
Supports Meta Tiles | \nYes | \nYes | \nYes | \n
Supports Meta Buffer | \nYes | \nYes | \nYes | \n
Reprojection on-the-fly | \nNo | \nYes (with Geoserver) | \nYes (native) | \n
Comparison of features between different open-source tile cache implementations: TileCache, GeoWebCache and MapProxy.
As can be seen, TileCache and MapProxy are both implemented in Python (interpreted language), while GeoWebCache is implemented in Java (compiled language). These three services implement the WMS-C, TMS and KML service interfaces. GeoWebCache and MapProxy also offer the WMTS service from OGC. In addition, GeoWebCache can recombine and resample tiles to answer arbitrary WMS requests, and can also be used to serve maps to Google Maps and Microsoft Bing Maps.
\nAll these services offer the possibility of storing map image tiles directly in the file system. TileCache and GeoWebCache also support the MBTiles speficication[1] - for storing tiled map data in a SQLite database for immediate use and for transfer. MapProxy supports the Apache CouchDB[1] -, a document-oriented database that can be queried and indexed in a MapReduce fashion, as backend to store tiles. Moreover, TileCache can store map tiles in the cloud through Amazon S3[1] - or to maintain them in memory using Memcached[1] -.
\nGeoWebCache maintain tile metadata, such as the last access time or the number of times that each tile has been requested. By using this metadata, it supports the LRU and LFU replacement policies. TileCache supports LRU by using the operating system\'s time of last access.
\nThese services allow to specify a geographic region for automatically seeding tiles. For example, TileCache can be configured to seed a particular regions defined by a rectangular bounding box or a circle by specifying its center and radius. GeoWebCache supports only the former. MapProxy offers three different ways to describe the extent of a seeding or cleanup task: a simple rectangular bounding box, a text file with one or more polygons in WKT format, or polygons from any data source readable with OGR (e.g. Shapefile, PostGIS).
\nThese three services support both metatiling and meta-buffer methods. The meta-buffer adds extra space at the edges of the requested area.
\nWhen a request of a tile in an unsupported coordinate reference system (CRS) is received, both GeoWebCache and MapProxy supports the reprojection on the fly from one of the available CRSs to the specified one. The former achieves this using GeoServer, while the latter offers it natively.
\nSignificant improvements can be achieved by using a cache of map tiles, like the ones discussed above. However, adequate cache management policies are needed, especially in local SDIs with lack of resources. In this section, our contributions to the main cache strategies are presented: cache population (or seeding), cache replacement and tile prefetching.
\nAnticipating the content that users will demand can guide server administrators to know which tiles to pregenerate and to include in their server-side caches of map tiles. With this objective in mind, a predictive model that uses variables known to be of interest to Web map users, such as populated places, major roads, coastlines, and tourist attractions, is presented in [8].
\nIn contrast, we propose a descriptive model based on the mining of the service\'s past history [7]. Past history can be easily extracted, for example, from server logs. The advantage of this model is that it is able to determine in advance which areas are likely to be requested in the future based exclusively on past accesses, and it is therefore very simple.
\nIn order to experiment with the proposed model, real-world logs from the IDEE-Base nation-wide public web map service have been used. Request logs were divided in two time ranges of the same duration. The first one was used as source to make predictions and the second one was used to prove the predictions created previously.\nDue to the difficulty of working with the statistics of individual tiles, the simplified model presented in Section ▭ has been used. Concretely, the experiment was conducted with the simplified model to the grid cell defined by the level of resolution 12.
\n![]() | ![]() |
(a) Scale 12 | (b) Scale 13 |
![]() | ![]() |
(c) Scale 14 | (d) Scale 15 |
![]() | ![]() |
(e) Scale 16 | (f) Scale 17 |
![]() | ![]() |
(g) Scale 18 | (h) Scale 19 |
Heatmap of the requests to the IDEE-BASE service propagated from levels 12-19 to level 12.
▭ shows the heatmaps of requests extracted from the web server logs of IDEE-Base service, propagated to level 12 through the proposed model. These figures demonstrate that some entities such as coast lines, cities and major roads are highly requested. These elements could be used as entities for a predictive model to identify priority objects, as explained in [8].
\nThese figures show that near levels are more related than distant ones, but all of them share certain similarity. This relationships between resolution levels encourages the use of statistics collected in a level to predict the map usage patterns in another level with detailer resolution. For example, as shown in
![]() | ![]() | ![]() | ![]() |
(a) Scale 12 | (b) Scale 13 | (c) Scale 14 | (d) Scale 15 |
Percentage of hits vs cached objects for IDEE-BASE service through the simplified model. Scales 12 to 15.
![]() | ![]() | ![]() | ![]() |
(a) Scale 16 | (b) Scale 17 | (c) Scale 18 | (d) Scale 19 |
Percentage of hits vs cached objects for IDEE-BASE service through the simplified model. Scales 16 to 19.
Table ▭ represents the hit percentage achieved by using this model for the IDEE-Base service. This table shows the percentage of hits obtained for the level identified by the column index from the statistics collected in the level identified by the row index. Last column shows the resources consumption, as a percentage of cached tiles. Last row collects the results of combining the statistics of all levels to make predictions over every level. Shadowed cell in Table ▭ indicates that using retrieved statistics of level 13 as the prediction source, a hit rate of 92.1573% is obtained for predictions made in the level 18, being necessary the storage of a 25.8049% of the tiles in cache.
\n\n | 12 | \n13 | \n14 | \n15 | \n16 | \n17 | \n18 | \n19 | \nresources | \n
12 | \n98.6417 | \n98.9362 | \n99.3573 | \n99.4737 | \n99.6901 | \n99.2637 | \n99.2993 | \n94.7561 | \n40.2172 | \n
13 | \n87.8163 | \n93.5760 | \n95.8939 | \n96.4146 | \n97.4372 | \n95.2686 | \n75.5073 | \n25.8049 | \n|
14 | \n53.0529 | \n61.5825 | \n86.7783 | \n88.2709 | \n91.1807 | \n81.6460 | \n63.4527 | \n43.9129 | \n9.3302 | \n
15 | \n37.1553 | \n47.9419 | \n77.9136 | \n84.0861 | \n83.7095 | \n69.9489 | \n57.0746 | \n33.3348 | \n5.2354 | \n
16 | \n46.9387 | \n57.5640 | \n84.3110 | \n86.7747 | \n91.8272 | \n78.7670 | \n64.3781 | \n41.8433 | \n7.7686 | \n
17 | \n30.2021 | \n37.6348 | \n57.0138 | \n60.1330 | \n62.2834 | \n69.5106 | \n55.5134 | \n23.4647 | \n3.2676 | \n
18 | \n23.5791 | \n25.5913 | \n41.7535 | \n46.1559 | \n45.8693 | \n41.4502 | \n61.9763 | \n33.3799 | \n2.3291 | \n
19 | \n8.8690 | \n8.6848 | \n12.4556 | \n13.1338 | \n14.3302 | \n12.2756 | \n13.6932 | \n44.1113 | \n1.2295 | \n
prop | \n98.9340 | \n99.3080 | \n99.6074 | \n99.6321 | \n99.7763 | \n99.4244 | \n99.4308 | \n97.2315 | \n41.3647 | \n
Nevertheless, it must be noted that the main benefit of using a partial cache is not the reduction in the number of cached tiles. The main benefits are the savings in storage space and generation time. As explained in [8], the amount of saved tiles is bigger than the storage saving. It reveals that the most interesting tiles come at a bigger cost. Mainly, popular areas are more complex, and it is necessary more disk space to store them.
\n▭ and
Results demonstrate that the simplified model obtains better results for predicting user behavior from near resolution levels. For low-resolution levels high cache hit ratios are achieved by using a reduced subset of the total tiles. However, descending in the scale pyramid, the requested objects percentage decreases, so the model prediction range and its ability to make predictions decrease too. For future work, instead of randomly selecting objects for caching in this interval, interesting features could be identified and used to define priority objects.
\nFor a given tile request, tile pre-fetching methods try to anticipate which tiles will be requested immediately afterwards. There are several works in the literature that address object prefetching in Web GIS: [9], [10] approximate which tiles will be used in advance based on the global tile access pattern of all users and the semantics of query; [11], [12] use an heuristic method that considers the former actions of a given user.
\nMetatile 3x3 centered in the requested tile.
We propose another pre-fetching strategy, known as metatiling, that works as follows [13]: when the proxy receives a tile request from a client and a cache miss is produced, it requests a larger image tile (called metatile) to the remote backend. This metatile includes the requested tile and also the surrounding ones contained in a specified buffer, as shown in
Tile request flow with metatiling.
Moreover metatiling reduces the problem of duplicating the labeling of features that span more than one tile. This problem is illustrated in
![]() |
(a) Buffer=0 |
![]() |
(b) Buffer=2 |
WMS labelling issues. (a) Requesting individual tiles yields duplicate labels between adjacent tiles. (b) With metatiling labels are not duplicated.
The analyzed tile cache implementations (see Section ▭) allow users to configure the size of metatiles. For a given request, the cache orders a metatile of pre-configured size to the WMS server, centered on the requested tile. Considering a scenario where the cache is neither complete nor empty, this selection of the area to generate may not be very efficient, because it is probable that some of the tiles contained in the metatile would already be cached.
\nUnder the assumption that the surrounding area of the requested tile is not uniformly cached, a novel algorithm for the optimal selection of the metatiles to generate has been developed. This procedure, illustrated in
\n | \n | \n | \n |
0 (no metatiling) | \n1454,10 ms | \n1454,10 ms | \n1 | \n
1 (metatile 3x3) | \n2933,94 ms | \n325,99 ms | \n4,46 | \n
2 (metatile 5x5) | \n5660,63 ms | \n226,42 ms | \n6,42 | \n
3 (metatile 7x7) | \n9561,54 ms | \n195,13 ms | \n7,45 | \n
In order to validate the hypothesis that a performance improvement can be achieved by using metatiles, the following experiment has been realized. A total of 2000 different tiles have been requested to the CORINE (CoORdination of INformation of the Environment) service[1] - proxied by the WMSCWrapper tile cache. The experiment has been repeated for different metatile sizes, always starting from an empty-cache state. The mean latencies measured for each configuration are collected in Table ▭.
\nThe first column of the table shows the mean latency of a cache miss for different metatile sizes. This delay includes the transmisission and propagation delays in the network, the map image generation time in the remote web map service and the processing time in the proxy cache. The values of the second column are computed by normalizing those of the first column by the number of tiles encompassed by each metatile (). The last column shows the cache gain achieved by the use of metatiling, computed as the average acceleration in the delivery of a tile versus not using metatiling, as depicted in Equation ▭.
\nResults reflect that the latency involved in the request of a metatile increases with the buffer size. However, it increases in less proportion than the number of tiles it is compossed by. Therefore, the mean latency to obtain each individual tile decreases when increasing the size of the metatile requested to the remote web map service. In other words, it is faster to retrieve a metatile composed by tiles than the tiles individually.
\nMetatile selection algorithm.
A limiting factor when choosing the metatile size is the overhead in memory consumption required to generate the map image. For example, by default the maximum amount of memory that a single request is allowed to use in Geoserver is 16MB, which are sufficient to render a 2048x2048 image at 4 bytes per pixel, or a 8x8 meta-tile of standard 256x256 pixel tiles.
\nTable ▭ shows the maximum gain that can be achieved by the use of metatiling techniques. This maximum gain occurs when the whole metatile is used to cache new tiles that were not yet cached. While this is the case when automatically seeding tiles in sequential order with non-overlapping metatiles from an empty cache or in the early startup of the service, it would be useful to evaluate metatiling in the most general scenario where the cache is partially filled. In that case, each metatile is likely to add redundant information, since it is probable that some of the tiles encompassed by the metatile were already cached, thus reducing the effective gain of this method.
\nThe performance of metatiling during dynamic cache population with users\' requests has been evaluated using the WMSCWrapper tile cache, described in Section ▭. Simulations were driven by trace files from the public WMS-C tiled web map service of Cartociudad. Being traces recorded in a real, working system, these logs represent a more realistic pattern of user behavior than a synthetic pattern. The CORINE WMS service was used as remote backend.
\nCache-hit ratios obtained for different buffer sizes and metatile configurations.
Number of cached tiles for different buffer sizes and metatile configurations.
A total of 1.000.000 requests were made to the cache. The experiment was repeated for different metatile configurations. For each configuration, the cache-hit ratio and the number of cached tiles after task completion have been collected, starting from an empty cache. Results are shown in
As can be shown, both the cache-hit ratio and the number of cached tiles grow with the buffer size. For a fixed buffer size, both metatiling strategies (centered and minimum-correlation) obtain similar results. However, the number of cached objects is significantly improved with the minimum-correlation configuration. The improvement increases with the metatile size.
\nThus, the advantage achieved with the minimum-correlation metatile configuration is that, maintaining the cache misses, and therefore maintaining the number of requests to the remote WMS server, a broaden population of the cache is achieved. These extra pre-generated map image tiles stored in the cache will allow a faster delivery of future requests.
\nWhen the tile cache runs out of space, it is necessary to determine which tiles should be replaced by the new ones.\nMost important characteristics of Web objects, used to determine candidate objects to evict in Web cache replacement strategies, are: recency (time since the last reference to the object), frequency (number of times the object has been requested), size of the Web object and cost to fetch the object from its origin server. These properties classifies replacement strategies as recency-based, frequency-based, recency/frequency-based, function-based and randomized strategies [14]. Recency-based strategies exploit the temporal locality of reference observed in Web requests, being usually extensions of the well-known LRU strategy, which removes the least recently referenced object. Another popular recency-based method is the Pyramidal Selection Scheme (PSS) [15]. Frequency-based strategies rely on the fact that popularity of Web objects is related to their frequency values, and are built around the LFU strategy, which removes the least frequently requested object. Recency/frequency-based strategies combine both, recency and frequency information, to take replacement decisions. Function-based strategies employ a general function of several parameters to make decisions of which object to evict from\nthe cache. This is the case of GD-Size [16], GDSF [17] and Least-Unified Value (LUV) [18]. Randomized strategies use a non-deterministic approach to randomly select a candidate object for replacement.
\nFor a further background, a comprehensive survey of web cache replacement strategies is presented in ([14]). According to that work, algorithms like GD-Size, GDSF, LUV and PSS were considered “good enough” for caching needs at the time it was published in 2003. However, the explosion of web map traffic did not happen until a few years later.
\nIn this section, we propose a cache replacement algorithm that uses a neural network to estimate the probability of a tile request occurring before a certain period of time, based on the previously discussed properties of tile requests: recency of reference, frequency of reference, and size of the referenced tile [19], [20]. Those tiles that are not likely to be requested shortly are considered as good candidates for replacement.
\nThe use of neural networks for cache replacement was first introduced by Khalid [21], with the KORA algorithm. KORA uses backpropagation neural network for the purpose of guiding the line/block replacement decisions in cache. The algorithm identifies and subsequently discards the dead lines in cache memories. It is based on previous work by [22], who suggested the use of a shadow directory in order to look at a longer history when making decisions with LRU. Later, an improved version of the former, KORA-2, was proposed [23], [24]. Other algorithms based on KORA were also proposed [25], [26]. A survey on applications of neural networks and evolutionary techniques in web caching can be found in [27]. [28], [29], [30], [31], [32] proposes the use of a backpropagation neural network in a Web proxy cache for taking replacement decisions. A predictor that learns the patterns of Web pages and predicts the future accesses is presented in [33]. [34] discusses the use of neural networks to support the adaptivity of the Class-based Least Recently Used (C-LRU) caching algorithm.
\nArtificial neural networks (ANNs) are inspired by the observation that biological learning systems are composed of very complex webs of interconnected neurons. In the same way, ANNs are built out of a densely interconnected group of units. Each artificial neuron takes a number of real-valued inputs (representing the one or more dendrites) and calculates a linear combination of these inputs. The sum is then passed through a non-linear function, known as activation function or transfer function, which outputs a single real-value, as shown in
Artificial neuron.
In this work, a special class of layered feed-forward network known as multilayer perceptron (MLP) has been used, where units at each layer are connected to all units from the preceding layer. It has an input layer with three inputs, two-hidden layers each one comprised of 3 hidden nodes, and a single output (
Learning an artificial neuron involves choosing values for the weights so the desired output is obtained for the given inputs. Network weights are adjusted through supervised learning using subsets of the trace data sets, where the classification output of each request is known.\nBackpropagation with momentum is the used algorithm for training. The parameters used for the proposed neural network are summarized in Table ▭.
\nProposed two-hidden layer feed-forward artificial neural network.
Parameter | \nValue | \n
Architecture | \nFeed-forward Multilayer Perceptron | \n
Hidden layers | \n2 | \n
Neurons per hidden layer | \n3 | \n
Inputs | \n3 (recency, frequency, size) | \n
Output | \n1 (probability of a future request) | \n
Activation functions | \nLog-sigmoid in hidden layers, Hyperbolic tangent sigmoid in output layer | \n
Error function | \nMinimum Square Error (mse) | \n
Training algorithm | \nBackpropagation with momentum | \n
Learning method | \nSupervised learning | \n
Weights update mode | \nBatch mode | \n
Learning rate | \n0.05 | \n
Momentum constant | \n0.2 | \n
Neural network parameters
The neural network inputs are three properties of tile requests: recency of reference, frequency of reference, and the size of the referenced tile. These properties are known to be important in web proxy caching to determine object cachability. Inputs are normalized so that all values fall into the interval , by using a simple linear scaling of data as shown in Equation ▭, where and are respectively the data values before and after normalization, and are the minimum and maximum values found in data, and and define normalized interval so . This can speed up learning for many networks.
\nRecency values for each processed tile request are computed as the amount of time since the previous request of that tile was made. Recency values calculated this way do not address the case when a tile is requested for the first time. Moreover, measured recency values could be too disparate to be reflected in a linear scale.
\nTo address this problem, a sliding window is considered around the time when each request is made, as done in [28]. With the use of this sliding window, recency values are computed as shown in Equation ▭.
\nwhere is the time since that tile was last requested.
\nRecency values calculated that way can already be normalized as stated before in Equation ▭.
\nFrequency values are computed as follows. For a given request, if a previous request of the same tile was received inside the window, its frequency value is incremented by 1. Otherwise, frequency value is divided by the number of windows it is away from. This is reflected in Equation ▭.\n
Size input is directly extracted from server logs. As opposite to conventional Web proxies where requested object sizes can be very heterogeneous, in a web map all objects are image tiles with the same dimensions (typically 256x256 pixels). Those images are usually rendered in efficient formats such as PNG, GIF or JPEG that rarely reach 100 kilobytes in size. As discussed in [8], due to greater variation in colors and patterns, the popular areas, stored as compressed image files, use a larger proportion of disk space than the relatively empty non-cached tiles. Because of the dependency between the file size and the “popularity” of tiles, tile size can be a very valuable input of the neural network to correctly classify the cachability of requests.
\nDuring the training process, a training record corresponding to the request of a particular tile is associated with a boolean target (0 or 1) which indicates whether the same tile is requested again or not in window, as shown in Equation ▭.
\nOnce trained, the neural network output will be a real value in the range [0,1] that must be interpreted as the probability of receiving a successive request of the same tile within the time window. A request is classified as cacheable if the output of the neural network is above 0.5. Otherwise, it is classified as non cacheable.
\nThe neural network is trained through supervised learning using the data sets from the extracted trace files. The trace data is subdivided into training, validation, and test sets, with the 70%, 15% and 15% of the total requests, respectivelly. The first one is used for training the neural network. The second one is used to validate that the network is generalizing correctly and to identify overfitting. The final one is used as a completely independent test of network generalization.
\nEach training record consists of an input vector of recency, frequency and size values, and the known target. The weights are adjusted using the backpropagation algorithm, which employs the gradient descent to attempt to minimize the squared error between the network output values and the target values for these outputs [36]. The network is trained in batch mode, in which weights and biases are only updated after all the inputs and targets are presented. The pocket algorithm, which saves the best weights found in the validation set, is used.
\nNeural network performance is measured by the correct classification ratio (CCR), which computes the percentage of correctly classified requests versus the total number of processed requests.
\n\n | CartoCiudad | \nIDEE-Base | \n
training | \n76.5952 | \n75.6529 | \n
validation | \n70.2000 | \n77.5333 | \n
test | \n72.7422 | \n82.7867 | \n
Correct classification ratios (%) during training, validation and testing for Cartociudad and IDEE-Base.
▭ shows the CCRs obtained during training, validation and test phases for Cartociudad and IDEE-Base services. As can be seen, the neural network is able to correctly classify the cachability of requests, with CCR values over the testing data set ranging between 72% and 97%, as shown in Table ▭. The network is stabilized to an acceptable CCR within 100 to 500 epochs.
\n![]() | ![]() |
(a) Cartociudad | (b) IDEE-Base |
Correct classification ratios achieved with the neural network for CartoCiudad and IDEE-Base.
Serving pre-generated map image tiles from a server-side cache has become a popular way of distributing map imagery on the Web. However, in order to achieve an optimal delivery of online mapping, adequate cache management strategies are needed. These strategies can benefit of the intrinsic spatial nature of map tiles to improve its performance. During the startup of the service, or when the cartography is updated, the cache is temporarily empty and users experiment a poor Quality of Service. In this chapter, a seeding algorithm that populates the cache based on the history of previous accesses has been proposed. The seeder should automatically cache tiles until an acceptable QoS is achieved. Then, tiles could be cached on-demand when they are first requested. This can be improved with short-term prefetching; anticipating the following tiles that will be requested after a particular request can improve users\' experience. The metatiling approach presented here requests, for a given tile request, a bigger map image containing adjacent tiles, to the remote WMS backend. Since the user is expected to pan continuously over the map, those tiles are likely to be requested. Finally, when the tile cache runs out of space, it is necessary to determine which tiles should be replaced by the new ones. A cache replacement algorithm based on neural networks has been presented. It tries to estimate the probability of a tile request occurring before a certain period of time, based on the following properties of tile requests: recency of reference, frequency of reference, and size of the referenced tile. Those tiles that are not likely to be requested shortly are considered as good candidates for replacement.
\nThis work has been partially supported by the Spanish Ministry of Science and Innovation through the project “España Virtual” (ref. CENIT 2008-1030), a FPI research fellowship from the University of Valladolid (Spain), the National Centre for Geographic Information (CNIG) and the National Geographic Institute of Spain (IGN).
\nAntimicrobial resistance is a global public health crisis. According to Public Health England [1], each year approximately 25,000 people die across Europe due to hospital-acquired infections caused by antibiotic-resistant and MDR bacteria such as Mycobacterium tuberculosis, Methicillin-resistant Staphylococcus aureus and multiresistant Gram-negative bacteria. Gram-negative infections include those caused by Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa [2]. Nevertheless, it is estimated that by 2050, the global yearly death toll will increase to 10 million. Accelerating emerge of antimicrobial resistance seriously threatens the effectiveness of treatments for pneumonia, meningitis and tuberculosis, in addition to diminishing prevention of infections acquired during surgeries and chemotherapies. The crisis of the antibiotic resistance requires urgent, coordinated action. Misuse and overuse of antibiotics must be controlled, implementation of new policies regarding prescriptions has to be internationally addressed; and development of new therapeutics is urgently required [1].
Félix d’Herelle, known as the father of bacteriophage (or phage) therapy [3], brought an evolutionary discovery of phages as therapeutics for various infections and conditions. Phage therapy was widely enforced in the 1920s and 1930s to combat the bacterial infections. However, in the 1940s, the newly discovered antibiotics replaced the phage therapy (except Russia, Georgia and Poland) [4].
The emergence of MDR bacteria prompted a renewal of the interest to the phage therapy as an alternative treatment to overcome a broad spectrum of resistant bacterial infections. Phage therapy and phage cocktails that contain a mixture of different bacteria-specific phages, drawn interest within molecular biology and modern medical research as potential antimicrobials that could tackle the crisis of antimicrobial resistance. Nonetheless, the phage therapy remains controversial due to its disadvantages such as bacteriophage resistance: bacteria-phage evolutionary arms race that could put a burden on a long-time application of phage therapy as an anti-infectious agent [5].
Phage therapy has many advantages, primary because phages are very specific (generally limited to one species) and easy to obtain as they are widely distributed in locations populated by bacterial hosts including soil and seawater, and they do not have any known chemical side effects like antimicrobials [6].
Understanding host-phage interactions and ‘the war between bacteria and phages’ are steps towards designing engineering ‘broad-spectrum phage’ that can overcome the limitations of phage therapy and potentially overcome a wide range of resistant bacterial infections [6].
Phages are obligate intracellular parasites that distinctively infect bacterial cells. Although phages are very specific to their host, generally limited to one species, they pose an enormous threat to bacteria as in some habitats they outnumber their hosts by nearly 10-fold number [7]. Phages are the most abundant, ubiquitous and diversified organisms in the biosphere [8, 9]. Phage-host interaction and fight for the survival led to the evolution of bacterial and viral genomes and, therefore, to the evolution of resistance mechanisms. Bacteria, continuously, evolve many molecular mechanisms, driven by gene expression to prevent phage infection. These evolving phage-resistance mechanisms in bacteria induce the parallel co-evolution of phage diversity and adaptability [10, 11]. The co-evolving genetic variations and counteradaptations, in bacteria and phages, drive the evolutionary phage-host arm race [11, 12].
Leigh Van Valen, an evolutionary biologist, metaphorised the co-evolutionary arm race and proposed the Red Queen hypothesis [13].
‘It takes all the running you can do, to stay in the same place’ the Red Queen says to Alice in Through the Looking-Glass.
The Red Queen hypothesis proposes that to survive, microorganisms must constantly adapt, evolve and thrive against ever-evolving antagonistic microorganisms within the same ecological niche [14].
Bacteria have developed various anti-phage mechanisms including non-adaptive defences (non-specific) and adaptive defences associated with Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) along with CRISPR-associated (Cas) proteins [7, 15, 16, 17, 18].
The non-specific adaptations (analogues to innate immunity in multicellular organisms) act as primary mechanisms to evade viral infection, and they include mechanisms that inhibit phage adsorption and prevent nucleic acid entry, superinfection exclusion systems, restriction-modification systems and abortive infection [7, 19].
On the other hand, the adaptive resistance (analogues to the acquired immunity in multicellular organisms) serves as a second line of defence, which is very efficient and phage-specific.
Interestingly, it was observed that the bacterial anti-phage mechanisms are generally present in a genomic array, known as ‘defence islands’ [20]. The ‘defence islands’ are enriched in putative operons and contain numerous overrepresented genes encoding diverged variants of antiviral defence systems. Moreover, scientific evidence and characteristic operonic organisation of ‘defence islands’ show that many more anti-phage mechanisms are yet to be discovered [21, 22, 23, 24].
Although bacteria have developed several resistance mechanisms against phages, phages can circumvent bacterial anti-phage mechanisms on the grounds of their genomic plasticity and rapid replication rates. These counterstrategies include point mutations in specific genes and genome rearrangements that allow phages to evade bacterial antiviral systems such as CRISPR/Cas arrays by using anti-CRISPR proteins and abortive infection by hijacking bacterial antitoxins, as well as escaping from adsorption inhibition and restriction-modification mechanisms [15, 16, 17, 18].
This chapter will comment on the genetic basis of bacterial resistance to phages and different strategies used by phages to evade bacterial resistance mechanisms.
Phage adsorption to host-specific receptors on the cell surface is the initial step of the infection and host-phage interaction. Depending on the nature of bacteria, whether it is Gram-positive or Gram-negative proteins, lipopolysaccharides, teichoic acids and other cell surface structures can serve as irreversible phage-binding receptors [19]. These receptors might be present in the cell wall, bacterial capsules, slime layers, pili or flagella [25].
Bacteria have acquired various barriers to inhibit phage adsorption, such as blocking of phage receptors, production of extracellular matrix (e.g. capsule, slime layers) and production of competitive inhibitors [26, 27, 28, 29, 30, 31]. The diversity of phage receptors in the host is influenced by co-evolutionary adaptations of phages to overcome these barriers [32]. This includes diversity-generating retroelements (DGRs) and phase variation mechanisms causing phenotypical differences within the bacterial colony [7, 33, 34].
Phase variation is a heritable, yet reversible process regulating gene expression in bacteria; genes can switch between a functional (expression) and a non-functional state leading to phenotypical variations within the bacterial population even when strains have identical genotype. Sørensen et al. [35] investigated the underlying resistance mechanism of Campylobacter jejuni (NCTC11168) to phage F336. They have discovered that phage F336 relies on the hypervariable O-methyl phosphoramidate (MeOPN) modification of capsular polysaccharides (CPS) for successful adsorption to the bacterial surface. Nevertheless, loss of MeOPN receptor on the bacterial cell surface due to phase variation in the cj1421 gene encoding the MeOPN-GalfNAc transferase (MeOPN transferase attaches MeOPN to GalfNAc and Hep side chains of CPS) results in phage resistance [35, 36].
DGRs are genetic elements diversifying DNA sequences and the proteins they encode ultimately mediating the evolution of ligand-receptor interactions. Error-prone DGRs and random mutations in the bacterial genes encoding cell surface receptors lead to the alternation and change in the structural composition of the phage receptors, making them non-complementary to the phage’s anti-receptors, known as receptor-binding proteins (RBP) [34] (Figure 1(1)).
Bacterial defence mechanisms preventing phage adsorption and phage’s counteradaptations. (1) Phage adsorption to a host-specific receptor site on a host cell surface. Bacterium evolves phage resistance by the modification of these cell surface receptors; phage is incapable of binding to the altered receptor. (2) Phage’s adaptation to these modifications through mutations in receptor-binding protein gene that leads to the co-evolution of bacterial genetic variation. Bacteria are also capable of producing proteins that mask the phage recognition site receptors (3 and 4), thus making the receptor inaccessible for phage adsorption [28, 29, 30, 31]. Image courtesy of springer nature: https://www.ncbi.nlm.nih.gov/pubmed/20348932.
Yet, phage’s replication is exceedingly error-prone, therefore causing many random mutations in the genes encoding the RBP or tail fibres. Phages also possess DGRs that mediate phage’s tropism by accelerating the variability in the receptor-coding genes through reverse transcription process [37]. The changes in the nucleotide sequence in the RBP-coding gene may ultimately lead to the adaptation to the modified receptor (Figure 1(2)), thus the ability to adsorb and infect the bacterial cell.
Unsurprisingly, bacteria also exhibit different strategies to block their receptors [28, 29, 30, 31].
Figure 1(4) demonstrates the findings from studies conducted on Staphylococcus aureus by Nordstrom and Forsgren [38]. Mutants of Staphylococcus aureus producing higher anticomplementary protein A were found to adsorb fewer phages than Staphylococcus aureus mutants with scarce of protein A, which had an apparent increased ability to adsorb phages [38]. These findings indicate that some bacteria, including Staphylococcus aureus, are capable of production of surface proteins that mask the phage receptors making them inaccessible for phage recognition and attachment (Figure 1(3)).
Receptors located on bacterial cell surface serve a vital role in bacterial metabolism; they may function as membrane porins, adhesions or chemical receptors [19]. Therefore, mutation or complete loss of the receptor might be lethal for bacteria. To inhibit phage adsorption, bacteria can produce surface molecules, such as exopolysaccharides.
Exopolysaccharides are extracellular polysaccharides acting as a physical barrier, composing slime or capsules surrounding bacterial cells that lead to inaccessible host receptors for efficient phage adsorption [39] (Figure 2). Studies conducted by Looijesteijn et al. [40] shown that exopolysaccharides produced by Lactococcus lactis function as external protection from phages and the cell wall destructing lysozyme, due to masked cell surface receptors [40].
Bacterial strategies to inhibit phage adsorption and phage strategies to access host receptors. Some bacteria are capable of the production of exopolysaccharides, which act as an outer shield, protecting a cell from the phage infection [28, 29, 30, 31]. If the phage does not possess any polysaccharide-degrading enzymes, it cannot access the host cell membrane receptor. However, some phages evolved mechanisms allowing them to recognise these extracellular matrixes and degrade them by the means of hydrolases and lyases [15, 16, 17, 18]. Image courtesy of Springer Nature: https://www.ncbi.nlm.nih.gov/pubmed/20348932.
Nevertheless, some phages evolved mechanisms allowing them to recognise these extracellular matrixes and degrade them by utilising hydrolases and lyases (Figure 2) [15, 16, 17, 18]. The polysaccharide-degrading enzymes allow phages to gain access to the receptor that may lead to the viral propagation. They are commonly present bound to the RBPs or exist as free soluble enzymes from previously lysed bacterial cells [41].
If phage bypasses primary antiviral strategies, it is now able to initiate infection by adsorption to a specific receptor site on a host cell surface through phage RBP [42, 43]. Upon interaction with the cell receptors, the phage injects its genetic material (single or double-stranded DNA or RNA) into the cytoplasm of the host. Depending on the nature of the phage and growth conditions of the host cell, it follows one of the two life cycles: lytic or lysogenic (Figure 3).
Lytic and lysogenic life cycles of a temperate coliphage λ that infects Escherichia coli [44, 45]. cos—cohesive sites: the joining ends that circularise the linear phage λ DNA. Image courtesy of Springer Nature: https://www.nature.com/articles/nrg1089.
In the lytic cycle, virulent phages degrade host’s genome leading to the biosynthesis of viral proteins and nucleic acids for the assembly of phage progeny. Eventually, the bacterial cell lysis, releasing a multitude of newly assembled phages, is ready to infect a new host cell [46].
In contrast, temperate phages might enter the lytic or lysogenic cycle, if the host cell exists in adverse environmental conditions that could potentially limit the number of produced progeny (Figure 3 demonstrates typical lifecycle of temperate phage using coliphage λ as an example) [44, 45]. In the lysogenic phase, repressed phage genome integrates into the bacterial chromosome as a prophage. This process causes the proliferation of prophage during replication and binary fission of bacterial DNA.
Prophage only expresses a repressor protein-coding gene. The repressor protein binds to the operator sites of the other genes and ultimately inhibits synthesis of phage enzymes and proteins required for the lytic cycle.
When the synthesis of the repressor protein stops or if it becomes inactivated, a prophage may excise from the bacterial chromosome, initiating a lytic cycle (induction) which leads to the multiplication and release of virulent phages and lysis of a host cell [44, 45].
If the phage remains in the nearly dormant state (prophage), the lysogenic bacterium is immune to subsequent infection by other phages that are the same or closely analogous to the integrated prophage by means of Superinfection exclusion (Sie) systems [47].
Sie systems are membrane-associated proteins, generally, phage or prophage encoded, that prevent phage genome entry into a host cell [47]. Figure 4 shows the role of Sie system (proteins Imm and Sp) in blocking phage T4 DNA entry into Gram-negative Escherichia coli. Despite successful attachment to the phage-specific receptor, phage DNA is directly blocked by Imm protein from translocating into the cytoplasm of the cell. Sp system, on the other hand, prevents the degradation of the peptidoglycan layer by inhibiting the activity of T4 lysozyme [26, 27, 28, 29, 30, 31, 48].
Superinfection exclusion systems preventing phage DNA entry in Gram-negative Escherichia coli. (a). Standard T4 phage: upon attachment to phage-receptor on the surface of the host cell, an inner-membrane protein aids the translocation of phage DNA into the cell’s cytoplasm. (b) Imm encoding phage T4: Imm protein directly blocks the translocation of the phage DNA into the cytoplasm of the cell. (c) Imm and Sp encoding phage T4: phage DNA is prevented from entering the cell’s cytoplasm by Imm; and Sp protein prevents degradation of the peptidoglycan layer by inhibiting the activity of T4 lysozyme [28, 29, 30, 31]. Image courtesy of Springer Nature: https://www.ncbi.nlm.nih.gov/pubmed/20348932.
The evolution of bacterial genomes allowed bacteria to acquire vast mechanisms interfering with every step of phage infection. In a case where a phage succeeded to inject its viral nucleic acid into a host cell, bacteria possess a variety of nucleic acid degrading systems such as restriction-modification (R-M) systems and CRISPR/Cas that protect bacteria from the phage invasion.
It has been reported that R-M systems can significantly contribute to bacterial resistance to phages [49].
R-M systems incorporate activities of methyltransferases (MTases) that catalyse the transfer of a methyl group to DNA to protect self-genome from a restriction endonuclease (REase) cleavage and REases, which recognise and cut foreign unmethylated double-stranded DNA at specific recognition sites, commonly palindromic. To protect self-DNA from the degradation, methylases tag sequences recognised by the endonucleases with the methyl groups, whereas unmethylated phage (nonself) DNA is cleaved and degraded (Figure 5) [26, 27, 50, 51, 52].
General representation of the bacterial restriction-modification (R-M) systems providing a defence against invading phage genomes. R-M systems consist of two contrasting enzymatic activities: a restriction endonuclease (REase) and a methyltransferase. REase recognises and cuts nonself unmethylated double-stranded DNA at specific recognition sites, whereas MTase adds methyl groups to the same genomic recognition sites on the bacterial DNA to protect self-genome from REase cleavage [50, 51]. Image courtesy of: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591985/.
R-M systems are diverse and ubiquitous among bacteria. There are four known types of R-M within bacterial genomes (Figure 6). Their classification is mainly based on R-M system subunit composition, sequence recognition, cleavage position, cofactor requirements and substrate specificity [26, 27, 50, 51].
Four distinct types of restriction-modification (R-M) systems. (a) Type I R-M system is composed of three subunits forming a complex: hsdR (restriction), hsdM (modification) and hsdS (specificity subunit that binds to an asymmetrical DNA sequence and determines the specificity of restriction and methylation). Two hsdM subunits and one hsdS subunit are involved in methylation of self-DNA. On the other hand, two complexes of hsdR, hsdM and hsdS (where each complex consists of two hsdR, two hsdM and one hsdS subunit) bind to the unmethylated recognition sites on phage DNA and cleave the DNA at random, far from their recognition sequences. Both reactions—methylation and cleavage—require ATP. (b) Type II R-M system is composed of two distinct enzymes: palindromic sequence methylating methyltransferase (mod) and endonuclease (res) that cleave unmethylated palindromic sequences close to or within the recognition sequence. (c) Type III R-M system is formed of methyltransferase (mod) and endonuclease (res) that form a complex. Methyltransferase transfers methyl group to one strand on the DNA, whereas two methyltransferases (endonuclease complexes) act together to bind to the complementary unmethylated recognition sites to cleave the DNA 24–26 bp away from the recognition site. (d) Type IV R-M system contains only endonuclease (res) that recognises methylated or modified DNA. Cleavage occurs within or away from the recognition sequences [26, 27, 50, 51]. Image courtesy of: https://www.annualreviews.org/doi/abs/10.1146/annurev-virology-031413-085500?journalCode=virology.
Due to the diversity of R-M systems, phages acquired several active and passive strategies to bypass cleavage by REases. Passive mechanisms include reduction in restriction sites, modification and change of the orientation of restriction sites, whereas more specific, active mechanisms include masking of restriction sites, stimulation of MTase activity on phage genome or degradation of an R-M system cofactor (Figure 7) [15, 16, 17, 18].
Phage’s passive and active strategies to bypass restriction-modification (R-M) systems. (a) Phages that possess fewer restriction sites in their genome are less prone to DNA cleavage by the host restriction endonuclease (REase). (b) Occasionally phage DNA might be modified by bacterial methyltransferase (MTase) upon successful injection into a host cell. Methylated recognition sites on viral DNA are, therefore, being protected from the cleavage and degradation by REase, leading to the initiation of the phage’s lytic cycle. In addition, some phages encode their own MTase that is cooperative with the host REase; thus viral DNA cannot be recognised as nonself. (c) Some phages, for example, coliphage P1, while injecting its DNA into a host cell, it also co-injects host-genome-binding proteins (DarA and DarB) that mask R-M recognition sites. (d) Phages such as Coliphage T7 possess proteins that can mimic the DNA backbone. Ocr, a protein expressed by Coliphage T7, mimics the DNA phosphate backbone and has a high affinity for the EcoKI REase component, thereby interfering with R-M system. (e) In addition, some phages (e.g. Ral protein of Coliphage λ) can also stimulate activity of the bacterial modification enzyme in order to protect own DNA from the recognition by the bacterial REase as nonself. The peptide Stp encoded by Coliphage T4 can as well disrupt the structural conformation of the REase-MTase complex [15, 16, 17, 18]. Image courtesy of: https://www.nature.com/articles/nrmicro3096.
Fewer restriction sites in the evading genome lead to the selective advantage of this phage as its DNA is less prone to cleavage and degradation by the host REase (Figure 7a). Also, some phages incorporate modified bases in their genomes that may lead to successful infection of the host cell as REase may not recognise the new sequences in the restriction sites. A decrease in the effective number of palindromic sites in DNA or change in the orientation of restriction-recognition sites can affect R-M targeting. Alternatively, the recognition sites within the viral genome can be too distant from each other to be recognised and cleaved by the REase [15, 16, 17, 18, 53].
Interestingly, phage genome might be methylated by bacterial MTase upon successful injection into a host cell. Methylated recognition sites on viral genomes are therefore being protected from the cleavage and degradation by REase, leading to the initiation of the phage’s lytic cycle. Viral progeny remains insensitive to this specific bacterial REase until it infects a bacterium that possesses a different type of REase, in which case the new progeny will become unmethylated again and will, therefore, be sensitive to the R-M system of the cognate bacterium [28, 29, 30, 31].
The fate of the host cell chiefly confides in the levels of R-M gene expression and ultimate proportion of the R-M enzymes and their competition for the sites in the invading phage genome [52].
Furthermore, some phages encode their own MTase that is cooperative with the host REase, and thereby viral DNA cannot be recognised as nonself. Phages can also stimulate the activity of host modification enzymes that can rapidly methylate viral DNA, thus protecting it from the activity of REase.
Alternatively, phages can bypass R-M systems by masking restriction sites. For example (Figure 7c), coliphage P1, while injecting its DNA into a host cell, it also co-injects host-genome-binding proteins (DarA and DarB) that mask R-M recognition sites [53, 54].
As shown on an example of a Coliphage T7 (Figure 7d), some phages code for proteins that directly inhibit REase. Coliphage T7 possesses proteins that can mimic the DNA backbone. Ocr, a protein expressed by Coliphage T7, directly blocks the active site of some REases by mimicking 24 bp of bent B-form DNA, and it has a high affinity for the EcoKI REase component, thereby interfering with R-M system [53].
Lastly, phage-bacteria arm race allowed phages to gain capabilities of degrading necessary cofactors of R-M systems. For instance, coliphage T3 encodes S-adenosyl-l-methionine hydrolase that destroys an essential host R-M cofactor (the S-adenosyl-l-methionine). The removal of this necessary co-factor will lead to the inhibition of the REase, thereby successfully infecting the host cell [15, 16, 17, 18].
CRISPR along with CRISPR-associated (Cas) proteins is the type of adaptive heritable ‘immunity’ of bacteria, thus very specific and effective; and it is prevalent within the bacterial domain [55]. The CRISPR are DNA loci consisting of short palindromic repeats (identical in length and sequence), interspaced by segments of DNA sequences (spacer DNA) derived from previous exposures to phages. The spacer DNA sequences act as a ‘memory’, allowing bacteria to recognise and destroy specific phages in a subsequent infection. Genes encoding Cas proteins are adjacent to CRISPR loci [56].
Although some studies have suggested that CRISPRs can be used for pathogen subtyping [57], it has been found that CRISPR typing is not useful for the epidemiological surveillance and outbreak investigation of Salmonella typhimurium [58].
The CRISPR/Cas phage resistance is mediated in three-step stages: adaptation (acquisition), where spacer phage-derived DNA sequences are incorporated into the CRISPR/Cas system; expression, where cas gene expression and CRISPR transcription lead to pre-CRISPR RNA (pre-crRNA) that is then processed into CRISPR RNA (crRNA); and interference, during which the crRNA guides Cas proteins to the target (subsequently invading DNA) for the degradation. The cleavage of the target (proto-spacer) depends on the recognition of complementary sequences in spacer and protospacer [59, 60].
CRISPR/Cas systems have been classified into three major types: Types I, II and III, which are further divided into subtypes that require different types of Cas proteins. Although the CRISPR/Cas array is diverse among the bacteria and it is continuously co-evolving in response to the host-phage interactions, the defence activity in all three types of the CRISPR is comparable [21, 22, 23] Figure 8 illustrates the defence mechanisms in three distinct CRISPR/Cas arrays.
Image showing mechanisms of adaptation, expression and interference in three different types of CRISPR/Cas arrays. Type I and Type II CRISPR/Cas arrays rely on the protospacer adjacent motif (PAM), contained within phage nucleic acid, to ‘select’ the phage-derived protospacer. Next steps in the adaptation stage are similar in all three types; protospacer is incorporated by Cas 1 and Cas2 proteins into the bacterial genome at the leader end of the CRISPR loci to form a new spacer. In expression step, CRISPR loci are transcribed into pre-crRNA. The crRNA processing and interference stage is distinct in each type of the CRISPR/Cas system. In Type I, the multisubunit CRISPR-associated complex for antiviral defence (CASCADE) binds crRNA to locate the target, and with the presence of Cas3 protein, the invading target genome is degraded whereas in Type II, Cas9 protein is essential in the processing of the crRNA. TracrRNA recognises and attaches to the complementary sequences on the repeat region that is then cut by RNase III in the presence of Cas9. Lastly, in Type III, processing of pre-crRNA into crRNA is dependent upon the activity of Cas6. Mature crRNA associated with Csm/Cmr complex targets foreign DNA or RNA for the degradation [21, 22, 23]. Image courtesy of: https://www.nature.com/articles/nrmicro2577.
The Type II, CRISPR/Cas9, which was first identified in Streptococcus pyogenes, gained considerable interest within scientific studies as a precise genome editing tool. CRISPR/Cas9 system is unique; a single Cas 9 protein (in addition to prevalent Cas 1 and Cas 2) is involved in the processing of crRNA and destruction of the target viral DNA [56, 61].
In the adaptation stage, phage-derived protospacer (snippet of DNA from the invading phage) is incorporated into the bacterial genome at the leader end of the CRISPR loci. In expression phase, the Cas9 gene expresses Cas9 protein possessing DNA cleaving HNH and RuvC-like nuclease domains; CRISPR locus is then transcribed and processed into mature crRNA. Finally, in interference step, the complex consisting of Cas9, crRNA and separate trans-activating crRNA (tracrRNA) cleave 20 base pairs crRNA-complementary target sequence that is adjacent to the protospacer adjacent motif (PAM) [62].
To bypass CRISPR/Cas that has an incredibly dynamic rate of evolution, phages acquired array of strategies to succeed in propagation; this includes mutations in the protospacers or in the PAM sequences and expression of anti-CRISPR proteins, and even some phages encode their own functional CRISPR/Cas systems [15, 16, 17, 18, 63].
Phages can evade interference step of Type I and Type II CRISPR/Cas system by a single point mutation or deletion in their protospacer region or in the PAM sequence (Figure 9). Phages with single-nucleotide substitutions or deletions positioned close to PAM sequence can bypass the CRISPR/Cas activity and complete their lytic cycles; in contrast, phages with multiple mutations at PAM-distal protospacer positions do not [15, 16, 17, 18, 28, 29, 30, 31].
Evasion by mutation. Mutations in the phage protospacers or in the PAM sequences allow the phage to escape interference step of the CRISPR/Cas system that would lead to the degradation of the phage genome [15, 16, 17, 18]. Adapted image courtesy of: https://www.nature.com/articles/nrmicro3096.
In some circumstances, however, although the phage successfully evades CRISPR/Cas interference, the host cell may survive by the acquisition of new spacer sequences (derived from invading phage) into their own CRISPR/Cas system. This new spacer provides the bacterium with an accelerated spectrum of phage resistance [15, 16, 17, 18].
Prophages integrated within Pseudomonas aeruginosa possess genes that encode anti-CRISPR proteins directly suppressing CRISPR/Cas-mediated degradation of the phage genome (Figure 10). According to Wiedenheft [64], these proteins might interrupt CRISPR RNA processing by preventing mature crRNA from binging to the crRNA-guide complex or by preventing the assembled crRNA-guided complex from interacting with target substrates through binding to it [64].
Anti-CRISPR proteins expressed against CRISPR subtype I-F systems. Temperate phages such as Pseudomonas aeruginosa possess genes encoding anti-CRISPR proteins that directly interfere with the bacterial CRISPR/Cas system [15, 16, 17, 18]. Adapted image courtesy of: https://www.nature.com/articles/nrmicro3096.
Prophages do not only contribute to bacterial resistance to invading phages, they can also encode proteins that contribute to bacterial virulence and antimicrobial resistance [58, 66].
Bacteria can also resist phages by possessing phage-inducible chromosomal islands (PICI) which prevent phage replication. Nevertheless, phages evolved their genomes to overcome this very specific antiviral strategy. For example, Vibrio cholerae ICP1 phages possess their own CRISPR/Cas systems that inactivate PICI-like elements (PLE) in Vibrio cholerae (Figure 11). Studies conducted by Naser et al. [67] have shown that phage CRISPR arrays have evolved by the acquisition of new spacers targeting diverse regions of PLEs carried by Vibrio cholerae strains. Furthermore, the addition of the new spacers within phage CRISPR/Cas loci enables the phages to expand their ability to counter PLE-mediated phage defence of diverse Vibrio cholerae strains [67].
Phage-encoded CRISPR/Cas systems in Vibrio cholerae ICP1 phages. Upon adsorption and injection of viral genome into a host cell, phage crRNAs and CRISPR/Cas complexes are expressed and target phage-inducible chromosomal island (PICI) in the host genome; in the Vibrio cholerae, they are termed as PICI-like elements (PLE). If the spacers within phage CRISPR locus are complementary to the bacterial PLE, the CRISPR machinery is then able to specifically target this genetic element and inactivate it, leading to the viral propagation. However, in the absence of such targeting, phage CRISPR/Cas system can acquire new spacers to evolve rapidly and ensure effective targeting of the PLE to restore phage replication [15, 16, 17, 18, 65]. Adapted image courtesy of: https://www.nature.com/articles/nrmicro3096.
Abortive infection (Abi) systems promote cell death of the phage-infected bacteria, inhibiting phage replication and providing protection for bacterial populations [68].
Abi systems require both toxins and antagonistic antitoxins. Antitoxins are proteins or RNAs that protect bacterial cell from the activity of toxins in a typical cell life cycle, whereas toxins are the proteins encoded in toxin-antitoxin locus that disrupt cellular metabolism (translation, replication and cell wall formation), causing cell death. During an infection, the expression of the antitoxin encoding gene is suppressed, leading to the lethal activation of the toxin [69]. Figure 12 illustrates the mechanism of Abi systems in Escherichia coli [70].
Abortive infection (Abi) systems in Escherichia coli. The Rex system is a two-component Abi system. A phage protein-DNA complex (formed during phage replication) activates the sensor protein RexA, which in turn activates RexB. RexB is an ion channel that causes depolarisation of the bacterial membrane leading to cell death [28, 29, 30, 31]. Image courtesy of Springer Nature: https://www.ncbi.nlm.nih.gov/pubmed/20348932.
Interestingly, phages evolved an array of tactics to circumvent Abi systems. This includes mutations in specific phage genes and encoding own antitoxin molecules that suppresses bacterial toxin [15, 16, 17, 18]. Figure 13 provides a broad overview of the strategies employed by the phages to by-pass Abi systems.
Escaping abortive infection mechanisms. (a) In a typical cell life cycle, antitoxins protect bacterial cell from the activity of toxins. (b) During phage infection, the expression of antitoxin encoding gene is suppressed, leading to the lethal activation of the toxin. (c) Mutations in certain phage genes can lead to escaping Abi systems activity, thereby a successful viral propagation without killing the host cell. (d) Some phages encode molecules that functionally replace the bacterial antitoxins, thus suppressing toxin activity and avoiding host cell death [15, 16, 17, 18]. Image courtesy of: https://www.nature.com/articles/nrmicro3096.
Bacteria-phage interaction is therefore very complex, and it is crucial to understand the molecular basis of this interaction and how bacteria and phages ‘fight’ each other. It has been reported that Anderson Phage Typing System of Salmonella Typhimurium can provide a valuable model system for study of phage-host interaction [71].
The rapid emergence and dissemination of MDR bacteria seriously threaten global public health, as, without effective antibiotics, prevention and treatment of both community- and hospital-acquired infections may become unsuccessful and lead to widespread outbreaks.
Carbapenems and colistin are antibiotics of last resort, generally reserved to treat bacteria which are resistant to all other antibiotics. Until not long ago, colistin resistance was only described as chromosomal, however, in 2016 Liu et al. reported the emergence of the first plasmid-mediated colistin resistance mechanism, MCR-1, in Enterobacteriaceae [72]. Furthermore, the increasing occurrence of colistin resistance among carbapenem-resistant Enterobacteriaceae has also been reported [73]. This is of significant concern as infections caused by colistin and carbapenem-resistant bacteria are very challenging to treat and control, as the treatment options are greatly limited or non-existent. Thus, the discovery and development of alternative antimicrobial therapeutics are the highest priorities of modern medicine and biotechnology.
Phages should be considered as great potential tools in MDR pathogens as they are species-specific (specificity prevents damage of normal microbiota), thus harmless to human; they have fast replication rate at the site of infection, and their short genomes can allow to further understand various molecular mechanisms implied to ‘fight’ bacteria. In addition, this understanding can enable scientists to ‘manipulate’ viral genomes and engineer a synthetic phage that combines the antibacterial characteristics of multiple phages into a single genome.
The escalating need for new antimicrobial agents attracted new attention in modern medicine, proposing several potential applications of phages as antibacterial therapeutics including phage therapy, phage lysins and genetically-engineered phages.
Phage therapy utilises strictly lytic phages that have bactericidal effect. As phages are host-specific, ‘phage cocktails’ containing multiple phages can broaden range of target cells. Nevertheless, selection of suitable phages is at the paramount to the successful elimination of clinically important pathogens, and it includes avoidance of adverse effects, such as anaphylaxis (adverse immune reaction) [74].
In order to hydrolyse and degrade the bacterial cell wall, phages possess lysins.
The spectrum of efficiency of natural lysins (derived from naturally occurring phages) is generally limited to Gram-positive bacteria; however, recombinant lysins have shown an ability to destabilise the outer membrane of Gram-negative bacteria and ultimately lead to rapid death of the target bacteria [74].
Bioengineered phages have the potential to solve inherent limitations of natural phages such as narrow host range and evolution of resistance. Various genetic engineering methods have been proposed to design phages with extended antimicrobial properties such as homologous recombination, phage recombineering of electroporated DNA, yeast-based platform, Gibson assembly and CRISPR/Cas genome editing [75].
Engineering of synthetic phages could be tailored to enhance the antibiotic activity, to reverse antibiotic resistance or to create sequence-specific antimicrobials [74].
The antagonistic host-phage relationship has led to the evolution of exceptionally disperse phage-resistance mechanisms in the bacterial domain, including inhibition of phage adsorption, prevention of nucleic acid entry, Superinfection exclusion, cutting phage nucleic acids via restriction-modification systems and CRISPR, as well as abortive infection.
Evolvement of these mechanisms has been induced by constant parallel co-evolution of phages as they attempt to coexist. To survive, phages acquired diverse counterstrategies to circumvent bacterial anti-phage mechanisms such as adaptations to new receptors, digging for receptors and masking and modification of restriction sites and point mutations in specific genes and genome rearrangements that allow phages to evade bacterial antiviral systems such as CRISPR/Cas arrays, as well as mutations in specific genes to bypass abortive infection system. Conclusively, the co-evolving genetic variations and counteradaptations, in both bacteria and phages, drive the evolutionary bacteria-host arm race.
Besides, accumulating evidence shows that phages contribute to the antimicrobial resistance through horizontal gene transfer mechanisms. Indeed, many bacterial strains have become insensitive to the conventional antibiotics, posing a growing threat to human; and although in the past, western counties withdrew phage therapy in response to the discovery of therapeutic antibiotics, now, phage therapy regains an interest within the research community. There are apparent advantages of phage therapy, such as specificity, meaning only target bacteria would encounter lysis, but not healthy microbiota inhabiting human’s system. Additionally, ‘phage cocktails’, containing multiple bacteria-specific phages, could overcome the issue of phage-resistance as phages do adapt to these resistance mechanisms. However, ‘phage cocktails’ would require large numbers of phages that would have to be grown inside pathogenic bacteria in the laboratory, putting laboratory staff and the environment at risk.
Alternatively, building up the understanding of host-phage interactions and ‘the war between bacteria and phages’ could potentially lead to defeating antimicrobial resistance by designing synthetic phages that can overcome the limitations of phage therapy.
Dr Manal Mohammed is funded by a Quinton Hogg start-up award, University of Westminster.
abortive infection capsular polysaccharides clustered regularly interspaced short palindromic repeats crispr RNA diversity-generating retroelement deoxyribonucleic acid multidrug-resistant O-methyl phosphoramidate methyltransferase protospacer adjacent motif phage-inducible chromosomal island PICI-like element receptor-binding protein restriction endonuclease restriction-modification ribonucleic acid superinfection exclusion trans-activating crRNA
In our mission to support the dissemination of knowledge, we travel throughout the world to present our publications, support our Authors and Academic Editors at international symposia, conferences, and workshops, as well as to attend business meetings with science, academic and publishing professionals. We are always happy to meet our contributors in our offices to discuss further collaborations. Take a look at where we’ve been, who we’ve met and where we’re going.
",metaTitle:"IntechOpen events",metaDescription:"In our mission to support the dissemination of knowledge, we travel worldwide to present our publications, authors and editors at international symposia, conferences, and workshops, as well as attend business meetings with science, academia and publishing professionals. We are always happy to host our scientists in our office to discuss further collaborations. Take a look at where we’ve been, who we’ve met and where we’re going.",metaKeywords:null,canonicalURL:"/page/events",contentRaw:'[{"type":"htmlEditorComponent","content":"16-18 June 2020 Smart University Forum #SUF20, Ankara, Turkey
\\n\\n19 December 2019 IntechOpen and Enago webinar: A Guide to Academic Book Writing and Publishing
\\n\\n27-28 November 2019 14th Munin Conference on Scholarly Publishing, UiT The Arctic University of Norway, Tromsø campus
\\n\\n23 October 2019 Break on Through to the Open Side - Global Online Panel Discussion
\\n\\n21 October 2019 SUFTalks - Istanbul, Sheraton Istanbul Ataköy Hotel, Istanbul, Turkey
\\n\\n21-27 October 2019 OPEN ACCESS WEEK
\\n\\n16-20 October 2019 Frankfurt Book Fair
\\n\\n10 October 2019 IntechOpen - Knowledge Unlatched Lecture & Drinks, The Shard, London, United Kingdom
\\n\\n16-18 September, 2019 Open Science Fair Porto, Portugal
\\n\\n12 September, 2019 ALPSP Annual Conference and Awards, De Vere Beaumont Estate, Old Windsor, United Kingdom. Panel: New Horizons in Open Research: Innovation in open books
\\n\\n27-28 August, 2019 Smart University Foundation, Ankara, Turkey
\\n\\n18-19 July, 2019 Spanish Research Council Meeting, Madrid, Spain
\\n\\n12 July, 2019 Lectures, Kings College London Waterloo Campus, United Kingdom Lecture. 1: Intro to Robotics (focus on robotics in the area of health) Lecture. 2: My career in publishing, my background, scientific open access publication and IntechOpen
\\n\\n24 June, 2019 Atypon Conference, Munich. The Future of Books
\\n\\n20-22 May, 2019 IntechOpen attends series of talks “Pint of Science Festival”, Bilbao. Glass and Txakoli, Nanoscience and Nanotechnology, Autonomous Cars
\\n\\n7 March, 2019 Humans in Space Lecture Series, Shard London
\\n\\n13 September, 2018 Peer Review Week, King’s College London
\\n\\n1-5 October, 2018 IROS Conference, Madrid. Legal issues, Cybersecurity and Policy in AI robotics, Interview with Prof. George Dekoulis
\\n\\n24-26 April, 2018 STM US 2018
\\n\\n19-23 March, 2018 Immuno Oncology Summit
\\n\\n19 March, 2018 Earth dynamics and the development of plate tectonics scientific meeting
\\n\\n15 March, 2018 5th symposium on molecular pathology in oncology – Hot Topics
\\n\\n13-14 March, 2018 WIRED Health
\\n"}]'},components:[{type:"htmlEditorComponent",content:'16-18 June 2020 Smart University Forum #SUF20, Ankara, Turkey
\n\n19 December 2019 IntechOpen and Enago webinar: A Guide to Academic Book Writing and Publishing
\n\n27-28 November 2019 14th Munin Conference on Scholarly Publishing, UiT The Arctic University of Norway, Tromsø campus
\n\n23 October 2019 Break on Through to the Open Side - Global Online Panel Discussion
\n\n21 October 2019 SUFTalks - Istanbul, Sheraton Istanbul Ataköy Hotel, Istanbul, Turkey
\n\n21-27 October 2019 OPEN ACCESS WEEK
\n\n16-20 October 2019 Frankfurt Book Fair
\n\n10 October 2019 IntechOpen - Knowledge Unlatched Lecture & Drinks, The Shard, London, United Kingdom
\n\n16-18 September, 2019 Open Science Fair Porto, Portugal
\n\n12 September, 2019 ALPSP Annual Conference and Awards, De Vere Beaumont Estate, Old Windsor, United Kingdom. Panel: New Horizons in Open Research: Innovation in open books
\n\n27-28 August, 2019 Smart University Foundation, Ankara, Turkey
\n\n18-19 July, 2019 Spanish Research Council Meeting, Madrid, Spain
\n\n12 July, 2019 Lectures, Kings College London Waterloo Campus, United Kingdom Lecture. 1: Intro to Robotics (focus on robotics in the area of health) Lecture. 2: My career in publishing, my background, scientific open access publication and IntechOpen
\n\n24 June, 2019 Atypon Conference, Munich. The Future of Books
\n\n20-22 May, 2019 IntechOpen attends series of talks “Pint of Science Festival”, Bilbao. Glass and Txakoli, Nanoscience and Nanotechnology, Autonomous Cars
\n\n7 March, 2019 Humans in Space Lecture Series, Shard London
\n\n13 September, 2018 Peer Review Week, King’s College London
\n\n1-5 October, 2018 IROS Conference, Madrid. Legal issues, Cybersecurity and Policy in AI robotics, Interview with Prof. George Dekoulis
\n\n24-26 April, 2018 STM US 2018
\n\n19-23 March, 2018 Immuno Oncology Summit
\n\n19 March, 2018 Earth dynamics and the development of plate tectonics scientific meeting
\n\n15 March, 2018 5th symposium on molecular pathology in oncology – Hot Topics
\n\n13-14 March, 2018 WIRED Health
\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{sort:"featured,name"},profiles:[{id:"6700",title:"Dr.",name:"Abbass A.",middleName:null,surname:"Hashim",slug:"abbass-a.-hashim",fullName:"Abbass A. Hashim",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/6700/images/1864_n.jpg",biography:"Currently I am carrying out research in several areas of interest, mainly covering work on chemical and bio-sensors, semiconductor thin film device fabrication and characterisation.\nAt the moment I have very strong interest in radiation environmental pollution and bacteriology treatment. The teams of researchers are working very hard to bring novel results in this field. I am also a member of the team in charge for the supervision of Ph.D. students in the fields of development of silicon based planar waveguide sensor devices, study of inelastic electron tunnelling in planar tunnelling nanostructures for sensing applications and development of organotellurium(IV) compounds for semiconductor applications. I am a specialist in data analysis techniques and nanosurface structure. I have served as the editor for many books, been a member of the editorial board in science journals, have published many papers and hold many patents.",institutionString:null,institution:{name:"Sheffield Hallam University",country:{name:"United Kingdom"}}},{id:"54525",title:"Prof.",name:"Abdul Latif",middleName:null,surname:"Ahmad",slug:"abdul-latif-ahmad",fullName:"Abdul Latif Ahmad",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20567",title:"Prof.",name:"Ado",middleName:null,surname:"Jorio",slug:"ado-jorio",fullName:"Ado Jorio",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Universidade Federal de Minas Gerais",country:{name:"Brazil"}}},{id:"47940",title:"Dr.",name:"Alberto",middleName:null,surname:"Mantovani",slug:"alberto-mantovani",fullName:"Alberto Mantovani",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"12392",title:"Mr.",name:"Alex",middleName:null,surname:"Lazinica",slug:"alex-lazinica",fullName:"Alex Lazinica",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/12392/images/7282_n.png",biography:"Alex Lazinica is the founder and CEO of IntechOpen. After obtaining a Master's degree in Mechanical Engineering, he continued his PhD studies in Robotics at the Vienna University of Technology. Here he worked as a robotic researcher with the university's Intelligent Manufacturing Systems Group as well as a guest researcher at various European universities, including the Swiss Federal Institute of Technology Lausanne (EPFL). During this time he published more than 20 scientific papers, gave presentations, served as a reviewer for major robotic journals and conferences and most importantly he co-founded and built the International Journal of Advanced Robotic Systems- world's first Open Access journal in the field of robotics. Starting this journal was a pivotal point in his career, since it was a pathway to founding IntechOpen - Open Access publisher focused on addressing academic researchers needs. Alex is a personification of IntechOpen key values being trusted, open and entrepreneurial. Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. He is an expert in structural, absorptive, catalytic and photocatalytic properties, in structural organization and dynamic features of ionic liquids, in magnetic interactions between paramagnetic centers. The author or co-author of 3 books, over 200 articles and reviews in scientific journals and books. He is an actual member of the International EPR/ESR Society, European Society on Quantum Solar Energy Conversion, Moscow House of Scientists, of the Board of Moscow Physical Society.",institutionString:null,institution:{name:"Semenov Institute of Chemical Physics",country:{name:"Russia"}}},{id:"62389",title:"PhD.",name:"Ali Demir",middleName:null,surname:"Sezer",slug:"ali-demir-sezer",fullName:"Ali Demir Sezer",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/62389/images/3413_n.jpg",biography:"Dr. Ali Demir Sezer has a Ph.D. from Pharmaceutical Biotechnology at the Faculty of Pharmacy, University of Marmara (Turkey). He is the member of many Pharmaceutical Associations and acts as a reviewer of scientific journals and European projects under different research areas such as: drug delivery systems, nanotechnology and pharmaceutical biotechnology. Dr. Sezer is the author of many scientific publications in peer-reviewed journals and poster communications. Focus of his research activity is drug delivery, physico-chemical characterization and biological evaluation of biopolymers micro and nanoparticles as modified drug delivery system, and colloidal drug carriers (liposomes, nanoparticles etc.).",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"61051",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"100762",title:"Prof.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"St David's Medical Center",country:{name:"United States of America"}}},{id:"107416",title:"Dr.",name:"Andrea",middleName:null,surname:"Natale",slug:"andrea-natale",fullName:"Andrea Natale",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Texas Cardiac Arrhythmia",country:{name:"United States of America"}}},{id:"64434",title:"Dr.",name:"Angkoon",middleName:null,surname:"Phinyomark",slug:"angkoon-phinyomark",fullName:"Angkoon Phinyomark",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/64434/images/2619_n.jpg",biography:"My name is Angkoon Phinyomark. I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. I had been a visiting research student at Faculty of Computer Science, University of Murcia, Murcia, Spain for three months.\n\nI have published over 40 papers during 5 years in refereed journals, books, and conference proceedings in the areas of electro-physiological signals processing and classification, notably EMG and EOG signals, fractal analysis, wavelet analysis, texture analysis, feature extraction and machine learning algorithms, and assistive and rehabilitative devices. I have several computer programming language certificates, i.e. Sun Certified Programmer for the Java 2 Platform 1.4 (SCJP), Microsoft Certified Professional Developer, Web Developer (MCPD), Microsoft Certified Technology Specialist, .NET Framework 2.0 Web (MCTS). I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. From 2004 to 2011, he was a Research Assistant with the Communications Engineering Department at the University of Málaga. In 2011, he became an Assistant Professor in the same department. From 2012 to 2015, he was with Ericsson Spain, where he was working on geo-location\ntools for third generation mobile networks. Since 2015, he is a Marie-Curie fellow at the Denmark Technical University. His current research interests include the areas of mobile communication systems and channel modeling in addition to atmospheric optical communications, adaptive optics and statistics",institutionString:null,institution:{name:"University of Malaga",country:{name:"Spain"}}}],filtersByRegion:[{group:"region",caption:"North America",value:1,count:5758},{group:"region",caption:"Middle and South America",value:2,count:5220},{group:"region",caption:"Africa",value:3,count:1711},{group:"region",caption:"Asia",value:4,count:10348},{group:"region",caption:"Australia and Oceania",value:5,count:895},{group:"region",caption:"Europe",value:6,count:15755}],offset:12,limit:12,total:118014},chapterEmbeded:{data:{}},editorApplication:{success:null,errors:{}},ofsBooks:{filterParams:{hasNoEditors:"0",sort:"dateEndThirdStepPublish"},books:[{type:"book",id:"10403",title:"Recent Advances on Numerical Simulations",subtitle:null,isOpenForSubmission:!0,hash:"d74c4bc8f3f49c49eb2e80810d938611",slug:null,bookSignature:"Dr. Francisco Bulnes and Dr. Jan Peter Hessling",coverURL:"https://cdn.intechopen.com/books/images_new/10403.jpg",editedByType:null,editors:[{id:"92918",title:"Dr.",name:"Francisco",surname:"Bulnes",slug:"francisco-bulnes",fullName:"Francisco Bulnes"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10615",title:"Recent Advances in Sport Science",subtitle:null,isOpenForSubmission:!0,hash:"725573ecd45f3f984f173d7d6dba0433",slug:null,bookSignature:"Prof. Redha Taiar",coverURL:"https://cdn.intechopen.com/books/images_new/10615.jpg",editedByType:null,editors:[{id:"81693",title:"Prof.",name:"Redha",surname:"Taiar",slug:"redha-taiar",fullName:"Redha Taiar"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10377",title:"Electric Power Conversion",subtitle:null,isOpenForSubmission:!0,hash:"9f41084eff07323bda451cd5c77dfaaf",slug:null,bookSignature:"Prof. Majid Nayeripour and Dr. Eberhard Waffenschmidt",coverURL:"https://cdn.intechopen.com/books/images_new/10377.jpg",editedByType:null,editors:[{id:"66929",title:"Prof.",name:"Majid",surname:"Nayeripour",slug:"majid-nayeripour",fullName:"Majid Nayeripour"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10633",title:"Biotechnology to Combat COVID-19",subtitle:null,isOpenForSubmission:!0,hash:"d834c746c5b159a201a9cdadfc473486",slug:null,bookSignature:"Dr. Megha Agrawal and Dr. Shyamasri Biswas",coverURL:"https://cdn.intechopen.com/books/images_new/10633.jpg",editedByType:null,editors:[{id:"193723",title:"Dr.",name:"Megha",surname:"Agrawal",slug:"megha-agrawal",fullName:"Megha Agrawal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10242",title:"Endotoxin Analysis",subtitle:null,isOpenForSubmission:!0,hash:"eb9043444d4ac2204178668cf3246342",slug:null,bookSignature:"Dr. Yanhuai (Richard) Ding",coverURL:"https://cdn.intechopen.com/books/images_new/10242.jpg",editedByType:null,editors:[{id:"340171",title:"Dr.",name:"Yanhuai (Richard)",surname:"Ding",slug:"yanhuai-(richard)-ding",fullName:"Yanhuai (Richard) Ding"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10450",title:"Evolutionary Psychology Meets Social Neuroscience",subtitle:null,isOpenForSubmission:!0,hash:"bd4df54e3fb185306ec3899db7044efb",slug:null,bookSignature:"Dr. Rosalba Morese, Dr. Vincenzo Auriemma and Dr. Sara Palermo",coverURL:"https://cdn.intechopen.com/books/images_new/10450.jpg",editedByType:null,editors:[{id:"214435",title:"Dr.",name:"Rosalba",surname:"Morese",slug:"rosalba-morese",fullName:"Rosalba Morese"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9615",title:"Chikungunya",subtitle:null,isOpenForSubmission:!0,hash:"c960d94a63867dd12a8ab15176a3ff06",slug:null,bookSignature:"Dr. Jean Engohang-Ndong",coverURL:"https://cdn.intechopen.com/books/images_new/9615.jpg",editedByType:null,editors:[{id:"180733",title:"Dr.",name:"Jean",surname:"Engohang-Ndong",slug:"jean-engohang-ndong",fullName:"Jean Engohang-Ndong"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9808",title:"Contemporary Topics in Patient Safety - Volume 1",subtitle:null,isOpenForSubmission:!0,hash:"fb6371607c2c6c02c6a2af8892765aba",slug:null,bookSignature:"Dr. Stanislaw P. Stawicki, Michael S. S Firstenberg and Dr. Vikas Yellapu",coverURL:"https://cdn.intechopen.com/books/images_new/9808.jpg",editedByType:null,editors:[{id:"181694",title:"Dr.",name:"Stanislaw P.",surname:"Stawicki",slug:"stanislaw-p.-stawicki",fullName:"Stanislaw P. Stawicki"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9796",title:"Cancers of Childhood and Adolescence - Epidemiology, Diagnosis, Treatment and Prognosis",subtitle:null,isOpenForSubmission:!0,hash:"7c90c97b84629336aa5af2e9797f4cf2",slug:null,bookSignature:"Prof. Dariusz Borys",coverURL:"https://cdn.intechopen.com/books/images_new/9796.jpg",editedByType:null,editors:[{id:"91258",title:"Prof.",name:"Dariusz",surname:"Borys",slug:"dariusz-borys",fullName:"Dariusz Borys"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8950",title:"Birds - Challenges and Opportunities for Business, Conservation and Research",subtitle:null,isOpenForSubmission:!0,hash:"404a05af45e47e43871f4a0b1bedc6fd",slug:null,bookSignature:"Dr. Heimo Juhani Mikkola",coverURL:"https://cdn.intechopen.com/books/images_new/8950.jpg",editedByType:null,editors:[{id:"144330",title:"Dr.",name:"Heimo",surname:"Mikkola",slug:"heimo-mikkola",fullName:"Heimo Mikkola"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10324",title:"Asthma",subtitle:null,isOpenForSubmission:!0,hash:"555c180ed3eefc77d38259cc57bd8dfe",slug:null,bookSignature:"Dr. Svetlana P. Chapoval",coverURL:"https://cdn.intechopen.com/books/images_new/10324.jpg",editedByType:null,editors:[{id:"70021",title:"Dr.",name:"Svetlana P.",surname:"Chapoval",slug:"svetlana-p.-chapoval",fullName:"Svetlana P. Chapoval"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10270",title:"Fog Computing",subtitle:null,isOpenForSubmission:!0,hash:"54853b3034f0348a6157b5591f8d95f3",slug:null,bookSignature:"Dr. Isiaka Ajewale Alimi, Dr. Nelson Muga, Dr. Qin Xin and Dr. Paulo P. Monteiro",coverURL:"https://cdn.intechopen.com/books/images_new/10270.jpg",editedByType:null,editors:[{id:"208236",title:"Dr.",name:"Isiaka",surname:"Alimi",slug:"isiaka-alimi",fullName:"Isiaka Alimi"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],filtersByTopic:[{group:"topic",caption:"Agricultural and Biological Sciences",value:5,count:12},{group:"topic",caption:"Biochemistry, Genetics and Molecular Biology",value:6,count:4},{group:"topic",caption:"Business, Management and Economics",value:7,count:1},{group:"topic",caption:"Chemistry",value:8,count:5},{group:"topic",caption:"Computer and Information Science",value:9,count:7},{group:"topic",caption:"Earth and Planetary Sciences",value:10,count:7},{group:"topic",caption:"Engineering",value:11,count:15},{group:"topic",caption:"Environmental Sciences",value:12,count:2},{group:"topic",caption:"Immunology and Microbiology",value:13,count:3},{group:"topic",caption:"Materials Science",value:14,count:4},{group:"topic",caption:"Mathematics",value:15,count:1},{group:"topic",caption:"Medicine",value:16,count:29},{group:"topic",caption:"Neuroscience",value:18,count:1},{group:"topic",caption:"Pharmacology, Toxicology and Pharmaceutical Science",value:19,count:2},{group:"topic",caption:"Physics",value:20,count:2},{group:"topic",caption:"Psychology",value:21,count:4},{group:"topic",caption:"Social Sciences",value:23,count:2},{group:"topic",caption:"Technology",value:24,count:1},{group:"topic",caption:"Veterinary Medicine and Science",value:25,count:1}],offset:12,limit:12,total:103},popularBooks:{featuredBooks:[{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.png",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7841",title:"New Insights Into Metabolic Syndrome",subtitle:null,isOpenForSubmission:!1,hash:"ef5accfac9772b9e2c9eff884f085510",slug:"new-insights-into-metabolic-syndrome",bookSignature:"Akikazu Takada",coverURL:"https://cdn.intechopen.com/books/images_new/7841.jpg",editors:[{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8620",title:"Mining Techniques",subtitle:"Past, Present and Future",isOpenForSubmission:!1,hash:"b65658f81d14e9e57e49377869d3a575",slug:"mining-techniques-past-present-and-future",bookSignature:"Abhay Soni",coverURL:"https://cdn.intechopen.com/books/images_new/8620.jpg",editors:[{id:"271093",title:"Dr.",name:"Abhay",middleName:null,surname:"Soni",slug:"abhay-soni",fullName:"Abhay Soni"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9668",title:"Chemistry and Biochemistry of Winemaking, Wine Stabilization and Aging",subtitle:null,isOpenForSubmission:!1,hash:"c5484276a314628acf21ec1bdc3a86b9",slug:"chemistry-and-biochemistry-of-winemaking-wine-stabilization-and-aging",bookSignature:"Fernanda Cosme, Fernando M. Nunes and Luís Filipe-Ribeiro",coverURL:"https://cdn.intechopen.com/books/images_new/9668.jpg",editors:[{id:"186819",title:"Prof.",name:"Fernanda",middleName:null,surname:"Cosme",slug:"fernanda-cosme",fullName:"Fernanda Cosme"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9660",title:"Inland Waters",subtitle:"Dynamics and Ecology",isOpenForSubmission:!1,hash:"975c26819ceb11a926793bc2adc62bd6",slug:"inland-waters-dynamics-and-ecology",bookSignature:"Adam Devlin, Jiayi Pan and Mohammad Manjur Shah",coverURL:"https://cdn.intechopen.com/books/images_new/9660.jpg",editors:[{id:"280757",title:"Dr.",name:"Adam",middleName:"Thomas",surname:"Devlin",slug:"adam-devlin",fullName:"Adam Devlin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9731",title:"Oxidoreductase",subtitle:null,isOpenForSubmission:!1,hash:"852e6f862c85fc3adecdbaf822e64e6e",slug:"oxidoreductase",bookSignature:"Mahmoud Ahmed Mansour",coverURL:"https://cdn.intechopen.com/books/images_new/9731.jpg",editors:[{id:"224662",title:"Prof.",name:"Mahmoud Ahmed",middleName:null,surname:"Mansour",slug:"mahmoud-ahmed-mansour",fullName:"Mahmoud Ahmed Mansour"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9864",title:"Hydrology",subtitle:null,isOpenForSubmission:!1,hash:"02925c63436d12e839008c793a253310",slug:"hydrology",bookSignature:"Theodore V. Hromadka II and Prasada Rao",coverURL:"https://cdn.intechopen.com/books/images_new/9864.jpg",editors:[{id:"181008",title:"Dr.",name:"Theodore V.",middleName:"V.",surname:"Hromadka II",slug:"theodore-v.-hromadka-ii",fullName:"Theodore V. Hromadka II"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9083",title:"Rodents",subtitle:null,isOpenForSubmission:!1,hash:"480148de5ecf236b3e0860fc3954b2d4",slug:"rodents",bookSignature:"Loth S. Mulungu",coverURL:"https://cdn.intechopen.com/books/images_new/9083.jpg",editors:[{id:"108433",title:"Dr.",name:"Loth S.",middleName:null,surname:"Mulungu",slug:"loth-s.-mulungu",fullName:"Loth S. Mulungu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],offset:12,limit:12,total:5220},hotBookTopics:{hotBooks:[],offset:0,limit:12,total:null},publish:{},publishingProposal:{success:null,errors:{}},books:{featuredBooks:[{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.png",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7841",title:"New Insights Into Metabolic Syndrome",subtitle:null,isOpenForSubmission:!1,hash:"ef5accfac9772b9e2c9eff884f085510",slug:"new-insights-into-metabolic-syndrome",bookSignature:"Akikazu Takada",coverURL:"https://cdn.intechopen.com/books/images_new/7841.jpg",editors:[{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8620",title:"Mining Techniques",subtitle:"Past, Present and Future",isOpenForSubmission:!1,hash:"b65658f81d14e9e57e49377869d3a575",slug:"mining-techniques-past-present-and-future",bookSignature:"Abhay Soni",coverURL:"https://cdn.intechopen.com/books/images_new/8620.jpg",editors:[{id:"271093",title:"Dr.",name:"Abhay",middleName:null,surname:"Soni",slug:"abhay-soni",fullName:"Abhay Soni"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"8558",title:"Aerodynamics",subtitle:null,isOpenForSubmission:!1,hash:"db7263fc198dfb539073ba0260a7f1aa",slug:"aerodynamics",bookSignature:"Mofid Gorji-Bandpy and Aly-Mousaad Aly",coverURL:"https://cdn.intechopen.com/books/images_new/8558.jpg",editors:[{id:"35542",title:"Prof.",name:"Mofid",middleName:null,surname:"Gorji-Bandpy",slug:"mofid-gorji-bandpy",fullName:"Mofid Gorji-Bandpy"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9668",title:"Chemistry and Biochemistry of Winemaking, Wine Stabilization and Aging",subtitle:null,isOpenForSubmission:!1,hash:"c5484276a314628acf21ec1bdc3a86b9",slug:"chemistry-and-biochemistry-of-winemaking-wine-stabilization-and-aging",bookSignature:"Fernanda Cosme, Fernando M. Nunes and Luís Filipe-Ribeiro",coverURL:"https://cdn.intechopen.com/books/images_new/9668.jpg",editors:[{id:"186819",title:"Prof.",name:"Fernanda",middleName:null,surname:"Cosme",slug:"fernanda-cosme",fullName:"Fernanda Cosme"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9731",title:"Oxidoreductase",subtitle:null,isOpenForSubmission:!1,hash:"852e6f862c85fc3adecdbaf822e64e6e",slug:"oxidoreductase",bookSignature:"Mahmoud Ahmed Mansour",coverURL:"https://cdn.intechopen.com/books/images_new/9731.jpg",editors:[{id:"224662",title:"Prof.",name:"Mahmoud Ahmed",middleName:null,surname:"Mansour",slug:"mahmoud-ahmed-mansour",fullName:"Mahmoud Ahmed Mansour"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}},{type:"book",id:"9660",title:"Inland Waters",subtitle:"Dynamics and Ecology",isOpenForSubmission:!1,hash:"975c26819ceb11a926793bc2adc62bd6",slug:"inland-waters-dynamics-and-ecology",bookSignature:"Adam Devlin, Jiayi Pan and Mohammad Manjur Shah",coverURL:"https://cdn.intechopen.com/books/images_new/9660.jpg",editors:[{id:"280757",title:"Dr.",name:"Adam",middleName:"Thomas",surname:"Devlin",slug:"adam-devlin",fullName:"Adam Devlin"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter"}}],latestBooks:[{type:"book",id:"9731",title:"Oxidoreductase",subtitle:null,isOpenForSubmission:!1,hash:"852e6f862c85fc3adecdbaf822e64e6e",slug:"oxidoreductase",bookSignature:"Mahmoud Ahmed Mansour",coverURL:"https://cdn.intechopen.com/books/images_new/9731.jpg",editedByType:"Edited by",editors:[{id:"224662",title:"Prof.",name:"Mahmoud Ahmed",middleName:null,surname:"Mansour",slug:"mahmoud-ahmed-mansour",fullName:"Mahmoud Ahmed Mansour"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8985",title:"Natural Resources Management and Biological Sciences",subtitle:null,isOpenForSubmission:!1,hash:"5c2e219a6c021a40b5a20c041dea88c4",slug:"natural-resources-management-and-biological-sciences",bookSignature:"Edward R. Rhodes and Humood Naser",coverURL:"https://cdn.intechopen.com/books/images_new/8985.jpg",editedByType:"Edited by",editors:[{id:"280886",title:"Prof.",name:"Edward R",middleName:null,surname:"Rhodes",slug:"edward-r-rhodes",fullName:"Edward R Rhodes"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9027",title:"Human Blood Group Systems and Haemoglobinopathies",subtitle:null,isOpenForSubmission:!1,hash:"d00d8e40b11cfb2547d1122866531c7e",slug:"human-blood-group-systems-and-haemoglobinopathies",bookSignature:"Osaro Erhabor and Anjana Munshi",coverURL:"https://cdn.intechopen.com/books/images_new/9027.jpg",editedByType:"Edited by",editors:[{id:"35140",title:null,name:"Osaro",middleName:null,surname:"Erhabor",slug:"osaro-erhabor",fullName:"Osaro Erhabor"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9083",title:"Rodents",subtitle:null,isOpenForSubmission:!1,hash:"480148de5ecf236b3e0860fc3954b2d4",slug:"rodents",bookSignature:"Loth S. Mulungu",coverURL:"https://cdn.intechopen.com/books/images_new/9083.jpg",editedByType:"Edited by",editors:[{id:"108433",title:"Dr.",name:"Loth S.",middleName:null,surname:"Mulungu",slug:"loth-s.-mulungu",fullName:"Loth S. Mulungu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9864",title:"Hydrology",subtitle:null,isOpenForSubmission:!1,hash:"02925c63436d12e839008c793a253310",slug:"hydrology",bookSignature:"Theodore V. Hromadka II and Prasada Rao",coverURL:"https://cdn.intechopen.com/books/images_new/9864.jpg",editedByType:"Edited by",editors:[{id:"181008",title:"Dr.",name:"Theodore V.",middleName:"V.",surname:"Hromadka II",slug:"theodore-v.-hromadka-ii",fullName:"Theodore V. Hromadka II"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7841",title:"New Insights Into Metabolic Syndrome",subtitle:null,isOpenForSubmission:!1,hash:"ef5accfac9772b9e2c9eff884f085510",slug:"new-insights-into-metabolic-syndrome",bookSignature:"Akikazu Takada",coverURL:"https://cdn.intechopen.com/books/images_new/7841.jpg",editedByType:"Edited by",editors:[{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9385",title:"Renewable Energy",subtitle:"Technologies and Applications",isOpenForSubmission:!1,hash:"a6b446d19166f17f313008e6c056f3d8",slug:"renewable-energy-technologies-and-applications",bookSignature:"Tolga Taner, Archana Tiwari and Taha Selim Ustun",coverURL:"https://cdn.intechopen.com/books/images_new/9385.jpg",editedByType:"Edited by",editors:[{id:"197240",title:"Associate Prof.",name:"Tolga",middleName:null,surname:"Taner",slug:"tolga-taner",fullName:"Tolga Taner"}],equalEditorOne:{id:"186791",title:"Dr.",name:"Archana",middleName:null,surname:"Tiwari",slug:"archana-tiwari",fullName:"Archana Tiwari",profilePictureURL:"https://mts.intechopen.com/storage/users/186791/images/system/186791.png",biography:"Dr. Archana Tiwari is Associate Professor at Amity University, India. Her research interests include renewable sources of energy from microalgae and further utilizing the residual biomass for the generation of value-added products, bioremediation through microalgae and microbial consortium, antioxidative enzymes and stress, and nutraceuticals from microalgae. She has been working on algal biotechnology for the last two decades. She has published her research in many international journals and has authored many books and chapters with renowned publishing houses. She has also delivered talks as an invited speaker at many national and international conferences. Dr. Tiwari is the recipient of several awards including Researcher of the Year and Distinguished Scientist.",institutionString:"Amity University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"Amity University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:{id:"197609",title:"Prof.",name:"Taha Selim",middleName:null,surname:"Ustun",slug:"taha-selim-ustun",fullName:"Taha Selim Ustun",profilePictureURL:"https://mts.intechopen.com/storage/users/197609/images/system/197609.jpeg",biography:"Dr. Taha Selim Ustun received a Ph.D. in Electrical Engineering from Victoria University, Melbourne, Australia. He is a researcher with the Fukushima Renewable Energy Institute, AIST (FREA), where he leads the Smart Grid Cybersecurity Laboratory. Prior to that, he was a faculty member with the School of Electrical and Computer Engineering, Carnegie Mellon University, Pittsburgh, PA, USA. His current research interests include power systems protection, communication in power networks, distributed generation, microgrids, electric vehicle integration, and cybersecurity in smart grids. He serves on the editorial boards of IEEE Access, IEEE Transactions on Industrial Informatics, Energies, Electronics, Electricity, World Electric Vehicle and Information journals. Dr. Ustun is a member of the IEEE 2004 and 2800, IEC Renewable Energy Management WG 8, and IEC TC 57 WG17. He has been invited to run specialist courses in Africa, India, and China. He has delivered talks for the Qatar Foundation, the World Energy Council, the Waterloo Global Science Initiative, and the European Union Energy Initiative (EUEI). His research has attracted funding from prestigious programs in Japan, Australia, the European Union, and North America.",institutionString:"Fukushima Renewable Energy Institute, AIST (FREA)",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Advanced Industrial Science and Technology",institutionURL:null,country:{name:"Japan"}}},equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8620",title:"Mining Techniques",subtitle:"Past, Present and Future",isOpenForSubmission:!1,hash:"b65658f81d14e9e57e49377869d3a575",slug:"mining-techniques-past-present-and-future",bookSignature:"Abhay Soni",coverURL:"https://cdn.intechopen.com/books/images_new/8620.jpg",editedByType:"Edited by",editors:[{id:"271093",title:"Dr.",name:"Abhay",middleName:null,surname:"Soni",slug:"abhay-soni",fullName:"Abhay Soni"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9423",title:"AI and Learning Systems",subtitle:"Industrial Applications and Future Directions",isOpenForSubmission:!1,hash:"10ac8fb0bdbf61044395963028653d21",slug:"ai-and-learning-systems-industrial-applications-and-future-directions",bookSignature:"Konstantinos Kyprianidis and Erik Dahlquist",coverURL:"https://cdn.intechopen.com/books/images_new/9423.jpg",editedByType:"Edited by",editors:[{id:"35868",title:"Prof.",name:"Konstantinos",middleName:"G.",surname:"Kyprianidis",slug:"konstantinos-kyprianidis",fullName:"Konstantinos Kyprianidis"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8990",title:"Current Concepts in Zika Research",subtitle:null,isOpenForSubmission:!1,hash:"f410c024dd429d6eb0e6abc8973ecc14",slug:"current-concepts-in-zika-research",bookSignature:"Alfonso J. Rodriguez-Morales",coverURL:"https://cdn.intechopen.com/books/images_new/8990.jpg",editedByType:"Edited by",editors:[{id:"131400",title:"Dr.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},subject:{topic:{id:"19",title:"Pharmacology, Toxicology and Pharmaceutical Science",slug:"pharmacology-toxicology-and-pharmaceutical-science",parent:{title:"Health Sciences",slug:"health-sciences"},numberOfBooks:78,numberOfAuthorsAndEditors:1902,numberOfWosCitations:1362,numberOfCrossrefCitations:1020,numberOfDimensionsCitations:2606,videoUrl:null,fallbackUrl:null,description:null},booksByTopicFilter:{topicSlug:"pharmacology-toxicology-and-pharmaceutical-science",sort:"-publishedDate",limit:12,offset:0},booksByTopicCollection:[{type:"book",id:"7847",title:"Medical Toxicology",subtitle:null,isOpenForSubmission:!1,hash:"db9b65bea093de17a0855a1b27046247",slug:"medical-toxicology",bookSignature:"Pınar Erkekoglu and Tomohisa Ogawa",coverURL:"https://cdn.intechopen.com/books/images_new/7847.jpg",editedByType:"Edited by",editors:[{id:"109978",title:"Prof.",name:"Pınar",middleName:null,surname:"Erkekoglu",slug:"pinar-erkekoglu",fullName:"Pınar Erkekoglu"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10143",title:"Molecular Pharmacology",subtitle:null,isOpenForSubmission:!1,hash:"2b2fce4ff393dff0d0f0581c7818087c",slug:"molecular-pharmacology",bookSignature:"Angel Catala and Usama Ahmad",coverURL:"https://cdn.intechopen.com/books/images_new/10143.jpg",editedByType:"Edited by",editors:[{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9086",title:"Drug Repurposing",subtitle:"Hypothesis, Molecular Aspects and Therapeutic Applications",isOpenForSubmission:!1,hash:"5b13e06123db7a16dcdae682eb47ac66",slug:"drug-repurposing-hypothesis-molecular-aspects-and-therapeutic-applications",bookSignature:"Farid A. Badria",coverURL:"https://cdn.intechopen.com/books/images_new/9086.jpg",editedByType:"Edited by",editors:[{id:"41865",title:"Prof.",name:"Farid A.",middleName:null,surname:"Badria",slug:"farid-a.-badria",fullName:"Farid A. Badria"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8720",title:"Topics in Local Anesthetics",subtitle:null,isOpenForSubmission:!1,hash:"593b219700438225954cb0905332ae9f",slug:"topics-in-local-anesthetics",bookSignature:"Víctor M. Whizar-Lugo and Enrique Hernández-Cortez",coverURL:"https://cdn.intechopen.com/books/images_new/8720.jpg",editedByType:"Edited by",editors:[{id:"169249",title:"Prof.",name:"Víctor M.",middleName:null,surname:"Whizar-Lugo",slug:"victor-m.-whizar-lugo",fullName:"Víctor M. Whizar-Lugo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9407",title:"Biochemical Toxicology",subtitle:"Heavy Metals and Nanomaterials",isOpenForSubmission:!1,hash:"892372c885d7a41fc85666f573c7a32b",slug:"biochemical-toxicology-heavy-metals-and-nanomaterials",bookSignature:"Muharrem Ince, Olcay Kaplan Ince and Gabrijel Ondrasek",coverURL:"https://cdn.intechopen.com/books/images_new/9407.jpg",editedByType:"Edited by",editors:[{id:"258431",title:"Associate Prof.",name:"Muharrem",middleName:null,surname:"Ince",slug:"muharrem-ince",fullName:"Muharrem Ince"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7110",title:"Opioids",subtitle:"From Analgesic Use to Addiction",isOpenForSubmission:!1,hash:"8bd70b93e5c8ff9ea766159555eb63da",slug:"opioids-from-analgesic-use-to-addiction",bookSignature:"Pilar Almela Rojo",coverURL:"https://cdn.intechopen.com/books/images_new/7110.jpg",editedByType:"Edited by",editors:[{id:"98258",title:"Dr.",name:"Pilar",middleName:null,surname:"Almela Rojo",slug:"pilar-almela-rojo",fullName:"Pilar Almela Rojo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8094",title:"Aflatoxin B1 Occurrence, Detection and Toxicological Effects",subtitle:null,isOpenForSubmission:!1,hash:"44f4ad52d8a8cbb22ef3d505d6b18027",slug:"aflatoxin-b1-occurrence-detection-and-toxicological-effects",bookSignature:"Xi-Dai Long",coverURL:"https://cdn.intechopen.com/books/images_new/8094.jpg",editedByType:"Edited by",editors:[{id:"202142",title:"Prof.",name:"Xi-Dai",middleName:null,surname:"Long",slug:"xi-dai-long",fullName:"Xi-Dai Long"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7994",title:"Metformin",subtitle:null,isOpenForSubmission:!1,hash:"4763270256096f776a58d75658fe1d9b",slug:"metformin",bookSignature:"Anca Mihaela Pantea Stoian and Manfredi Rizzo",coverURL:"https://cdn.intechopen.com/books/images_new/7994.jpg",editedByType:"Edited by",editors:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8700",title:"Anticoagulation Drugs",subtitle:"the Current State of the Art",isOpenForSubmission:!1,hash:"436d368db26a1bb7c56a32524819feb2",slug:"anticoagulation-drugs-the-current-state-of-the-art",bookSignature:"Mina Kelleni",coverURL:"https://cdn.intechopen.com/books/images_new/8700.jpg",editedByType:"Edited by",editors:[{id:"247606",title:"Dr.",name:"Mina",middleName:"T.",surname:"Kelleni",slug:"mina-kelleni",fullName:"Mina Kelleni"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"9013",title:"Zebrafish in Biomedical Research",subtitle:null,isOpenForSubmission:!1,hash:"b81f6e1a8fc1196718fa50b77a5c77bf",slug:"zebrafish-in-biomedical-research",bookSignature:"Yusuf Bozkurt",coverURL:"https://cdn.intechopen.com/books/images_new/9013.jpg",editedByType:"Edited by",editors:[{id:"90846",title:"Prof.",name:"Yusuf",middleName:null,surname:"Bozkurt",slug:"yusuf-bozkurt",fullName:"Yusuf Bozkurt"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7867",title:"Drug Discovery and Development",subtitle:"New Advances",isOpenForSubmission:!1,hash:"5dd2483e8a643b7da16c4be006fd61cf",slug:"drug-discovery-and-development-new-advances",bookSignature:"Vishwanath Gaitonde, Partha Karmakar and Ashit Trivedi",coverURL:"https://cdn.intechopen.com/books/images_new/7867.jpg",editedByType:"Edited by",editors:[{id:"221897",title:"Dr.",name:"Vishwanath",middleName:null,surname:"Gaitonde",slug:"vishwanath-gaitonde",fullName:"Vishwanath Gaitonde"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"8634",title:"Veterinary Medicine and Pharmaceuticals",subtitle:null,isOpenForSubmission:!1,hash:"db391e7122c6eb34af53134b5cd50027",slug:"veterinary-medicine-and-pharmaceuticals",bookSignature:"Samuel Oppong Bekoe, Mani Saravanan, Reimmel Kwame Adosraku and P K Ramkumar",coverURL:"https://cdn.intechopen.com/books/images_new/8634.jpg",editedByType:"Edited by",editors:[{id:"186990",title:"Dr.",name:"Samuel Oppong",middleName:null,surname:"Bekoe",slug:"samuel-oppong-bekoe",fullName:"Samuel Oppong Bekoe"}],equalEditorOne:{id:"201185",title:"Dr.",name:"Mani",middleName:null,surname:"Saravanan",slug:"mani-saravanan",fullName:"Mani Saravanan",profilePictureURL:"https://mts.intechopen.com/storage/users/201185/images/system/201185.jpeg",biography:"Dr. Mani Saravanan, B.V.Sc., M.V.Sc., Ph.D., is working as Assistant Professor in Veterinary Clinical Complex with the specialization in Veterinary Medicine. He is working on canine internal medicine especially on liver and intestinal disorders. Dr. Saravanan has completed his Ph.D research work on Biodynamic measures to evaluate ascites and its catalytic therapy in dogs. He has expertise in gastrointestinal endoscopy and abdominal ultrasound.",institutionString:"Tamil Nadu Veterinary and Animal Sciences University",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"Tamil Nadu Veterinary and Animal Sciences University",institutionURL:null,country:{name:"India"}}},equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],booksByTopicTotal:78,mostCitedChapters:[{id:"40253",doi:"10.5772/50486",title:"Lipid Nanoparticulate Drug Delivery Systems: A Revolution in Dosage Form Design and Development",slug:"lipid-nanoparticulate-drug-delivery-systems-a-revolution-in-dosage-form-design-and-development",totalDownloads:10428,totalCrossrefCites:11,totalDimensionsCites:70,book:{slug:"recent-advances-in-novel-drug-carrier-systems",title:"Recent Advances in Novel Drug Carrier Systems",fullTitle:"Recent Advances in Novel Drug Carrier Systems"},signatures:"Anthony A. Attama, Mumuni A. Momoh and Philip F. Builders",authors:[{id:"142947",title:"Prof.",name:"Anthony",middleName:null,surname:"Attama",slug:"anthony-attama",fullName:"Anthony Attama"}]},{id:"42016",doi:"10.5772/55187",title:"Why are Early Life Stages of Aquatic Organisms more Sensitive to Toxicants than Adults?",slug:"why-are-early-life-stages-of-aquatic-organisms-more-sensitive-to-toxicants-than-adults-",totalDownloads:3037,totalCrossrefCites:22,totalDimensionsCites:63,book:{slug:"new-insights-into-toxicity-and-drug-testing",title:"New Insights into Toxicity and Drug Testing",fullTitle:"New Insights into Toxicity and Drug Testing"},signatures:"Azad Mohammed",authors:[{id:"147061",title:"Dr.",name:"Azad",middleName:null,surname:"Mohammed",slug:"azad-mohammed",fullName:"Azad Mohammed"}]},{id:"28120",doi:"10.5772/19206",title:"Experimental and Computational Methods Pertaining to Drug Solubility",slug:"experimental-and-computational-methods-pertaining-to-drug-solubility",totalDownloads:6721,totalCrossrefCites:19,totalDimensionsCites:63,book:{slug:"toxicity-and-drug-testing",title:"Toxicity and Drug Testing",fullTitle:"Toxicity and Drug Testing"},signatures:"Abolghasem Jouyban and Mohammad A. A. Fakhree",authors:[{id:"34056",title:"Prof.",name:"Abolghasem",middleName:null,surname:"Jouyban",slug:"abolghasem-jouyban",fullName:"Abolghasem Jouyban"},{id:"38073",title:"Dr.",name:"Mohammad Amin",middleName:null,surname:"Abolghassemi Fakhree",slug:"mohammad-amin-abolghassemi-fakhree",fullName:"Mohammad Amin Abolghassemi Fakhree"}]}],mostDownloadedChaptersLast30Days:[{id:"57717",title:"In Vitro Cytotoxicity and Cell Viability Assays: Principles, Advantages, and Disadvantages",slug:"in-vitro-cytotoxicity-and-cell-viability-assays-principles-advantages-and-disadvantages",totalDownloads:12470,totalCrossrefCites:31,totalDimensionsCites:62,book:{slug:"genotoxicity-a-predictable-risk-to-our-actual-world",title:"Genotoxicity",fullTitle:"Genotoxicity - A Predictable Risk to Our Actual World"},signatures:"Özlem Sultan Aslantürk",authors:[{id:"211212",title:"Dr.",name:"Özlem Sultan",middleName:null,surname:"Aslantürk",slug:"ozlem-sultan-aslanturk",fullName:"Özlem Sultan Aslantürk"}]},{id:"64762",title:"Mechanism and Health Effects of Heavy Metal Toxicity in Humans",slug:"mechanism-and-health-effects-of-heavy-metal-toxicity-in-humans",totalDownloads:6177,totalCrossrefCites:31,totalDimensionsCites:60,book:{slug:"poisoning-in-the-modern-world-new-tricks-for-an-old-dog-",title:"Poisoning in the Modern World",fullTitle:"Poisoning in the Modern World - New Tricks for an Old Dog?"},signatures:"Godwill Azeh Engwa, Paschaline Udoka Ferdinand, Friday Nweke Nwalo and Marian N. Unachukwu",authors:[{id:"241837",title:"Mr.",name:"Godwill Azeh",middleName:null,surname:"Engwa",slug:"godwill-azeh-engwa",fullName:"Godwill Azeh Engwa"},{id:"274194",title:"BSc.",name:"Paschaline Ferdinand",middleName:null,surname:"Okeke",slug:"paschaline-ferdinand-okeke",fullName:"Paschaline Ferdinand Okeke"},{id:"286975",title:"Dr.",name:"Friday",middleName:null,surname:"Nweke Nwalo",slug:"friday-nweke-nwalo",fullName:"Friday Nweke Nwalo"},{id:"286976",title:"Dr.",name:"Marian",middleName:null,surname:"Unachukwu",slug:"marian-unachukwu",fullName:"Marian Unachukwu"}]},{id:"66742",title:"Introductory Chapter: Alkaloids - Their Importance in Nature and for Human Life",slug:"introductory-chapter-alkaloids-their-importance-in-nature-and-for-human-life",totalDownloads:1745,totalCrossrefCites:4,totalDimensionsCites:4,book:{slug:"alkaloids-their-importance-in-nature-and-human-life",title:"Alkaloids",fullTitle:"Alkaloids - Their Importance in Nature and Human Life"},signatures:"Joanna Kurek",authors:[{id:"214632",title:"Dr.",name:"Joanna",middleName:null,surname:"Kurek",slug:"joanna-kurek",fullName:"Joanna Kurek"}]},{id:"49459",title:"Pharmacokinetics of Drugs Following IV Bolus, IV Infusion, and Oral Administration",slug:"pharmacokinetics-of-drugs-following-iv-bolus-iv-infusion-and-oral-administration",totalDownloads:13101,totalCrossrefCites:8,totalDimensionsCites:13,book:{slug:"basic-pharmacokinetic-concepts-and-some-clinical-applications",title:"Basic Pharmacokinetic Concepts and Some Clinical Applications",fullTitle:"Basic Pharmacokinetic Concepts and Some Clinical Applications"},signatures:"Tarek A. Ahmed",authors:[{id:"175649",title:"Dr.",name:"Tarek A",middleName:null,surname:"Ahmed",slug:"tarek-a-ahmed",fullName:"Tarek A Ahmed"}]},{id:"66259",title:"Antioxidant Compounds and Their Antioxidant Mechanism",slug:"antioxidant-compounds-and-their-antioxidant-mechanism",totalDownloads:4989,totalCrossrefCites:17,totalDimensionsCites:46,book:{slug:"antioxidants",title:"Antioxidants",fullTitle:"Antioxidants"},signatures:"Norma Francenia Santos-Sánchez, Raúl Salas-Coronado, Claudia Villanueva-Cañongo and Beatriz Hernández-Carlos",authors:[{id:"143354",title:"Dr.",name:"Raúl",middleName:null,surname:"Salas-Coronado",slug:"raul-salas-coronado",fullName:"Raúl Salas-Coronado"},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez"},{id:"193718",title:"Dr.",name:"Beatriz",middleName:null,surname:"Hernández-Carlos",slug:"beatriz-hernandez-carlos",fullName:"Beatriz Hernández-Carlos"},{id:"278133",title:"Dr.",name:"Claudia",middleName:null,surname:"Villanueva-Cañongo",slug:"claudia-villanueva-canongo",fullName:"Claudia Villanueva-Cañongo"}]},{id:"64420",title:"Medicinal Plants for Treatment of Prevalent Diseases",slug:"medicinal-plants-for-treatment-of-prevalent-diseases",totalDownloads:3225,totalCrossrefCites:1,totalDimensionsCites:5,book:{slug:"pharmacognosy-medicinal-plants",title:"Pharmacognosy",fullTitle:"Pharmacognosy - Medicinal Plants"},signatures:"Susana Oteng Mintah, Tonny Asafo-Agyei, Mary-Ann Archer, Peter Atta-Adjei Junior, Daniel Boamah, Doris Kumadoh, Alfred Appiah, Augustine Ocloo, Yaw Duah Boakye and Christian Agyare",authors:[{id:"182058",title:"Dr.",name:"Christian",middleName:null,surname:"Agyare",slug:"christian-agyare",fullName:"Christian Agyare"},{id:"186987",title:"Dr.",name:"Yaw Duah",middleName:null,surname:"Boakye",slug:"yaw-duah-boakye",fullName:"Yaw Duah Boakye"},{id:"268666",title:"Ms.",name:"Susana",middleName:null,surname:"Oteng Mintah",slug:"susana-oteng-mintah",fullName:"Susana Oteng Mintah"},{id:"282286",title:"Ms.",name:"Mary-Ann",middleName:null,surname:"Archer",slug:"mary-ann-archer",fullName:"Mary-Ann Archer"},{id:"282288",title:"Mr.",name:"Tonny",middleName:null,surname:"Asafo-Agyei",slug:"tonny-asafo-agyei",fullName:"Tonny Asafo-Agyei"},{id:"282290",title:"Mr.",name:"Peter",middleName:null,surname:"Atta-Adjei Junior",slug:"peter-atta-adjei-junior",fullName:"Peter Atta-Adjei Junior"},{id:"282291",title:"Dr.",name:"Daniel",middleName:null,surname:"Boamah",slug:"daniel-boamah",fullName:"Daniel Boamah"},{id:"282293",title:"MSc.",name:"Newman",middleName:null,surname:"Osafo",slug:"newman-osafo",fullName:"Newman Osafo"},{id:"282294",title:"Dr.",name:"Alfred",middleName:null,surname:"Appiah",slug:"alfred-appiah",fullName:"Alfred Appiah"},{id:"282297",title:"Prof.",name:"Augustine",middleName:null,surname:"Ocloo",slug:"augustine-ocloo",fullName:"Augustine Ocloo"}]},{id:"48805",title:"Biopharmaceutics and Pharmacokinetics",slug:"biopharmaceutics-and-pharmacokinetics",totalDownloads:24723,totalCrossrefCites:1,totalDimensionsCites:3,book:{slug:"basic-pharmacokinetic-concepts-and-some-clinical-applications",title:"Basic Pharmacokinetic Concepts and Some Clinical Applications",fullTitle:"Basic Pharmacokinetic Concepts and Some Clinical Applications"},signatures:"S. Lakshmana Prabu, T.N.K. Suriyaprakash, K. Ruckmani and R.\nThirumurugan",authors:[{id:"91590",title:"Dr.",name:"Sakthivel",middleName:null,surname:"Lakshmana Prabu",slug:"sakthivel-lakshmana-prabu",fullName:"Sakthivel Lakshmana Prabu"},{id:"128690",title:"Dr.",name:"Suriyaprakash",middleName:null,surname:"Tnk",slug:"suriyaprakash-tnk",fullName:"Suriyaprakash Tnk"}]},{id:"65128",title:"Natural Products in Drug Discovery",slug:"natural-products-in-drug-discovery",totalDownloads:4873,totalCrossrefCites:5,totalDimensionsCites:13,book:{slug:"pharmacognosy-medicinal-plants",title:"Pharmacognosy",fullTitle:"Pharmacognosy - Medicinal Plants"},signatures:"Akshada Amit Koparde, Rajendra Chandrashekar Doijad and Chandrakant Shripal Magdum",authors:[{id:"268668",title:"Mrs.",name:"Akshada",middleName:null,surname:"Koparde",slug:"akshada-koparde",fullName:"Akshada Koparde"}]},{id:"72744",title:"Drug Repurposing (DR): An Emerging Approach in Drug Discovery",slug:"drug-repurposing-dr-an-emerging-approach-in-drug-discovery",totalDownloads:716,totalCrossrefCites:1,totalDimensionsCites:1,book:{slug:"drug-repurposing-hypothesis-molecular-aspects-and-therapeutic-applications",title:"Drug Repurposing",fullTitle:"Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications"},signatures:"Mithun Rudrapal, Shubham J. Khairnar and Anil G. Jadhav",authors:[{id:"314279",title:"Dr.",name:"Mithun",middleName:null,surname:"Rudrapal",slug:"mithun-rudrapal",fullName:"Mithun Rudrapal"}]},{id:"63768",title:"1,4-Benzodiazepines and New Derivatives: Description, Analysis, and Organic Synthesis",slug:"1-4-benzodiazepines-and-new-derivatives-description-analysis-and-organic-synthesis",totalDownloads:3140,totalCrossrefCites:2,totalDimensionsCites:3,book:{slug:"medicinal-chemistry",title:"Medicinal Chemistry",fullTitle:"Medicinal Chemistry"},signatures:"Elisabet Batlle, Enric Lizano, Miquel Viñas and Maria Dolors Pujol",authors:[{id:"252409",title:"Prof.",name:"Maria Dolors",middleName:null,surname:"Pujol",slug:"maria-dolors-pujol",fullName:"Maria Dolors Pujol"},{id:"262535",title:"Dr.",name:"Elisabet",middleName:null,surname:"Batlle",slug:"elisabet-batlle",fullName:"Elisabet Batlle"},{id:"262756",title:"Mr.",name:"Enric",middleName:null,surname:"Lizano",slug:"enric-lizano",fullName:"Enric Lizano"},{id:"274188",title:"Dr.",name:"Miquel",middleName:null,surname:"Viñas",slug:"miquel-vinas",fullName:"Miquel Viñas"}]}],onlineFirstChaptersFilter:{topicSlug:"pharmacology-toxicology-and-pharmaceutical-science",limit:3,offset:0},onlineFirstChaptersCollection:[{id:"75373",title:"Historical Evidence and Documentation of Remedial Flora of Azad Jammu and Kashmir (AJK)",slug:"historical-evidence-and-documentation-of-remedial-flora-of-azad-jammu-and-kashmir-ajk",totalDownloads:0,totalDimensionsCites:null,doi:"10.5772/intechopen.96472",book:{title:"Pharmacognosy - Medicinal Plants"},signatures:"Fozia Abasi, Muhammad Shoaib Amjad and Huma Qureshi"},{id:"75043",title:"Pharmacogenetics of Direct Oral Anticoagulants",slug:"pharmacogenetics-of-direct-oral-anticoagulants",totalDownloads:7,totalDimensionsCites:0,doi:"10.5772/intechopen.95966",book:{title:"Pharmacogenetics"},signatures:"Natalia Shnayder, Marina Petrova, Elena Bochanova, Olga Zimnitskaya, Alina Savinova, Elena Pozhilenkova and Regina Nasyrova"},{id:"74758",title:"Ivan Illich, Iatrogenesis and Pharmacogenetics",slug:"ivan-illich-iatrogenesis-and-pharmacogenetics",totalDownloads:30,totalDimensionsCites:0,doi:"10.5772/intechopen.95751",book:{title:"Pharmacogenetics"},signatures:"José Antonio Diniz de Oliveira"}],onlineFirstChaptersTotal:12},preDownload:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:0,limit:8,total:null},route:{name:"publish",path:"/publish",hash:"",query:{},params:{},fullPath:"/publish",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()