Performance comparison of standard HEVC, JPEG, JPEG2000, and the two proposed CGC+SF model based approaches in terms of coded rate (bpp), PSNR, and the absolute RMS contrast error.
\r\n\t
",isbn:"978-1-83768-472-4",printIsbn:"978-1-83768-471-7",pdfIsbn:"978-1-83768-473-1",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,isSalesforceBook:!1,isNomenclature:!1,hash:"be61949c97a884e4342d41ec7414e678",bookSignature:"Dr. Rahul Shukla",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/12326.jpg",keywords:"Preformulation Studies, Kinetics, Drug Delivery, Analysis, Stability, Drug Content, Optimization, Toxicity, Nanotechnology, Biosensors, Biocompatible, Market Approval",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"June 24th 2022",dateEndSecondStepPublish:"July 22nd 2022",dateEndThirdStepPublish:"September 20th 2022",dateEndFourthStepPublish:"December 9th 2022",dateEndFifthStepPublish:"February 7th 2023",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"24 days",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Researcher in the fields of Nanomedicine, Particle engineering, nanomaterials, dendrimers for drug delivery, Polymeric nanoparticles, nanocrystals, nanogels, nanoemulsions, and Nano-nutraceuticals for therapeutic applications. Member of Indian Red Cross Society, Association of Pharmaceutical Teachers of India (APTI), Indian Pharmacy Graduate Association.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"319705",title:"Dr.",name:"Rahul",middleName:null,surname:"Shukla",slug:"rahul-shukla",fullName:"Rahul Shukla",profilePictureURL:"https://mts.intechopen.com/storage/users/319705/images/system/319705.jpg",biography:"Currently working as Assistant Professor at Department of Pharmaceutics, NIPER Raebareli, India, did Ph.D. in Pharmaceutical Sciences from CSIR CDRI and J.N.U New Delhi, India, M Pharm from IIT BHU,Varanasi, India and B. Pharm from Jamia Hamdard, New Delhi. He has the past experience of as Research Scientist at Dr Reddys Laboratories, India and D.S Kothari Post-Doctoral Fellow at Panjab University, India. He has more than ten years of research and academic experience. 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His current research interests include targeted drug delivery systems, particle engineering, controlled delivery for neurodegenerative diseases, dendrimer mediated drug delivery, solubilization and bioavailability enhancements.\nEmail id: rahulshuklapharm@gmail.com, rahul.shukla@niperraebareli.edu.in \nhttps://scholar.google.com/citations?hl=en&user=PegtvC0AAAAJ",institutionString:"National Institute of Pharmaceutical Education and Research",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"National Institute of Pharmaceutical Education and Research",institutionURL:null,country:{name:"India"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"19",title:"Pharmacology, Toxicology and Pharmaceutical Science",slug:"pharmacology-toxicology-and-pharmaceutical-science"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"478197",firstName:"Veronika",lastName:"Radosavac",middleName:null,title:"Dr.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"veronika@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. 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It is estimated that more than 100 billion digital photos and videos are recorded, transmitted, and viewed annually just in the United States. Today, the tremendous popularity of ubiquitously connected digital imaging devices has made the Internet the standard means by which to share imagery. Of course, digital images/videos have many uses beyond entertainment, including online education, video conferencing, remote medical diagnoses, and many others. Such widespread use of digital images and videos places a great demand on compression algorithms which are absolutely crucial for reducing the bandwidth requirements of storing and transmitting these images and videos.
\nTo this end, state-of-the-art image/video compression algorithms exploit the fact that the human visual system (HVS) is an imperfect sensor. When a digital image/video is to be viewed by a human, an exact bit-for-bit reconstruction is unnecessary; rather, the data can be coded in a non-invertible or
With the release of each new coding standard, the emphasis in perceptual coding research has largely shifted from the mid-quality regime toward the ultra-high-quality regime, with the aim of producing compressed images and videos which are visually equivalent to the originals. Thus, research in visually lossless compression has seen a recent resurgence in importance. In this chapter, we focus exclusively on visually lossless image compression. The key challenge in visually lossless compression is to automatically determine, on a per image basis, the maximum amount of compression that can be applied before the resulting image appears distorted. However, to tackle this challenge requires the ability to accurately and efficiently predict the visibility of local distortions in an image, a task which still remains elusive in the current research.
\nPerceptual coding strategies have long relied on well-known properties of the HVS largely derived from the visual psychophysics literature (e.g., see [1, 2]). Perhaps, the most well-known and widely used property is the
The CSF can be thought of as a baseline visual sensitivity measure because the CSF is traditionally measured for targets shown against a blank background. However, for targets consisting of compression distortions, this blank-background scenario occurs only when the distortions happen to appear in very smooth regions such as in the sky. In other image regions, such as in structures, textures, and hybrids regions, the distortions are generally more difficult to detect (i.e., they exhibit higher contrast detection thresholds), and therefore, visual sensitivity to the distortions is said to be reduced in these regions. This concept of
At the most general level, visual masking refers to a reduction or elimination in the visibility of one signal (called the “target”) caused by the presence of another signal (called the “mask”). For image compression, the image serves as the mask, and the compression distortions serve as the targets of detection. There are various forms of visual masking which can occur and co-occur in images and video. For example, it is well-known that humans have a harder time seeing distortions in very bright regions of an image, an HVS property called
These low-level aspects of the HVS are so commonly used in image/video coding for two simple reasons: (1) they are easy to incorporate and (2) such low-level aspects have been well-documented in the visual psychology literature with accompanying computational models. However, most existing models of masking (and thus, existing perceptual coding techniques) are largely based on findings using artificial stimuli rather than on a true database of natural scenes. The advantage of these artificial masks is that they have well-defined features and parameters, which allows one to investigate the effects of specific mask properties on the detection thresholds. However, in image compression, the mask is necessarily an image, and thus, it remains unclear whether the results obtained using artificial masks can be used to predict the results obtained using natural scene masks. There are some studies using natural scenes as masks, but these studies either employed only a limited number of tested images, or the thresholds were limited to select spatial locations within images (e.g., [3–5]).
\nIn this chapter, we present our latest research in visually lossless image compression which operates based on the concept of
This chapter is organized as follows: Section 2 provides a brief review of current visually lossless perceptual image compression algorithms. In Section 3, we describe the computational models used to predict the masking map for any given input image. In Section 4, we describe how to incorporate the masking map to perform spatially adaptive compression using HEVC. In Section 5, we analyze and discuss the performance of the proposed visually lossless compression method. General conclusions are presented in Section 6.
\nAs we mentioned, the goal of visually lossless image compression is to generate images containing distortions at or just below the visual detection threshold. To this end, previous work in this area has exploited properties of the HVS (most notably the CSF and visual masking) and has taken a variety of approaches toward incorporating these visual properties into the transform, quantization, and/or encoding stages. In this section, we briefly review previous work on perceptual (HVS-based) image compression.
\nPerceptual image compression techniques can be dated back as early as 1990s when Safranek et al. [7] published one of earliest attempts at incorporating HVS properties into compression through a system called perceptually tuned subband image coder (PIC). Three properties of low-level vision were modeled in PIC: (1) contrast sensitivity, (2) luminance masking, and (3) contrast masking. These properties were used to guide the selection of per-subband quantization step sizes designed to yield visually lossless results. Although PIC was initially designed for visually lossless compression, Pappas et al. [8] reported that this system can also be used for visually lossy compression, and high performance can be achieved when the perceptual thresholds are properly scaled. Also, Hontsch et al. [9] extended PIC by exploiting visual masking; they proposed a locally adaptive perceptual coder, which discriminates between image components based on their perceptual relevance.
\nLater research on compression has exploited the properties of the HVS and employed the CSF to regulate the quantization step size in order to minimize the visibility of compression artifacts. For example, Nadenau et al. [10] incorporated HVS properties into a wavelet-based coding algorithm via a noise-shaping filtering stage which preceded quantization. Albanesi [11] proposed a method for incorporating HVS characteristics directly into the transform stage of a wavelet-based coder via the design of analysis and synthesis filters based on the CSF. Antonini et al. [12] introduced a wavelet coder which employed a CSF-weighted distortion criterion during bit allocation. O’Rourke et al. [13] proposed a wavelet-based image compression technique based on two properties of the HVS: orientation sensitivity and contrast sensitivity. Specifically, the diamond-shaped frequency passband of the HVS was exploited for the design of the compression scheme, and the logarithm of the contrast sensitivity was employed for bit allocation. Lai et al. [14] presented an image compression scheme in which contrast-sensitivity and visual masking adjustments were performed within a wavelet-based coder using a low-pass model of the CSF and a local measure of visual distortion. In two similar approaches, Beegan et al. [15] used a “CSF mask” to adjust transform coefficients prior to the quantization, and Wei et al. [16] used a “visual compander.” Also, in [17], Zhang et al. proposed luminance and chrominance CSF-based weighting in the discrete-wavelet-packet-transform domain to reduce perceptible information of the high-dynamic-range images.
\nThere are also some researchers who conducted psychophysical experiment to measure visibility thresholds for compression artifacts in unnatural images and/or on natural scenes. For example, Watson et al. [18] measured visual detection thresholds for both individual wavelet basis functions and simulated wavelet subband quantization distortions presented against a gray background. The thresholds were modeled as a function of the spatial frequency of the distortions, and the model was then used to compute quantizer step sizes for each wavelet subband. In [19], Watson’s approach was extended to lower rate coding via models of visual masking and summation. Nadenau et al. [5] measured the visibility thresholds of quantization noise in natural scenes and compared five visual masking models to predict the visibility thresholds. They concluded that a masking model considering local activity of the wavelet subbands performed better than point-wise contrast masking models.
\nIn a recent study, Chandler et al. [3] proposed a new kind of masking called the
Several other studies have specifically focused on the visually lossless compression of JPEG and JPEG2000 compression schemes. For example, Oh et al. [22] developed a visually lossless compression model which allocates the code streams of the JPEG2000 encoder by measuring visibility thresholds via a wavelet statistics-based quantization distortion model and a visual masking model. In [23], Ponomarenko et al. pointed out that the visual quality of input (to-be-compressed) image has a large effect on the compression performance. Thus, they adaptively adjusted the scaling factor of the JPEG quantization matrix based on the estimated blur and noise content of the input image and showed that such a compression scheme gives larger compression ratio compared to super-high quality mode of consumer digital cameras. Leung et al. [24] proposed a JPEG2000-based visually lossless compression scheme for CT images in which the visibility thresholds varied according to the viewing window/display size of the CT image.
\nThis section describes the computational masking models that we developed to predict the masking map for the given input (to-be-compressed) image. First, we describe the ground-truth database used to train the models. Next, we describe a modified version of the model put forth by Watson and Solomon, which operates by simulating V1 neural responses with contrast gain control (CGC). Here, we have modified the model and optimized its parameters to provide the best predictions for the aforementioned database. In addition, we describe an extension of the model to deal with structural facilitation which we earlier reported in [3]. Structural facilitation refers to the reduction in threshold (increased distortion visibility) in parts of the image containing highly recognizable structure.
\nIn [6], we performed a large-scale psychophysical experiment in which we measured thresholds for detecting simulated distortions placed within each 85 × 85 block of every image from the CSIQ database [25]. The simulated distortion was a narrowband log-Gabor noise target whose center frequency was chosen to be near the peak of visual sensitivity (3.6 cycles/degree of visual angle). The thresholds were obtained using a three-alternative forced-choice procedure [26]; we employed at least three subjects per image, with at least two trials per subject. The end result of the experiment was a masking map for each of the 30 CSIQ images; each entry in each map denotes the minimum contrast required for a human subject to detect distortions at that location in the image.
\nMasking maps and the corresponding standard deviation maps for all 30 images in the CSIQ database. See text for details.
Figure 1 shows the masking maps from the database. Each map consists of 36 values corresponding to the 36 blocks of the associated image. Brighter map values denote higher thresholds (i.e., more masking); darker maps values denote lower thresholds (less masking). The first and seventh rows of Figure 1 show the 30 mask images. Below the mask images, the first, second, and third images show the average maps of the two trials of Subject 1, Subject 2, and Subject 3. The remaining rows show the average maps (taken across all six trials; 2 × 3 subjects), and the corresponding maps of the standard deviations of each average. Note that the averages and standard deviations are on different scales; please refer to the respective color bars shown in Figure 1. Overall, the subjects were in high agreement with each other and with themselves across separate trials.
\nIn the following subsection, we describe the contrast gain control with structure facilitation model which operates by simulating V1 neural responses to predict these masking maps.
\nContrast masking [27] has been widely used for predicting distortion visibility in images and videos [28, 42–44]. Among the many existing models of contrast masking, those which simulate the contrast gain-control response properties of V1 neurons are most widely used. Although several
The Watson and Solomon model [20] is a model of V1 simple-cell responses that includes CGC from neighboring neurons. Figure 2 shows a block diagram of the model. The model takes two images as input: (1) the mask image (original image), and (2) the mask+target image (distorted image). Both of these images are then subjected to the following stages:
\nA spatial filter designed to mimic the human contrast sensitivity function (CSF).
A local spatial-frequency decomposition designed to mimic the initially linear response properties of individual V1 neurons.
Excitatory and inhibitory nonlinearities designed to mimic the nonlinear response properties of individual V1 neurons.
Divisive inhibition designed to mimic the interactions among groups of V1 neurons.
Here,
Flow of Watson and Solomon contrast gain control model.
All of the abovementioned parameters (
We refer interested readers to [6] for more specific details of the database and model.
\nUsing the optimized parameters described in the previous subsection, our implementation of the Watson and Solomon CGC model is quite accurate in predicting detection thresholds. On our database, the model is able to achieve a Pearson correlation coefficient (PCC) of 0.83 between the ground-truth and predicted thresholds. Generally, the model works best on regions containing textures and is worst on regions containing more complex structure. In particular, the model tends to overestimate thresholds for regions containing recognizable structure. This notion is demonstrated in Figure 3, which shows the ground-truth and predicted thresholds for two images; observe that the model predict the thresholds to be higher than ground-truth near the top of the gecko’s body and in the child’s face.
Examples of the Watson and Solomon model overestimating thresholds for distortion in some image regions that contain recognizable structures.
As we mentioned in [3], recognizable structures within the local regions of natural scenes facilitate (rather than mask) the distortion visibility. Thus, to model this “structure facilitation,” we employ an inhibition modulation factor (
where we adjust
The inhibition multiplier
Observe that the inhibition modulation is applied in a block-based fashion. Here,
The variable
The structure map
Here,
Structure maps of two example images. The color bar at right denotes the structure strength at each spatial location of the structure map.
The prediction performance of the Watson and Solomon CGC model can be greatly improved when the structure facilitation is taken into account [as specified in Eq. (2)]. As demonstrated in Figure 6, the proposed SF model was able to improve the CGC model’s prediction performance in local image regions that contain recognizable structures, while not adversely affecting the prediction results of the others. For example, near the top of the gecko’s body and in the child’s face, the contrast detection thresholds predicted using the combined CGC+SF model match the ground-truth thresholds better than using the CGC model. Furthermore, the Pearson correlation coefficients between the CGC+SF model predictions and ground-truth thresholds also improved as compared to using the CGC model alone.
Structural facilitation improves the distortion visibility predictions in local regions of images containing recognizable structures. Pearson correlation coefficient (PCC) of each map with the experiment map is shown below the map.
The masking model described in the previous section provides a way of predicting a masking map for any given input image. In this section, we show how to use this masking map to achieve visually lossless compression. In particular, we describe two different ways of incorporating the masking maps into an HEVC image coder: (1) by adjusting the
Similar to H.264/AVC, HEVC employs a uniform reconstruction quantizer for the transform coefficients. It is the quantization stage that introduces distortions; thus, to generate visually lossless results requires direct or indirect modification of the quantization step sizes (
Our approach assumes that each local area within an image should have its own
Let
The primary difficulty in determining the relationship between
Specifically, prior to using HEVC, we perform the following steps:
\nQuantize the block using a corresponding
Perform an inverse 2D DCT of each block.
Measure and record the contrast of the resulting distortions.
In this way, for each block, we record a table that can be used to look up the closest
The relationship between distortion contrast
Given the
The other approach, which can be used with any lossy compression algorithm, effects the spatially adaptive quantization using pre-processing and post-processing stages. Let
where
For standard HEVC, the quantization step sizes relate to the
where
Block diagram of the second approach to achieve spatially adaptive quantization. Although in this chapter, we show results using HEVC as the encoder and decoder, this second approach can be used with any image compression algorithm.
where
In this chapter, we set
In the post-processing stage, an inverse scaling map (dented by
In standard HEVC stage, the global
where
Two problems can occur with this approach. First, the
Gaussian filtering of the
In the following section, we show qualitative and quantitative results of using these two schemes with HEVC.
\nIn this section, we analyze the performance of the proposed visually lossless image coding algorithm. For this task, all 30 reference images in the CSIQ database were compressed at visually lossless rates using the proposed method and compared against standard HEVC. The main difference is that standard HEVC employs a uniform
Furthermore, we have found that it is possible to induce distortions at up to 10 dB above the predicted
The CGC+SF model takes the 64 × 64-pixels image patch as input and predicts the distortion contrast threshold (
Eight sample reference images in CSIQ and their corresponding
Observe that the
Again, we remind the reader that the
The proposed coding approach assumes that to compress an image in a visually lossless manner, the RMS contrast of the distortion in any compressed image region should be near or below the ground truth RMS contrast threshold. Thus, to verify the effectiveness of our proposed approach, Figure 11 shows the contrast threshold maps (masking maps) for four sample images (as predicted by the CGC+SF model), as well as the resulting distortion contrast maps of the corresponding images coded with standard HEVC and the two proposed approaches. Note that the displayed contrast threshold maps are all 10 dB greater than predicted by the CGC+SF model due to the fact that the experimental contrast thresholds are overly conservative for normal viewing conditions. As we have found in our research, distortions with a contrast up to 10 dB above threshold can still remain visually undetectable under normal viewing conditions. Observe from Figure 11 that images coded by standard HEVC have quite different contrast patterns with the ground truth, whereas images coded by the proposed approaches appear quite similar in pattern to the masking maps. These figures demonstrate that it is possible to achieve better compression performance than standard HEVC if using
The ground truth RMS contrast threshold maps for four sample images, as well as the RMS contrast maps of their corresponding compressed images coded by standard HEVC, and two proposed approaches.
Image | \nStandard HEVC | \nJPEG | \nJPEG2000 | \nApproach 1 | \nApproach 2 | \n|||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
\n | QP | \nbpp | \nPSNR | \nError | \nbpp | \nPSNR | \nError | \nbpp | \nPSNR | \nError | \nbpp | \nPSNR | \nError | \nbpp | \nPSNR | \nError | \n
1600 | \n24 | \n1.98 | \n40.21 | \n733.48 | \n3.31 | \n45.83 | \n563.06 | \n2.21 | \n45.88 | \n594.24 | \n1.88 | \n39.21 | \n676.20 | \n1.49 | \n41.94 | \n786.39 | \n
Aerial_city | \n23 | \n1.75 | \n40.29 | \n794.63 | \n2.52 | \n42.29 | \n841.94 | \n2.21 | \n45.05 | \n692.72 | \n2.09 | \n38.36 | \n716.19 | \n2.10 | \n46.09 | \n653.83 | \n
Boston | \n20 | \n2.41 | \n43.02 | \n502.98 | \n2.61 | \n42.31 | \n712.80 | \n2.34 | \n45.43 | \n534.92 | \n1.81 | \n38.53 | \n699.00 | \n1.61 | \n44.37 | \n703.05 | \n
Bridge | \n22 | \n1.73 | \n41.97 | \n706.05 | \n1.46 | \n38.41 | \n1017.83 | \n2.09 | \n46.57 | \n575.40 | \n1.85 | \n39.83 | \n689.23 | \n1.67 | \n43.35 | \n645.30 | \n
Butter_flower | \n23 | \n1.13 | \n42.10 | \n1036.55 | \n2.17 | \n47.32 | \n1153.96 | \n0.60 | \n41.29 | \n890.83 | \n0.87 | \n35.58 | \n1005.51 | \n0.71 | \n42.64 | \n1282.70 | \n
Cactus | \n21 | \n2.14 | \n42.64 | \n638.78 | \n1.75 | \n39.16 | \n876.22 | \n2.20 | \n46.97 | \n651.90 | \n1.55 | \n33.40 | \n757.97 | \n1.65 | \n47.20 | \n642.46 | \n
Child_swimming | \n25 | \n2.17 | \n38.35 | \n577.45 | \n3.32 | \n43.14 | \n438.94 | \n2.49 | \n43.83 | \n426.37 | \n1.74 | \n33.67 | \n715.74 | \n1.67 | \n43.80 | \n641.40 | \n
Couple | \n25 | \n1.60 | \n39.22 | \n460.92 | \n2.74 | \n45.07 | \n323.70 | \n1.47 | \n42.61 | \n431.27 | \n1.21 | \n34.76 | \n618.40 | \n1.45 | \n42.21 | \n375.91 | \n
Elk | \n29 | \n1.02 | \n35.60 | \n740.88 | \n1.94 | \n40.37 | \n616.10 | \n1.23 | \n39.80 | \n665.91 | \n1.38 | \n34.09 | \n660.53 | \n1.47 | \n42.92 | \n521.01 | \n
Family | \n22 | \n0.94 | \n42.60 | \n962.12 | \n1.15 | \n43.74 | \n966.63 | \n1.13 | \n47.04 | \n794.78 | \n1.65 | \n45.80 | \n586.11 | \n0.74 | \n51.36 | \n845.01 | \n
Fisher | \n21 | \n1.27 | \n42.25 | \n936.04 | \n1.41 | \n43.27 | \n1034.82 | \n1.16 | \n44.84 | \n953.55 | \n1.63 | \n43.02 | \n789.65 | \n0.93 | \n46.91 | \n995.65 | \n
Foxy | \n26 | \n2.43 | \n37.42 | \n415.59 | \n3.00 | \n39.33 | \n427.49 | \n2.48 | \n42.08 | \n434.99 | \n1.62 | \n29.47 | \n680.18 | \n2.14 | \n42.65 | \n374.69 | \n
Geckos | \n28 | \n1.57 | \n35.70 | \n546.44 | \n2.03 | \n37.41 | \n593.12 | \n2.48 | \n43.83 | \n242.22 | \n1.48 | \n31.78 | \n696.98 | \n2.05 | \n39.93 | \n294.62 | \n
Lady_liberty | \n22 | \n0.70 | \n43.55 | \n948.07 | \n2.36 | \n50.94 | \n691.58 | \n0.52 | \n44.55 | \n1027.35 | \n1.26 | \n39.56 | \n767.69 | \n0.58 | \n50.48 | \n932.29 | \n
Lake | \n23 | \n3.14 | \n40.59 | \n433.81 | \n2.26 | \n34.64 | \n937.05 | \n3.99 | \n48.82 | \n420.27 | \n2.24 | \n31.84 | \n634.87 | \n2.42 | \n39.93 | \n517.14 | \n
Log_seaside | \n25 | \n2.53 | \n38.40 | \n582.71 | \n2.34 | \n36.49 | \n867.01 | \n3.99 | \n50.95 | \n359.16 | \n2.15 | \n33.74 | \n651.16 | \n2.52 | \n41.75 | \n462.66 | \n
Monument | \n22 | \n1.49 | \n41.51 | \n687.93 | \n2.01 | \n43.03 | \n741.39 | \n1.52 | \n44.17 | \n692.42 | \n1.48 | \n36.64 | \n696.29 | \n1.12 | \n42.84 | \n737.65 | \n
Native_american | \n23 | \n1.57 | \n40.63 | \n801.26 | \n1.60 | \n41.28 | \n911.87 | \n1.98 | \n46.68 | \n633.27 | \n1.70 | \n38.14 | \n713.70 | \n1.62 | \n43.99 | \n676.87 | \n
Redwood | \n22 | \n1.97 | \n41.59 | \n675.00 | \n1.57 | \n38.18 | \n942.47 | \n2.34 | \n46.40 | \n539.17 | \n1.81 | \n35.81 | \n710.60 | \n1.33 | \n46.47 | \n778.18 | \n
Roping | \n23 | \n1.67 | \n41.63 | \n573.60 | \n1.57 | \n40.85 | \n737.25 | \n1.47 | \n43.79 | \n682.79 | \n1.10 | \n32.22 | \n653.10 | \n1.42 | \n40.88 | \n586.43 | \n
Rushmore | \n21 | \n2.88 | \n42.16 | \n558.05 | \n3.34 | \n42.79 | \n627.87 | \n2.48 | \n43.70 | \n622.51 | \n2.29 | \n34.39 | \n726.84 | \n2.89 | \n44.70 | \n461.22 | \n
Shroom | \n19 | \n2.35 | \n43.94 | \n410.47 | \n1.52 | \n42.36 | \n630.61 | \n1.28 | \n43.89 | \n549.87 | \n1.25 | \n36.79 | \n610.10 | \n0.79 | \n43.71 | \n683.36 | \n
Snow_leaves | \n28 | \n1.08 | \n37.26 | \n675.15 | \n1.58 | \n38.92 | \n787.26 | \n1.47 | \n41.99 | \n612.13 | \n1.31 | \n35.25 | \n548.25 | \n1.35 | \n40.54 | \n519.24 | \n
Sunset_sparrow | \n23 | \n1.56 | \n40.27 | \n1012.00 | \n1.37 | \n40.27 | \n1142.99 | \n1.52 | \n45.13 | \n907.72 | \n2.04 | \n40.10 | \n721.38 | \n0.91 | \n44.04 | \n1052.54 | \n
Sunsetcolor | \n22 | \n0.32 | \n44.57 | \n1165.65 | \n0.50 | \n46.37 | \n1166.02 | \n0.26 | \n47.32 | \n1137.51 | \n1.42 | \n48.35 | \n810.06 | \n0.60 | \n49.00 | \n1061.84 | \n
Swarm | \n21 | \n1.03 | \n42.60 | \n1001.60 | \n1.42 | \n44.85 | \n1014.01 | \n0.91 | \n45.19 | \n1024.93 | \n1.59 | \n41.05 | \n813.39 | \n0.67 | \n44.27 | \n1066.44 | \n
Trolley | \n22 | \n2.57 | \n41.14 | \n482.71 | \n3.17 | \n41.55 | \n589.34 | \n3.31 | \n47.75 | \n387.67 | \n1.95 | \n34.47 | \n668.14 | \n1.94 | \n43.13 | \n581.13 | \n
Turtle | \n19 | \n1.49 | \n44.15 | \n839.82 | \n0.97 | \n42.85 | \n1038.58 | \n1.16 | \n46.64 | \n866.72 | \n1.46 | \n40.26 | \n778.86 | \n1.06 | \n44.96 | \n880.51 | \n
Veggies | \n24 | \n1.64 | \n40.83 | \n497.75 | \n1.96 | \n41.98 | \n696.02 | \n1.72 | \n44.79 | \n602.85 | \n1.01 | \n31.49 | \n584.03 | \n1.23 | \n41.48 | \n616.87 | \n
Woman | \n24 | \n1.72 | \n39.61 | \n654.98 | \n2.09 | \n41.17 | \n730.93 | \n1.98 | \n44.55 | \n538.89 | \n1.51 | \n36.76 | \n710.15 | \n1.45 | \n43.25 | \n655.77 | \n
Average | \n23 | \n1.73 | \n40.86 | \n701.75 | \n2.03 | \n41.87 | \n793.96 | \n1.86 | \n45.05 | \n649.81 | \n1.61 | \n36.81 | \n703.01 | \n1.45 | \n44.03 | \n701.07 | \n
Performance comparison of standard HEVC, JPEG, JPEG2000, and the two proposed CGC+SF model based approaches in terms of coded rate (bpp), PSNR, and the absolute RMS contrast error.
Table 1 shows the compression results of 30 images using standard HEVC, JPEG, JPEG2000, and the two proposed approaches. To compare with the standard HEVC, JPEG, and JPEG2000 coding methods, a visual quality matching experiment was performed by three experienced subjects. The purpose of the experiment was to find at which compression rate, the three reference coding methods (i.e., HEVC, JPEG, and JPEG2000) yielded images with just detectable distortions; the corresponding bit-rates of these “at-threshold” compressed images were then recorded. Note that all these five coding methods only add near or below-threshold distortions, and thus judging the quality of the images is quite difficult. Although the human subjective judgment is a more reliable way for assessing the intensities of the near/below threshold distortions, we also report the PSNRs and the absolute RMS contrast errors between the reference images and the coded images for reference.
\n\nFrom Table 1, observe that the second approach of the CGC+SF model demonstrates a reduction in coded rate (bpp) by an average factor of about 16% as compared with standard HEVC, while still maintaining relatively higher PSNR values and equivalent RMS contrast errors. In comparison, the first approach seems to work less effectively. This might due to the fact that fixed local
This chapter described a computational model which predicts masking maps for any given input images, and two approaches which employ the predicted masking map to achieve visually lossless compression. The proposed computational model consists of a contrast gain control model, which was trained on a database of local masking thresholds in natural images, and a structural facilitation model, which was incorporated to take into account the effects of recognizable structures on distortion visibility. Compared with standard HEVC, our approach shows an average of 16% improvement in bit-rate when testing on the CSIQ database
\nHumans are persistently exposed to various chemical and physical agents that have the potential to damage genomic DNA, such as, irradiation (IR), ultraviolet (UV) light, reactive oxygen species (ROS), et cetera [1]. The integrity and survival of a cell is critically dependent on genome stability and mammalian cells have established multiple pathways to repair different types of target DNA lesions to safeguard the genome from deleterious consequences of various kinds of stresses [2]. The significance of the DNA repair in the protection of genomic stability is highlighted by the fact that many proteins/factors involved have been preserved through evolution [3].
DNA damage, induced by endogenous and exogenous agents, is a common event and must undergo a variety of DNA damage repair in order to ensure the faithful transfer of genetic information during cell division [3]. Four main DNA polymerases are involved with nuclear DNA replication: DNA polymerase α, β, δ and ε [1] (Figure 1). DNA repair pathways, which are also recognized as guardians of the genome, protect cells from numerous damages leading to DNA breaks [4]. Failure to restore DNA lesions or inappropriate repair of DNA damage give rise to genomic instability, which is a hallmark of cancer. Remarkably, mild and massive DNA damage are differentially integrated into the cellular signaling networks and, in consequence, provoke different cell fate decisions. After mild damage, the cellular response is cell cycle arrest, DNA repair, and cell survival, whereas severe damage, drives the cell death response. The inability of the DNA damage response (DDR) to repair following endogenous and exogenous insults can lead to (i) an accumulation of errors in genomic DNA, (ii) subsequent malignant transformation, (iii) cancer progression and (iv) further impairment of the DNA repair capacity. DNA repair mechanisms comprise the detection and deletion (excision) of the lesion, the rejoining of DNA ends and the restoration of the complementary sequence based on a DNA template.
Sub-cellular localization of eukaryotic and retroviral DNA polymerases.
Since cancer cells typically have many mutations compared to a non-cancer cell, it was proposed that one of the earliest changes in the development of a cancer cell is a mutation that increases the spontaneous mutation rate [5]. The presence of a “mutator phenotype” could increase the acquisition of alterations that could lead to enhanced drug resistance limiting the effectiveness of anti-cancer drug treatment.
Viral infection is characterized by the high genetic variability found in virus populations [6]. This phenomenon is attributed to the inaccuracy of the replication machinery that is unique to the viral life cycle. Virulence, pathogenesis and the ability to develop effective antiretroviral drugs and vaccines are largely dependent on genetic diversity in viruses [7]. Retroviruses are RNA viruses that replicate through a DNA intermediate in a process catalyzed by the viral reverse transcriptase (RT) in cytoplasm (Figure 1) [7]. Human immunodeficiency virus type 1 (HIV-1), the etiological agent of AIDS, exhibits exceptionally high mutation frequencies [8]. The accepted explanations for the inaccuracy of HIV-1 RT are the relatively low fidelity of the enzyme during DNA synthesis and the deficiency of intrinsic proofreading activity. A strong mutator phenotype is also observed for herpes viral DNA polymerase mutants with reduced intrinsic 3′ → 5′ exonuclease activity [9].
Mitochondrial DNA (mtDNA) alterations have been associated with various human diseases with impaired mitochondrial function [10]. Mitochondrial DNA polymerase γ (pol γ) is responsible for replication of mtDNA and is implicated in all repair processes (Figure 1) [11]. Mitochondrial DNA is prone to mutations, since it is localized near the inner mitochondrial membrane in which reactive oxygen species are generated. Additionally, mtDNA lacks histone protection and the highly efficient DNA repair mechanisms [12]. The mutation rate of mtDNA is estimated to be about 20–100-fold higher than that of nuclear DNA [13]. The mutagenic mechanisms were shown to be replication errors caused by mis insertion (as a result of a dNTP excess), or decreased proofreading efficiency [14, 15].
Thus, in various compartments of the cell, enhanced DNA replication fidelity is a vital activity for the preservation of genomic stability for many organisms.
Genomic integrity of the cell is crucial for the successful transmission of genetic information to the offspring and its survival [16]. DNA is constantly being damaged. Essentially, DNA lesions can occur in two major ways, affecting either a single-stranded break (SSB) or double-stranded (DSB) or mono-adducts and inter-strand crosslinks, respectively. To combat this, eukaryotes have developed complex DNA damage repair (DDR) pathways (Figure 2). The active pathways for DNA repair are base excision repair (BER), nucleotide excision repair (NER), and mismatch repair MMR for SSB repair, whereas homologous recombination (HR) and non-homologous end-joining (NHEJ) for DSB repair [16]. Nucleotide excision repair (NER) removes a variety of helix-distorting lesions such as typically induced by UV irradiation, whereas base excision repair (BER) targets oxidative base modifications. Mismatch repair (MMR) scans for nucleotides that have been erroneously inserted during replication. The most deleterious types of damage in DNA are DSBs that are typically induced by IR and resolved either by NHEJ or by HR, whereas RECQ helicases assume various roles in genome maintenance during recombination repair and replication.
DNA damage and repair mechanisms. Various DNA damaging agents cause a range of DNA lesions with different outcomes at both the genomic and cellular levels. Each are corrected by a specific DNA repair mechanism, namely, base-excision repair (BER), nucleotide excision repair (NER), homologous recombination (HR)/non-homologous end-joining (NHEJ) or mismatch repair (MMR).
A low fidelity of DNA synthesis in various compartments of the cell by main replicative DNA polymerases leads to genomic instability (mutator phenotype) [17]. The errors produced during DNA synthesis could result from three fidelity determining processes: a) nucleotide misinsertion into the nascent DNA, b) lack of exonucleolytic proofreading activity, that is, the mechanism to identify and excise incorrect nucleotide incorporated during DNA synthesis, and c) extension of mismatched 3′-termini of DNA (Table 1) [18].
Biochemical properties of cellular DNA polymerases | |||
---|---|---|---|
Function | 3′ → 5′ exonuclease | Proofreading | |
Nuclear DNA polymerases | |||
α | primase | no | no |
β | repair | no | no |
δ | Lagging DNA synthesis, repair | yes | yes |
ε | Leading DNA synthesis, repair | yes | yes |
Mitochondrial DNA polymerase | |||
γ | DNA synthesis | yes | yes |
Retroviral DNA polymerase | |||
HIV-1 RT | DNA synthesis | no | no |
Biochemical properties of eukaryotic and retroviral DNA polymerases.
Incorrectly repaired DNA lesions can lead to mutations, genomic instability, changes in the regulation of cellular functions, progression of cancer and premature aging. Cells can repair the large variety of DNA lesions through a variety of sophisticated DNA-repair machineries, recognizing and activating battery of proteins/factors for the repair of damaged DNA. DNA replication is a complex process influenced by numerous proteins/factors. The most important part of the DNA damage response is the activation of tumor repressor p53 protein [18].
The p53 represents a major factor for the maintenance of genome stability and for the suppression of cancer [19, 20]. The p53 protein is commonly referred to as the “
Under normal conditions within the cell, p53 is maintained at low levels by the E3 Ubiquitin ligase MDM2, mediating p53 proteasomal degradation [23]. In response to exposure to various endogenous and exogenous stress signals (such as DNA damage, oncogene activation, hypoxia, and nutrient depletion), the protein is stabilized and functionally activated by a series of post-translational modifications (
In response to various endogenous and exogenous stress signals, the activated p53 arrests the cell cycle until the DNA damage is repaired thereby preventing the cancer. If the DNA damage cannot be repaired apoptosis occurs for eliminating cells that contained excessive and irreparable damaged DNA.
p53 exhibits the functional heterogeneity in its basal (non-induced) state and under various p53 inducible circumstances [20]. Increasing evidences suggest various “non-transcriptional functions” of p53, that can contribute to tumor suppressor activity [25]. p53 may modulate DNA repair through processes, which are independent of its transactivation function. p53 is actively transported between the nucleus and cytoplasm. Furthermore, p53 translocate to mitochondria [26]. p53 can directly interact with DNA repair related cellular factors [27]. The origin, duration, intensity of the stress signals, the interaction with other cellular or viral proteins, and stress-mediated subcellular localization of p53 determines the outcome of the p53 response, namely, its pro- or anti-survival functions [28]. p53 protein executes multi-compartmental functions in the cell by either numerous p53-regulated proteins or by its intrinsic biochemical activities [28].
The functioning of the eukaryotic genome relies on effective and accurate DNA replication and repair [2]. DNA replication in the nucleus of eukaryotic cells employs DNA polymerases (pols) α, β, δ, and ϵ, that are the key enzymes required to maintain the integrity of the genome under all these circumstances [1, 3]. However, the maintenance of genomic integrity is complicated by the fact that the genome is persistently challenged by a variety of endogenous and exogenous DNA-damaging factors [4]. DNA lesion can block DNA replication, which can lead to double-strand breaks (DSB) or alter base coding potential, leading to mutations. The accumulation of damage in DNA can affect gene expression leading to the malfunction of many cellular processes [4]. Various DNA repair systems operate in cells to remove DNA lesions, and several proteins are known to be the key components of these repair systems.
The presence of p53 was demonstrated in different nuclear compartments and suggested that the p53 population not engaged in transcriptional regulation could exert functions other than induction of growth arrest or apoptosis and directly participate in processes of repair [25]. p53 mediating various activities are correlated with the levels of the p53 protein in the cells [27, 29]. The non-genotoxic stress may include a long-lasting, moderate accumulation of p53 in nucleus. Conversely, acute genotoxic stress may induce rapid and transient accumulation of very high levels of p53 with preferential activation of target genes involved in apoptosis [29]. There is a possibility that both transcriptional and transcription-independent pathways act in synergy thereby amplifying the potency of involvement of p53 in DNA repair.
p53 localized in cell nuclei in response to replication stress actively participate in various processes of DNA repair and DNA recombination via its ability to interact with components of the repair and recombination machinery and by its various biochemical activities [30, 31]. Both
The C-terminal 30 amino acids of p53 were shown to recognize several DNA damage-related structures.
In addition, full range of various intrinsic biochemical features of the p53 protein support its possible roles in DNA repair. After DNA damage: (a) p53 is able to recognize and bind sites of DNA damage, such as ssDNA and dsDNA ends [33, 34], (b) p53 catalyzes DNA and RNA strand transfer and promotes the annealing of complementary DNA and RNA single-strands [35, 36], (c) p53 binds insertion/deletion mismatches and bulges [37], (d) p53 binds to three-stranded heteroduplex joints and four-stranded Holliday junction DNA structures with localization specifically at the junction, suggesting that p53 directly participates in recombination repair [38], (e) it can bind DNA in a non-sequence-specific manner [39], (f) p53 exhibits a Mg2+ dependent 3′ → 5′ exonuclease activity [40, 41, 42, 43].
Noticeably, the same central region within p53, where tumorigenic mutations are clustered, recognizes DNA sequence specifically, is required for junction-specific binding of heteroduplex joints and is necessary and sufficient for the 3′ → 5′ exonuclease activity on DNA [28]. In addition to p53’s biochemical activities, numerous reports on physical and functional protein interactions further strengthened the proposal of a direct role of p53 in BER, NER, and DSB repair.
Oxidative DNA damage is largely repaired by the BER pathway. p53 might directly facilitate BER mainly via association with BER components. Wtp53 directly enhanced BER activity measured both
The cellular response depends on the dose of genotoxic agent introduced to the cells. Increasing doses of genotoxic agents cause the accumulation of activated p53 that determines the onset of BER or apoptosis. Low doses of DNA damaging agent resulted in the enhancement of p53-dependent BER activity whereas high levels induced different p53 post-translational modifications that down regulate BER pathway and instead provoked an apoptotic response [29]. The quantitative changes in p53 protein level were associated with qualitative changes in p53 phosphorylation status. In all, this may indicate that increasing doses of genotoxic agents cause the accumulation of activated p53 that determines the onset of BER or apoptosis.
NER is an important DNA repair process that detects and eliminates lesions including both chemical alteration and structural distortion of the DNA helix (
Pathogenic mutations in the GG components XPC and DDB2 (XPE) result in xeroderma pigmentosum (XP) a disease characterized by increased UV-sensitivity and skin cancer incidence [46]. Conversely, mutation in TC genes result in Cockayne’s syndrome that is characterized by neurological abnormalities but no increase in skin cancer incidence. Some NER proteins, particularly the GG damage recognition proteins, can decide a cell’s fate by triggering the initiation of the repair pathway or by signaling apoptosis [46]. Therefore, if the GG pathway is defective, neither DNA repair nor apoptosis occurs, resulting in a cancer cell containing high levels of UV-induced mutations that does not undergo apoptosis. How this non-transcriptional function of p53 contributes to tumor suppression is unclear.
DNA mismatch repair (MMR) is an important DNA repair pathway, which facilitates removal of incorrect nucleotides incorporated during replication. p53 facilitates excision of incorrect nucleotides produced from the error prone nature of DNA polymerases and misincorporation of the incorrect base [25]. Mismatched bases can be either a G/T or A/C pair. To initiate MMR a nick in the DNA either 5′ or 3′ to the mismatch must occur. Proteins that bind the mismatch in humans are
Mutator phenotypes (with the potential for cancer progression) have been reported for cells that lack a proofreading 3′ → 5′ exonuclease activity associated with the DNA polymerase [54]. Excision of incorrectly polymerized nucleotides by exonucleases is an imperious mechanism diminishing the errors during DNA polymerization [55]. Certain organisms with a deficiency of exonucleolytic proofreading, have an increased susceptibility to cancer, especially under conditions of stress. Because the misincorporation of non-complementary dNTPs during DNA replication represents a chief mechanism of gene mutation [56], the removal of the wrong nucleotides from DNA is critical for genomic stability. The intrinsic limited accuracy of DNA polymerases and the imbalance of intracellular dNTP pools are the two most important factors responsible for DNA replication errors [57, 58]. The proofreading for such replication errors by the 3′ → 5′ exonuclease activity associated with the DNA replication machinery is extremely important in reduction of the occurrence of mutations. Interestingly, the mammalian DNA pol α, an enzyme considered to be responsible for the lagging strand replication [59], lacks the 3′ → 5′ exonuclease proof-reading activity and is prone to making replication errors [60].
Three steps, base selection, exonucleolytic proofreading, and DNA elongation, ensure the high fidelity of DNA replication. wtp53 exhibits an intrinsic 3′ → 5′ exonuclease activity. wtp53, co-located with the DNA replication machinery [61], specifically interacts with pol α and has been shown to preferentially eliminate mismatched nucleotides from DNA with its 3′ → 5′ exonuclease activity, thereby enhancing the DNA replication fidelity of pol α
Hydroxyurea (HU), an inhibitor of ribonucleotide reductase involved in the
The functional interaction of DNA polymerase and exonuclease activity was observed with p53/pol-prim complex. p53-containing DNA pol-prim complex excised preferentially a 3′-mispaired primer end over a paired one and replaced it with a correctly paired nucleotide [63]. In contrast, a pol-prim complex containing the hot spot mutant p53R248H did not display exonuclease activity and did not elongate a mispaired 3′-end, representing that the p53 exonuclease from the p53/pol-prim complex was indispensable for the subsequent elongation of the primer by DNA polymerase. These findings support the view that p53 might fulfill a proofreading function for pol-prim and suggest that the defect in proofreading function of p53 may contribute to genetic instability associated with cancer development and progression [63].
DSBs are the most severe type of DNA damage, and these DSBs generated at the replication fork are repaired by two principal repair pathways: homology-based repair (HR) and non-homologous end-joining (NHEJ) [25, 31]. Furthermore, replication blocking lesions such as bulky adducts are subject to HR repair, thereby rescuing the replication fork. HR is considered the most error-free pathway, because sister chromatids are the preferred template, however, it can also produce genetic instability upon up- or down-regulation [25].
Depending on the type and quality of the DSB repair pathway involved, the repair process may end up with deletions, loss of heterozygosity, and chromosomal translocations which may accelerate the multistep process of tumorigenesis. p53 can control HR
p53 prevents the accumulation of DSBs at stalled-replication forks induced by UV or hydroxyurea (HU) treatment. When DNA replication is blocked, p53 becomes phosphorylated on serine 15 and associates with key enzymes of HR such as, Rad51, and Rad54 [68, 69]. Notably, during replication arrest p53 remains inactive in transcriptional transactivation, further supporting the direct involvement in HR regulatory functions unrelated to transcriptional transactivation activities.
p53 preferentially represses HR between certain mispaired DNA sequences. p53 specifically recognizes preformed heteroduplex joints structurally resembling early recombination intermediates, when comprising these mispairings [68]. p53 is able to attack DNA by 3′–5′ exonuclease activity principally during Rad51-mediated strand transfer and to display a DNA substrate preference for heteroduplex recombination intermediates with a further enhancement of the exonucleolytic activity for mispaired as compared to correctly paired heteroduplex DNA [38].
Highlighting the significance of p53 DNA interactions in the regulation of strand exchange events, p53 inhibits branch migration of Holliday junctions (HJs) [25, 31]. p53 recognizes this HJs -like structure and controls the generation and branch migration of the replication fork as well as its resolution, to prevent error-prone DSB repair and to cause replication pausing until the DNA lesion is repaired.
Mammalian cells repair the majority of double-strand breaks by NHEJ [69, 70] which is regarded as principally inaccurate process. The role of p53 in NHEJ remains unclear. p53 has an inhibitory effect on error-prone NHEJ but not error-free NHEJ [71], thereby suppressing genomic instability arising from low-fidelity repair. Remarkably, after the exposure to IR, DSB rejoining increases with loss of wtp53function. Inhibition of in vitro end-joining was observed with the oncogenic mutant p53(175H), whereas the phosphorylation-mimicking mutant p53(15D) failed to inhibit, thereby providing evidence for possible role of phosphorylated p53 in the regulation of NHEJ [72].
Various
Under normal conditions a basal pool of p53 is retained intra-cellular, with the distribution of p53 between the different subcellular compartments dependent on the cellular stress milieu [28]. Indeed, wtp53 occurs in cytoplasm in a subset of human tumor cells such as breast cancers, colon cancers and neuroblastoma [73, 74, 75]. Shuttling between nucleus and cytoplasm not only regulates protein localization, but also often impacts on protein function.
p53, localized in the cytoplasmic lysates of non-stressed p53-proficient cell lines [e.g. LCC2, HCT116 (p53+/+)] exerts an inherent 3′ → 5′ exonuclease activity displaying identical biochemical functions characteristic for recombinant wtp53 [76, 77]: 1) it removes 3′-terminal nucleotides from various nucleic acid substrates: ssDNA, dsDNA, and RNA/DNA template-primers, 2) it hydrolyzes ssDNA in preference to dsDNA substrate, 3) it shows a marked preference for excision of a mismatched vs. correctly paired 3′ terminus with RNA/DNA and DNA/DNA substrates, 4) it excises nucleotides from nucleic acid substrates independently from DNA polymerase, 6) it fulfills the requirements for proofreading function; acts coordinately with the exonuclease-deficient viral DNA polymerases.
Viruses exploits their cellular host for their successful replication, they utilize cell proteins for multiple purposes during their intracellular replication [78]. Since viral infection evokes cellular stress, the infected cells harbor stabilized activated p53 and manipulate p53’s guardian role. Interestingly, increased p53 levels have been noted following infection of cells with various viruses including retrovirus-human immunodeficiency virus [79], which exhibits exceptionally high genetic variability [6], due to the low fidelity of the replication apparatus that is exclusive to the retroviral life cycle.
Reverse transcriptase (RT) of HIV-1 is responsible for the conversion of the viral genomic ssRNA into the proviral DNA in the cytoplasm [7]. The lack of intrinsic 3′ → 5′ exonuclease activity, the formation of 3′-mispaired DNA and the subsequent extension of this DNA were shown to be determinants for the low fidelity of HIV-1 RT [80]. p53 can proofread for HIV-1 RT, increasing the fidelity of DNA synthesis by excising incorrectly polymerized nucleotides from RNA/DNA and DNA/DNA temple-primers in the direct exonuclease assay, when first binding to a 3′-terminus and during ongoing DNA synthesis
DNA polymerase (pol) γ is the sole DNA polymerase that is responsible for replication and repair of mtDNA [81]. It is well established that defects in mtDNA replication lead to mitochondrial dysfunction and disease [56, 60]. Mutations in mtDNA can arise from exogenous sources, from endogenous oxidative stress, or as spontaneous errors of replication during either DNA synthesis or repair events [82]. Mitochondrial DNA is replicated by DNA polymerase γ in concert with replisome accessory proteins such as the mitochondrial DNA helicase, single-stranded DNA binding protein, topoisomerase, the multifunctional mitochondrial transcription factor A (TFAM) with important roles in mtDNA replication and initiating factors.
A high frequency of mutations within mtDNA, resulting in mitochondrial dysfunctions, is an important source of various diseases including cancer and human aging [81, 82]. To verify mtDNA integrity, cells hold various DNA damage response pathway(s) comprising mtDNA replication/repair preservation programs that either preclude or repair damage [83]. The mutagenic mechanisms were shown to be replication errors formed by either pol γ during DNA synthesis by incorporation of incorrect nucleotide or produced due to the presence of unbalanced dNTP concentrations, or by diminished proofreading efficiency. MtDNA is not protected by histones and mtDNA repair is ineffective [81]. Furthermore, a potentially important source of replication infidelity is damage due to ROS. pol γ, was demonstrated to stably misincorporate highly mutagenic 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) opposite template adenine in a complete DNA synthesis reaction
Because of the susceptibility of mtDNA to oxidative damage and replication errors, it is vital to protect mtDNA genomic stability to preserve health. Mitochondrial localization of p53 was observed in non-stressed and stressed cells [26]. Mitochondrial p53 (mit-p53) levels are proportional to total p53 levels, and the majority of p53 was present inside the intra-mitochondrial compartment-matrix, in which mtDNA is located [85]. The mit-p53 physically and functionally interacts with both, mtDNA and pol γ [86].
Notably, with the exception of NER, components of these nuclear DNA repair pathways are also shared in mtDNA maintenance. Several studies illustrated the participation of p53 in mtDNA repair:
53 enhances mitochondrial BER (mtBER) through direct interaction with the repair complex in mouse liver and cancer cells [87]. p53 modulates mtBER through the stimulation of the nucleotide incorporation step.
p53 interacts physically with human mtSSB (HmtSSB)
Intra-mitochondrial p53 provides an error-repair proofreading function for pol γ by excision of misincorporated nucleotides [89]. The p53 in mitochondria may affect the accuracy of DNA synthesis by acting as an external proofreader, thus reducing the production of polymerization errors.
In addition to having a critical role in preservation of genome integrity, alterations in the expression, and function of DNA repair proteins are a major facilitator of tumor responses to chemo- and radiotherapy, commonly functioning by inducing DNA damage in tumor cells. Nucleoside analogs, clinically active in cancer chemotherapy (
The cytotoxic activity of gemcitabine (2′2’-difluorodeoxycitidine, dFdC) was strongly correlated with the amount of dFdCMP incorporated into cellular DNA [92]. The p53 protein recognizes dFdCMP-DNA in whole cells, as evidenced by the fact that p53 protein rapidly accumulated in the nuclei of the gemcitabine treated ML-1 cells [93]. Although, the excision of the dFdCMP from the 3′-end of the DNA was slower than the excision of mismatched nucleotides in whole cells with wtp53 (ML-1) and not detectable in CEM cells harboring mutant p53. ML-1 cells were more sensitive to the cytotoxic effect of the drugs compared to the p53-null or mutant cells. The recognition of the incorporated NAs in DNA by wtp53 did not confer resistance to gemcitabine, but may have facilitated the apoptotic cell death process. It was reported that treatment with gemcitabine resulted in an increased production of DNA-dependent protein kinase (DNA-PK) and p53 complex in nucleus, that interacts with the gemcitabine-containing DNA [93, 94]. DNA-PK and p53 sensor complex may serve as a mechanism to activate the pro-apoptosis function of p53. Apparently, the prolonged existence of the NA-stalled DNA end induced the kinase activity, which subsequently phosphorylated p53 and activated the downstream pathways leading to apoptosis.
Remarkably, p53 present in complex with DNA-PK exhibited 3′ → 5′ exonuclease activity with mismatched DNA, however the active p53 was unable of excising efficiently the incorporated drug from NA-DNA construct containing gemcitabine at the 3′-end [94]. Notably, the specific effects of gemcitabine exposure appeared to vary depending on the duration of treatment and upon the cell line.
It should be pointed out, that wtp53 in ML-1 cells removed the purine nucleoside analog fludarabine (F-ara-A) more efficiently than gemcitabine [93]. Further studies are needed to assess the role of p53 in cellular response to various anti-cancer purine and pyrimidine NA-induced DNA damage.
HIV-1 RT readily utilizes many NAs and the incorporation of nucleoside RT inhibitors (NRTIs) into the 3′-end of viral DNA leads to chain termination of viral DNA synthesis in cytoplasm [88, 95]. p53 protein in the cytoplasm excises the incorporated NAs during both RNA-dependent and DNA-dependent DNA polymerization reactions, although less efficiently than the mismatched nucleotides; longer incubation times were required for excision of the terminally incorporated analogs [96]. The data suggest that p53 in cytoplasm may act as an external proofreader for NA incorporation and confer cellular resistance mechanism to the anti-viral compounds.
Pol γ is unique among the cellular replicative DNA polymerases as it is sensitive to inhibition by nucleoside analogue reverse transcriptase inhibitors (NRTIs) used in the treatment of HIV, which can cause an induced mitochondrial toxicity [97]. Acquired mitochondrial toxicity occurs as a consequence of incorporation of NA into mtDNA or inhibition of mtDNA replication or both. A terminally incorporated NA may be removed by p53 in mitochondria [97]. The removal of the incorporated NA by p53 exonuclease, indicates that the presence of the cellular component-p53 in mitochondria may be important in defining the cytotoxicity of NAs toward mitochondrial replication, thus affecting risk–benefit approach (NA toxicity versus viral inhibition) [98, 99]. Apparently, the presence of p53 in mitochondria may be important, as the excision of the mispair and NA by p53 is favorable event for mitochondrial function.
p53 is a multifunctional protein with positive and negative effects. In general, drug resistance that occurs in cancer chemotherapy and antiviral therapy is a negative event that will decrease the efficacy of the treatment. The recognition and removal of NA from drug-containing DNAs by p53 exonuclease activity in various compartments of the cell may play a role in decreasing drug activity, leading to various biological outcomes: 1)the excision of the incorporated NA from DNA in nucleus may confer resistance to the drugs (negative effect) [93]; 2)the removal of the NA by p53 from DNA incorporated by HIV-1 RT in cytoplasm may confer resistance to the drugs by non-viral mechanism (negative effect) [96] and 3)the excision of NAs from mitochondrial DNA may decrease the potential for chain termination and host toxicity (positive effect) [97].
The genome is constantly under attack from extrinsic and intrinsic damaging agents. Uracil (dU) mis-incorporation in DNA is an intrinsic factor resulting in genomic instability and DNA mutations. The excessive levels of genomic uracil in DNA can modify gene expression by interfering with promoter binding and transcription inhibition, can change transcriptional stalling, or induce DNA strand breaks leading to apoptosis. The factors that influence uracil levels in DNA are cytosine deamination, de novo thymidylate (dTMP) biosynthesis, salvage dTMP biosynthesis, and DNA repair. Furthermore, mis-incorporation occurs when DNA polymerases incorporate dUTP into DNA, in place of dTTP, and the rate of misincorporation is believed to be determined by the intracellular dUTP:dTTP ratio [100, 101]. The enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase), which facilitates the conversion of dUTP to dUMP further utilized by thymidylate synthase (TS) for synthesis of dTMP, avoids mis-incorporation of dU into DNA in nucleus by decreasing the dUTP/dTTP ratio [101]. The misincorporation of dU, as a result of accumulation of dUTP, plays a critical role in cytotoxicity mediated by TS inhibitors, such as the commonly used anticancer drug 5-fluorouracil (5-FU) [102]. DNA directed cytotoxicity of chemotherapeutic agents (e.g.5-FU) not only depends on accumulation of dUTP, but may also be determined by the efficiency of the DNA repair mechanisms (e.g. excision repair) which preclude the incidence of the mistake.
Pol γ in mitochondria is incapable to readily correct U:A mismatches [11]. HIV-1 RT in the cytoplasm of HIV-infected cells efficiently inserts the non-canonical dUTP into the proviral DNA and extends the dU-terminated DNA [103]. The misincorporation of dUTP leads to mutagenesis, and to down-regulation of viral gene expression [104].
Within the context of error-correction events, p53 as a DNA binding protein, contributes an external proofreading function; upon excision of the dU, the p53 dissociates, thus letting the transfer of the substrate with the correct 3′-terminus to DNA polymerase and renewal of DNA synthesis.
The biochemical data show that the procession of U:A and mismatched U:G lesions enhances in the presence of recombinant or endogenous cytoplasmic or mitochondrial p53 [105]. p53 in cytoplasm can participate through the intermolecular pathway in a dU-damage-associated repair mechanism by its ability to remove preformed 3′-terminal dUs, thus preventing further extension of 3’ dU-terminated primer during DNA synthesis by HIV-1 RT. Similarly, p53 in mitochondria can function as an exonuclease/proofreader for pol γ by either decreasing the incorporation of non-canonical dUTP into DNA or by promoting the excision of incorporated dU from nascent DNA, thus expanding the spectrum of DNA damage sites exploited for proofreading as a trans-acting protein [106].
During genomic DNA replication another form of replication errors arises during the incorporation of nucleotides carrying the correct base, but the wrong sugar at substantial rates [107]. DNA polymerases often incorporate ribonucleoside triphosphates (rNTPs) into DNA because of the much higher concentration of rNTPs than that of dNTPs in the cellular nucleotide pool. Indeed, more than 106 rNMPs are incorporated during one round of replication of a mammalian genome [107]. Newly incorporated rNMPs destabilize DNA and pose a major threat to genome integrity due to their reactive 2’OH group. The inserted rNs are the most abundant non-canonical nucleotides in the genome. Failure of rN removal is associated with genome instability in the form of mutagenesis, replication stress, DNA breaks, and chromosomal rearrangements. The aberrant accumulation of rNs in the genome leads to human diseases including Aicardi–Goutières syndrome (AGS), the severe autoimmune disease, and tumorigenesis [108]. Mammalian cells have developed strategies to prevent persistent rN accumulation. In eukaryotes, rNs embedded into DNA are primarily repaired by RNase H2-initiated repair pathway. Ribonucleotide excision repair (RER) may be directly coupled to replication and results in rapid post-replicative repair of rNMPs [108]. Remarkably, exonuclease-proficient yeast and human DNA polymerases can proofread incorporated rNs, albeit inefficiently [107].
Recent studies have demonstrated the importance of p53 in 3′-terminal RER pathway through a functional collaboration with HIV-1 RT, acting in a coordinated manner to attain higher fidelity. p53, functioning as a trans-acting proofreader in cytoplasm, can decrease the stable incorporation of rNs, into DNA by HIV-1 RT [109]. p53 can influence events needed for RER by possessing the compatible biochemical properties: p53 is pertinent in the correction of replication errors produced by HIV-1 RT during distinct steps of rN incorporation through intermolecular pathway: by removal pre-existing 3′-terminal rN; by reducing rN incorporation; by preventing extension of a 3′ rN-terminated primer, by attenuating stable incorporation of rNs. Thus, p53, functioning as a trans-acting proofreader in cytoplasm, can decrease the stable incorporation of rNs.
The fact that p53 in cytoplasm can edit an incorrect sugar irrespective of the nature of base, expands the role of p53 as a proofreader in the repair of replication errors by removing both a base mismatch and an incorrect sugar.
Mammalian cells have evolved multiple strategies to safeguard the genetic information to prevent the fixation of genetic damage induced by endogenous and exogenous mutagens [16]. p53 protein plays a crucial role in the regulation of cell fate determination in response to a variety of cellular stresses. p53 may exert the functional heterogeneity in its non-induced and in its activated state [16]. Remarkably, DNA repair transcription-independent functions of wtp53, contributing to tumor suppression, were found to protect cells from DNA damage independently of the transcription-mediated functions of p53 [25]. Thus, a more comprehensive understanding of how p53 transcription- independent functions are induced in response to a variety of cellular insults is vital. This report focuses on direct roles of p53 in DNA repair during DNA replication in various compartments of the cell. Apparently, p53 has more than one contributions to DNA replication fidelity, which could depend on sub-cellular localization of p53, on the type and incidence of replication obstacles, on the levels of p53 protein [28].
p53 is able to elicit a spectrum of different effective DNA repair pathways in nucleus, cytoplasm and mitochondria (Figure 4). Within the nucleus, p53 regulates different repair mechanisms, in response to endogenous and exogenous replicative stress
p53 functions in DNA repair. p53 under both normal and stress conditions, can help cellular and viral DNA polymerases to promote the repair of DNA in various cellular compartments. The result of p53 activation depends on many variables, including the extent of the stress or damage. In this model, basal p53 activity or that induced by stress signals elicits the protector responses that support the repair of genotoxic damage by various pathways.
In the cytoplasm, p53 may contribute effective proofreading for exonuclease-deficient DNA polymerases (
Within the mitochondria, various studies illustrated the participation of p53 in mtDNA repair in a variety of systems: a)p53 enhances BER through direct interaction with the repair complex in mouse liver and cancer cells [87]. b) Intra-mitochondrial p53 provides an error-repair proofreading function for pol γ by excision of misincorporated nucleotides [89]. c)p53 is proficient of hydrolyzing the 8-oxo-7,8-dihydro-2′-deoxy-guanosine (8-oxodG) present at the 3′-end of DNA, a well-known marker of oxidative stress [88]. d)p53 regulates mtDNA copy number, which may impact mitochondrial and cellular functions [112].
Therapeutic strategies based on p53 are particularly interesting because they exploit the cancer cell’s intrinsic genome instability and predisposition to cell death-apoptosis [90, 91]. The role of p53 is predominantly relevant with respect to the development of anticancer and antiviral therapies. Removal of drugs by 3′ → 5′ exonuclease activity may also facilitate resistance to anti-cancer or anti-viral treatments. Clinical drug resistance limits the efficacy of these compounds. Uncovering the mechanisms, which are responsible for DNA repair of NA-induced DNA damage will have therapeutic value. The p53 protein is able to remove incorporated NA. The stress induced activation of p53 that occurs during anti-cancer or anti-viral therapy has negative and positive effects. p53 may remove incorporated therapeutic NAs from DNA or trigger apoptosis. More studies regarding functions of p53 in genome integrity and cancer evolution may facilitate drug screening and better design of therapeutic approaches.
The functional interaction between p53 and DNA polymerase may have important consequences for the maintenance of genomic integrity and in the development of p53- targeted clinical therapies. Further assessments are required to establish the role of p53 in DNA replication and the significance of these functions in various cellular compartments and treatment responses. Studies on the biology of various mutant p53 isoforms and their interaction with the factors involved in DNA repair and apoptosis, will be relevant to establish whether the direct involvement of p53 in DNA repair is a tumor suppressor function of this important anti-oncogene. Characterization of exonuclease-deficient H115N mutant p53 revealed that although exonuclease-mutant H115N p53 can induce cell cycle arrest more efficiently than wild-type p53, its ability to produce apoptosis in DNA damaged cells is markedly impaired [113]. By utilizing various function-mutant p53 isoforms, more studies must be conducted on the biology of mutant p53 forms and their interaction with the factors involved in DNA repair and apoptosis, in order to recognize the molecular mechanisms that mediate p53-dependent control of DNA replication by cellular and viral DNA polymerases.
p53 has a dual role in response to therapy, as exonuclease that by excision of incorporated anti-cancer drugs may confer resistance to drugs or as mediator of cell death induced by chemotherapy [93]. p53, by removal of the incorporated NA, could confer a cellular resistance mechanism to the antiviral compounds. Finally, the excision of NAs from mitochondrial DNA may decrease the potential for chain termination and host toxicity. These features could serve as a template for the development of p53-targeting therapies.
The control of the viral mutation rate could be a practical anti-retroviral strategy. The mutagenic capacity of a low fidelity DNA polymerase will be decreased through increase in exonuclease concentration or exonuclease targeting (increase in local p53 concentration). It is important to further elucidate the molecular mechanisms involved in governing fidelity not only at a molecular level (
A major issue in the future would be to characterize the cellular and biological functions of p53 in mitochondria in response to various stresses. There are many missing links about the biological functions of mitochondrial p53 that are required to be investigated. Whether p53 defines the percent of mutated mtDNA (heteroplasmy in a cell)? Uncovering the mechanisms by which pol γ-mediated mtDNA mutations and depletion are manifested in cells in the absence and presence of p53 is significant step in understanding underlying causes for mtDNA–related diseases. Depletion and mutation of mtDNA may lead to cellular respiratory dysfunction and release of reactive oxidative species, resulting in cellular damage [99]. Future NAs should provide higher specificity for HIV-RT and lower incorporation by pol γ to diminish mitochondrial toxicity. Whether the effective targeting of p53 in mitochondria by error-correction functions, may result in decrease of mitochondrial toxicity in response to conventional anti-viral therapies? Understanding how p53 can be imported into mitochondria, will be important and could contribute toward the design of new therapies for various diseases.
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Evidence indicates that 20-50% of children with ADHD meet criteria for ASD, and 30-80% of ASD children meet criteria for ADHD.",book:{id:"4611",slug:"adhd-new-directions-in-diagnosis-and-treatment",title:"ADHD",fullTitle:"ADHD - New Directions in Diagnosis and Treatment"},signatures:"Maria Carmen Carrascosa-Romero and Carlos De Cabo- De La Vega",authors:[{id:"61718",title:"Dr.",name:"María Carmen",middleName:null,surname:"Carrascosa-Romero",slug:"maria-carmen-carrascosa-romero",fullName:"María Carmen Carrascosa-Romero"},{id:"61719",title:"Dr.",name:"Carlos",middleName:null,surname:"De Cabo De La Vega",slug:"carlos-de-cabo-de-la-vega",fullName:"Carlos De Cabo De La Vega"}]}],mostDownloadedChaptersLast30Days:[{id:"71112",title:"Stress 0.0. Experimental Program of Meditations for Stress Reduction",slug:"stress-0-0-experimental-program-of-meditations-for-stress-reduction",totalDownloads:818,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"Welcome to the 0.0 Stress program. A practical trip integrator to reduce stress to its minimum expression. In this chapter, we will deepen our transpersonal experiential program, which can be very useful for anyone who experiences any signs or symptoms of stress such as anxiety, irritability, muscular tension, burnout, apathy, restlessness, headache, fatigue, digestive problems, concentration difficulties, worry, overwork, substance abuse, smoking, eating disorders, sleep disturbances, or simply feeling overwhelmed by events. 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Evidence indicates that 20-50% of children with ADHD meet criteria for ASD, and 30-80% of ASD children meet criteria for ADHD.",book:{id:"4611",slug:"adhd-new-directions-in-diagnosis-and-treatment",title:"ADHD",fullTitle:"ADHD - New Directions in Diagnosis and Treatment"},signatures:"Maria Carmen Carrascosa-Romero and Carlos De Cabo- De La Vega",authors:[{id:"61718",title:"Dr.",name:"María Carmen",middleName:null,surname:"Carrascosa-Romero",slug:"maria-carmen-carrascosa-romero",fullName:"María Carmen Carrascosa-Romero"},{id:"61719",title:"Dr.",name:"Carlos",middleName:null,surname:"De Cabo De La Vega",slug:"carlos-de-cabo-de-la-vega",fullName:"Carlos De Cabo De La Vega"}]},{id:"49032",title:"Mindfulness Meditation — A New Preventive Intervention for ADHD",slug:"mindfulness-meditation-a-new-preventive-intervention-for-adhd",totalDownloads:2100,totalCrossrefCites:3,totalDimensionsCites:1,abstract:"Medication and behavioral treatments have been used for ADHD treatments; however, both have limitations. Mindfulness meditation has been shown to improve attention and self-control, (or self-regulation), which could help the core ADHD symptoms of inattention, impulsivity, and hyperactivity. 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It was reported that it is a disease that affects 5.29% of children and adolescents in the entire world. Although ADHD is a disorder with high inheritability, genetic factors are not the only explanation to ADHD etiology. ADHD is a disorder etiology which has genetic and environmental components and gene-environment interaction. In spite of the fact that many environmental factors are linked to ADHD, the number of environmental factors that are proven to be in significant cause-effect relation is too small. In other words, in presence of proper genetic basis, disease appears in presence of many environmental factors each of which have a slight effect, its severity or prognosis is variable. Environmental factors that are most commonly linked to ADHD pathophysiology are; complications during pregnancy, natal and postnatal period, several toxins and food substances. It has been considered that exposure to risk factors that may affect development of the brain in any of these periods will have long-term effects on behavior. Along with mother’s cigarette or alcohol use during pregnancy, emotional difficulties, medical diseases and complications of pregnancy; natal complications, low birth weight, premature birth, post mature birth, physical traumas that may affect brain development in early childhood, psychosocial difficulties are also found to be related to ADHD. Studies of gene-environment interaction also note the importance of environmental factors. For example, a study showed that in cases which carry 7 repeated alleles of DRD4, exposure to prenatal cigarettes causes more severe symptoms of ADHD. 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He is currently the Director of the Postgraduate Program in Implantology of the Bioface/UCAM/PgO (Montevideo, Uruguay), Director of the Cathedra of Biotechnology of the Catholic University of Murcia (Murcia, Spain), an Extraordinary Full Professor of the Catholic University of Murcia (Murcia, Spain) as well as the Director of the private center of research Biotecnos – Technology and Science (Montevideo, Uruguay). Applied biomaterials, cellular and molecular biology, and dental implants are among his research interests. He has published several original papers in renowned journals. 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Vikhe",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/323731/images/13613_n.jpg",biography:"Dr Deepak M.Vikhe .\n\n\t\n\tDr Deepak M.Vikhe , completed his Masters & PhD in Prosthodontics from Rural Dental College, Loni securing third rank in the Pravara Institute of Medical Sciences Deemed University. He was awarded Dr.G.C.DAS Memorial Award for Research on Implants at 39th IPS conference Dubai (U A E).He has two patents under his name. He has received Dr.Saraswati medal award for best research for implant study in 2017.He has received Fully funded scholarship to Spain ,university of Santiago de Compostela. He has completed fellowship in Implantlogy from Noble Biocare. \nHe has attended various conferences and CDE programmes and has national publications to his credit. His field of interest is in Implant supported prosthesis. Presently he is working as a associate professor in the Dept of Prosthodontics, Rural Dental College, Loni and maintains a successful private practice specialising in Implantology at Rahata.\n\nEmail: drdeepak_mvikhe@yahoo.com..................",institutionString:null,institution:{name:"Pravara Institute of Medical Sciences",country:{name:"India"}}},{id:"204110",title:"Dr.",name:"Ahmed A.",middleName:null,surname:"Madfa",slug:"ahmed-a.-madfa",fullName:"Ahmed A. Madfa",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204110/images/system/204110.jpg",biography:"Dr. Madfa is currently Associate Professor of Endodontics at Thamar University and a visiting lecturer at Sana'a University and University of Sciences and Technology. He has more than 6 years of experience in teaching. 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Dr. Madfa also regularly attends international conferences and holds administrative positions (Deputy Dean of the Faculty for Students’ & Academic Affairs and Deputy Head of Research Unit).",institutionString:"Thamar University",institution:null},{id:"210472",title:"Dr.",name:"Nermin",middleName:"Mohammed Ahmed",surname:"Yussif",slug:"nermin-yussif",fullName:"Nermin Yussif",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/210472/images/system/210472.jpg",biography:"Dr. Nermin Mohammed Ahmed Yussif is working at the Faculty of dentistry, University for October university for modern sciences and arts (MSA). Her areas of expertise include: periodontology, dental laserology, oral implantology, periodontal plastic surgeries, oral mesotherapy, nutrition, dental pharmacology. She is an editor and reviewer in numerous international journals.",institutionString:"MSA University",institution:null},{id:"204606",title:"Dr.",name:"Serdar",middleName:null,surname:"Gözler",slug:"serdar-gozler",fullName:"Serdar Gözler",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204606/images/system/204606.jpeg",biography:"Dr. Serdar Gözler has completed his undergraduate studies at the Marmara University Faculty of Dentistry in 1978, followed by an assistantship in the Prosthesis Department of Dicle University Faculty of Dentistry. Starting his PhD work on non-resilient overdentures with Assoc. Prof. Hüsnü Yavuzyılmaz, he continued his studies with Prof. Dr. Gürbüz Öztürk of Istanbul University Faculty of Dentistry Department of Prosthodontics, this time on Gnatology. He attended training programs on occlusion, neurology, neurophysiology, EMG, radiology and biostatistics. In 1982, he presented his PhD thesis \\Gerber and Lauritzen Occlusion Analysis Techniques: Diagnosis Values,\\ at Istanbul University School of Dentistry, Department of Prosthodontics. As he was also working with Prof. Senih Çalıkkocaoğlu on The Physiology of Chewing at the same time, Gözler has written a chapter in Çalıkkocaoğlu\\'s book \\Complete Prostheses\\ entitled \\The Place of Neuromuscular Mechanism in Prosthetic Dentistry.\\ The book was published five times since by the Istanbul University Publications. Having presented in various conferences about occlusion analysis until 1998, Dr. Gözler has also decided to use the T-Scan II occlusion analysis method. Having been personally trained by Dr. Robert Kerstein on this method, Dr. Gözler has been lecturing on the T-Scan Occlusion Analysis Method in conferences both in Turkey and abroad. Dr. Gözler has various articles and presentations on Digital Occlusion Analysis methods. He is now Head of the TMD Clinic at Prosthodontic Department of Faculty of Dentistry , Istanbul Aydın University , Turkey.",institutionString:"Istanbul Aydin University",institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"256417",title:"Associate Prof.",name:"Sanaz",middleName:null,surname:"Sadry",slug:"sanaz-sadry",fullName:"Sanaz Sadry",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256417/images/8106_n.jpg",biography:null,institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"240870",title:"Ph.D.",name:"Alaa Eddin Omar",middleName:null,surname:"Al Ostwani",slug:"alaa-eddin-omar-al-ostwani",fullName:"Alaa Eddin Omar Al Ostwani",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/240870/images/system/240870.jpeg",biography:"Dr. Al Ostwani Alaa Eddin Omar received his Master in dentistry from Damascus University in 2010, and his Ph.D. in Pediatric Dentistry from Damascus University in 2014. Dr. Al Ostwani is an assistant professor and faculty member at IUST University since 2014. \nDuring his academic experience, he has received several awards including the scientific research award from the Union of Arab Universities, the Syrian gold medal and the international gold medal for invention and creativity. Dr. Al Ostwani is a Member of the International Association of Dental Traumatology and the Syrian Society for Research and Preventive Dentistry since 2017. He is also a Member of the Reviewer Board of International Journal of Dental Medicine (IJDM), and the Indian Journal of Conservative and Endodontics since 2016.",institutionString:"International University for Science and Technology.",institution:{name:"Islamic University of Science and Technology",country:{name:"India"}}},{id:"42847",title:"Dr.",name:"Belma",middleName:null,surname:"Işik Aslan",slug:"belma-isik-aslan",fullName:"Belma Işik Aslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/42847/images/system/42847.jpg",biography:"Dr. Belma IşIk Aslan was born in 1976 in Ankara-TURKEY. After graduating from TED Ankara College in 1994, she attended to Gazi University, Faculty of Dentistry in Ankara. She completed her PhD in orthodontic education at Gazi University between 1999-2005. Dr. Işık Aslan stayed at the Providence Hospital Craniofacial Institude and Reconstructive Surgery in Michigan, USA for three months as an observer. She worked as a specialist doctor at Gazi University, Dentistry Faculty, Department of Orthodontics between 2005-2014. She was appointed as associate professor in January, 2014 and as professor in 2021. Dr. Işık Aslan still works as an instructor at the same faculty. She has published a total of 35 articles, 10 book chapters, 39 conference proceedings both internationally and nationally. Also she was the academic editor of the international book 'Current Advances in Orthodontics'. She is a member of the Turkish Orthodontic Society and Turkish Cleft Lip and Palate Society. She is married and has 2 children. Her knowledge of English is at an advanced level.",institutionString:"Gazi University Dentistry Faculty Department of Orthodontics",institution:null},{id:"202198",title:"Dr.",name:"Buket",middleName:null,surname:"Aybar",slug:"buket-aybar",fullName:"Buket Aybar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/202198/images/6955_n.jpg",biography:"Buket Aybar, DDS, PhD, was born in 1971. She graduated from Istanbul University, Faculty of Dentistry, in 1992 and completed her PhD degree on Oral and Maxillofacial Surgery in Istanbul University in 1997.\r\nDr. Aybar is currently a full-time professor in Istanbul University, Faculty of Dentistry Department of Oral and Maxillofacial Surgery. She has teaching responsibilities in graduate and postgraduate programs. Her clinical practice includes mainly dentoalveolar surgery.\r\nHer topics of interest are biomaterials science and cell culture studies. She has many articles in international and national scientific journals and chapters in books; she also has participated in several scientific projects supported by Istanbul University Research fund.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178412",title:"Associate Prof.",name:"Guhan",middleName:null,surname:"Dergin",slug:"guhan-dergin",fullName:"Guhan Dergin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178412/images/6954_n.jpg",biography:"Assoc. Prof. Dr. Gühan Dergin was born in 1973 in Izmit. He graduated from Marmara University Faculty of Dentistry in 1999. He completed his specialty of OMFS surgery in Marmara University Faculty of Dentistry and obtained his PhD degree in 2006. In 2005, he was invited as a visiting doctor in the Oral and Maxillofacial Surgery Department of the University of North Carolina, USA, where he went on a scholarship. Dr. Dergin still continues his academic career as an associate professor in Marmara University Faculty of Dentistry. He has many articles in international and national scientific journals and chapters in books.",institutionString:null,institution:{name:"Marmara University",country:{name:"Turkey"}}},{id:"178414",title:"Prof.",name:"Yusuf",middleName:null,surname:"Emes",slug:"yusuf-emes",fullName:"Yusuf Emes",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178414/images/6953_n.jpg",biography:"Born in Istanbul in 1974, Dr. Emes graduated from Istanbul University Faculty of Dentistry in 1997 and completed his PhD degree in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery in 2005. He has papers published in international and national scientific journals, including research articles on implantology, oroantral fistulas, odontogenic cysts, and temporomandibular disorders. Dr. Emes is currently working as a full-time academic staff in Istanbul University faculty of Dentistry Department of Oral and Maxillofacial Surgery.",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"192229",title:"Ph.D.",name:"Ana Luiza",middleName:null,surname:"De Carvalho Felippini",slug:"ana-luiza-de-carvalho-felippini",fullName:"Ana Luiza De Carvalho Felippini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192229/images/system/192229.jpg",biography:null,institutionString:"University of São Paulo",institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"256851",title:"Prof.",name:"Ayşe",middleName:null,surname:"Gülşen",slug:"ayse-gulsen",fullName:"Ayşe Gülşen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/256851/images/9696_n.jpg",biography:"Dr. Ayşe Gülşen graduated in 1990 from Faculty of Dentistry, University of Ankara and did a postgraduate program at University of Gazi. \nShe worked as an observer and research assistant in Craniofacial Surgery Departments in New York, Providence Hospital in Michigan and Chang Gung Memorial Hospital in Taiwan. \nShe works as Craniofacial Orthodontist in Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi, Ankara Turkey since 2004.",institutionString:"Orthodontist, Assoc Prof in the Department of Aesthetic, Plastic and Reconstructive Surgery, Faculty of Medicine, University of Gazi",institution:null},{id:"255366",title:"Prof.",name:"Tosun",middleName:null,surname:"Tosun",slug:"tosun-tosun",fullName:"Tosun Tosun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255366/images/7347_n.jpg",biography:"Graduated at the Faculty of Dentistry, University of Istanbul, Turkey in 1989;\nVisitor Assistant at the University of Padua, Italy and Branemark Osseointegration Center of Treviso, Italy between 1993-94;\nPhD thesis on oral implantology in University of Istanbul and was awarded the academic title “Dr.med.dent.”, 1997;\nHe was awarded the academic title “Doç.Dr.” (Associated Professor) in 2003;\nProficiency in Botulinum Toxin Applications, Reading-UK in 2009;\nMastership, RWTH Certificate in Laser Therapy in Dentistry, AALZ-Aachen University, Germany 2009-11;\nMaster of Science (MSc) in Laser Dentistry, University of Genoa, Italy 2013-14.\n\nDr.Tosun worked as Research Assistant in the Department of Oral Implantology, Faculty of Dentistry, University of Istanbul between 1990-2002. \nHe worked part-time as Consultant surgeon in Harvard Medical International Hospitals and John Hopkins Medicine, Istanbul between years 2007-09.\u2028He was contract Professor in the Department of Surgical and Diagnostic Sciences (DI.S.C.), Medical School, University of Genova, Italy between years 2011-16. \nSince 2015 he is visiting Professor at Medical School, University of Plovdiv, Bulgaria. \nCurrently he is Associated Prof.Dr. at the Dental School, Oral Surgery Dept., Istanbul Aydin University and since 2003 he works in his own private clinic in Istanbul, Turkey.\u2028\nDr.Tosun is reviewer in journal ‘Laser in Medical Sciences’, reviewer in journal ‘Folia Medica\\', a Fellow of the International Team for Implantology, Clinical Lecturer of DGZI German Association of Oral Implantology, Expert Lecturer of Laser&Health Academy, Country Representative of World Federation for Laser Dentistry, member of European Federation of Periodontology, member of Academy of Laser Dentistry. Dr.Tosun presents papers in international and national congresses and has scientific publications in international and national journals. He speaks english, spanish, italian and french.",institutionString:null,institution:{name:"Istanbul Aydın University",country:{name:"Turkey"}}},{id:"260116",title:"Dr.",name:"Mehmet",middleName:null,surname:"Yaltirik",slug:"mehmet-yaltirik",fullName:"Mehmet Yaltirik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/260116/images/7413_n.jpg",biography:"Birth Date 25.09.1965\r\nBirth Place Adana- Turkey\r\nSex Male\r\nMarrial Status Bachelor\r\nDriving License Acquired\r\nMother Tongue Turkish\r\n\r\nAddress:\r\nWork:University of Istanbul,Faculty of Dentistry, Department of Oral Surgery and Oral Medicine 34093 Capa,Istanbul- TURKIYE",institutionString:null,institution:{name:"Istanbul University",country:{name:"Turkey"}}},{id:"171887",title:"Prof.",name:"Zühre",middleName:null,surname:"Akarslan",slug:"zuhre-akarslan",fullName:"Zühre Akarslan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/171887/images/system/171887.jpg",biography:"Zühre Akarslan was born in 1977 in Cyprus. She graduated from Gazi University Faculty of Dentistry, Ankara, Turkey in 2000. \r\nLater she received her Ph.D. degree from the Oral Diagnosis and Radiology Department; which was recently renamed as Oral and Dentomaxillofacial Radiology, from the same university. \r\nShe is working as a full-time Associate Professor and is a lecturer and an academic researcher. \r\nHer expertise areas are dental caries, cancer, dental fear and anxiety, gag reflex in dentistry, oral medicine, and dentomaxillofacial radiology.",institutionString:"Gazi University",institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"272237",title:"Dr.",name:"Pinar",middleName:"Kiymet",surname:"Karataban",slug:"pinar-karataban",fullName:"Pinar Karataban",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272237/images/8911_n.png",biography:"Assist.Prof.Dr.Pınar Kıymet Karataban, DDS PhD \n\nDr.Pınar Kıymet Karataban was born in Istanbul in 1975. After her graduation from Marmara University Faculty of Dentistry in 1998 she started her PhD in Paediatric Dentistry focused on children with special needs; mainly children with Cerebral Palsy. She finished her pHD thesis entitled \\'Investigation of occlusion via cast analysis and evaluation of dental caries prevalance, periodontal status and muscle dysfunctions in children with cerebral palsy” in 2008. She got her Assist. Proffessor degree in Istanbul Aydın University Paediatric Dentistry Department in 2015-2018. ın 2019 she started her new career in Bahcesehir University, Istanbul as Head of Department of Pediatric Dentistry. In 2020 she was accepted to BAU International University, Batumi as Professor of Pediatric Dentistry. She’s a lecturer in the same university meanwhile working part-time in private practice in Ege Dental Studio (https://www.egedisklinigi.com/) a multidisciplinary dental clinic in Istanbul. Her main interests are paleodontology, ancient and contemporary dentistry, oral microbiology, cerebral palsy and special care dentistry. She has national and international publications, scientific reports and is a member of IAPO (International Association for Paleodontology), IADH (International Association of Disability and Oral Health) and EAPD (European Association of Pediatric Dentistry).",institutionString:null,institution:null},{id:"172009",title:"Dr.",name:"Fatma Deniz",middleName:null,surname:"Uzuner",slug:"fatma-deniz-uzuner",fullName:"Fatma Deniz Uzuner",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/172009/images/7122_n.jpg",biography:"Dr. Deniz Uzuner was born in 1969 in Kocaeli-TURKEY. After graduating from TED Ankara College in 1986, she attended the Hacettepe University, Faculty of Dentistry in Ankara. \nIn 1993 she attended the Gazi University, Faculty of Dentistry, Department of Orthodontics for her PhD education. After finishing the PhD education, she worked as orthodontist in Ankara Dental Hospital under the Turkish Government, Ministry of Health and in a special Orthodontic Clinic till 2011. Between 2011 and 2016, Dr. Deniz Uzuner worked as a specialist in the Department of Orthodontics, Faculty of Dentistry, Gazi University in Ankara/Turkey. In 2016, she was appointed associate professor. Dr. Deniz Uzuner has authored 23 Journal Papers, 3 Book Chapters and has had 39 oral/poster presentations. She is a member of the Turkish Orthodontic Society. Her knowledge of English is at an advanced level.",institutionString:null,institution:null},{id:"332914",title:"Dr.",name:"Muhammad Saad",middleName:null,surname:"Shaikh",slug:"muhammad-saad-shaikh",fullName:"Muhammad Saad Shaikh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Jinnah Sindh Medical University",country:{name:"Pakistan"}}},{id:"315775",title:"Dr.",name:"Feng",middleName:null,surname:"Luo",slug:"feng-luo",fullName:"Feng Luo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Sichuan University",country:{name:"China"}}},{id:"344229",title:"Dr.",name:"Sankeshan",middleName:null,surname:"Padayachee",slug:"sankeshan-padayachee",fullName:"Sankeshan Padayachee",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"315727",title:"Ms.",name:"Kelebogile A.",middleName:null,surname:"Mothupi",slug:"kelebogile-a.-mothupi",fullName:"Kelebogile A. Mothupi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"423519",title:"Dr.",name:"Sizakele",middleName:null,surname:"Ngwenya",slug:"sizakele-ngwenya",fullName:"Sizakele Ngwenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"337613",title:"Mrs.",name:"Tshakane",middleName:null,surname:"R.M.D. Ralephenya",slug:"tshakane-r.m.d.-ralephenya",fullName:"Tshakane R.M.D. Ralephenya",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of the Witwatersrand",country:{name:"South Africa"}}},{id:"419270",title:"Dr.",name:"Ann",middleName:null,surname:"Chianchitlert",slug:"ann-chianchitlert",fullName:"Ann Chianchitlert",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419271",title:"Dr.",name:"Diane",middleName:null,surname:"Selvido",slug:"diane-selvido",fullName:"Diane Selvido",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}},{id:"419272",title:"Dr.",name:"Irin",middleName:null,surname:"Sirisoontorn",slug:"irin-sirisoontorn",fullName:"Irin Sirisoontorn",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Walailak University",country:{name:"Thailand"}}}]}},subseries:{item:{id:"14",type:"subseries",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",hasOnlineFirst:!0,hasPublishedBooks:!0,annualVolume:11410,editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",slug:"rosa-maria-martinez-espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",biography:"Dr. Rosa María Martínez-Espinosa has been a Spanish Full Professor since 2020 (Biochemistry and Molecular Biology) and is currently Vice-President of International Relations and Cooperation development and leader of the research group 'Applied Biochemistry” (University of Alicante, Spain). Other positions she has held at the university include Vice-Dean of Master Programs, Vice-Dean of the Degree in Biology and Vice-Dean for Mobility and Enterprise and Engagement at the Faculty of Science (University of Alicante). She received her Bachelor in Biology in 1998 (University of Alicante) and her PhD in 2003 (Biochemistry, University of Alicante). She undertook post-doctoral research at the University of East Anglia (Norwich, U.K. 2004-2005; 2007-2008).\nHer multidisciplinary research focuses on investigating archaea and their potential applications in biotechnology. She has an H-index of 21. She has authored one patent and has published more than 70 indexed papers and around 60 book chapters.\nShe has contributed to more than 150 national and international meetings during the last 15 years. Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,series:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983"},editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",slug:"ana-isabel-flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",slug:"christian-palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},onlineFirstChapters:{paginationCount:17,paginationItems:[{id:"82751",title:"Mitochondria-Endoplasmic Reticulum Interaction in Central Neurons",doi:"10.5772/intechopen.105738",signatures:"Liliya Kushnireva and Eduard Korkotian",slug:"mitochondria-endoplasmic-reticulum-interaction-in-central-neurons",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82716",title:"Advanced glycation end product induced endothelial dysfunction through ER stress: Unravelling the role of Paraoxonase 2",doi:"10.5772/intechopen.106018",signatures:"Ramya Ravi and Bharathidevi Subramaniam Rajesh",slug:"advanced-glycation-end-product-induced-endothelial-dysfunction-through-er-stress-unravelling-the-rol",totalDownloads:13,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82195",title:"Endoplasmic Reticulum: A Hub in Lipid Homeostasis",doi:"10.5772/intechopen.105450",signatures:"Raúl Ventura and María Isabel Hernández-Alvarez",slug:"endoplasmic-reticulum-a-hub-in-lipid-homeostasis",totalDownloads:17,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"82103",title:"The Role of Endoplasmic Reticulum Stress and Its Regulation in the Progression of Neurological and Infectious Diseases",doi:"10.5772/intechopen.105543",signatures:"Mary Dover, Michael Kishek, Miranda Eddins, Naneeta Desar, Ketema Paul and Milan Fiala",slug:"the-role-of-endoplasmic-reticulum-stress-and-its-regulation-in-the-progression-of-neurological-and-i",totalDownloads:15,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Updates on Endoplasmic Reticulum",coverURL:"https://cdn.intechopen.com/books/images_new/11674.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"80954",title:"Ion Channels and Neurodegenerative Disease Aging Related",doi:"10.5772/intechopen.103074",signatures:"Marika Cordaro, Salvatore Cuzzocrea and Rosanna Di Paola",slug:"ion-channels-and-neurodegenerative-disease-aging-related",totalDownloads:12,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Ion Channels - From Basic Properties to Medical Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/10838.jpg",subseries:{id:"14",title:"Cell and Molecular Biology"}}},{id:"81647",title:"Diabetes and Epigenetics",doi:"10.5772/intechopen.104653",signatures:"Rasha A. 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